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Clinical Practice Guidelines
Non-melanoma skin cancer:
Guidelines for treatment and
management in Australia
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Prepared by the Australian Cancer Network Management
of Non-Melanoma Skin Cancer Working Party
Endorsed 24 October 2002
CONTENTS
© Commonwealth of Australia 2003
ISBN Print: 1864961996
Online: 1864962054
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1968, no part may be reproduced by any process without prior written
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Box 1920, Canberra ACT 2601. Email address: [email protected]
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The strategic intent of the NHMRC is to provide leadership and work with other
relevant organisations to improve the health of all Australians by:
• fostering and supporting a high quality and internationally recognised
research base;
• providing evidence-based advice;
• applying research evidence to health issues thus translating research into
better health practice and outcomes; and
• promoting informed debate on health and medical research, health ethics and
related issues.
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NHMRC web address: http://www.nhmrc.gov.au
Disclaimer
This document is a general guide to appropriate practice, to be followed only
subject to the clinician’s judgement in each individual case.
The guidelines are designed to provide information to assist decision-making
and are based on the best information available at the date of compilation
(August 2001).
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ii
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
CONTENTS
CONTENTS
Executive summary
vii
Summary of recommendations and guidelines
1.
Introduction
2.
Epidemiology
1
5
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Basal cell carcinoma
Incidence and mortality
Genetic epidemiology
Environmental risk factors
3.
4.
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6
6
7
8
Squamous cell carcinoma and related keratinocyte tumours
Incidence and mortality
Genetic epidemiology
Environmental risk factors
9
9
10
11
Clinical features
13
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Basal cell carcinoma
Accuracy of clinical diagnosis of basal cell carcinoma
Superficial
Nodular
Morphoeic
14
14
14
15
16
Squamous cell carcinoma and related keratinocyte tumours
Squamous cell carcinoma
Solar keratoses
Bowen’s disease
Keratoacanthoma
17
17
18
19
20
Pathology (including biopsy)
21
Histopathological classification and prognosis
Basal cell carcinoma
Squamous cell carcinoma
Solar keratoses
Bowen’s disease
21
21
21
22
22
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
iii
CONTENTS
Bowenoid solar keratoses
Keratoacanthoma
5.
22
22
Biopsy of non-melanoma skin cancer
23
Histopathological report
24
Prognosis
27
Basal cell carcinoma
27
Squamous cell carcinoma
6.
Surgical treatment
35
Introduction
35
Objectives of treatment
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Principles of surgical management
Advantages and disadvantages
Basal cell carcinoma
Incompletely resected BCC
Recurrent BCC
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Squamous cell carcinoma
Mohs’ surgery
7.
Radiotherapy
Introduction
Side effects of radiotherapy
8.
iv
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35
35
37
38
40
42
43
46
49
49
50
Relative indications for radiotherapy
51
Relative contraindications for radiotherapy
51
Basal cell carcinoma
52
Squamous cell carcinoma and related keratinocyte tumours
Solar keratosis and Bowen’s disease
Keratoacanthoma
55
56
57
Cryotherapy, curettage and diathermy
59
Cryotherapy
59
Basal cell carcinoma
60
Squamous cell carcinoma and related keratinocyte tumours
Squamous cell carcinoma
Solar keratoses
62
62
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
CONTENTS
Bowen’s disease
Keratoacanthoma
9.
64
65
Relative indications
66
Relative contraindications
66
Curettage and diathermy
67
Basal cell carcinoma
67
Squamous cell carcinoma and related keratinocyte tumours
Squamous cell carcinoma
Bowen’s disease
Keratoacanthoma
69
69
69
70
Other treatments (intralesional interferon, topical imiquimod,
photodynamic therapy, laser therapy)
71
Interferon
71
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Basal cell carcinoma
Squamous cell carcinoma
Topical imiquimod
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Photodynamic therapy
Laser therapy
Basal cell carcinoma
10.
11.
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73
74
75
76
77
Squamous cell carcinoma and related keratinocyte tumours
Squamous cell carcinoma
Solar keratoses
Bowen’s disease
Keratoacanthomas
77
77
78
79
79
Prevention (including chemoprevention)
81
Prevention
81
Chemoprevention
Synthetic retinoids
Betacarotene supplementation
83
83
84
Metastasis from non-melanoma skin cancer
85
Basal cell carcinoma
85
Squamous cell carcinoma
86
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
v
CONTENTS
12.
13.
Follow up
91
Detection of further primary tumours
91
Local persistence of the previously treated tumour
91
Early detection of metastatic disease
92
Who treats and problems to refer
93
Introduction
93
To treat or to refer
Problem areas requiring experience and care
Problems to refer
14.
94
95
Economics of the public health problem due to
non-melanoma skin cancer in Australia
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Prevention
15.
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101
101
Questions and concerns that may arise during consultation
103
Specific topics
104
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In general
Appendices
1
106
International Union Against Cancer (UICC) TNM—
Classification of malignant tumours
107
2
Sources for cancer information
109
3
Members of the ACN Management of Non-Melanoma
Skin Cancer Working Party
111
Abbreviations
113
Glossary
115
References
119
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
EXECUTIVE
S U M M A RY
E X E C U T I V E S U M M A RY
•
•
•
•
•
•
•
•
•
•
•
•
Non-melanoma skin cancer is a major public health problem in Australia
causing substantial national health cost and disfigurement resulting from
treatment.
Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) together
are the most costly cancers in Australia, accounting for $A232.2 million per
year.
Non-Melanoma Skin Cancer: Guidelines for treatment and prevention in
Australia provides evidence-based documentation to assist in sound
decision-making. The Guidelines are guides and are neither rules nor are
they prescriptive in any way.
The Guidelines are produced primarily for those practitioners who are
providing the majority of care to people with non-melanoma skin cancer
(NMSC) in Australia. The data indicate that general practitioners comprise
the majority providing this care; hence the Guidelines primarily should be
of benefit to them.
Solar radiation is the major environmental cause of non-melanoma skin
cancer.
Protection against solar radiation is recommended. It is best achieved by
seeking shade when outdoors, and by wearing protective clothing.
Clothing should be used as the primary means of photo-protection. Broad
spectrum sunscreens with an SPF of 15 or greater may be used as an
adjunct to sun avoidance and together with other sun protective measures.
Surgery is prime treatment for non-melanoma skin cancers. Confirmation
of complete removal of lesions is required.
Recurrence is more frequent after excision of ill-defined basal cell
carcinomas such as morphoeic and microlobular forms.
Radiotherapy should be reserved for the small minority of primary BCC
and SCC that present peculiar problems for conventional surgery and for
cases of persistent, recurrent or advanced BCC and SCC where surgery can
be complemented by radiotherapy to improve control rates in this small,
poorer prognosis category.
Cryotherapy, curettage and diathermy treatments have specific
advantages and disadvantages, which should be considered and discussed
before implementation.
Other treatments eg, intralesional interferon, imiquimod, photodynamic
therapy and laser therapy have limited but definite roles in some selected
circumstances.
Becoming familiar with the clinical features of non-melanoma skin cancer
is important in leading to correct diagnosis, effective and efficient
treatment, minimal morbidity, better quality of life for affected patients
and a reduction of overall cost.
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
vii
S U M M A RY
OF
R E C O M M E N D AT I O N S
AND
GUIDELINES
S U M M A RY O F R E C O M M E N D AT I O N S
AND GUIDELINES
Level of
Evidence
Guideline
Refs
Page
4, 12,
13
6
III–2
14, 33,
36, 39
12
III–2
47,48
26
Higher recurrence rates have been
observed for all treatment modalities
in the facial region compared with
non-facial sites and particularly on and
around the nose, eyelids and ears.
IV
24,56, 57,
62, 63,68,
69, 70, 71,
72
28
The estimated prevalence of perineural spread
from cutaneous SCC is in the order of 2.5%.
IV
107, 108,
109, 118
31
SCCs of the scalp, ear and vermilion have a
IV
higher recurrence and subsequent nodal metastasis
rate than SCCs elsewhere, being in the order of
10 to 20% overall.
49, 115,
116, 117
33
2.
EPIDEMIOLOGY
Solar radiation is the major cause of
non-melanoma skin cancer.
III–2
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The chances that an individual solar keratosis
will develop into an SCC are extremely small;
however when one encounters an SCC,
the chance that it has arisen in association
with solar keratosis is very high.
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4.
P AT H O L O G Y
Confirmation of complete removal of the
tumours is important. Recurrence from
incomplete removal is seen more frequently
in clinically ill-defined basal cell carcinomas
such as morphoeic and microlobular forms.
5.
D
E
PROGNOSIS
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
ix
S U M M A RY
OF
R E C O M M E N DAT I O N S
GUIDELINES
AND
Level of
Evidence
Guideline
The prognosis for SCC in chronically immunosuppressed patients is worse than in other
people. Rates of local recurrence or metastasis
are increased overall and increase with duration
of immunosupression.
6.
SURGICAL
Refs
Page
III–2
16,17,
119
34
IV
58, 121,
124, 125
T R E AT M E N T
The majority of clinically favourable BCCs can be
excised with a margin of at least 3mm with a very
high chance of achieving complete excision and
long term control.
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39
Patients with BCCs which are large (> 2cm), poorly IV
defined or multiple lesions, unfavourable tumour
types, ie infiltrative, ulcerative or morphoeic
types or tumours located in sites where the rate of
local recurrence is predicted to be high (central
face and peri-aural regions) should be considered
for referral for specialist care.
3,4,5,6,7,
11, 48,58,
63
40
Patients with incompletely excised BCC should be IV
considered for re-excision to achieve clear margins.
Radiotherapy may be a reasonable alternative
for the patient unwilling or unable to undergo
further surgery.
98,99,100,
101, 102,
103, 104
41
Consideration of specialist therapy should occur
for patients with an SCC showing perineural
spread (See chapter 13). Wide excision is
recommended and consideration should
be given to post operative radiotherapy.
IV
107, 108,
109, 144,
146
45
Patients with recurrent SCC have an increased
risk of further local recurrence as well as regional
and distant metastases. Excision of the previous
treatment site should be undertaken in continuity
with the recurrent tumour. Specialist referral
is recommended.
IV
11, 147,
148, 149
45
Chronically immunosuppressed patients
frequently develop multiple SCC which
behave aggressively. These patients should be
referred for specialist management.
IV
16,17,119
46
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S U M M A RY
OF
R E C O M M E N D AT I O N S
Level of
Evidence
Guideline
AND
GUIDELINES
Refs
Page
68,69,
70,71,72,
73, 82,85,
89,94,155,156
49
II & IV
68,70,73,82,
85, 89,
156
54
A radiotherapist’s opinion should be considered
for T4 primary, persistent and recurrent BCC.
III
71
54
Radiotherapy gives comparable control
rates as re-excision for incompletely excised
BCC and is an alternative to re-excision if
further treatment is deemed advisable and
re-excision is disadvantageous or not feasible.
IV
101
54
68,69, 70,
73, 155,
158
57
III & IV
167, 180,
184
62
IV
163, 165,
176, 177,
181, 182,
184, 187
62
Cryotherapy achieves lower cure rates for larger
IV
BCCs, except for the superficial (non-invasive) type.
165, 167,
176, 178,
179, 183,
185, 186,
189
62
7.
R A D I OT H E R A P Y F O R B A S A L C E L L
CARCINOMA & SQUAMOUS CELL
CARCINOMA
Radiotherapy should be reserved for the small
IV
minority of primary BCC and SCC that present
peculiar problems for conventional surgery
and for cases of persistent, recurrent or advanced
BCC and SCC where surgery can be complemented
by radiotherapy to improve control rates in this
small poorer prognosis category.
Radiotherapy for T1 and T2 primary BCC has
comparable outcomes (marginally inferior) to
specialist surgery.
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As the late results of radiotherapy can be poor,
III
it is generally not recommended for patients
younger than 60 years with uncomplicated primary
SCC anticipated to have excellent outcomes
with surgery alone.
8.
C RYOT H E R A P Y ,
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C U R E T TA G E A N D
D I AT H E R M Y T R E AT M E N T
Cryotherapy achieves high cure rates
for primary BCC on trunk and limbs if
tumour selection and treatment protocols
are optimal.
Cryotherapy for primary BCC on head and neck
achieves cure rates equivalent to the other
standard modalities if tumour selection and
treatment protocols are optimal.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
xi
S U M M A RY
OF
R E C O M M E N DAT I O N S
GUIDELINES
AND
Level of
Evidence
Guideline
Refs
Page
Cryotherapy achieves lower cure rates for BCCs
at high risk facial sites and is not recommended.
IV
94,163,184,
187,183,
186,188
62
Cryotherapy is contraindicated for ill-defined
or morphoeic (infiltrative) BCCs at any site.
IV
165,168,
179
62
Long term follow up is essential after treatment
of BCC with cryotherapy, as late recurrences
may occur.
III
Cryotherapy achieves consistently high cure rates
for solar keratoses.
Cryotherapy of Bowen’s disease achieves high
cure rates with optimal treatment protocols,
but delayed healing may occur on lower limbs.
D
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60
62
IV
162,165,
211,212
65
IV
166,169
65
Recurrence rates of less than 6% may be
IV
achievable if curettage and electrodesiccation is used for appropriately selected BCC.
57, 234
68
III–2
2,3,11,
241,243,
249
73
IV
224,225,
269,270,
271,272,
273,274,
275,276,
277
76
Use broad spectrum sunscreens with an SPF of 15
or greater as an adjunct to sun avoidance and
other sun protective measures.
*
Squamous cell carcinoma; there is no evidence
for BCC.
II*
298,299
83
Use clothing, where possible, as the primary
means of photoprotection.
III
295
83
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9.
OTHER
T R E AT M E N T S
(INTRALESIONAL
I N T E R F E R O N , I M I Q U I M O D , P H OTO DY N A M I C
THERAPY, LASER THERAPY)
Intralesional interferon has a limited but
definite role in treatment of selected BCCs.
Laser therapy offers some treatment advantages
for select skin cancers. However, the great
majority of tumours are better managed by the
less expensive commonly available techniques.
10. PREVENTION (INCLUDING
CHEMOPREVENTION)
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
S U M M A RY
OF
R E C O M M E N D AT I O N S
Level of
Evidence
Guideline
AND
GUIDELINES
Refs
Page
III
319,320,
321,322,
323,324,
325
86
Intralesional 5-FU with epinephrine injectable gel III
has also been used. More recently, electrochemotherapy which involves intralesional
bleomycin and electric pulses locally has achieved
response rates approaching 100%.
118, 255,
326, 327,
328
86
1 1 . M E TA S TA S I S
OF NON-MELANOMA
SKIN CANCER
Response rates have been reported of up to
83% with 37% being complete.
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Clinically suspected lymph node metastases should IV
be confirmed by fine needle aspiration cytology
(under radiological guidance if required). Open
surgical biopsy should be avoided.
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330
87
IV
49,117,
329,331
87
III
118,319,
320,321,
322,323,
324,325,
326,
90
Small studies have investigated intra lesional
III
cisplatin with epinephrine or 5-fluorouracil
with epinephrine gels. Topical 5-fluorouracil has
activity in squamous cell carcinoma in small series.
252,255,
327,328,
335,336
90
Nil
92
The treatment of metastatic disease to lymph
nodes is primarily surgical.
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Most regimens are based on cisplatin with the
most commonly reported phase II studies
using cisplatin and doxorubicin. Other drugs
include methotrexate, 5-fluorouracil, bleomycin
and vindesine. Objective response rates of > 80%
have been reported with complete response rates
of around 30%. Patients should be considered for
referral to a suitable cancer specialist centre for
multidisciplinary care.
1 2 . F O L L OW
UP
There are no data available as yet to underpin a
O
recommendation on the frequency or nature of
follow up after the treatment of primary cutaneous
non-melanoma skin cancer.
NB: For details regarding levels of evidence, see page 3 of introduction.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
xiii
1 . I N T RO D U C T I O N
1.
INTRODUCTION
There have been a number of Guidelines on prevention, early detection and
management of cancers produced by the Australian Cancer Network in recent
years which have been endorsed by and then become Guidelines of the National
Health and Medical Research Council (NHMRC). These have been produced on
the basis of need with the primary reasons being identified by the NHMRC* as:
•
The size of the health burden
•
The cost of the health burden
•
Variations in practice
•
The existence of available evidence
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(*A guide to the development, implementation and evaluation of clinical practice
guidelines, NHMRC 1998)
There is no doubt that basal cell carcinomas (BCCs) and squamous cell
carcinomas (SCCs) comprise the commonest cancers in Australia, adding
substantially to the cost of provision of health care to the community. There are
other non-melanoma skin cancers (NMSCs) apart from these but, despite the fact
that they can cause considerable morbidity in those affected, their overall
contribution to the size of the public health problem is relatively small. These
include Merkel’s cell carcinoma and atypical fibroxanthoma. For that reason,
these tumours have not been included in these Guidelines. There is no doubt
also, even just examining the Medicare Benefit payments, that BCCs and SCCs
are being treated by a variety of different medical practitioners in Australia.
These include general practitioners, dermatologists, plastic surgeons, general
surgeons and radiotherapists. All of these practitioners will have different levels
of training and experience and, in many instances, they may have different
therapeutic approaches to the tumours. For example, general practitioners may
use surgery and on occasion cryotherapy and curettage. Dermatologists use most
of the modalities of therapy including surgery, radiotherapy, curettage,
cryotherapy and some of the biological response-modifying treatments.
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The Guidelines are produced primarily for those practitioners who are providing
the majority of care to people with NMSC in Australia. The data indicate that
general practitioners comprise the majority providing this care; hence the
Guidelines primarily should be of benefit to them.
Although NMSC does not make a large contribution to the mortality figures in
Australia, it still has the potential to cause considerable morbidity and require
treatment which itself may be associated with some morbidity. It will be clear on
reading this report that morbidity due to treatment is a concern. We have
reinforced in the text that practitioners who wish to treat them in Australia
should be well-trained so that they are competent, as well as feeling comfortable
when they do so.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
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1 . I N T RO D U C T I O N
It was clear on assessment of the available evidence that there are substantial
gaps and questions that need to be answered regarding therapy. Similarly, there
has been considerable discussion and debate recently on the terminology of
potential precursor lesions for SCC. This is leading to some confusion between
the meaning and implication of terms such as solar keratosis, Bowenoid solar
keratosis, intra-epidermal carcinoma, Bowen’s disease, in-situ squamous cell
carcinoma, and others. This certainly is an area for further work and clarification
as there is insufficient agreement as yet amongst pathologists and clinicans. For
the purposes of these Guidelines, we have tried to use the traditional terms of
solar keratosis and Bowen’s disease, with an explanation in the section on
Pathology of the term Bowenoid solar keratosis. The latter term is being used in
Australian pathology reporting with increasing frequency. We have deliberately
not entered the debate about what is the correct terminology at this stage, but
await the outcome of further research in this area. Part of the role of Guidelines
such as these being produced is to make recommendations for future research
which may provide the answers that the working party has found are necessary
and that are currently missing.
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In view of the factors mentioned, the Australian Cancer Network initiated a
project to develop evidence-based guidelines for the management of nonmelanoma skin cancer (NMSC) following the principles outlined in the 1999
edition of the NHMRC Guide to the development, implementation and evaluation
of clinical practice guidelines.
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A working party comprising representatives from each of the areas involved in
NMSC in Australia including general practice, general surgery, plastic surgery,
dermatology, radiotherapy, epidemiology, public health and consumers was
established to develop the Guidelines. The initial process was for working party
members to develop draft documents covering each of the sections outlined in
the full document including the epidemiology of the tumours, a brief clinical
description, the modes of therapy currently advocated, a public health approach
to NMSC prevention and a consumer section indicating concerns of the patients
that the treating practitioner might keep in mind. The latter have been written as
a series of critical questions that may need to be answered.
It became apparent very early in the process that there are very few, if any,
randomised controlled trials related to most of the various forms of therapy that
are used for BCC and SCC. Nevertheless, levels of evidence have been presented
in the manner prescribed by the NHMRC guide.
The NHMRC designates levels of evidence which have been followed in this
document.
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
1 . I N T RO D U C T I O N
Level of evidence ratings
I
Evidence obtained from a systematic review of all relevant randomised controlled trials.
II
Evidence obtained from at least one properly designed randomised controlled trial.
III–1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternative
allocation or some other method).
III–2
Evidence obtained from comparative studies with concurrent controls and allocation not
randomised (cohort studies), case-control studies, or interrupted time series with a
control group.
III–3
Evidence obtained from comparative studies with historical control, two or more singlearm studies, or interrupted time series without a parallel control group.
IV
Evidence obtained from case series, either post-test or pre-test and post-test.
D
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Within the body of the text, the levels of evidence underlying a recommendation
are highlighted.
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Another problem that arose in attempting to deal with these tumours was the fact
that there may be different therapeutic approaches according to whether or not
the treatment is the treatment for a primary tumour or whether it is for a tumour
that has recurred. The working party noted that there is some confusion created
by the word ‘recurrence’ used to describe where there is residual tumour which
may or may not become clinically apparent in the future. For this reason, it was
decided to present treatment of the tumours in three categories:
1.
Treatment of the primary tumour,
2.
Treatment when it is clear at the end of the primary treatment, either
clinically or from histopathology (or both), that the treatment has been
inadequate and that there is tumour still present (residual tumour),
3.
Treatment of clinically recurrent disease which becomes apparent some
time (months to years) after the primary treatment in which there was no
suggestion, either clinically or histopathologically, at the completion of
treatment that there was residual tumour present.
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The production of draft Guidelines was the first stage. The second stage was a
widespread consultation seeking input from all individuals or organisations who
have a stake in the diagnosis and management of NMSC in Australia.
Dissemination of this document is part of that process.
It must be stated clearly that the Guidelines are designed as information to assist
decision making and are based on the best evidence available at the time of
preparation. They are not meant to be prescriptive, being a guide to appropriate
practice. They are to be used only subject to the clinician’s judgement in each
individual case, taking into account all factors that might influence the decision
on which therapy is appropriate for which person.
Finally, the Guidelines are only a first step in a process which aims to improve
initially the treating practitioner’s knowledge and skill in treating these tumours
and, as a result, the outlook for the person with a tumour who requires
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
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1 . I N T RO D U C T I O N
treatment. A major requirement of the NHMRC in the development of any
Guidelines is also the development of an implementation strategy and an
evaluation which shows that they are making a worthwhile contribution. Both of
these are important on-going tasks for the working party set up by the Australian
Cancer Network following development of the guidelines.
Professor Robin Marks AM
Chairman
ACN Management of Non-Melanoma Skin Cancer Working Party
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
2. EPIDEMIOLOGY
2.
EPIDEMIOLOGY
O V E RV I E W
D
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Non-melanoma skin cancers represent a large public health problem among the
Australian population in terms of both prevailing health care costs and cosmetic
ill effects such as facial disfigurement. Of the 10 most expensive cancers in
Australia, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC)
together are the most costly, accounting for some $A232.2 million per year1. Skin
cancers are avoidable however and these costs potentially could be reduced
through primary prevention2. Because cancer registries do not routinely report
skin cancers apart from melanoma, exact incidence rates are not known. National
surveys have been conducted however (as part of household market surveys)
and these confirm that the incidence rates of skin cancer in people aged 14 years
and over are very high. In 1995, the year of the most recent national survey,
incidence was estimated to be 788 per 100,000 for BCC and 321 per 100,000 for
SCC, with 190,000 people treated for at least one BCC and almost 80,000 for at
least one SCC3. These are the highest reported rates in the world , and
represented a rise by some 20% for BCC and over 90% for SCC between 1985
and 19953. In 1995, men were more commonly affected by BCC than women
were after age 40, and by SCC at all ages. The median age at diagnosis was
around 54 years in both sexes3. In Australia about 200 people die each year from
skin cancers other than melanoma2.
K
O
V
E
R
Numerous descriptive epidemiological studies of skin cancer4 have been highly
consistent in confirming that, when sun exposure of skin cells is low or absent,
then cancers rarely develop5. In Australia, this means that the high ambient solar
ultraviolet (UV) radiation plays a pre-eminent role in skin cancer causation and
that those with white skins are especially susceptible, having the highest known
incidence rates. On the other hand skin cancers are exceedingly rare in
Aboriginal and Torres Strait Islander Australians. The face is one of the most
heavily sun-exposed skin sites and is the site most densely affected by skin
cancers in the population5—hence their major cosmetic impact. In contrast sites
that are virtually never sun-exposed like the buttocks are not affected.
Inhabitants of temperate countries who migrate to Australia take on a higher risk
of skin cancer than those who do not emigrate6. Analytic epidemiological studies
also point to solar radiation as a major cause of NMSC4.
A very small proportion of skin cancers in Australia (<1%) is attributable to
causative factors apart from solar UV. For BCC these include arsenic7, ionising
radiation therapy8,9,10 and scars, and for SCC, immune suppression, tobacco,
human papilloma virus (HPV) (in patients with epidermodysplasia verruciformis)
and chronic ulcers, sinus tracts and scars11.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
5
2. EPIDEMIOLOGY
Eradication of skin cancer among Australians is unlikely because sun exposure in
this country is ubiquitous and because a small proportion of the population is
highly susceptible to this disease.
•
Primary prevention of the majority of NMSCs is theoretically possible
however, through avoidance of excessive sun exposure starting from
childhood.
•
Skin cancer control could be achieved through national education
programs including a national primary prevention campaign, which has
been proposed, and would be potentially cost-effective in reducing current
expenditure on skin cancer1.
Key point:
D
E
In Australia annual health care costs for non-melanoma skin
cancers are around $A232.2 million per year (1993–94)
(greater than for any other cancer)1.
Guideline
V
E
R
K
O
Level of
Evidence
Solar radiation is the major cause of non-melanoma skin cancer
BASAL
CELL CARCINOMA
III–2
Refs
4, 12, 13
Incidence and mortality
General population
In the most recent national survey3, the incidence rate of BCC in 1995 was
estimated to be 788 per 100,000 in people aged 14 years and over (in men, 955
and in women, 629 per 100,000) and there was a strong inverse association with
latitude. Rates in women were higher in younger age groups, while rates in men
were higher in older age groups. Compared with 1985, rates of BCC increased by
19% overall, with the increase occurring mostly in men and in the elderly, but
there was an apparent decrease in people under 40 years. In Queensland in the
Nambour study, age-adjusted annual incidence rates of BCC in men and women
aged 25 to 75 years were estimated to be 2,074 and 1,579 per 100,000,
respectively in 199214. In the northern city of Townsville estimated incidence
rates in 1997 were 2,058 and 1,195 per 100,000 for men and women
respectively15. Native-born Australians are at higher risk of BCC than migrants
6
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
2. EPIDEMIOLOGY
and, among migrants, age of arrival in Australia is inversely associated with BCC
risk16. In people less than 40 years the incidence of BCC was higher in women
than men in the national survey3 while BCC rates were similar in men and
women under 40 in the Townsville study. After 40 years of age, BCC rates in
men have generally been found to be progressively greater than in women, with
advancing age3,15. When surface area is taken into account highest rates in men
and women are found on the face, especially the eyelid, lip and nasolabial fold,
followed by ears, nose and cheek15. Very high rates are also seen on the neck,
back and shoulders in men and neck, shoulders and outer arms in women15.
Immunosuppressed patients
D
E
In the follow-up study in Queensland of the 1,158 renal transplant patients with
no skin cancer prior to transplantation, 1969 to1994, BCC was diagnosed as first
skin cancer in 35%. 52 patients (19%) developed only BCCs (mean number of
BCCs, 2.2), and 50% developed both SCCs and BCCs (mean number of BCCs,
4.3)17. Cumulative incidence of BCCs was approximately 25% at 10 years and
54% at 20 years17. Among the first 455 heart transplant patients in Sydney, the
cumulative incidence of BCC was approximately 7% at 5 years and 10% at 10
years18.
K
O
Genetic epidemiology
V
E
R
Southern European ancestry is strongly protective while people with fair skin,
light coloured or red hair14, an inability to tan and a history of childhood
freckling16 are at significantly raised risk of BCC. This suggests that common
variants and mutations in the melanocyte stimulating hormone receptor gene
(MC1R) play a role19,20. Xeroderma pigmentosum (XP) patients who inherit a
mutation which makes them unable to repair UV-induced DNA damage in their
skin cells are highly susceptible to all types of skin cancers including BCC21.
Patients with the nevoid basal cell carcinoma (Gorlin’s) syndrome are also highly
susceptible to BCC22. Nevoid basal cell carcinoma syndrome is characterised by
prominent forehead, jaw cysts, and increased incidence of a variety of tumours.
Both XP and Gorlin’s syndrome are rare disorders characterised by early onset
and relentless lifelong high frequency of BCCs21,22. The most frequent genetic
abnormality in BCC is loss of heterozygosity for the region on chromosome 9
containing the patched gene, and inactivation of this tumour suppressor gene is
thought to be a principal cause of both sporadic and familial BCC21. BCCs show
p53 mutations and ras mutations, but allelic loss is uncommon apart from the
Gorlin locus (in contrast to SCCs)22. BCC case subjects have been reported as
three times more likely to have a p53 mutation in normal skin taken from the
mirror-image site to the cancer site (excluding face and ears) than normal skin
taken from a random site in control subjects23. Frequency of CC to TT mutations
(involving codons 247 and 248) did not reflect recalled total UV-radiation
exposure however.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
7
2. EPIDEMIOLOGY
Environmental risk factors
The predominant role of solar UV radiation in the aetiology of BCC is supported
by the consistent observation that clinical signs of chronic sun damage to the
skin are the strongest predictors of BCC, although there is an overall lack of
association between BCC and reported chronic sun exposure14,12. Various theories
of UV dose-rate dependence have been proposed to explain the apparent
differences in dose-response between BCC and SCC, eg, the intermittent UV
exposure theory which proposes that pattern of sun exposure rather than the
total amount of exposure determines risk of BCC12. It is also speculated that
target epithelial cells, maybe highly mitotic, and may require a relatively low
threshold of total solar radiation for malignant transformation13 (cf. a higher total
dose needed to transform epithelial cells from which SCCs arise). The occurrence
of BCC at earlier ages than SCC and on the trunk as well as the face would
support this13.
K
O
D
E
Ultraviolet dose dependence may also vary among the commonest BCC subtypes
as suggested by their clinical and histological differences. In particular superficial
BCCs appear to differ from the nodular subtype as demonstrated in two large
series, one comprising all BCCs diagnosed in a pathology laboratory in
Melbourne in a five month period (N=3885)24 and the other, all BCCs diagnosed/
treated in a teaching hospital in The Netherlands in an 11 year period
(N=2990)25. In both series more of the superficial BCCs diagnosed (49%24 and
62%25) occurred on the trunk than on any other site while the majority of nodular
BCCs (64%24 and 77%25) occurred on the head and neck. This finding and the
younger ages of patients with superficial compared with patients with nodular
BCCs suggest that superficial BCCs have a lower threshold for UV carcinogenesis
than the nodular subtype. The subtype relation with site is complex however,
since nodular BCC predominated over superficial BCCs on the trunk in the
Australian series24 and they occurred in similar proportions on the trunk in the
Dutch series25.
V
E
R
Other risk factors for BCC are
•
exposure to ionising radiation therapy8
•
exposure to arsenic11,26—this would play a relatively small part in the
overall burden of BCCs in Australia
•
some dietary factors27, 28
Among immunosuppressed patients, determinants of BCC in immunosuppressed
patients in the Queensland follow-up study were a history of previous skin
cancer and duration of immunosuppressive therapy17. Level of ambient UV also
affects incidence of BCC and other skin cancers after organ transplantation as
seen by the far higher rates and earlier times of onset of skin cancer in
transplant patients in Australia than in The Netherlands17.
8
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
2. EPIDEMIOLOGY
Key points:
•
When surface area is taken into account highest rates in
men and women are found on the face, especially the
eyelid, nonmucosal skin of the lip and nasolabial fold,
followed by ears, nose and cheek. Very high rates are also
seen on the neck, back and shoulders in men and neck,
shoulders and outer arms in women15.
•
The occurrence of BCC at earlier ages than SCC and its
common occurrence on the trunk as well as the face
would support the suggestion that BCC requires a lower
threshold of total solar radiation before malignant
transformation than is required for SCC13.
SQUAMOUS
K
O
D
E
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
TUMOURS
Incidence and mortality
V
E
R
General population
In the most recent national survey of treated skin cancer, the incidence rate of
SCC in 1995 was estimated to be 321 per 100,000 in people aged 14 years and
over3, with a significant latitude gradient: the highest rates are seen in those
living at latitudes less than 29°S. Overall SCC incidence had risen by 93% since
1985, but this was mostly in people in the south of Australia (greater than 37°).
Surveys in Queensland have confirmed that SCC rates are highest in tropical and
subtropical latitudes. In the township of Nambour (26°S), annual incidence rates
of SCC in men and women aged 25 to 75 years were estimated to be 1,035 and
472 per 100,000 respectively in 199214. Further north in Townsville (19°S)
incidence rates of 1,332 per 100,000 men and 755 per 100,000 women have been
reported15. The incidence of SCC increases with increasing age and highest rates
in both men and women are found on the face, especially the lip region, ears,
nose, cheek and eyelid when surface area is taken into account, with neck,
dorsa of hands and forearms next most affected15. Migrants to Australia have
lower risks of SCC than people born in Australia29. The mortality rate of nonmelanoma skin cancer (predominantly SCC, but could include a small number of
deaths from BCC and Kaposi’s sarcoma) in Australia in the years 1995–1998 was
2.0 per 100,000 men and 0.5 per 100,000 women30.
There are no published population-based incidence rates of people who develop
solar keratoses (SKs) and this would be difficult to calculate given the lability of
these lesions. However it has been found in a follow-up study of 424 volunteer
adult residents of Maryborough, Victoria (37°S) who were initially lesion-free,
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9
2. EPIDEMIOLOGY
that 81 (19%) had a prevalent solar keratosis at 12 months31. In Queensland, in a
population-based prevalence study in Nambour (26°S), 44% of men and 37% of
women between the ages of 20 and 69 years had at least one solar keratosis on
examination of head, neck, hands and arms32, the most common sites of
occurrence. Prevalence of SKs is strongly age-dependent33,34 reflecting incidence
and recurrence rates that exceed rates of regression as people age. A
spontaneous remission rate of 10% has been reported based on follow-up after
12 months, though with more intense lesion surveillance34, substantially higher
rates of remission are seen35. On rare occasions a solar keratosis may undergo
malignant transformation to SCC, though definitive evidence from a long-term,
closely monitored study is lacking. In a medium-term (5-year) study based in
Maryborough, Victoria36, the rate of malignant transformation was estimated to be
less than 1:1000 (though without histological confirmation of the initial lesion,
the possibility remains that the lesion was an SCC at the outset33. None of more
than 1000 SKs in 200 Nambour residents who were followed up every 2 to 6
months for 18 months underwent malignant transformation35. In summary, the
chances that an individual solar keratosis will develop into an SCC are extremely
small. However when one encounters an SCC, the chance that it has arisen in
association with solar keratoses is very high.
K
O
D
E
Relatively little is known about the specific epidemiology of other keratinocyte
tumours in Australia. The incidence of keratoacanthoma (KA) was estimated as
36 per 100,000 person-years in a national survey of treated skin cancers in
199037. The incidence rate of seborrhoeic keratoses is not known but the
prevalence was recently estimated to be 12% in people 15–25 years; 79% at ages
26–50; and 100% in those over 50 in a volunteer sample of 100 adults in
Victoria38.
V
E
R
Immunosuppressed patients
In a long-term retrospective follow-up study in Queensland, the risk of skin
cancer was evaluated in people who received renal transplants from 1969 to
1994 in that state16. Of 1158 Caucasian patients without a history of skin cancer
prior to transplantation, SCC was diagnosed as the first skin cancer in 56%; 83
patients (31%) developed only SCCs (mean number of SCCs, 3.9) while 136
(50%) developed both SCCs and BCCs (mean number of SCCs, 12.6). Cumulative
incidence of SCCs was approximately 30% at 10 years and 60% at 20 years16. In a
study of histologically proven skin cancers in the first 455 heart transplant
patients in Sydney, the cumulative incidence of SCC was approximately 24% at 5
years and 33% at 10 years17.
Genetic epidemiology
Native Australians of southern European ancestry have much lower risk than
those of British or northern European origin and, in general, people with fair
skin colour who sunburn easily without tanning are at increased risk of SCC30
and SKs34. This is because white skin lacks melanin protection from ultraviolet
(UV) radiation. Hair and skin colour are influenced by the common variants of
10
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
2. EPIDEMIOLOGY
the melanocyte stimulating hormone receptor gene (MC1R)19, and it is likely that
mutations in this gene are linked to risk of non-melanoma skin cancer20. XP
patients are highly susceptible to SCC, SKs and KAs21. UV-induced mutations
(distinctive mutations especially CC to TT tandem base mutations) in the p53
gene can be found in the majority of SCCs, and there is also a high rate in
related keratinocyte tumours. Loss of heterozygosity studies show that allelic loss
is common, found in 25–30% of SCCs22.
Environmental risk factors
D
E
The strongest environmental risk factor for SCCs and related keratinocyte
tumours is chronic sun exposure and their anatomic site distribution reflects sites
of maximal sun exposure. The UV radiation spectral regions of sunlight—the
wavelengths 290–320nm (UVB) and 320–400nm (UVA)—are those specifically
implicated in carcinogenesis. In studies in Queensland and Western Australia
there were strong associations with clinical signs of chronic skin damage,
especially SKs14,39 and in Western Australia total site-specific sun exposure based
on recall was strongly related to risk of SCC39. In the Nambour study population,
high levels of occupational exposure and sunburns were strongly and
significantly associated with SK prevalence, especially in those people with
multiple SKs34. While SKs share many of the same determinants as SCC, they may
be a more sensitive indicator of intense sunlight exposure40.
V
E
R
K
O
There are other risk factors for SCC including tobacco; HPV (in patients with
epidermodysplasia verruciformis); arsenic (in association with arsenical
keratoses); polycyclic aromatic hydrocarbons; and chronic ulcers, sinus tracts and
scars11. However only a very small proportion of SCCs in Australia would be
attributable to these other risk factors compared with solar UV.
Immunosuppressed patients
Determinants of SCC were as for BCC in the Queensland study17. HPV is also
believed to play a role41.
Key point:
•
The overall incidence rate of SCC in 1995 was estimated
to be 321 per 100,000 in people aged 14 years and over
in Australia3. There is a significant latitude gradient such
that the highest SCC rates (2–4 times the national
average) are seen in those living at low latitudes such as
Townsville, North Queensland15.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
11
2. EPIDEMIOLOGY
Guideline
Level of
Evidence
Refs
1II–2
14,33,
36,39
The chances that an individual solar keratosis will
develop into an SCC are extremely small; however
when one encounters an SCC, the chance that it has
arisen in association with solar keratosis is very high.
K
O
V
E
R
12
D
E
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
3. CLINICAL
3.
F E AT U R E S
C L I N I C A L F E AT U R E S
I N T RO D U C T I O N
D
E
The high prevalence rates of NMSC in Australia make it imperative that all
clinicians are familiar with its various presentations Early detection of these
lesions is important in minimising morbidity, costs of treatment and mortality
associated with these lesions. Clinical examination that is conducted for other
purposes, particularly in the general practice context, provides opportunities for
screening and early detection of NMSC.
K
O
In addition to the clinical features that are evident at any one point in time,
clinical history also provides important evidence on which to base diagnosis.
NMSCs are changing lesions and the time course of the change is generally
evident over a period of months. Many are also symptomatic. These features vary
with different skin cancers.
V
E
R
Key point:
•
The importance of asking about change and
symptomatology in the course of assessing a lesion cannot
be underestimated.
Some lesions will be confidently diagnosed on clinical examination and history
and others, particularly early lesions with subtle clinical features, will require
biopsy. Partial biopsy techniques such as punch, shave and incisional biopsy are
considered appropriate in the assessment of NMSCs. Consideration should be
given to the role of pre-treatment biopsy in confirming the presence of skin
cancer, the type, its growth pattern, prognostic features and the most appropriate
modality to maximise the chance of cure and minimise the morbidity of
treatment.
Examination for skin cancer should be considered in the general practice context
for all patients over the age of 40 and particularly for the elderly. Patients with
special risk factors (see chapter 2) should be considered for entry to a regular
surveillance program with their general practitioner or dermatologist. A
substantial proportion of NMSCs occur on the intermittently exposed parts of the
trunk and limbs and it is worthwhile to examine these areas in addition to the
head and neck, hands and forearms. The examination should be conducted in a
well lit area and magnification may be useful. Atlases are available that illustrate
the clinical features of NMSCs.42
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
13
3. CLINICAL
F E AT U R E S
Key points:
BASAL
•
Clinical history is important in diagnosis.
•
Partial biopsy techniques such as punch, shave and
incisional biopsy are appropriate.
•
Examination for skin cancer should be considered during
physical examination for all patients over the age of 40
and particularly for the elderly
CELL CARCINOMA
D
E
Numerous histological types of BCC have been described but most are
uncommon and do not have distinctive clinical presentations. There are three
common growth patterns of BCC (superficial multifocal, nodular and morphoeic)
that have a distinctive clinical presentation24. Superimposed on any of these
growth patterns may be ulceration or pigmentation. Though these latter features
lead to a distinctive clinical appearance, they do not correspond to a specific
histological growth pattern and are therefore no longer considered to represent
separate types of BCC. Immunosuppression for organ transplanation predisposes
to BCC17,18.
K
O
V
E
R
Accuracy of clinical diagnosis of basal cell carcinoma
The diagnostic accuracy of experienced dermatologists surveying people selected
at random from the general community is around 59%43 to 65%43. This is
somewhat lower than would be expected in clinical practice because of the
much lower prevalence of skin cancers in the community compared with the
clinical setting. No data are available regarding the diagnostic accuracy of
clinicians in Australia but in a clinical practice setting in the United States, a
diagnostic accuracy of 70% has been reported for university-based
dermatologists44. These observations indicate that, in spite of the frequency of
BCC and in spite of high levels of clinical experience, diagnosis may be difficult.
Superficial
Superficial BCC is a common subtype of BCC occurring in Australians. They
generally occur on the trunk or limbs and in younger people more than other
growth patterns 5.
Clinical features
Superficial BCC presents as a bright pink, shiny, usually well-defined
erythematous macular lesion. The degree of erythema present may fluctuate
greatly and will be increased by stretching or rubbing the lesion. Stretching the
14
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
3. CLINICAL
F E AT U R E S
lesion will highlight the shiny surface and may reveal a peripheral, thread-like,
pearly rim or islands of pearliness distributed through the lesion.
A minority of superficial BCCs are symptomatic with itching being the most
common symptom. Though these lesions are readily eroded by minor trauma, a
history of ulceration or bleeding is uncommon.
Causation
Multiple superficial BCCs may occur in the context of arsenic intoxication. Other
stigmata of arsenic intoxication include punctate palmoplantar keratoderma,
scattered macular hyperpigmentation and longitudinal pigmented bands or
horizontal hyperpigmented stripes in fingernails and toenails.
Clinical course
D
E
Many superficial BCCs will progressively enlarge over months to years and, if
left, may reach 5–10 cm in diameter. Some may be relatively stable and a few
will regress. With time areas of nodular and even sclerosing growth pattern may
supervene within the original superficial BCC.
K
O
Differential diagnosis
Superficial BCC can generally be distinguished from Bowen’s disease by its shiny
surface and lack of hyperkeratosis. Superficial BCC has a brighter pink hue than
Bowen’s disease (see p19) or amelanotic melanoma. Amelanotic melanoma will
frequently show some ill-defined light brown pigmentation. Like Bowen’s
disease, solar keratoses will usually be somewhat hyperkeratotic though this may
be difficult to distinguish from the scaling seen in some superficial BCCs.
V
E
R
The appearances may suggest an inflammatory dermatosis such as eczema or
psoriasis, however, the clinical history is one of inexorable enlargement over
months or years. Inflammatory lesions, on the other hand, would generally be
more transient.
Nodular
Nodular BCCs are more often found on the head and neck in subjects who are,
on average, somewhat older than those with superficial BCC24,25. These findings
suggest that they may be more closely tied to chronic cumulative sun exposure
than superficial BCC.
Clinical features
Nodular BCC typically presents as a shiny, translucent (pearly), telangiectatic
papule or nodule. As the lesion enlarges the pearliness becomes more evident
and dilated capillaries may be seen coursing across the surface of the lesion.
These are often radially arranged. Recurrent ulceration is frequent and this may
lead to central umbilication of the lesion with a more raised, rolled border.
Islands of pigmentation may become clinically visible and the lesion may
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
15
3. CLINICAL
F E AT U R E S
become darkly pigmented, suggesting melanoma. Like superficial BCC these may
be associated with sensory symptoms in a minority of cases but unlike superficial
BCC, nodular lesions will repeatedly ulcerate and bleed.
Differential diagnosis
Nodular BCCs need to be differentiated from SCC and amelanotic nodular
melanoma. Nodular BCCs are distinguished by pearliness and horizontal,
branching telangiectasia.
Clinical course
D
E
Nodular BCCs will progressively enlarge and may raise up over a period of
months to years.
Morphoeic
K
O
Morphoeic or sclerosing BCC has a similar body site distribution to nodular BCC.
Morphoeic BCCs are usually of long standing and tend to be deeply invasive.
Clinical features
As the name ‘morphoeic’ suggests, these lesions have a sclerosing growth pattern
with fibrosis surrounding areas of BCC. BCCs that are predominantly morphoeic
present the appearances of a pale scar. These can be clinically difficult to detect
and the patient may be unaware of them. Morphoeic BCCs constitute an
aggressive growth pattern and are often associated with significant tissue
destruction. Palpation usually reveals firm induration which may extend more
widely and deeply than is evident on inspection. Morphoeic changes will
frequently supervene in long standing nodular BCCs and these lesions may retain
some clinical features of nodular BCC. Morphoeic BCCs are frequently
asymptomatic. Those with nodular elements may show all the same symptoms as
nodular BCCs.
V
E
R
Clinical course
Morphoeic BCCs may remain undetected by doctor and patient for many years
and may slowly enlarge and deepen to reach a large size before therapy is
instituted.
The major differential diagnosis of morphoeic BCC is scar and biopsy is
frequently necessary to establish the diagnosis.
16
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
3. CLINICAL
F E AT U R E S
Key points:
•
Superficial basal cell carcinomas present as a bright pink,
shiny, usually well-defined erythematous macular lesion.
•
Nodular basal cell carcinoma typically presents as a shiny,
translucent (pearly), telangiectatic papule or nodule.
•
Basal cell carcinomas that are predominantly morphoeic
look like a scar.
SQUAMOUS
D
E
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
TUMOURS
K
O
Squamous cell carcinoma
The majority of SCCs are thought to arise from solar keratoses42. The age and
body site distribution is therefore similar to solar keratosis. A few develop from
chronic ulcers or scars, sites of chronic radiation dermatitis or from infrared
irradiation. Immunosuppression for organ transplantation strongly predisposes to
SCC.
V
E
R
Clinical features
SCC typically begins as a tender erythematous papule or nodule. This may be
surmounted by a variable amount of hyperkeratosis, some producing a keratotic
horn. The lesion enlarges over a period of months and becomes increasingly
tender. Recurrent ulceration and bleeding may develop. Some, particularly on the
scalp and legs may present as an ulcer without a preexisting nodule or
surrounding induration.
Accuracy of diagnosis of squamous cell carcinoma
Experienced dermatologists working in a Queensland prevalence study achieved
a diagnostic accuracy of 39%, considerably lower than the 59% found for BCC45.
The clinical diagnosis of early SCC is difficult, particularly to distinguish it from a
hypertrophic solar keratosis. It is likely that many early SCCs are treated with
cryotherapy based on a clinical diagnosis of solar keratosis. Lesions that are
initially considered to be solar keratoses that persist following cryotherapy,
enlarge or become tender should be biopsied to explore for the presence of SCC.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
17
3. CLINICAL
F E AT U R E S
Clinical course
The course of an SCC is generally one of progressive enlargement. Ulceration
and bleeding become more likely as the lesion enlarges. A few will become
locally aggressive with perineural spread. Large lesions have greater potential for
metastasis which generally occurs to regional lymph nodes.
Differential diagnosis
SCC may be difficult to differentiate clinically from nodular BCC and amelanotic
nodular melanoma. Nodular BCC will generally display a brighter pink colour
than the dull red typical of SCC. Pearliness, telangiectasia and islands of pigment
are also helpful features of BCC. Amelanotic nodular melanoma may show some
light brown pigmentation. Excision and histological assessment may provide the
only way to establish the diagnosis.
K
O
Key points:
D
E
•
The majority of squamous cell carcinomas are thought to
arise from solar keratoses.
•
Squamous cell carcinoma typically presents as a tender
erythematous papule or nodule that may show
hyperkeratosis.
V
E
R
•
Immunosuppression for organ transplantation strongly
predisposes to squamous cell carcinoma.
•
The clinical diagnosis of early squamous cell carcinoma is
difficult.
Solar keratoses
These lesions are usually found on the chronically sun exposed sites of head and
neck, dorsae of hands and forearms. They are generally multiple and may be
very numerous or confluent.
Clinical features
Solar keratoses present as an erythematous macule with superimposed
hyperkeratosis. Hyperkeratosis may be gross enough to produce a keratotic horn
but the erythematous base of the lesion remains macular and impalpable. There
is no underlying induration when the lesion is palpated and they are generally
non tender. Solar keratoses may be symptomatic. A variety of sensory symptoms
including pricking, burning and stinging may be felt with sun exposure or
perspiration.
18
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
3. CLINICAL
F E AT U R E S
Differential diagnosis
Pigmented solar keratoses may need to be differentiated from solar lentigines
and lentigo maligna. Hyperkeratosis is the most helpful distinguishing feature of
solar keratosis. Solar keratoses are smaller and less well defined at the periphery
than Bowen’s disease and are also less well defined than seborrhoeic keratoses.
Thickening and tenderness on lateral palpation are signs that a solar keratosis
may have developed into invasive SCC.
Clinical course
D
E
Only a small percentage of solar keratoses evolve into invasive SCC. One
estimate suggests that the rate of malignant transformation is less than one in
1000 per year36. Many SCCs, however, evolve from solar keratoses40.
K
O
Key points:
•
Solar keratoses present as an erythematous macule with
superimposed hyperkeratosis.
•
Only a small percentage of solar keratoses evolve into
invasive squamous cell carcinoma.
V
E
R
•
Thickening and tenderness on lateral palpation are signs
that a solar keratosis may have developed into invasive
squamous cell carcinoma.
Bowen’s disease
Bowen’s disease has a predilection for the lower limbs, particularly in females,
but may occur at any site.
Clinical features
Bowen’s disease presents as a sharply defined, erythematous, round to oval
hyperkeratotic plaque. The degree of hyperkeratosis may vary, some lesions
producing a keratotic horn. Hypertrophic Bowen’s disease may show epidermal
hyperplasia only without keratin production and present as a raised, moist, juicy
plaque or tumour. Bowen’s disease is generally asymptomatic. The clinical
history is usually of a long standing, slowly enlarging lesion.
Differential diagnosis
Bowen’s disease may be distinguishable from psoriasis by its long history though
the clinical appearances may be very similar. Superficial BCC can be
distinguished from Bowen’s disease by lack of hyperkeratosis, the shiny surface
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
19
3. CLINICAL
F E AT U R E S
and bright pink colour. Hypertrophic Bowen’s disease may mimic SCC and a
biopsy is frequently necessary to distinguish this from invasive SCC. Pigmented
Bowen’s disease may mimic superficial BCC or superficial spreading melanoma.
Clinical course
Bowen’s disease will generally enlarge very slowly and will appear to the patient
as a stable lesion. The rate of transformation to invasive SCC has not been
established but would appear to be low.
Keratoacanthoma
D
E
Keratoacanthoma is a well differentiated form of SCC that is characterised by
spontaneous resolution. Many of these lesions arise in association with solar
keratoses and the age and site distribution is similar to solar keratosis and SCC.
The chronically exposed sites of the head and neck, hands and forearms are
most commonly affected though multiple keratoacanthomas most often occur on
the limbs, particularly the lower limbs.
K
O
Clinical course
The most characteristic feature of a keratoacanthoma is its clinical course. These
begin as a small papule that rapidly enlarges to form an erythematous nodule
with a central keratotic plug. The lesion continues to enlarge over a period of
four to eight weeks, remains stable for a period as an asymmetrical, dome
shaped erythematous nodule with a central keratotic plug. It may reach a size of
several centimetres in diameter. Keratoacanthomas are typically exquisitely
tender until regression is well established. The fleshy rim then begins to recede,
exposing more of the central keratin plug until there is an erythematous collar
surrounding a keratotic horn. The central keratin plug then falls out and the
remainder of the lesion resolves sometimes leaving a scar. Rare differential
diagnoses include amelanotic melanoma, atypical fibroxanthoma and Merkel cell
tumour. Not all lesions with this initial clinical course appearance will resolve
and a minority will persist as SCC. Resolution of keratoacanthoma generally takes
6–12 weeks.
V
E
R
Aids to diagnosis
Partial biopsy will generally be unhelpful in differentiating keratoacanthoma
from carcinoma. Partial biopsy will almost always be reported as well
differentiated SCC because the pathologist requires the architecture of the entire
lesion to suggest the possibility of keratoacanthoma.
20
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
4 . P AT H O L O G Y ( I N C L U D I N G
4.
BIOPSY)
P AT H O L O G Y ( I N C L U D I N G B I O P S Y )
H I S T O P AT H O L O G I C A L
C L A S S I F I C AT I O N A N D P R O G N O S I S
Basal cell carcinoma
D
E
BCCs are a group of tumours which are composed of lobules of basaloid cells
characterised by hyperchromatic nuclei and scant cytoplasm. These represent
pluripotential cells derived or closely related to basal keratinocytes and follicular
or epidermal stem cells. Metastases rarely develop from BCC 46 and the main risk
is that of recurrence after incomplete removal. Nodular (and nodulocystic)
tumours as well as superficial BCCs comprise the majority of tumours. Morphoeic
(sclerosing, fibrosing) BCC, infiltrative BCC and microlobular tumours have less
well defined clinical margins and are associated with increased rates of
recurrence47, 48. Although numerous cytological types of BCCs (clear cell,
pleomorphic, granular cell, adamantinoid) have been described, most of these
are uncommon and these subtypes do not have established prognostic
significance.
K
O
V
E
R
There may be pitfalls in the histological diagnosis of BCC. BCCs often have
recognisable appendageal differentiation, most commonly follicular type, and
may need to be distinguished from eccrine or sebaceous carcinomas which have
an increased risk of metastases. The distinction between morphoeic BCC and
desmoplastic trichoepithelioma as well as sclerosing sweat duct carcinoma may
be difficult in small biopsy samples. Similarly some SCCs may have a basaloid
appearance (basosquamous carcinoma, SCC with basaloid keratinocytes) and are
also associated with increased risk of metastases. The basaloid cells of Merkel
cell carcinoma or small cell melanoma may also be mistaken for BCC and have a
worse prognosis. In doubtful cases immunohistochemistry may be vital for
diagnosis if definite diagnosis cannot be achieved. The appendageal tumours
simulating BCC are relatively rare and are not covered in this guideline of nonmelanoma tumours.
Squamous cell carcinoma
SCCs are a group of non-melanoma skin cancers characterised by lobular
proliferation of keratinocytes and intradermal invasion of keratinocytes that show
prominent keratin production. The risk of metastases increases with tumour
thickness, the presence of clinical immunosuppression and with poorly
differentiated tumours49, 50. Tumour recurrence is more common with infiltrative
and desmoplastic lesions demonstrating spindle or single cell infiltration within a
dense connective tissue stroma particularly as initial surgical margins may be
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
21
4 . P AT H O L O G Y ( I N C L U D I N G
BIOPSY)
difficult to define as being clear of tumour. Perineural invasion by SCC when
close to the excision margins also increases the likelihood of residual tumours.
SCCs are usually graded into well differentiated (resembling the differentiation of
normal epidermis), poorly differentiated (difficult to diagnose without keratin
markers) and moderately differentiated between these two extremes.
Acantholytic (adenoid, pseudoglandular) SCCs are associated with loss of
cohesion of keratinocytes but the prognostic significance of this variant remains
to be determined.
Solar keratoses
D
E
Solar keratoses represent a potential precursor for invasive SCC and are
associated with confluent dysplasia involving the interfollicular epidermis
concentrated particularly within basal keratinocytes. Only a small fraction of
solar keratoses progress to invasive SCC31,51. The distinction between some
hyperplastic solar keratoses and early invasive SCC is not sharp.
K
O
Bowen’s disease
Bowen’s disease (intraepidermal SCC) is associated with full thickness epidermal
dysplasia with follicular involvement. The presence of papilloma virus has been
found in Bowen’s disease particularly in non sun-exposed sites and on the hands
and feet52. This may represent an oncogenic factor. Despite the full thickness
epidermal dysplasia the majority of intraepidermal SCC classified as Bowen’s
disease have a prolonged in situ phase which may last many years53.
V
E
R
Bowenoid solar keratoses
Bowenoid solar keratoses share histological features with both of these
precursors and is a term used by some pathologists. Many examples of bowenoid
solar keratoses probably represent true Bowen’s disease particularly when only a
small sample is available for diagnosis and follicular involvement cannot be
adequately assessed. Solar keratoses that evolve to invasive SCCs may not have
progressed to full thickness bowenoid changes prior to invasion in contrast to
the sequence of tumour progression seen in many mucosal precursors. The
prognostic significance of bowenoid lesions induced by the sun as compared to
papilloma virus associated lesions remains to be determined.
Keratoacanthoma
Keratoacanthoma is usually a spontaneously involuting atypical (dysplastic)
squamous proliferation with intradermal invasion which undergoes rapid terminal
keratinisation and has a characteristic clinical and histological pattern. The
histopathology in some keratoacanthomas may have an infundibulocystic
follicular component. Giant keratoacanthomas and centrifugally enlarging lesions
22
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
4 . P AT H O L O G Y ( I N C L U D I N G
BIOPSY)
may provide difficulties in diagnosis. Keratoacanthomas may be difficult to
differentiate from SCCs particularly in small biopsies, shave biopsies or curette
fragments. Immunosuppression may alter the biological behaviour of
keratoacanthomas and increased caution in management needs to be used as
such lesions in this setting may follow a progressive growth history rather than
involuting and represent a SCC54.
BIOPSY
OF NON-MELANOMA SKIN CANCER
D
E
For the majority of skin cancers primary excision represents the main treatment
modality and also provides tissue for definite diagnosis as well as assessing the
adequacy of surgery. Preliminary biopsy may be required when a firm clinical
diagnosis cannot be made or when the treatment choice may be dictated by the
tumour type or pattern of growth. Biopsy is also often obtained prior to
undertaking extensive surgery and in order to confirm the diagnosis in
cosmetically sensitive areas such as the face. Multiple small 2 mm punch
biopsies may be used to define poorly demarcated tumours. For superficial
lesions such as for Bowen’s disease or superficial BCC, particularly when the
tumour may be multifocal and associated with areas of regression, shave biopsy
may be a suitable technique as it maximises the area sampled. This method
should be avoided when the aim is to detect the presence of SCC in a setting of
solar keratoses as the samples are often too shallow for adequate assessment.
Similarly the distinction between SCC and keratoacanthoma cannot always be
made on shave specimens. Shave biopsy sites may heal rapidly and may be
difficult to locate when the patient returns for further therapy. The site of shave
biopsies should be mapped or photographed for future identification. In the
majority of deeper tumours an incisional or punch biopsy is a preferable method
and allows both pathological diagnosis and assessment of the pattern of
differentiation. The technique can also be used to provide a guide to tumour
depth particularly prior to using radiotherapy when the biopsy is obtained from
the most infiltrated focus.
K
O
V
E
R
Curettage specimens are often used for diagnosis when this technique is used for
treatment, but are associated with disruption of tumour architecture. Pitfalls in
diagnosis with curette specimens may be associated with poor technique, with
insufficient material and inclusion of cauterised fragments. Small cell melanoma
as well as some appendageal tumours dominated by cells with hyperchromatic
nuclei and scant cytoplasm may closely resemble BCC on curettings and mistakes
may occur.
When multiple biopsies are obtained these should be carefully marked and sent
in separate containers. For excision specimens, a reference suture or other
marker should be used for orientation of the specimen so that the site of tumour
extension to the margin can be indicated in the histological report.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
23
4 . P AT H O L O G Y ( I N C L U D I N G
BIOPSY)
H I S T O P AT H O L O G I C A L
R E P O RT
In reference to non-melanoma skin cancers, the histopathological report deals
with the tumour type, degree of differentiation, pattern of growth, cell
morphology and in excisional material the presence or absence of tumour free
surgical margins. In order to provide an optimal report the clinician needs to
provide patient identification including the age and sex of the patient, exact site
of the specimen and a provisional clinical diagnosis. Any history of previous
therapy or biopsy of the tumour site should also be included. The presence of a
longstanding burn scar, radiodermatitis or ulcer should also be indicated. The
final histopathological report should contain the clinical and macroscopic
description of each specimen. For specimens containing a reference suture or
surgical nick at a specified margin, a diagram indicating the orientation of tissue
blocks and colour inks used to identify the cut surfaces should be included in
the final report. Individual specimens should be reported separately with their
final diagnoses. The measured tumour margins should be included in the report
particularly when the tumour extends closer to a border. Measured tumour depth
may also be included in the report particularly in biopsies taken prior to
radiotherapy. The presence of perineural vascular or lymphatic tumour invasion
should also be included in the report.
K
O
D
E
The validation of tumour clearance margins is partially dependent on the number
of tissue blocks and sections examined when the conventional technique of
bread loafing the excisional specimen is used. Using this technique infiltrative
morphoeic and microlobular subtypes may have undetected extensions to
surgical margins. The Mohs’ (see p37,41–2,45–8,61,77) technique which is
usually carried out intraoperatively, using frozen sections, samples both the base
and all margins and examines the actual surgical marginal planes. This method
has less than 1% recurrence rate reflecting its superiority for checking tumour
free margins but the technique is not practical for use in all skin specimens
submitted for histopathology.
V
E
R
A provisional pathological diagnosis may be issued by a laboratory prior to a
final diagnosis particularly when immunoperoxidase markers, further
consultation or more rarely ultrastructural studies are needed for definite
classification of non-melanoma tumours. The clinician should be aware that these
tests may alter the diagnosis and subsequent approach to further management.
Clinical information recommended to be provided on request form:
1.
2.
3.
4.
5.
Patient identification.
Clinical diagnosis.
Any history of previous therapy or previous biopsy of tumour.
Diagram of excision specimen with markers for orientation.
Specimens from separate sites should be submitted in individual
containers.
24
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
4 . P AT H O L O G Y ( I N C L U D I N G
BIOPSY)
Keywords with prognostic significance
Poorly differentiated refers to tumours in which products of differentiation
such as keratin, desmosomal attachments or glandular differentiation are poorly
expressed. Immunohistochemistry techniques for keratin subsets are often used
to identify such tumours.
Basosquamous or metatypical carcinoma are terms used for basaloid tumour
which show evidence of squamatisation. These tumours should be viewed as
equivalent to squamous cell carcinoma.
D
E
Desmoplasia refers to tumours which induce sclerotic and extensive fibrous
stroma that may be mistaken for a scar. The tumours often present as infiltrative
cords of cells that may have ill defined boundaries and are prone to recurrence.
Both squamous cell carcinoma and BCC may produce this pattern.
Large tumour size particularly in SCC have twice an increased risk of
reccurrence (tumour greater than 2 cm in diameter 15.2% vs 7.4%) and three
times the risk of metastasis (30.3% vs 9.1%) as compared to small squamous cell
carcinomas49.
K
O
Neural involvement by tumours takes the form of perineural spread that may
extend into the deep tissue and is particularly important in facial lesions.
Perineural involvement near the surgical margins is an indication that further
measures are required for tumour clearance.
V
E
R
Dermal lymphatic spread in satellite nodules may be seen as separate from
the primary lesion and represents a poor prognostic sign.
Key points:
•
Only a small percentage of solar keratoses progress to
invasive squamous cell carcinoma31,51.
•
Metastasis rarely develops from basal cell carcinomas55.
•
The risk of metastasis in SCCs increases with tumour
thickness, clinical immunosuppression and in poorly
differentiated tumours49,50.
Guideline
Confirmation of complete removal of the tumours is
important. Recurrence from incomplete removal is seen
more frequently in clinically ill defined basal cell carcinomas
such as morphoeic and microlobular forms.
Level of
Evidence
Refs
III–2
47, 48
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
25
5 . P RO G N O S I S
5.
PROGNOSIS
BASAL
CELL CARCINOMA
Key point:
•
D
E
The endpoint for measuring success of BCC treatment
(excluding cosmetic, functional and patient convenience
factors) is not universally defined. Survival is a poor
measure, and BCC can have a very long history in
recurrence pattern (10 to over 20 years being familiar). A
chronologically defined local control rate is the best
available endpoint. Five year and ten year control rates or
recurrence rates are valid instruments.
K
O
V
E
R
Introduction
The factors affecting the outocome of both the BCC itself plus the treatment
necessary to manage it can be subdivided into:
1.
Recurrent tumours
2.
Size and depth of invasion (stage)
3.
Site
4.
Morphological and histological subtype
5.
Treatment modality
6.
Incomplete excision
7.
Perineural spread
8.
Naevoid basal cell carcinoma syndrome
1.
Recurrent tumours56,57,58,59,60,61,62,63,64,65,66,67
Recurrent BCC has lower control rates after treatment than primary BCC
treatment. In early stage tumours recurrence rates after treatment of previously
treated (recurrent) BCC are reported in the range of 15 to 30% compared with
previously untreated (primary) BCC of 1 to 10%. However, most series also
report still excellent salvage results with radical surgery (or less commonly using
radiotherapy). These recurrence figures increase with increasing tumour stage
and salvage becomes harder to achieve. Furthermore, control rates are likely to
progressively diminish with each successive episode of recurrence and salvage
treatment.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
27
5 . P RO G N O S I S
Size and depth of invasion (stage)2,3,7,17,19,20,21,22,23
2.
Control rates diminish with increasing size. See TNM Staging Appendix 1.
Overall estimated control rates of treated primary BCC by stage
T stage
Size
(maximum diameter)
% Control rates
at 5 years
T1
≤ 2 cm
95
T2
> 2 cm but ≤ 5 cm
T3
> 5 cm
T4
tumour deeply invaded beyond
subcutaneous tissues
D
E
88
50
K
O
Cartilage and bone invasion are surrogates of more advanced stage, deeper
invasion and/or recurrent BCC. BCC infiltration of cartilage or bone is markedly
less controllable, because of the inability to define extent of spread, larger
tumour burden, and considerably greater morbidity of radical treatment that may
not be possible, acceptable or tolerated by the affected patient.
Rarely very large primary BCC > 10 to 20 cms present due to patient neglect or
denial and usually occur on the trunk, where they remain hidden. Due to their
large size they are usually deeply invasive and incurable.
V
E
R
3.
Site
Guideline
Higher recurrence rates have been observed for
all treatment modalities in the facial region compared
with non-facial sites and particularly on and around
the nose, eyelids and ears.
Level of
Evidence
Refs
IV
24, 56,
57, 62,
63, 68,
69, 70,
71, 72
There is a tendency to a different spectrum of morphological BCC sub-type,
occurring on the trunk and limbs compared to head and neck BCC21. The face
and scalp subcutaneous anatomy is far more complex and critical (posing
potentially graver consequences for deep invasion of BCC and greater risk of
morbidity from injudicious treatment), than in non-facial sites.
28
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
5 . P RO G N O S I S
4.
Morphological and Histological Subtype64,73,74,75,76,77
Superficial and nodular BCC are usually clinically and histologically well
circumscribed and curable with all treatment modalities. Morphoeic, and
infiltrative (deeper induration) BCC are harder to macroscopically define and
microscopically clear and associated with higher recurrence rates. Basi-squamous
(or metatypical) BCC represent 5% of all BCC and are also more likely to recur.
However the quality of data supporting these observations is poor.
5.
Treatment Modality 57,58,59,60,62,63,64,67,68,69,70,71,72,74,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95
D
E
Surgical excision remains the treatment of choice. Complete excision delivers the
highest and most prognostically reliable control rates.
Radiotherapy, curettage with electrodessication and cryotherapy respectively
deliver increasingly lower control rates.
K
O
Intralesional Interferon, lasertherapy and photodynamic therapy for treatment of
BCC should be considered investigational until confirmed and reproducible
treatment outcomes are established in prospective trials.
6.
Incomplete Excision63,65,84,96,97,98,99,100,101,102,103,104
Incomplete excision is accompanied by a 30% recurrence rate. The risk of
recurrence is highest in lesions where both lateral and deep margins are
involved. Re-excision or radiotherapy reduces the recurrence rate after
incomplete excision to the same rates as complete excision.
7.
V
E
R
Perineural Spread84,105,106,107,108,109
This feature is a rare event for BCC and even rarer than in SCC (refer p 31). It
occurs in head and neck BCC and specialist opinion on management is advised.
8.
Naevoid Basal Cell Carcinoma Sydnrome110,111,112
Gorlin’s syndrome is a rare inherited disorder with early onset and a relentless
lifelong high frequency of BCC. Diminishing reserves of normal skin with
increasing age in these patients can eventually compromise control (refer
Epidemiology, p 7).
SQUAMOUS
CELL CARCINOMA
Introduction
The prediction of the biological potential for early SCC and the risk of metastasis
can be derived from evidence on the following prognostic indicators covered
under seven broad categories. These prognostic findings are frequently multiple
in single case scenarios.
1.
Staging T, N, M (Appendix 1)
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
29
5 . P RO G N O S I S
2.
3
4.
5.
6.
7.
1.
Local metastatic spread via lymphatics or nerves not embraced by current
staging systems and most often associated with recurrent or persistent
tumours.
Locally recurrent and/or persistent SCC and/or inadequately treated SCC.
Histological grade and clinical expressions of growth rate.
Anatomic site of primary.
SCCs arising from aetiological factors other than ordinary sun exposure in
otherwise healthy people.
Patient factors … immunosuppression and other patient and skin related
co-morbidities.
Stage
D
E
Staging is a fundamental tool in cancer clinical research for improving outcomes
for patients. The application of the generic TNM staging system for carcinoma to
SCC of the skin is a poor fit, as a large proportion are classified as T 1NoMo.
However, until a more sophisticated universal staging system for cutaneous SCC
is developed, it remains an interim instrument.
K
O
T Stage … Size and Depth of Invasion of the Primary
The size of a primary SCC is three dimensional. The maximum clinical diameter
is the most reproducible measurement, but also a reasonable surrogate for depth
of invasion and/or tumour burden. The rare exception is Bowen’s disease that
can grow to a large area and even be exophytic, but remain insitu.
V
E
R
The T4 staging category identifies advanced (beyond subcutis) clinical invasion
and has the poorest prognosis. However, lesser intermediatory levels of depth of
invasion are not directly accounted for in the T1 to 3 staging system. There is
limited evidence in T1 and 2 tumours that shows a rising incidence of nodal
metastases with increasing depth of invasion of the dermis or by measuring
tumour thickness histologically113,114. Other clinical parameters useful for
assessing depth of invasion include palpable thickness, diffuse infiltration and
induration with poor demarcation of tumour edges and tenderness and
inflammation, and are all valid crude signs of a more aggressive tumour.
T Stage
5 year disease free survival of treated primary SCC
T1
95–99%
T2
85–60%
T3
60–75%
T4
<40%
(see Radiotherapy, p49)
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5 . P RO G N O S I S
N Stage – Nodal Status115,116,117
The presence of nodal metastasis confers an overall 5 year survival of 40%.
Recurrence in a nodal basin after standard lymphadenectomy (radical node
dissection) almost invariably proves fatal.
The risk of regional recurrence after radical lymphadenectomy has been shown
to be related to two important factors—histopathologically to the number of
nodes containing metastases and the presence of extra-nodal spread (being
grossly clinical fixation of node(s)).
The N staging for cutaneous SCC is too simplistic.
D
E
In modern oncology practice, the criteria for determining risk of regional relapse
and indication for adjuvant therapies is based on the surgical pathology findings,
and pre-operative attempts at predicting this on pre-operative clinical and
radiological (CT) assessment.
K
O
No of nodes involved
1
49%
2
30%
⊕3
V
E
R
ECE
84
Absent
Present
M Stage
5 year survival79
13%
23%
47%
Once haematogenous metastases have occurred, the patient is no longer curable.
2.
Perineural spread
Guideline
The estimated prevalence of perineural spread from
cutaneous SCC is in the order of 2.5%.
Level of
Evidence
Refs
IV
107, 108,
109, 118
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
31
5 . P RO G N O S I S
The vast majority of cases involve the Trigeminal (IV) and Facia (VII) cranial
nerves with the primary site being on the face, lips, ears or perimeter zone of
the face.
Perineural invasion is identified in two ways with different clinical significance
and prognosis.
(i)
The earliest indication of perineural invasion is incidentally (asymptomatic)
on histopathological examination of a primary SCC of usually a minor
dermal nerve. While relatively uncommon, the frequency of this
occurrence is unknown as no controlled pathology studies have been
undertaken.
The presence of incidental perineural invasion, however, appears to confer
a poorer prognosis25 and on current data requires adoption of a more
aggressive management approach (eg wider excision, Mohs’ surgery, postoperative radiotherapy or at the least, an opinion from a specialist skin
cancer centre).
(ii) The second, later indication of perineural invasion is symptomatic
presentation with either neuralgic type pain, progressive paraesthesia and
anaesthesia (due to involvement of various divisions of the sensory
trigeminal nerve), a palpable lump along the course of a nerve (eg a lump
at a supraorbital or infraorbital notch or mental foramen) or paresis of
facial muscles due to involvement of the facial nerve. These symptoms and
signs most often occur sometime after seemingly initial successful
treatment of the primary SCC and not uncommonly the cutaneous primary
SCC is no longer traceable by any means.
While MRI is the imaging modality of choice in diagnosing or assessing
perineural spread—in the event of symptoms occurring, a normal MRI
does not preclude the diagnosis.
K
O
V
E
R
D
E
Key point:
•
3.
Clinically diagnosed perineural invasion carries a poor
prognosis108.
Locally recurrent, persistent or inadequately treated primary SCC
These two clinical expressions of ‘uncontrolled SCC at its primary site’ are
considered under one category as their pathogenesis, prognosis and treatment
are similar.
Locally recurrent SCC is clinically manifest by regrowth of a lump or ulcer at the
primary site after initially seemingly clinically adequate treatment (eg complete
excision) or clearance of the primary tumour (eg after radiotherapy).
32
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
5 . P RO G N O S I S
Persistent SCC is a term signifying high histopathological risk of residual SCC due
to incomplete excision being reported by a pathologist. Alternatively it can be a
clinical observation of macroscopic tumour not completely resolving after
treatment.
Key points:
4.
•
Incomplete excised SCC has a recurrence rate of 50% or
more and should be prophylactically re-excised or treated
with radiotherapy.
•
In the event of recognising recurrent, persistent or
inadequately treated cutaneous SCC the prognosis is
unequivocally poorer and demands more aggressive
clinical treatment, which includes fully advising the patient
of its lethal potential in discussion of salvage management
options.
K
O
Histology and growth rate
D
E
SCCs are graded histologically into well, moderately or poorly differentiated
tumours.
V
E
R
Less well differentiated and more infiltrative growth patterns are associated with
an increasing risk of recurrence and metastases.
Spindle cell variants are particularly aggressive. Identification of perineural and/
or lymphatic infiltration carry a poorer prognosis49.
5.
Anatomal site of primary
Guideline
SCCs of the scalp, ear and vermilion have a higher
recurrence and subsequent nodal metastasis rate than
SCCs elsewhere, being in the order of 10 to 20% overall.
6.
Level of
Evidence
Refs
IV
49, 115,
116, 117
Cutaneous SCCs unrelated to UV irradiation
SCCs arising in a chronic scar
•
•
•
Chronic osteomyelitis sinus
Burns scars—‘Marjolins’ ulcer
X-irradiation damaged skin
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
33
5 . P RO G N O S I S
The observed latent period of scar presence and SCC development is in the order
of 10 to 30 years. They are a particularly poor prognosis group of tumours.
7.
Host factors
Immunosuppression
Immunosuppression occurs in a number of clinical situtations, including:
1.
Long term immunosuppressive therapy (see Epidemiology, p5)
2.
Chronic leukaemia, myelodysplasias and lymphomas
D
E
The most studied group are organ transplant patients who require long term
immunosuppressive therapy. The incidence of skin cancer in transplant patients
is twenty-fold the normal rate. The number and risk of more aggressive lesions
increases with duration of immunosuppression. Recurrences and metastatic rates
are also higher16,17,119.
K
O
Guideline
The prognosis for SCC in chronically immunosuppressed patients is worse than in other people.
Rates of local recurrence or metastasis are increased
overall and increase with duration of immunosuppression.
V
E
R
Level of
Evidence
Refs
III–2
16,17,119
General and skin specific co-morbidities
Skin co-morbidity can be site specific related to areas of poor healing—most
typically below the knee and pretibial region. In older patients this is heightened
by a higher incidence of peripheral vascular disease, varicosities and oedema.
No treatment is favourable in this situation where there is a high risk of post
treatment chronic benign ulcers or recurrence with compromised treatment. The
optimal treatment is surgical excision and skin grafting that can demand several
days of strict bed rest in hospital, that patients can be reluctant to undertake with
asymptomatic lesions, and that may compound their co-morbidities (such as
arthritis, thrombosis, diabetes and fear in the elderly).
Another site-specific co-morbidity occurs in the younger adult (especially
women) with facial skin cancers, who seeks unattainable guarantees of perfect
cosmetic results from treatment, potentially placing stress on receiving
appropriate and timely cancer treatment.
In all these instances careful patient counselling and education on the prognosis
and results of treatment are essential.
34
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
6.
T R E AT M E N T
S U R G I C A L T R E AT M E N T
I N T RO D U C T I O N
D
E
Surgery is the most common method of management of non-melanoma skin
cancer. Compared with non surgical modalities, surgery has the advantage that it
is definitive treatment, provides a complete specimen for histological
confirmation of the diagnosis and the adequacy of excision and is associated
with a very high rate of local control. Complete excision can be expected to cure
the vast majority of patients. Although the overwhelming majority of NMSCs are
easily managed by small surgical procedures with excellent functional and
cosmetic outcomes, some NMSCs behave aggressively resulting in extensive
tissue destruction. Surgery is the primary treatment modality for these lesions
which may necessitate extensive surgical resections with less than optimal
functional and cosmetic outcomes. At the present time and for the foreseeable
future, surgery will remain the gold standard against which all other non-surgical
treatments of NMSC should be judged.
V
E
R
K
O
OBJECTIVES
O F T R E AT M E N T
The objectives of surgical treatment of NMSC are:
•
To achieve histologically confirmed complete excision of the tumour with
an adequate margin in width and depth.
•
To maintain normal function where possible.
•
To achieve a good cosmetic result.
For both BCCs and SCCs complete excision of the primary tumour is the goal as
recurrent tumours have a higher further recurrence rate which may be associated
with a worse cosmetic and functional outcome. In the case of SCC, local
recurrence is associated with a higher rate of metastasis to regional lymph nodes
and other distant sites.
PRINCIPLES
OF SURGIC AL MANAGEMENT
The general principles of performing surgical excision of NMSC are:
1.
Patients should be informed of the options (surgical and non-surgical) and
the risks and benefits as well as the outcome and need for further
treatment and surveillance. The treatment should be explained to the
patient including what should be expected in the post-operative period
and the possible complications as well as the long term outcome including
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
35
6. SURGICAL
2.
3.
4.
5.
6.
T R E AT M E N T
cosmesis and function. A clear description of the ultimate cosmetic and
functional result is essential. The patient should also understand that any
tissue removed will undergo pathological evaluation and that further
surgery may be necessary to obtain complete removal of the lesion.
Familiarity with the clinical features of NMSC is essential in the effective
planning of the procedure. Features effecting the margin and depth of the
excision (and consequently the risk of local recurrence) in particular
should be considered (see below). The mobility of the lesion on
underlying tissues should be carefully evaluated as it may indicate deep
fixation and the need for extensive surgical procedures.
If there is any doubt concerning the clinical diagnosis an appropriate
biopsy, eg punch biopsy, should be considered prior to definitive surgical
excision. In some cases it may be more expeditious to completely remove
a small lesion.
The majority of cutaneous NMSC can be excised under local anaesthetic on
an outpatient basis.
The majority of surgical wounds after excision of NMSC can be closed
primarily by simple direct suture.
Excision of small clinically favourable lesions located in straightforward
sites should be within the skills of general practitioners who are capable
and confident in the performance of minor surgical procedures.
As the injection of local anaesthetic may distort the tissues, the excision
margins should be marked out prior to infiltration (see discussion on width
of margins below). The lesion should be excised as an ellipse with a
suggested ratio of length to width of 3 or 4 to 1. The long axis of the
ellipse should be placed in the line of the local skin creases which is
usually the line of least skin tension. In the extremities the long axis
should preferably be orientated longitudinally. The skin should be cut
vertically with the blade at 90o to the skin. The depth of excision should
be through uninvolved subcutaneous fat. Simple interrupted closure with a
monofilament suture eg nylon or polypropylene rather than silk is
recommended. Thick skin, particularly if there is any tension in the
wound, requires a thicker suture such as 3.0. Sutures in sites with
significant skin tension eg the back should be left in for up to two weeks.
Facial wounds on the other hand deserve a light suture such as 5.0 and the
sutures can be removed as early as 5 days.
All resected tissue should be sent for pathological evaluation. A careful
description of the site of excision is essential as is orientation of the
specimen to allow identification of any areas where excision is
incomplete. A simple diagram particularly if multiple lesions are removed
can be of great assistance to the pathologist.
Tumour resections likely to result in cosmetic or functional defects require
specialised reconstructive techniques and should be referred for specialist
care. Occasionally sacrifice of major structures eg eyelid, tear duct, facial
nerve is necessary to achieve complete resection. The skills required for
performance of such procedures and the immediate functional
K
O
V
E
R
7.
8.
36
D
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
9.
10.
reconstruction are generally only available in specialist tumour centres.
Tumours on the face are best treated by trained and experienced
practitioners to minimise alteration in function of the eyelids or mouth and
ensure a satisfactory cosmetic outcome. Lesions on the nose or ear present
specific challenges including the thinness of the subcutaneous tissue,
proximity to bone and cartilage and the tightness of the skin envelope
which may prevent direct closure of the defect.
A knowledge of superficial anatomy is vital in planning even minor skin
tumour excisions. Care should be taken with excisions in sites where
nerves and other structures may be at risk. Special care should be taken
with the temporal branches of the facial nerve which are superficial and
may be damaged during excision of lesions which overly the course of the
nerve over the zygoma and lateral peri-orbital and temple regions. The
Accessory nerve after it emerges from behind the posterior border of the
sternomastoid is at risk when excisions are performed in the posterior
triangle.
Local flap repair providing cover with skin of appropriate colour and
texture is the preferred method of closure when direct closure is not
possible. Morbidity and post-operative recovery is less and the cosmetic
result, particularly achievement of a satisfactory skin colour and texture
match, is far superior. At times skin grafting will be necessary and full
thickness grafts are used choosing skin from an inconspicuous donor site
with similar skin characteristics.
Careful planning of surgical procedures based on close attention to the
clinical features of the lesion provide very high rates of local control.
Similar rates of local control for unfavourable lesions can be approached
by attention to the clinical features supported by intra-operative margin
control with frozen section. Mohs’ surgery (see below) which also relies on
intra-operative margin control also provides excellent and equivalent
results for patients with high risk lesions.
K
O
V
E
R
11.
T R E AT M E N T
D
E
Advantages and disadvantages
Specific training and expertise are necessary to achieve optimum results. The
advantages of surgical excision in treating NMSCs are:
1.
An excellent overall cure rate.
2.
Pathological evaluation of complete tumour removal.
3.
A generally acceptable cosmetic and functional result with rapid healing.
The disadvantages of surgical intervention include the potential complications of:
1.
Haematoma, infection, wound dehiscence.
2.
Damage to neurovascular and other structures.
3.
Cosmetic deformity, variation in pigmentation, hypertrophic scarring. It
should be noted that cosmetic results of surgical excision typically improve
with time. Delayed scar revision may be helpful.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
37
6. SURGICAL
BASAL
T R E AT M E N T
CELL CARCINOMA
BCCs are distinguished by the fact they rarely metastasise and can be cured in
the vast majority of cases by complete excision. Surgical excision provides
excellent five year cure rates estimated at between 90 and 98% for previously
untreated tumours.120,121,58
Key point:
•
D
E
The majority of basal cell carcinomas are clinically
favourable ie small, nodular or superficial types, not
located in the central face. They can be satisfactorily
excised under local anaesthetic with direct primary
closure in an ambulatory care setting.
K
O
The completeness of the excision (assessed histologically) is the most critical
factor in determining the rate of local recurrence and cure. The margins of
excision should be wide enough to completely excise the tumour. In evaluating
studies of excision margins, the variation in behaviour of BCCs needs to be
considered. A number of factors including the experience of the operator, type of
BCC, histological features, size and location have been related to higher
recurrence rates and need to be considered in the planning of the surgical
procedure. These features must be considered in deciding the appropriate
margin of excision for a particular lesion. Consequently any recommendations
concerning the width of excision must remain a guide only. In reviewing
published studies which have attempted to define an appropriate excision
margin it is clear that the majority describe patients with small favourable
lesions. Recommendations on the width of excision have varied from thin, ie 2
mm, to more extensive margins of 5mm or more122. Careful histological
evaluation of excised BCCs demonstrate irregular (and unpredictable) extension
of the tumour beyond the macroscopic margins for a variable but usually limited
distance.123 This probably explains why as many as one-third of careful excisions
may have close or involved margins. The frequency of histologically involved
margins decreased in one series from 25% for a margin of 2mm to 5% with a
margin of 4mm.124 For small favourable lesions (see below) not located in the
central face, a margin of 3 to 4 mm has a high likelihood of complete removal
and cure.
V
E
R
The depth of excision has not been as comprehensively studied as the width of
excision because the majority of BCCs are thin and with a depth of excision
including subcutaneous fat, the deep margin is usually not a problem. In certain
situations such as recurrent lesions, BCC in sites such as the ear or nose where
the skin is closely applied to underlying cartilage or bone, the depth of excision
is critically important and must be considered during the planning of the
proposed surgery.
38
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
Guideline
The majority of clinically favourable BCCs can be
excised with a margin of at least 3mm with a very
high chance of achieving complete excision and long
term control.
T R E AT M E N T
Level of
Refs
IV
58, 121,
124, 125
D
E
It is important to acknowledge that there is considerable variation in the
behaviour of BCCs126. Factors known to be associated with the development of
recurrent disease include:
1.
Tumour size and site
Tumour size has been noted to be associated with an increased risk of local
recurrence by some60 but not by all.56 The effect of tumour size on recurrence is
confounded by the location of the lesion. BCCs of the head, particularly the
central face and peri-auricular region have a higher rate of local recurrence.
Whether this is due to features specific to this site or is related to difficulties in
obtaining complete excision due to reluctance or inability to perform a wide and
complete excision which may result in significant aesthetic or functional
impairment is unknown. It has been suggested that the lack of a barrier to
invasion at sites of embryological fusion may explain higher rates of local recurrence
in the face although there is little evidence to support this position.127, 128
V
E
R
K
O
Size of lesion
5 year Local Recurrence
Rate All Sites (no of cases)
0–5 mm
2.9% (138)
6–9 mm
6.9% (185)
10–15 mm
6.7% (146)
>15 mm
1.9% (128)
5 year Local Recurrence
Rate Head only (no of cases)
3.2% (123)
8.0% (130)
9.0% (127)
Silverman et al J Dermatol Surg Oncol 1992;18:471–476
2.
Tumour type
Several studies have confirmed variation in behaviour of tumours associated with
the histologic type of the lesion. BCCs showing histological appearances of
sclerosis, ulceration and infiltration which are clinically recognizable as thick,
morpheaform or infiltrative types are associated with larger occult extensions
with a higher rate of positive margins after excision and a consequent higher rate
of local recurrence 129,130,78. The nodular and superficial forms of BCCs which
account for the majority of lesions and lack aggressive histological features have
a higher rate of complete excision and lower rate of local recurrence.78
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
39
6. SURGICAL
3.
T R E AT M E N T
Perineural invasion
Perineural invasion is more frequently associated with SCC although it may
occasionally be seen with BCC. The lesions tend to be of a more aggressive
histological subtype and located in the head and neck131. (see p29)
Guideline
Level of
Evidence
Patients with BCCs which are large (> 2cm), poorly
defined or multiple lesions, unfavourable tumour types,
ie infiltrative, ulcerative or morphoeic types or tumours
located in sites where the rate of local recurrence is
predicted to be high (central face and peri-aural regions)
should be considered for referral for specialist care.
K
O
Incompletely resected BCC
4.
Refs
D
E
IV
3, 4, 5, 6,
7, 11, 48,
58, 63
Incompletely resected BCC are defined as histologically incompletely or
inadequately excised BCC
V
E
R
There is considerable debate concerning the most appropriate management of
these cases and arguments can be made for any of the three possible options: reexcision, radiotherapy or observation.
Many authors have estimated the rate of local recurrence for persistent BCC to be
approximately 30%132,104 although rates as high as 67% have been reported.97 In
evaluating the evidence for a rational management plan the volume of residual
disease needs to be but is rarely considered. Tumour within one high power
field of a margin was associated with a recurrence rate (12%) approximately one
third that of the rate when the margin was involved with tumour.98 The time
course to recurrence is of importance when considering an observational policy.
Most recurrences occur within 3 years, although cumulative studies show 82% of
recurrences occur in the first 5 years post-treatment and 18% at 6–10 years. 60,133
From a practical point of view, diagnosis of recurrent disease can be difficult
because normal wound changes are difficult to distinguish from recurrent disease
and the recurrence may be initially deep without any obvious superficial
features.
Salvage of recurrent BCCs appears to be highly effective although the series are
selective and retrospective. Richmond et al reported a 10 year local control rate
of 92% for patients who underwent immediate re-excision versus 90% for
patients undergoing excision of clinically recurrent disease although the 10 year
40
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
T R E AT M E N T
relapse free rate was 91% versus 40%100. Similar results were reported by Liu et
al who managed limited persistent disease with adjuvant radiotherapy101. A cost
benefit analysis provided with this study did not support immediate post–
operative treatment with adjuvant radiotherapy. In the untreated group 6% of
patients developed recurrent disease which was never able to be controlled.
Features predictive of recurrence of persistent BCCs have not been extensively
studied. In one series patients with inadequate deep margins had approximately
twice the local recurrence rate (33% v 17%) of patients with inadequate lateral
margins.101
D
E
On the basis that the majority of patients with persistent disease will not develop
a recurrence, it has been suggested that incompletely excised BCCs can be
followed unless there are unfavourable characteristics including the extent of
residual disease, deep as compared to a superficial margin involvement and the
histological subtype. At the present time it is not possible to accurately identify
patients with minimal residual disease who may benefit from a conservative
approach. As recurrent disease is harder to eradicate, subsequent management
may involve significant morbidity and occasionally the disease may prove
resistant to control, it is prudent to recommend that patients with persistent
disease should undergo histologically complete re-excision.
K
O
Mohs’ surgery or standard surgical procedures with intraoperative frozen section
margin control has been used successfully in the management of persistent
disease (see below). The role of adjuvant radiotherapy for persistent disease is
unresolved. Limited studies suggest that it probably provides similar rates of
control to complete surgical re-excision but is more expensive and inconvenient
in many instances.100 Generally it should be avoided in younger patients. Most
authorities agree that adjuvant radiotherapy for persistent disease is justified for
minimal residual disease in patients who are unsuitable for or refuse further
surgery or the morbidity of re-excision is not justifiable.
V
E
R
It must be remembered however that many of these patients with persistent BCC
are elderly and infirm and further surgery particularly if likely to be major and
associated with functional and cosmetic impairment may not be appropriate.
Referral to a specialist unit should be considered in this situation.
Guideline
Patients with incompletely excised BCC should be
considered for re-excision to achieve clear margins.
Radiotherapy may be a reasonable alternative for
the patient unwilling or unable to undergo further surgery.
Level of
Evidence
Refs
IV
98, 99,
100, 101,
102, 103,
104
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
41
6. SURGICAL
T R E AT M E N T
Recurrent BCC
Among recurrent BCCs, lesions located in the central face and peri-auricular
region, large tumours (>2cm), aggressive subtypes (infiltrative, ulcerated and
morpheaform) and persistent BCCs are over represented101. The type of primary
treatment, ie surgery, radiotherapy, curettage, electro-desiccation for
appropriately selected lesions give very high similar rates of local control,
however, larger lesions treated by non-surgical techniques are more likely to
develop a recurrence47. At least two thirds of recurrences occur within 3 years of
initial treatment although up to 20% will recur between 5 and 10 years75.
D
E
Recurrent BCCs are associated with a higher risk of further local recurrence, at
least 50% higher than previously untreated lesions58. Undetected subclinical
extension, aggressive tumour type, irregular invasion of scar tissue and multiple
foci of disease have all been suggested as explanations for this higher recurrence
rate134,135. Recurrence after non-surgical treatments (radiotherapy, cryotherapy,
curettage and electro-desiccation) have been held to be associated with a higher
risk of further local recurrence (and metastasis) although there is little objective
evidence to support this136. There is no doubt, however, that the changes in the
skin such as atrophy, hypo-pigmentation and scarring following non-surgical
treatments, make accurate assessment of extent of recurrent tumour difficult. For
this reason and because of poor healing due to the previous therapy, particularly
radiotherapy, most authorities recommend resection of the scar, macroscopic
tumour and all surrounding previously treated skin. Local flap repair rather than
primary closure or skin grafting is usually necessary to ensure healing following
surgery.
K
O
V
E
R
Tumours recurring after previous cryotherapy can be difficult to assess due to
treatment related scarring with the possibility that tumour persists deep to an
apparently normal dermis. The scarred area should be removed in its entirety to
minimise the chance of residual disease.
Tumours recurring after previous curettage and electro-desiccation may also have
occult deep extensions not obvious clinically. These deep extensions are
particularly troublesome in skin creases such as the naso-labial fold and care
must be taken to ensure complete excision.
Frozen section margin control is invaluable in ensuring complete removal of
BCCs but does add to the cost and time required for the procedure and should
be limited to situations where there is a risk of persistent disease post
operatively such as in the management of recurrent BCCs137. It is both highly
sensitive and specific in evaluating margins. For small favourable lesions where
the risk of positive margins is small, frozen section is not indicated. Alternatively
Mohs’ technique is particularly useful in the management of recurrent lesions
(see below).
42
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
T R E AT M E N T
Key point:
•
Recurrent BCCs should be considered for referral for
specialist management. Complete excision of the lesion
with the scar and any previously treated area is usually
necessary58.
SQUAMOUS
CELL CARCINOMA
D
E
The surgical management of SCC is similar to BCC in that the main objective is
histologically confirmed complete removal of the tumour. In general, surgical
management of SCC is more radical than for BCC because SCCs are potentially
more aggressive, have a greater potential for local recurrence and may spread to
regional lymph nodes and distant sites. Local recurrence is due to incomplete
primary excision (and is therefore preventable). The development of local
recurrence is associated with a high rate of subsequent local recurrence (23%)
and subsequent metastasis predominantly to the regional lymph nodes (30%) if
further local recurrence does occur.137 Approximately one third of patients who
develop regional metastases will die of SCC.
K
O
V
E
R
Satisfactory primary excision is therefore mandatory and will result in a high rate
of cure in excess of 90%.49,138 The recommended surgical margin of excision for
SCC varies from 2 to 10mm.139,140 Favourable lesions eg well differentiated lesions
less than 2cm in diameter will be adequately excised with a 4mm margin in 95%
of cases.141 Tumours larger than 2cm require larger margins up to 10mm to obtain
similar rates of local control.142 For very large lesions even wider margins may be
necessary.143 The depth of excision should be through normal underlying fat. For
larger lesions and those predicted to be associated with a higher rate of local
recurrence some form of intra-operative margin evaluation is indicated. Frozen
section margin control evaluation is generally available only in hospitals and
although time consuming and expensive is highly sensitive and specific.137
Alternatively Mohs’ technique with intra-operative evaluation of the margins if
available is an option.
Key point:
•
The majority of SCCs are small and clinically favourable
and can be excised expeditiously under local anaesthetic
with direct primary closure as an outpatient.
Factors associated with increased risk of local recurrence and which need to be
considered in the planning of surgery include the following:
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
43
6. SURGICAL
T R E AT M E N T
1.
Tumour size
The diameter of SCC correlates with risk of recurrence. Tumours less than
2cm in diameter have a 5 year recurrence rate of 7.4% compared with
15.2% for tumours greater than 2cm in diameter.144
2.
Anatomic site
Sites associated with a higher risk of local recurrence include the scalp,
peri-ocular region, ears, lips and nose. Five year recurrence rates from a
large collective review were 18.7% for SCC of the ear, 10.5% for SCC of the
lip and 7.9% for SCC at other sites. Rates of metastasis were respectively
13.7%, 11% and 5.2%.144
3.
Histological features
D
E
a)
Patients with poorly differentiated tumours had twice the risk of local
recurrence compared to those with well differentiated lesions.144 The
local recurrence rate increased from 7% for well differentiated tumours
to 28% for high grade lesions.145 In addition poorly differentiated
tumours are more likely to metastasise to regional nodes and other
sites.114
b)
The depth of invasion of SCC has also been reported as a predictor of
local recurrence and metastasis. Lesions thicker than 4mm or
extending to at least the reticular dermis are associated with a higher
rate of local recurrence.114,146 The risk increases with further thickness.
In one small series only tumours extending to and beyond the
reticular dermis developed local recurrence.145
K
O
V
E
R
c)
Several histological variants of SCC have been reported to be more
aggressive and pose a higher risk of both recurrence and metastasis.
These include spindle cell carcinoma, acantholytic SCCs and
adenosquamous tumours.114
Key points:
•
The majority of clinically favourable SCCs less than 2cm
can be excised with a margin of at least 4mm with a very
high chance of achieving complete excision and long term
control.
•
SCC of the central face, scalp, lip and ear should also be
considered for referral for specialist care in view of the
higher risk of local recurrence and the possible need for
specialist reconstruction techniques to optimise both
cosmesis and function49,137,138,141.
4.
Perineural invasion
Perineural invasion is far more common in SCC than BCC complicating the
course of up to 5% of all patients with SCC.143 Perineural invasion appears
44
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
T R E AT M E N T
to be more common in lesions located in the head and neck. Tingling,
pain, paraesthesia, reduced sensation or motor function suggest perineural
invasion but most patients have no pre-operative symptoms or signs of
neural involvement. Intra-operative margin control with frozen section or
alternatively Mohs’ surgery can be used to attempt complete excision.
Post-operative radiotherapy is an important part of management.
The presence of perineural invasion is reported as posing a very high risk
of both local recurrence which may be as high as 50% and distant spread
in 35%.146 The addition of radiotherapy to the site of the primary lesion
and the course of the involved nerve in an uncontrolled series was
associated with a very high rate of local control and reduced rate of
metastasis.144
Guideline
5.
IV
107,108,
109,144,
146
V
E
R
Previously treated SCC
SCCs that recur following previous treatment have an increased incidence
of further recurrence with approximately one third developing regional
metastasis.11 The rate appears to be higher for SCC of the ear (45%) than
lip (32%) or other sites (25%).137
Guideline
Patients with recurrent SCC have an increased risk of
further local recurrence as well as regional and distant
metastases. Excision of the previous treatment site
should be undertaken in continuity with the recurrent
tumour. Specialist referral is recommended.
6.
Refs
K
O
Consideration of specialist therapy should occur for
patients with an SCC showing perineural spread.
(See chapter 13). Wide excision is recommended
and consideration should be given to post-operative
radiotherapy.
D
E
Level of
Evidence
Level of
Evidence
Refs
IV
11,147,
148,149
Immunosuppressed patients
Patients who are chronically immunosuppressed as a consequence of
either disease or medication have an increased incidence of cutaneous SCC
and these lesions tend to behave more aggressively with a high rate of
both local recurrence and metastasis. In an Australian study of patients
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
45
6. SURGICAL
T R E AT M E N T
after renal transplantation the incidence of SCC was seen to increase by 5%
per year with a 44% incidence after nine years.119 The fact that each patient
had so many aggressive SCCs led to an overall metastatic rate of 13%.
Guideline
Level of
Evidence
Chronically immunosuppressed patients frequently
develop multiple SCC which behave aggressively.
These patients should be referred for specialist management.
7.
IV
Refs
16,17, 119
D
E
Aetiology
A number of pre-existing factors which appear to influence the
aggressiveness of cutaneous SCC and the likelihood of both local
recurrence and metastasis have been identified. SCCs arising in previously
irradiated tissues demonstrated a significant incidence of metastasis (10–
30%) and local recurrence150,151. SCCs arising in scars from previous burns,
(Marjolin’s Ulcers) not only had a high frequency of regional metastases
(35%) but most patients were dead of disease within 5 years 152. SCC arising
in other scars including osteomyelitis and chronic stasis ulcers etc are
characterised by similar rates of local and regional recurrence and poor
survival.
V
E
R
K
O
MOHS’
S U R G E RY ( S E E P P 3 7 , 4 1 , 4 2 , 4 5 – 8 , 6 1 , 7 7 )
An alternative to standard surgical practice is Mohs’ Surgery (also known as
micrographically controlled surgery) named after Frederic Mohs, Professor of
Surgery from the University of Wisconsin, who first described the technique. His
original procedure has been modified to what is now referred to as the fresh
tissue technique, using so-called horizontal frozen sections to intra-operatively
assess the completeness of the margins of excision153.
Mohs’ surgery is generally performed under local anaesthesia. Following excision
of the tumour, the whole of the outer layer of excised tissue is examined by
frozen section. Mapping and staining of the excised tissue and specialised tissue
sectioning enables precise localisation of any residual tumour, which is then
excised and examined again by the same process. This is repeated until the
margin is free of tumour. The resulting defect is then ready for repair by
conventional surgical techniques154.
The technique has been found to be particularly suitable for excision of skin
cancers which might otherwise prove difficult to excise completely or where a
higher than usual recurrence rate might be expected.
46
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
6. SURGICAL
T R E AT M E N T
Indications for Mohs’ surgery
Basal
1.
2.
3.
4.
5.
cell carcinomas or squamous cell carcinomas which are:
Located on the central face or periorificial areas (eyes, mouth, ears).
Recurrent following previous treatment.
Incompletely excised histologically.
High risk histological types, eg micronodular, infiltrating or morphoeic
BCCs.
Large or ill-defined.
Advantages of Mohs’ surgery
1.
2.
3.
4.
K
O
Disadvantages of Mohs’ surgery
1.
2.
3.
4.
D
E
Minimises amount of tissue removed.
Has a very high cure rate.
Enables defect repair to be carried out with the knowledge that the tumour
is likely to have been completely removed.
Is performed under local anaesthetic.
Time consuming—may take several hours.
Expensive.
Capital intensive—both in equipment and staff.
Requires specific training and expertise.
V
E
R
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
47
7 . R A D I OT H E R A P Y
7.
R A D I OT H E R A P Y
I N T RO D U C T I O N
D
E
Radiotherapy (RT) is the use of ionising radiation to treat cancer and allied
disease. Radiotherapy has been used successfully to treat all stages of basal cell
carcinoma (BCC) and squamous cell carcinoma (SCC) for over 80 years with
results comparable to surgery68, 69,70,71,72,73,82,85,89,94,155,156. However, radiotherapy often
requires a number of weeks for receiving and then healing from the treatment.
The vast majority of BCC and SCC present as small, early lesions amenable to
surgery which is commonly simpler, more convenient and expedient for patients,
being single episode, highly efficacious (curative with good cosmesis) and
delivering a complete specimen for pathology examination. Thus, radiotherapy is
seldom used to treat small lesions and is limited to a specialised role in the
overall spectrum of the disease.
Guideline
V
E
R
K
O
Radiotherapy should be reserved for the small
minority of primary BCC and SCC that present
peculiar problems for conventional surgery and for
cases of persistent, recurrent or advanced BCC and
SCC where surgery can be complemented by
radiotherapy to improve control rates in this small
poorer prognosis category.
Level of
Evidence
Refs
IV
68,69,
70,71,
72,73,
82,85,
89,94,
155, 156
Ionising radiation (x and γ rays {photons}, β rays {electrons; particles}) can be
delivered by external beam therapy or brachytherapy. External beam therapy is
produced by kilovoltage machines Superficial X-ray Therapy (SXRT), Deep X-ray
Therapy (DXRT), teletherapy machines (Cobalt and caesium Units) and linear
accelerators (Megavoltage Therapy (MVT) and electron beam therapy).
Brachytherapy is the use of sealed isotopes applied directly to the tumour as a
surface treatment or implanted into the tumour.
This range of treatment delivery allows the radiation oncologist a very wide
selection of precise physical characteristics and radiobiological outcomes to
optimally treat the various unique problems skin cancers can present for
management. Dermatology ionising radiation practice is limited to SXRT alone,
which is low energy, and penetration x-rays, suitable only for small and
superficial skin cancers (T1 lesions <0.5cm thick).
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
49
7 . R A D I OT H E R A P Y
Radiotherapy is non-invasive, painless and can be technically tailored to treat
skin cancers of any size, or depth of invasion and at any site while minimising
damage to adjacent normal tissues. It may also incorporate regions where the
skin cancer has spread away from the primary site.
Standard curative dose schedules for treatment of T1 small lesions <2cm usually
requires fewer treatments (4–12 attendances over two weeks) than large lesions
(15–30 over three to six weeks). In general, more fractionated schedules give
superior control rates and cosmesis. However small, early BCC and SCC can be
cured with smaller doses than larger lesions and because the treatment areas are
smaller, these tumours can be safely given fewer treatments, conveniently
reducing the number of patient attendances. Sealed isotopes applied to the
surface or implanted into the tumour involve two visits to the radiotherapy
department or a short inpatient stay.
K
O
Key point:
•
D
E
All BCC and SCC should be confirmed histologically by
biopsy prior to radiotherapy treatment.
Normal tissue margins (the perimeter of normal appearing skin adjacent to the
skin cancer) can be 0.5cm width for small, well defined BCC and well
differentiated SCC, but may need to be more generous, 1–1.5cm for larger, illdefined BCC and more aggressive SCC. A minimum margin of 1cm will be
required when treating with electrons to ensure that the 90% isodose line
encompasses the tumour at depth.
V
E
R
SIDE
E F F E C T S O F R A D I OT H E R A P Y
Acute side effects arise two to three weeks after starting radiotherapy and last
some days to weeks before completely resolving. These include variably and
sequentially, erythema (skin redness), dry desquamation (skin peeling) and
finally moist desquamation (patchy or confluent superficial ulceration) due to
loss of the epidermis.
Late side effects occur from several months to years and are permanent. All
treatments for skin cancer result in scarring. The long term features of radiation
damage to the skin include atrophy (thinning), loss of skin appendages
(alopecia, loss of sweating), variable change in colour (pallor or pigmentation),
variable telangiectasia (fine blood vessels) development, subcutaneous fibrosis
and rarely, skin breakdown (radionecrotic ulcer, <2–5% risk). Most importantly,
the visible features of late radiation skin damage can change with time. An initial
highly favourable cosmetic result can potentially deteriorate with passing years.
Thus radiotherapy is not generally recommended for persons under 60 years of
age, when surgery gives a better and long term stable cosmetic outcome.
50
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
7 . R A D I OT H E R A P Y
When advanced BCC and SCC invades cartilage (classically the pinna) or bone
(eg mandible) the risk of chondro- or osteoradio-necrosis is higher.
Factors affecting cosmesis include how the radiotherapy is given (the number of
treatments, the size of the treatment area/volume), the extent of normal tissue
destruction by the tumour, idiosyncratic variability of repair response by
individuals, past and future sun damage and site of the skin. Convex and
concave contoured sites of the face give optimal cosmesis (eg ala nasi, inner
canthus, nose, ear and eyelids); flat skin areas (eg forehead, back) and sites of
reduced vascularity or greater wear and tear (eg below the knee) lead more
often to visible scarring.
D
E
Radiotherapy rarely damages nerves or muscle and does not cause major tissue
deficit. Radiotherapy may provide a superior functional and cosmetic outcome
when anaesthesia (numbness), paralysis or bulk volume tissue loss are planned
consequences of surgery for treatment of a (usually larger, more infiltrating) BCC
or SCC. Such examples may be facial nerve sacrifice, major anaesthesia of the
lip, nasectomy, resection of lip or eyelid commissures.
K
O
Based on the limitations and advantages of RT already outlined, the following
checklist is useful when considering referral for an RT opinion in treatment of
BCC or SCC.
V
E
R
R E L AT I V E
1.
2.
3.
4.
5.
6.
Older patients where long term scar deterioration is inconsequential.
Multiple, especially superficial lesions when impractical to excise.
Patients wishing or needing to avoid invasive procedures (eg refuse or
unfit for surgery, or anaesthesia, or have anticoagulation problems).
Patients prone to keloid formation.
When surgery would be mutilating or result in major loss of function (eg
nasectomy, resection of lateral eyelid commissure, resection of lip
commissure, large superficial lesions with loss of tissue or facial nerve
sacrifice).
Palliation in advanced neglected inoperable lesions.
R E L AT I V E
1.
2.
3.
4.
I N D I C AT I O N S F O R R A D I O T H E R A P Y
C O N T R A I N D I C AT I O N S F O R R A D I O T H E R A P Y
Patients younger than 60 years if the lesion is readily excisable.
Lesions on freely mobile skin amenable to simple excision.
Lesions in hair bearing areas or overlying the lacrimal gland.
Advanced lesions invading tendon, joint or bone. Cartilage involvement
however, is not a contraindication for RT, it can occasionally be the
preferred treatment for the nose or for small lesions of the ear. However
RT is best avoided in larger pinna lesions with extensive, inflamed or
painful cartilage invasion.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
51
7 . R A D I OT H E R A P Y
5.
6.
7.
8.
9.
10.
Sites of poor vascularity or healing and wear and tear sites (eg pretibial
lesions).
Previous radiotherapy to the skin lesion in question.
Lesions over bony prominences that are prone to trauma tolerate RT
poorly.
Lesions on the lower limb and upper eye lid tolerate RT poorly.
Bony infiltrations. Poor results are achieved with RT alone.
Basal cell naevus syndrome (Gorlins Syndrome) and ataxia telangiectasia.
BASAL
97%
D
E
92%
89%
60%
50%
CELL CARCINOMA
Primary untreated basal cell carcinoma
Control rates for BCC ≤2cm (T1) with radiotherapy are 95–99% at 5 years to 93–
95% at 10 years.82,73,70,68,89,85,156
K
O
Control rates for BCC treated with radiotherapy, by stage 1,2,3,6,8,9,10,11
Lesion size
T Stage
V
E
R
<2cm
T1
2–5 cm
T2
>5cm
T3
T4 lesions
T4
•
•
5 years
10 years
95%
RT has a limited role in treatment of small primary BCC as complete
excisional surgery is more accessible, expedient and convenient with
optimal outcomes (control rates and cosmesis).
RT should be reserved for the minority of T1, T2 and T3 primary BCC
when surgery is disadvantageous or not feasible in generally older
patients.
Residual basal cell carcinoma
Complete clinical resolution of a BCC following curative RT can occasionally
take up to 4 months. Most small BCC have disappeared by the time the acute
radiation reaction has healed (2 to 8 weeks after finishing RT).
Clinical persistence or progression of a BCC after a standard curative dose of RT
should be confirmed in consultation with the treating radiation oncologist,
biopsied and treated with excisional surgery by an experienced specialist
surgeon.
52
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
7 . R A D I OT H E R A P Y
Radiotherapy for residual BCC after surgery (incompletely excised BCC)
The observed recurrence rate of incompletely excised BCC is on average
33%.65,96,97,98,63,99,100,101,102,103,104
As approximately two thirds of incompletely excised BCC do not recur and some
authors claim salvage of recurrent lesions gives similar outcomes, the arguments
for and against re-excision have been debated in the literature. However, Liu101
noted 6% were eventually not controlled after salvage. While no statistically
significant evidence is available, there is a trend for higher recurrence when the
deep margin is involved versus a lateral margin alone, and higher again when
both are involved.100,101
Key points:
K
O
D
E
•
If advice for patients regarding re-excision of an
incompletely excised lesion is contentious, then the
recommendation for RT is equally difficult.
•
Immediate re-excision or RT for incompletely excised
primary BCC reduces the recurrence rate to less than
9%101.
V
E
R
The recurrence rate of one third for incompletely excised BCC applies to the
natural presentation incidence spectrum of primary BCC that is vastly small
lesions. However, in the very small subset of primary BCC presenting in an
advanced state incomplete, close (and anatomically restrained) or inassessible
normal tissue margins carry a higher relapse rate. The confidence of adequate
treatment margins will be further eroded by perineural spread, micronodular,
infiltrative and metatypical (basisquamous) histology patterns and invasion of
skeletal muscle, cartilage and bone. In these uncommon cases referral to a
specialist skin cancer or head and neck cancer (>75% will be head and neck
lesions) clinic for individual assessment and advice re: merit of post-op RT or
additional treatment is recommended.
Recurrent basal cell carcinoma
Recurrence can occur at any time after RT but 88–90% of recurrences are
reported to occur within the first five years.73,85
Recurrent BCC should be treated with excisional surgery including the irradiated
tissues by a specialist surgeon, but can also be salvaged with re-irradiation, when
surgery cannot be performed.73,103 Surgery is preferred to re-irradiation as the risk
is higher of more serious late sequelae (radionecrosis of skin and other
underlying tissues).
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
53
7 . R A D I OT H E R A P Y
The recurrence rate after recurrence following RT salvaged by surgery is
between 14 and 18%64 65,66,75,85,133
Surgery is the treatment of choice for recurrent BCC and RT is used when
surgery is not feasible, incomplete (& further surgery not reasonable) or
confidence in surgical clearance is diminished.
Control rates after salvage therapy157 are lower than primary treatment and
dependent on the same factors viz. size of the recurrent tumour, number of
recurrences and T4 invasion (invasion of skeletal muscle, cartilage or bone).
Guidelines
Radiotherapy for T1 and T2 primary BCC has comparable
outcomes (marginally inferior) to specialist surgery.
K
O
A radiotherapist’s opinion should be considered for
T4 primary, persistent and recurrent BCC.
Radiotherapy gives comparable control rates as re-excision
for incompletely excised BCC and is an alternative to
re-excision if further treatment is deemed advisable
and re-excision is disadvantageous or not feasible.
V
E
R
Key points:
D
E
Level of
Evidence
II & IV
68, 70,
73, 82,
85,89, 156
III
71
IV
101
•
All salvage therapy for recurrent BCC has lower control
rates than for primary BCC73.
•
Adjunctive RT post salvage excision for recurrent BCC
should be considered in poorer prognosis cases viz:
– T4 primaries
– Larger recurrent lesions
– Multiple recurrences
– Poor prognosis histology subtypes
– Inadequate normal tissue margins
– Perineural invasion
– Node positive BCCs
on an individual basis by referral to a specialist cancer
centre
54
Refs
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
7 . R A D I OT H E R A P Y
SQUAMOUS
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
TUMOURS
Key points:
•
Radiotherapy is an alternative curative treatment for
primary untreated SCC in a minority of patients when
surgery is disadvantageous. Radiotherapy is a more time
consuming and inconvenient treatment for primary SCC
amenable to surgery where cosmetic and functional
outcomes are anticipated to be excellent. Radiotherapy is
an alternate efficacious treatment for primary SCC:
D
E
i) when surgery is not feasible eg patient unfit for
surgery, patient refuses surgery, anticoagulation poses
problems
K
O
ii) when surgery will cause cosmetic or functional
morbidity unacceptable to the patient eg nasectomy,
loss of function of lips or eyelids, large tissue deficits,
multiple lesions
•
Radiotherapy is indicated as an adjunct to surgery for
incompletely excisable (persistent) SCC or resected
locally recurrent SCC to improve cure rates.
V
E
R
•
Radiotherapy is important in the management of
metastatic SCC (refer Chapter on Metastatic Disease)
Primary untreated squamous cell carcinoma
1.
Primary untreated invasive SCC
Radiotherapy for primary SCC has comparable outcomes to surgery73,155,158. Five
year control rates of primary SCC treated with curative doses of radiotherapy are
for T1 lesions 93%, T2 lesions 65–85% and T3-4 lesions 50–60%70,69,155,68,89,72,71,159,160
(see Appendix 1).
2.
Residual and recurrent SCC
Incompletely excised SCC carries a local recurrence rate of over 50% 147,148,149.
Overall tumour control of all stages of previously untreated primary SCC with
radiotherapy is 87%, but the tumour control rate for recurrent SCC treated with
radiotherapy is 65%.149 Recurrent SCC has higher mortality rates than primary
SCC. Any SCC residual or recurrent after a standard curative dose of RT should
be excised including the accompanying irradiated tissues.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
55
7 . R A D I OT H E R A P Y
Key points:
•
Recurrent SCC after radiotherapy should be treated with
surgical excision including the irradiated field.
•
An incompletely excised SCC can be treated with RT if
further excision is not possible or reasonable148,149.
D
E
Recurrent SCC despite an initially reported complete excision may be an
indication of aggressive biological behaviour. The recurrence and scar should be
widely excised. If wide excision is not feasible or local recurrence occurs more
than once then RT is recommended.
Local recurrence may be an early manifestation of dermal lymphatic or
perineural spread which can continue to arise up to many centimetres, distant
from the primary site (see chapter on metastatic spread). If the histopathology
report of an excised recurrent SCC reports lymphovascular space invasion or
perineural spread, or a poorly differentiated and widely infiltrative pattern, or
spindle cell tumour type referral to a specialist centre for opinion regarding
further treatment is recommended.
K
O
Recurrent SCC should be referred to a specialist skin or head and neck cancer
clinic for opinion and management as specialist surgery or combined modality
treatment may be indicated.
V
E
R
Solar keratosis and Bowen’s disease
Radiotherapy is rarely used as solar keratoses do not require treatment, and are
routinely cleared with cryotherapy or 5-fluorouracil (5FU) cream or surgery.
These modalities are more convenient and generally less morbid for patients
than radiotherapy. Occasionally long-standing Bowen’s disease can grow to a
large diameter and not respond to other treatment modalities. Radiotherapy can
provide an alternative where surgery for large superficial areas may require
grafting.
Key point:
•
56
Radiotherapy is rarely indicated for solar keratoses or
Bowen’s disease, except for the uncommon long-standing
large superficial Bowen’s disease refractory to
dermatological care and unsuitable for excision.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
7 . R A D I OT H E R A P Y
Keratoacanthoma
Radiotherapy hastens the natural history of resolution of keratoacanthomas with
advantages to the patient of shorter lesion duration and less scarring. However,
keratoacanthomas can clinically and on incisional biopsy be difficult to
distinguish from aggressive primary SCCs and should be excised if doubt
exists.161
Guideline
As the late results of radiotherapy can be poor, it is
generally not recommended for patients younger than
60 years with uncomplicated primary SCC anticipated
to have excellent outcomes with surgery alone.
Refs
III
68,69,
70, 73,
155, 158
K
O
Key points:
D
E
Level of
evidence
•
Radiotherapy for primary SCC has comparable outcomes
to specialist surgery in a specialist skin cancer
clinic70,73,69,155.
•
Incompletely excised SCC is an option with radiotherapy
if re-excision is not feasible147,148,149.
•
Radiotherapy is important in the management of
recurrent and metastatic SCC (see chapter on Metastatic
Disease).
V
E
R
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
57
8 . C RYO T H E R A P Y ,
8.
C U R E T TA G E A N D D I AT H E R M Y
C RYOT H E R A P Y, C U R E T TA G E A N D
D I AT H E R M Y
C RY O T H E R A P Y
Introduction
D
E
Cryotherapy is the destruction of tissue by the direct application of a cryogenic
agent such as carbon dioxide snow, nitrous oxide or liquid nitrogen. It is a
widely used, rapid, cost-efficient and effective therapy for solar keratoses
(SKs).162,163 In addition, cryotherapy (cryosurgery) has been employed for more
than thirty years for the treatment of selected skin cancers
60,94,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182, 183,184,185,186,187,188,189
.
K
O
In general, the technique is most ideal for low risk primary tumours with welldefined margins on the trunk or limbs viz. Bowen’s disease (intra-epidermal
squamous cell carcinoma)166,170,171,172, primary superficial or small papular basal
cell carcinomas (BCCs)167,176,180,184, keratoacanthomas (KAs)166,175 and small primary
well-differentiated squamous cell carcinomas (SCCs)164,166,175,176,180.
V
E
R
It is often combined with initial curettage to provide a specimen for histological
analysis177,182,185,190,191.
Cryosurgery may offer special advantages for elderly high-risk surgical patients
especially those with a pacemaker or coagulopathy,191,192,138 for those who refuse
surgery and for sites where scar contracture is best avoided eg digits193.
Occasionally, in certain areas, cost and accessibility to surgical care may make
cryotherapy the preferred treatment option182.
Alternative forms of treatment, especially surgical excision, are indicated for
large nodular, morphoeic or ill-defined BCCs166,182,184,187, moderately to poorly
differentiated SCCs164,176, 177, recurrent tumours and for certain high risk facial
sites163,164,166,177,186,187,188.
Nevertheless, many studies attest to the efficacy and acceptable cosmetic results
achieved by cryosurgery in specialist clinics, even for difficult
cancers163,165,168,177,180,181,182,183,185 ,187,188,189.
If used for invasive tumours, a biopsy giving histological confirmation of the
tumour is mandatory before treatment, or if there is evidence of residual tumour
following treatment165,166,192.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
59
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Rarely, cryosurgery may be used for palliation of incurable cancers to lessen
tumour bulk or pain and reduce malodorous discharge194.
Key point:
•
Cryotherapy is a simple and effective form of therapy for
solar keratoses. If treatment protocols are optimal,
cryotherapy achieves high cure rates for select low risk
BCCs and SCCs on the trunk and limbs. Acceptable cure
rates, comparable to other standard treatment modalities,
may be achieved for higher risk tumours in specialist
clinics
D
E
162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,60,183,184,185,186,187,188,189,94
.
BASAL
K
O
CELL CARCINOMA
Basal cell carcinomas may be successfully treated by cryosurgery with many
large series by specialist clinics demonstrating cure rates equivalent to other
treatment modalities94, 164,165,166,167,168,176,177,178,179,180,181,182,60,183,184,185,186,187,188,189.
V
E
R
The importance of careful tumour selection is emphasised to achieve acceptable
results95,166,184,187. Histological confirmation of the BCC and analysis for high-risk
features is strongly recommended166,195,196,197. Cryosurgery is most effective for
primary well-defined lesions of non-aggressive type at sites away from the head
and neck167,176,178,180,184.
In general, it would be contraindicated for morphoeic or ill-defined
BCCs163,166,177,178,182,187,188 and relatively contraindicated for high-risk facial sites such
as lips184,192, alar creases192, inner canthi192,196 and periauricular regions196.
Repeated freeze thaw cycles with 3–5mm margins are
recommended166,184,198,196,199,200. Thermocouple needles may be used to monitor the
temperature at the base of lesions. However, several clinical parameters correlate
well with adequate depth freeze and are more routinely employed192,201,198,202,196,
197,199
. Curettage is often combined with cryosurgery and may help improve the
cure rate177,182,185,190,199,200.
Cure rates for BCC by cryosurgery are technique dependent. The aim of therapy
is to produce a selective volume of tissue necrosis equivalent to that removed by
simple excision. Cure rates consistently exceed 95% in specialty clinics where
optimal selection and treatment protocols are used60,163,164,166,167,168,176,178,180,181,182,
184,185,187,188
. Suboptimal cryotherapy technique results in unacceptably low
clearance rates94. One extensive review of multiple series reported a 5 year
recurrence rate for cryosurgery of 7.5%, comparable to other standard treatment
modalities60.
60
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Most large series utilise liquid nitrogen in an open spray technique with
repeated freeze-thaw cycles163,164,166,176,177,180,181,182,184,185,186,188,189. However, superficial
BCCs have been successfully treated with single freeze-thaw cycle cryotherapy
achieving cure rates of 96%167,178. Thermocouple needle monitoring of the
temperature produced at the base of tumours (–40 to –60 degrees centigrade)
may be employed163,164,176,178,180,181,188,189.
Histological confirmation of all invasive tumours by pre-treatment biopsy is
mandatory. Certain microscopic features are associated with a greater depth of
invasion and a higher risk of recurrence126.
D
E
Curettage provides a sample for histology, facilitates cryotherapy of larger
tumours by reducing the tissue volume to be ablated185, and may offer some
advantages at sites such as nose and ears to define the full extent of tumour
growth prior to cryosurgery177,178,179,180,181,182.
Clinical features are fundamental in choosing those BCCs suitable for
cryosurgery. Primary BCCs constitute the great majority of tumours treated in
reported series163,167,176,177,178,182,60,184. In general, such tumours are well-defined and
non-morphoeic in type. Most series exclude ill-defined or fibrosing basal cell
carcinoma in their selection criteria due to unacceptably high recurrence
rates163,165.166,177,178,182,186,187,188 .
K
O
The size of a BCC also determines its response to cryosurgery. In general, the
greater the diameter of a tumour, the lower the cure rate165,167,183,185,186,189.
V
E
R
Recurrent BCCs respond less well to cryosurgery with lower cure rates164,167, and
Mohs’ surgery (see pp 37, 41–2, 45–8, 77) is the preferred treatment for such
lesions60.
Site criteria are also essential in selecting BCCs suitable for cryosurgery. Tumours
on the trunk and limbs respond with consistently high cure rates of greater than
97%176,180,184. Less optimal results are achieved for sites on the head and
neck164,167,168,183,186,188,189,94, although acceptable cure rates have been reported for
selective cancers in experienced specialist clinics163,165,176,177,181,182,184,187.
Routine follow up is essential for all patients treated by cryosurgery. Most
recurrences will become evident within 5 years176,185 and many within 2
years166,187. However, some BCCs have recurred as late as 10–12 years after
treatment60,196.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
61
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Guidelines
Cryotherapy achieves high cure rates for primary
BCC on trunk and limbs if tumour selection and
treatment protocols are optimal.
Level of
Evidence
Refs
III & IV
167, 180,
184
IV
163, 165,
176, 177,
181, 182,
184, 187
Cryotherapy for primary BCC on head and neck
achieves cure rates equivalent to the other standard
modalities if tumour selection and treatment protocols
are optimal.
Cryotherapy achieves lower cure rates for larger BCCs,
except for the superficial (non-invasive) type.
K
O
Cryotherapy achieves lower cure rates for BCCs at
high risk facial sites and is not recommended.
Cryotherapy is contraindicated for ill-defined or
morphoeic (infiltrative) BCCs at any site.
V
E
R
Long term follow up is essential after treatment of
BCC with cryotherapy, as late recurrences may occur.
SQUAMOUS
D
E
IV
167, 165,
176, 178,
179, 183,
185, 186,
189
IV
94, 163,
184, 187,
183, 186
188
IV
165, 179,
168
III
60
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
TUMOURS
Squamous cell carcinoma
Squamous cell carcinomas (SCC) of low risk type can be similarly treated by
cryosurgery. It may be indicated for small, primary, well-defined and nonulcerated tumours on the trunk and limbs and acceptable cure rates have been
reported164,166,167,176,178,179. In general, less-well differentiated SCCs, recurrent SCCs
and those on the head and neck are treated by surgical excision164,176,177,138,203.
Repeated freeze thaw cycles with a minimum of 5mm margins are
recommended176,190,204. Curettage may be used initially to debulk the lesion and is
followed by cryosurgery177,204.
Histological confirmation and analysis for high risk features is essential prior to
cryosurgery195.
62
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Fewer SCCs are treated by cryotherapy than BCCs relative to their prevalence,
implying that most published studies employ strict selection guidelines164,166,176,178.
In general, low risk tumours are selected. The criteria for such SCCs include:
•
primary tumour176,180
•
small size164,176
•
well defined164,176
•
clinically and histologically well-differentiated164,176,177,180
•
on trunk or limbs166,175,180
D
E
Cure rates of greater than 95% are consistently achieved if selection criteria are
strict and optimal treatment protocols are employed164,165,166,167,168,174,175,176,177,178,180,181.
The risks of recurrence and metastasis are increased at certain facial sites
especially lips, ears, periocular regions and perhaps scalp49,205.
K
O
One retrospective Australian study on deaths from SCC of the skin found that
76.5% originated from the head and neck205.
Even with strict selection criteria in experienced clinics, some recurrences occur
following cryosurgery for head and neck lesions163,165,166,176, in contrast to the very
rare recurrences for those on the trunk and limbs166,175.
Management of SCC on the head and neck with cryosurgery should generally
limited to specialist clinics with the full range of treatment options available.
V
E
R
Residual or recurrent SCCs are better removed surgically as cryosurgery leads to
unacceptably low cure rates167.
Solar keratoses
Solar (actinic) keratoses are common skin lesions displaying different clinical and
histological features. They represent both markers of solar damage and potential
precursors of SCCs206.
A continuum of clinical and histological dysplasia occurs from SK to in-situ SCC
(Bowen’s disease) and invasive SCC. However, not all SKs progress to SCC and
some can regress spontaneously31, or following routine use of sunscreen
application207,208. No clinical feature of SKs allows identification of those which
will become malignant. However, early progression to SCC may be indicated by
increased erythema, thickening, alteration or change in size209.
The diagnosis of SKs is usually made clinically but biopsy may be indicated to
exclude malignancy.
SKs may be treated for cosmetic reasons, due to irritation, or because of the
potential for developing SCC. This risk may be greater for immunosuppressed
patients210.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
63
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Topical 5-fluorouracil cream may be used initially to highlight subclinical
keratoses prior to cryotherapy treatment211.
Successful clearance of SKs with cryotherapy with good cosmetic results requires
accurate diagnosis and adequately timed treatment protocols138,201,198,202. A single
freeze-thaw cycle is usually recommended. Cure rates of greater than 98.8% have
been reported162,163.
Hyperkeratotic or suspicious SKs may be better treated by curettage alone, or
curettage followed by cryotherapy, electrodessication or laser cautery to the
base209. These techniques provide a specimen for histological confirmation.
D
E
Widespread SKs may be treated by cryopeels212 but are more efficiently dealt
with by field techniques, such as topical 5-fluorouracil cream211,213,214,215,
Masoprocol cream216, chemical peeling217,218 dermabrasion219,220,221,222 or laser
resurfacing223,224,225. Alpha-hydroxy acid226,227 or retinoid formulations228,150,229,230 may
be used topically to reduce signs of photodamage including SKs.
K
O
Long term follow-up, education and prevention are an integral part of the care of
patients with SKs.
Discrete SKs are cleared by single freeze cryotherapy achieving cure rates of
98.8% and 100% in two major studies162,163. Individual lesions were mapped and
followed up for signs of recurrence for periods ranging from 6 months to 8.5
years. Both series employed open spray liquid nitrogen with total freeze times
based on the palpable thickness of SKs.
V
E
R
Extensive confluent SKs on the face may be similarly cured by cryotherapy212,
and can be made visible by 10 days of pre-treatment with topical 5-fluorouracil
cream211.
SKs are clinically graded (especially by palpable thickness) to determine
treatment parameters. The great majority of lesions are treated by single freeze
cycle cryotherapy162,163, but some thicker SKs may require double freeze-thaw
cycles of treatment212.
Sites of treatment predominately involve face and upper limbs in the reported
series with no difference in response rates. SKs of the periocular area responded
equally well with no recurrences in a single study. 163
Bowen’s disease
Bowen’ disease is SCC confined to the epidermis. Bowen’s disease has been
treated successfully with cryosurgery with many studies reporting greater than
95% cure rates and reasonable follow up periods164,165,166,168,169,170. Non-optimal
treatment protocols produce less satisfactory results10,11,12,13. A pre-treatment
biopsy is usually recommended166,169,171,173.
64
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
A single freeze-thaw treatment cycle of 30 seconds with a 3mm margin is
advised166,169. Slow healing was reported for lesions greater than 20mm in
diameter and for those on the lower legs172,231,232.
Cure rates greater than 99% are achieved with optimal cryotherapy166,169. That is,
liquid nitrogen used in an open spray technique with a single freeze cycle of 30
seconds or greater, achieving a minimal 3mm freeze halo around the marked
lesion.
Cure rates vary from 66% to 97% with less aggressive protocols164,167,169,171,172,173.
D
E
Body site appears to make no difference in response to cryotherapy, but delayed
healing was reported for lesions on the lower limbs172.
Size does not adversely affect response and large lesions can be managed with
overlapping treatment fields170,172.
K
O
Keratoacanthoma
Keratoacanthomas can also be treated with cryotherapy achieving cure rates
equivalent to curettage plus electrodessication, simple excision or
radiotherapy163,166,175,176,178,179,191,233. Larger lesions are often removed by curettage
(providing a specimen for histology) followed by double freeze-thaw cycle
cryotherapy to the base of the lesion.
V
E
R
Limited studies exist on cryotherapy of KAs163,166,175. A cure rate of 87.5% was
achieved in one series of 5 lesions on the head and neck and 3 lesions on the
trunk and limbs166. Double freeze-thaw cycles of 30 seconds or more with 3 to
5mm treatment margins were used 163,166,175.
Site differences in response to cryotherapy have not been noted in the small
series reported166.
Size appears to have been a factor in the choice of cryotherapy with almost all
lesions treated less than 20mms in diameter. One large KA responded to
cryotherapy after initial shave excision175.
Guidelines
Level of
evidence
Refs
Cryotherapy achieves consistently high cure rates
for solar keratoses.
IV
165, 162,
211, 212
Cryotherapy of Bowen’s disease achieves high cure
rates with optimal treatment protocols, but delayed
healing may occur on lower limbs.
IV
166, 169
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65
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Key points:
•
Cryotherapy is not often used for keratoacanthomas, but
may represent reasonable treatment for smaller lesions. If
the diagnosis is in doubt after biopsy, then treatment
should be as for SCC163,166,175.
•
Cryotherapy produces cure rates equivalent to other
standard treatment modalities for low risk SCCs on the
trunk and limbs166,175,176,180.
•
SCC on the head and neck are high risk tumours.
Cryotherapy in specialist clinics achieves acceptable cure
rates if tumour selection and treatment protocols are
optimal166,168,174, 176,177,181.
•
Cryotherapy is contraindicated for recurrent SCC167.
K
O
R E L A T I V E I N D I C AT I O N S
1.
Elderly patients, especially those with medical disorders less tolerant of
surgical procedures, eg with pacemakers, coagulopathies.
In geographic areas with poor access to surgical facilities.
At body sites with higher risk of cicatricial scarring from other treatment
modalities eg digits, penis.
At body sites with increased risk of keloid scars from other treatment
modalities eg upper arms and upper trunk.
Solar keratoses at any site if discrete and non-suspicious.
Bowen’s disease especially on trunk or limbs.
Keratoacanthomas if small and at low risk sites.
BCCs and SCCs of low-risk type especially on the trunk and limbs.
Palliation of inoperable tumours.
V
E
R
2.
3.
4.
5.
6.
7.
8.
9.
R E L AT I V E
1.
2.
3.
4.
66
D
E
C O N T R A I N D I C AT I O N S
Cosmetic sites especially face and neck in younger patients.
High risk body sites especially on face and neck ie. sites where it is
difficult to ascertain depth of tumour penetration, or where deep
recurrence poses greater potential risks.
High risk tumour categories ie. moderately to poorly differentiated SCC,
and ill-defined or morphoeic BCC.
Recurrent cancers—surgical excision with histological confirmation of clear
margins is essential.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
8 . C RYO T H E R A P Y ,
C U R E T TA G E
C U R E T TA G E A N D D I AT H E R M Y
A N D D I AT H E R M Y
Curette and diathermy (C & D) is specialised technique used in the management
of basal cell carcinoma, squamous cell carcinoma, keratoacanthoma and Bowen’s
disease.
To achieve the cure rates described both careful lesion selection, as well as
critical attention to technique are required57,234. It is considered that specialist
training is a necessary prerequisite for the use of C & D.
Mechanism
D
E
The dermis surrounding those skin cancers appropriate for C & D is gelatinous
by comparison to normal dermis and can be easily enucleated using a curette.
The curette makes no further progress when it reaches the surrounding healthy
dermis and thus the operator can differentiate between normal and cancerous
tissue. It follows from this that, if the lesion penetrates through into
subcutaneous fat, the technique loses its selectivity, as fat is not able to resist the
curette like healthy dermis. It is therefore not appropriate for lesions penetrating
to the depth of the dermis. It also will not be effective in the treatment of
cicatricial lesions which do not have a gelatinous stroma eg morphoeic BCC.
K
O
The technique varies slightly between operators but essentially involves 1–3
cycles of curettage each followed by the application of diathermy to the base.
Some operators now use CO2 laser in place of the diathermy.
V
E
R
The procedure is not appropriate on very thin skin such as eyelids, lip or
genitalia where tearing of tissue would allow the curette to break through to the
subcutaneous layer.
BASAL
CELL CARCINOMA
Curettage and diathermy is anecdotally regarded as effective for superficial BCCs
on the trunk and limbs. It is useful in the treatment of BCCs on the legs of older
patients as an alternative to skin grafting. Unpredictable cosmetic results restrict
use on the face to situations where the cosmetic result is not a high priority. It
has the advantage of being rapid to perform, tissue conserving and is not contraindicated in anti-coagulated patients.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
67
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Control rates for BCC treated by serial curettage by diameter57, 67,75
Lesion: Size/type/location
Cure rate at 5 years
< 1cm all sites
98.77%
< 1cm nose
93.55%
> 2cm all sites
84%
> 2cm ears
67%
All sizes not head
< 1cm cheek, forehead & temple
> 1cm as above
D
E
> 96%
94.7%
166, 169
77.3%
< 0.5cm nasal, paranasal, periorbital, lips, chin,
jawline and ears166, 169
94.7%
K
O
> 0.5cm as above
77.3%
As indicated by the above data, lesion selection by site and size is critical.
Higher recurrence rates have also been noted with previously treated
lesions57,67,75. Morphoeic BCCs are not treated as they are not curettable due to
the lack of a gelatinous stroma. Excisional data does confirm that histological
type is a significant factor in recurrence; morphoeic and other infiltrating types
of BCC characterised histologically by small cell clumps, showing higher
recurrence rates75.
V
E
R
Guideline
Recurrence rates of less than 6% may be achievable if
curettage and electrodesiccation is used for appropriately
selected BCC.
68
Level of
Evidence
Ref
IV
57, 234
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
Key points:
Curettage and diathermy:
•
Is not used on high-risk areas (nasal, paranasal, lips, chin,
jawline and ears) or at least not for lesions larger than
5mm at these sites57.
•
Is not used on lesions larger than 10mm on middle risk
sites (face forehead, temples and scalp)57.
•
Is used for all sizes of lesion on low risk areas (neck, trunk
and limbs) 57.
•
Is not used on morphoeic lesions75.
•
Is not used for recurrent lesions57,67.
•
Is carried out by operators with appropriate supervised
training in the procedure57.
SQUAMOUS
K
O
D
E
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
V
E
R
TUMOURS
Squamous cell carcinoma
The use of curettage and diathermy in the management of SCC is subject to
differences of opinion.
There are some limited data in the literature to support the procedure. One study
demonstrates a cure rate of 96% in a group of 48 patients followed for 5 years
and 98% in a group of 101 patients observed over 4 years. In both groups
selection was based on a lesion size of less than 2 cm and ‘unusually invasive,
destructive, or sclerosing lesions were treated by irradiation or surgery’ 158.
With the increasing number of organ transplant patients developing very large
numbers of SCCs, the use of curettage and diathermy in selected tumours can be
of value where surgical excision may be impractical.
Bowen’s disease
Curette and diathermy is one of a number of modalities used by dermatologists
in the management of Bowen’s disease on exposed areas.
As mentioned previously the technique requires that the skin can be stabilised
by stretching to provide a firm base against which to curette. It is also important
that the dermis will not allow the curette to break through to the deeper tissues.
This precludes the use of the technique on eyelids or the genital area and lip. As
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
69
8 . C RYO T H E R A P Y ,
C U R E T TA G E A N D D I AT H E R M Y
many cases occur on the legs of elderly women this method has the advantage
of not requiring reconstruction.
Published data are limited to retrospective, uncontrolled studies with inadequate
follow-up. These studies report recurrence rates ranging from 6.25% to
20%171,235,236.
Keratoacanthoma
D
E
Keratoacanthoma is regarded as a benign tumour and commonly treated by
dermatologists using the technique of curettage and electrodesiccation. The
cosmetic results are anecdotally regarded as good237,238.
Published studies show acceptable cure rates but are compromised by follow-up
times of less than 5 years237,238.
K
O
Curettage of keratoacanthoma involving the nail bed is controversial239,240.
Curettage seems an acceptable procedure for keratoacanthoma provided that:
•
It has not been previously treated.
•
It is not on the ear or lip.
•
It is less than 1 cm in diameter on other parts of the head.
•
It strictly satisfies the clinical diagnostic criteria for keratoacanthoma.
•
The curette is used to obtain the largest and deepest single piece of tissue
possible for histology and the report is consistent with the diagnosis.
•
Close follow-up can be achieved with immediate excision at the first sign
of recurrence.
•
It is carried out by operators with appropriate supervised training in the
procedure.
V
E
R
70
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9. OTHER
9.
T R E AT M E N T S
O T H E R T R E AT M E N T S
(INTRALESIONAL
I N T E R F E R O N , TO P I C A L I M I Q U I M O D,
P H O T O DY N A M I C T H E R A P Y, L A S E R T H E R A P Y )
I N T E R F E RO N
Introduction
D
E
Interferons are proteins synthesised by leukocytes, fibroblast and lymphocytes in
response to microbes, tumours and antigens. Acting as cytokines via interaction
with cell surface receptors, these proteins have antiviral, antimicrobial,
antitumour and immunomodulatory actions. Antitumour effects of interferons
may be direct (antiproliferative, cytotoxic or enhanced cell surface receptors) or
indirect (partly immune system activation).
K
O
Apoptosis can be induced by CD95 receptor ligand interactions241.
V
E
R
Systemic (subcutaneous) interferon a, b, d have been successfully utilised in the
management of Kaposi’s sarcoma, cutaneous T-cell lymphoma, viral papilloma
and malignant melanoma242. Subcutaneous interferon α-2a combined with noral
retinoids may be useful for multiple lesions of Bowen disease243. The following
recommendations apply to the use of intralesional interferon for basal cell
carcinoma and squamous cell carcinoma.
BASAL
CELL CARCINOMA
Intralesional injection of interferon α-2b as the treatment for nodular and
superficial basal cell carcinoma has been reported as having response rates of
24–100%, reflecting dose regimens, technique and duration of
followup241,244,245,246,247,248.
A large placebo controlled study utilising interferon α-2b 1.5 million units 3
times weekly for 3 weeks revealed tumour free rates at 1 year in 81% of
interferon treated patients compared to 20% of placebo treated patients245.
Aggressive (morphoeiform and recurrent) subtypes of basal cell carcinoma
treated with the above regimen do poorly with surgical excision at 2 months
revealing no residual tumour in only 27%249.
Side effects with the above dose regimens are universal with most patients
suffering mild flu-like symptoms. Fever and myalgia are common, chills and
arthralgia are observed and swelling and erythema often noted at the injection
site244,249.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
71
9. OTHER
T R E AT M E N T S
The cost effectiveness of interferon has been considered by Shiell250. Interferon
may be cost-effective in some patients who would otherwise be hospitalised for
treatment of their basal cell carcinoma.
Indications242
For the vast majority of patients surgery and radiotherapy are the preferred
modes of treatment for basal cell carcinoma. Interferon therapy may be
considered for patients with well defined nodular or superficial basal cell
carcinoma who fulfil the following criteria:
1.
Those who reject surgery or radiotherapy.
2.
Whose tumours are considered problematic for surgery or radiotherapy
because of functional location or cosmetic reasons.
3.
Those with or without potential wound healing disorders.
K
O
Contraindications244
1.
2.
3.
4.
5.
Poorly defined or aggressive histological basal cell carcinoma subtype.
Organ transplant recipients (including renal, corneal, cardiac, other)—
increased risk of transplant rejection244,251.
Pregnancy, lactating females, children.
Elderly patients, particularly with cardiac, renal and/or liver disease.
Multiple sclerosis.
V
E
R
Treatment regimen
1.
2.
3.
4.
5.
6.
7.
8.
72
D
E
The diagnosis of basal cell carcinoma and histological subtype should be
confirmed by a small punch biopsy taken under local anaesthetic.
Indications and contraindications assessed as above.
Informed consent obtained from the patient, including adverse effects,
efficacy, treatment course and need for prolonged follow-up.
1.5 million IU of interferon α-2b drawn into tuberculin syringe with
integrated 30 gauge needle: 0.15 ml using ten million unit 1cc diluent.
Except in large lesions the 0.15 mls is injected via a single site, using a fan
approach to distribute the interferon throughout the tumour.
The most effective regimen appears to be 1.5 million IU given three times
weekly for three weeks—total dose 13.5 million IU245.
Systemic side effects may be reduced by the use of paracetamol prior to
and following injections. Cool compresses may reduced local adverse
effects242.
Clinical follow-up to ensure resolution of tumour and absence of
recurrence should continue for 5 years242.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9. OTHER
SQUAMOUS
T R E AT M E N T S
CELL CARCINOMA
Intralesional interferon has been used since 1975252. There is a very significant
difference between intralesional and systemic interferon proving that local
antitumour effects are the important factors. There are no randomised studies
assessing the use of interferon as local therapy for squamous cell carcinoma242.
Small doses of interferon can be used when injecting intralesionally which
reduces the systemic toxicity (eg 1.5 million units into the lesion 3 times a week
for 3 weeks). Short and medium term studies of the effect of intralesional
interferon on primary invasive and in-situ squamous cell carcinoma show
moderate to good response rates244,253,254. One pilot study assessing lip squamous
cell carcinoma revealed a complete response of only 17%. In another study
injecting 33 lesions the response in squamous cell carcinoma was 97.1% with a
complete response rate of 88.2%.
D
E
Systemic side effects included fever, headache, myalgia and flu like symptoms
but were only severe in 10% of patients. Using much lower doses (eg 100,000
units per ml at each injection yielded lesser response rates)244,254. Long term,
follow-up after use of human natural leukocyte interferon suggests reduction in
the recurrences254.
K
O
In patients with squamous cell carcinoma unsuitable for surgical therapy and at
low risk of metastatic disease intralesional α-2b may be considered but long term
and detailed follow-up is mandatory. The role of interferon as adjuvant therapy
for patients with progressive or metastatic squamous cell carcinoma remains
uncertain.
V
E
R
Interferon and retinoids
Vitamin A derivatives slow growth of squamous cell carcinoma in preclinical
studies.118 Thirteen cis retinoic acid can be given orally daily and combined with
subcutaneous interferon α-2a daily for two to three months. It can be considered
for severe or extensive squamous cell carcinoma in situ218. Response rates of up
to 69% have been reported with complete response rates of 25%243,255. The
likelihood of response depends on the extent of disease. The major toxicity was
cumulative fatigue which is not uncommon with such biological agents.
Guideline
Intralesional interferon has a limited but definite
role in treatment of selected BCCs.
Level of
Evidence
Refs
III–2
2,3,11,
241, 243,
249
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
73
9. OTHER
T R E AT M E N T S
TOPICAL
IMIQUIMOD*
Imiquimod is an immune response modifier that induces cytokines related to cell
mediated immune responses including interferon-α (IFN-α), IFN-γ, and
interleukin256. It has been approved for use in the treatment of external and
perianal genital warts257. Because of the efficacy of intralesional interferon in the
treatment of BCC, it was believed that a topical interferon inducer may be of
therapeutic value in these tumours.
Topical imiquimod 5% cream has been reported to have clinical efficacy when
used in the treatment of BCC, both nodular and superficial. A double-blind
placebo controlled trial evaluated different dose frequencies until 2 weeks after
clinical resolution or to a maximum of 16 weeks258. The medium application time
was between 10 and 16 weeks for the lesions that cleared. A total of 35 patients
(7 nodular BCC, 28 superficial BCC) were included in regimens including twice
per day, once per day, three times per week, twice per week and once per
week. There was a dose response with 100% tumour clearance in those dosed
twice daily, once daily and three times weekly; a 60% clearance in those dosed
twice weekly, and a 50% clearance in those dosed weekly compared with a 9%
clearance in those treated with the vehicle.
K
O
D
E
In a larger phase II dose response study imiquimod 5% cream was studied at
different frequencies for a fixed duration of 6 weeks in the treatment of
superficial basal cell carcinoma259. There was a 100% clearance in those treated
twice daily; 87.9% clearance in a once every day regimen; 73.3% clearance in a
twice daily three times per week regimen; and 69.7% clearance in a once daily
three times per week regimen. The twice daily regimen was used on only three
patients as that arm of the study was stopped early as a result of intense
inflammatory skin reactions at the site of application. Application site reactions
were common in the studies reported and were dose related.
V
E
R
Sixteen patients with Bowen’s disease (carcinoma in situ) were treated in a
open-label study with once daily application of imiquimod 5% cream for a
designated 16 weeks260. A complete response rate of 93% was seen in 15 of the
patients who completed the study. One patient died of unrelated intercurrent
illness before a biopsy specimen could be obtained and therefore was not
included in the analysis. Once again, local skin reactions were common with six
patients ceasing treatment between four and eight weeks.
Further studies are ongoing to assess the value of imiquimod 5% cream in the
treatment of solar keratoses.
*
74
R Marks and S Kossard have participated in clinical studies of imiquimod 5% cream
initiated by and supported with grants from 3M Pharmaceuticals, St. Paul, Minnesota.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9. OTHER
T R E AT M E N T S
Key point:
•
Imiquimod 5% cream, a topical interferon inducer,
potentially offers another treatment option in the
management of basal cell carcinoma and other
keratinocyte tumours. Its exact role awaits the results of
further studies.
P H O T O DY N A M I C
THERAPY
D
E
A broad range of procedures is covered under the definition of photodynamic
therapy (PDT)261,262,263. The practicality of PDT is still in the stage of evolution
with multiple clinical trials being conducted to develop suitable agents, light
sources, etc, to obtain optimal tumour clearance with optimal cosmetic outcome.
The principle of cutaneous PDT involves:
1.
Exposure of the skin lesion to a photosensitising chemical either by
systemic or topical application.
2.
Absorption of this chemical into the tumour that is being treated.
3.
Exposure of the lesion to a light source that is capable of photoactivating
the sensitiser and penetrating the depth of the tumour.
4.
Destruction of the tumour as a result of this photoactivation process via
the generation of reactive oxygen intermediates that irreversibly destroys
essential cellular elements and pathways.
5.
Selective sparing of the normal cell lines within and adjacent to the tumour
being targeted. In an ideal state the normal cells would be spared.
K
O
V
E
R
Potentially, PDT can result in excellent cosmetic outcomes. Scarring can occur
following treatment in some body sites. The area reacts initially in a similar
manner to cryotherapy with some peeling and occasionally blistering to the
treated tumour area.
PDT has some advantages in patients who have bleeding disorders, pacemakers,
have multiple lesions or who are physically frail where standard surgical
intervention poses difficulties.
At present, the most suitable tumours to treat are those that are superficial
including solar keratoses (80% or greater response rate) and superficial basal cell
carcinomas (BCCs) (85–90% response rate)264,265,266. Bowen’s disease
(intraepidermal squamous cell carcinoma) has also been reported to have high
cure rates in the order of 90–100%173.
More invasive tumours such as nodular BCCs have had lower response rates in
the order of 60–85% cure261,262. The same applies to squamous cell carcinomas
with long term cure rates in the order of 40–70% 267,268.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
75
9. OTHER
T R E AT M E N T S
Key point:
•
LASER
Photodynamic therapy potentially offers another
treatment option in the management of non-melanoma
skin cancer being most suitable for patients who have
superficial tumours. Its exact role awaits the results of
further studies.
THERAPY
Introduction
K
O
D
E
Lasers have been used within dermatology in the treatment of skin cancers for
more than 10 years269. Nevertheless they remain largely a specialist tool due to
costs and specific training required for their applications. They may be employed
as laser scalpels for cancer excisions270, or more routinely for laser cautery
following curettage271 or shave excision272. While offering some advantages in the
precision of tissue removal, they are impractical for widespread usage.
V
E
R
Guideline
Laser therapy offers some treatment advantages for
select skin cancers. However, the great majority of
tumours are better managed by the less expensive
commonly available techniques.
Level of
Evidence
Refs
IV
224, 225,
269, 270,
271, 272,
273, 274,
275, 276,
277
Although various laser formats have been employed for the superficial
destruction of cutaneous lesions or skin resurfacing, including Argon272,
YAG274,278,279, or more recently Erbium280, Carbon Dioxide lasers (CO2) have
proved to be the most useful and versatile269,270,271,224,225,273,275,276,277. CO2 lasers
produce infrared monochromatic light with a wavelength of 10,600 nanometers.
This wavelength delivers heat energy to tissue resulting in its vaporisation. The
effect on target tissue depends on the rate of energy delivery per unit area per
unit of time (energy fluence = joules per second per centimetre squared). If laser
energy is delivered as a single focused pulse then a defined well of tissue is
vaporised. If delivered in a continuous or repeat pulse manner then a precise
incision is achieved by a focused beam (laser scalpel technique), or a broader
area of depth ablation by a defocused beam (paintbrush technique). Most
applications involve delivery of variable energy fluences for precise removal of
76
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9. OTHER
T R E AT M E N T S
layers of tissue to predictable depths. Good visual control is achieved as
bleeding points are automatically cauterised270,281. The laser may be used as a
sole ablative tool or as an adjunctive therapy after initial curettage 271 or shave
excision272. In the latter respect it is used as a laser cautery similar to
electrodessication, electrofulguration or hot wire cautery. Laser ablation
following tumour debulking has some theoretical advantages over other
modalities of treatment in terms of the precision and control of marginal and
deep tissue removal. Laser light may also be used to activate the photosensitising
agent in the treatment of skin cancer by photodynamic therapy261,55.
BASAL
CELL CARCINOMA
D
E
Cure rates equivalent to other modalities can be achieved for superficial or
nodular BCCs if laser technique is optimal271,278,277. Clearance is increased by more
laser passes271,275,276, or by the addition of curettage271. It is especially useful for
large or multiple lesions over the trunk or limbs271. Its speed of operation may
offer advantages in the occasional patient with extensive numbers of superficial
BCCs requiring treatment in one session277.
K
O
Good haemostasis and a dry surgical bed are achieved with a laser scalpel for
advanced cancers270 and for Mohs’ surgery281.
V
E
R
Key points:
•
Serial laser ablation achieves high cure rates for superficial
and nodular BCCs271,275,277.
•
Large numbers of BCCs may be removed rapidly in single
session277.
•
Laser ablation may be followed by light curettage to
increase the cure rate271.
SQUAMOUS
C E L L C A R C I N O M A A N D R E L A T E D K E R AT I N O C Y T E
TUMOURS
Squamous cell carcinoma
Squamous cell carcinomas of low risk type may be similarly removed by
curettage combined with laser ablation of further tissue at the base and margins.
This is analogous to curettage plus electrodessication or cautery203,193.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
77
9. OTHER
T R E AT M E N T S
Key points:
•
Laser ablation is highly effective for removal of
widespread solar keratoses and
•
in-situ malignant changes on the lower lip (laser
vermilionectomy) or face (laser resurfacing)55,224,225,223,261,282.
•
Bowen’s disease may be successfully treated by laser
ablation. This may be especially advantageous at difficult
sites eg digits224,225,273.
•
Keratoacanthomas and low risk SCC may be similarly
removed by laser therapy. Initial debulking by curettage or
shave excision may improve cure rates 272.
•
The laser scalpel may offer advantages of better
haemostasis in Mohs’ surgery or for excision of advanced
SCCs on the face270.
K
O
Solar keratoses
D
E
Individual solar keratoses (SKs) can be removed by laser therapy with some
possible cosmetic advantages225, but it remains impracticable for the great
majority of lesions, and cryotherapy and 5-fluorouracil cream are the preferred
treatments162,215.
V
E
R
Potentially the greatest application for laser therapy is in regard to field skin
resurfacing for reducing extensive solar keratoses and other signs of
photodamage224,225,282.
The success and long-term benefits of procedures designed to ablate the
epidermis and papillary dermis such as dermabrasion283,219,222, chemical peeling
(trichloroacetic acid or phenol)222,217,284, manual sanding with or without added
chemical peels285, cryopeeling212 and laser resurfacing224,225,223,282,286 have been well
documented. One significant recent study on laser resurfacing demonstrated
sustained improvements in the epidermis and dermis at two years follow-up223.
Compared to pre-treatment biopsies, the epidermis remained thickened with
normalised basal cell polarity and absent dyskeratosis, while the dermis
demonstrated thickening of the grenz zone, increased collagen fibres and
reduced solar elastosis. Laser ablation offers some advantages of predictable
depth ablation, accessibility to difficult sites and safety compared to other
methods of skin resurfacing. The whole subject of cutaneous laser resurfacing
has been recently reviewed286 and the histologic changes summarised287.
Actinic cheilitis may be successfully treated by laser vermilionectomy269,55,261,288,289.
This technique removes extensive solar keratoses, leukoplakia and other signs of
photodamage from the lower lip. Good cosmetic and functional outcomes with a
78
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
9. OTHER
T R E AT M E N T S
lower risk of complications than standard surgical vermilionectomy have been
reported261,55.
Bowen’s disease
Bowen’s disease may be removed by carbon dioxide laser therapy and several
treatment series give high cure rates224,225,275,231. It is especially useful in difficult
areas where maximal tissue preservation is desired eg digits273,290,232.
D
E
Extensive experience has been obtained in removal of genital leukoplakia and
intraepithelial squamous cell carcinomas291,292.
Keratoacanthomas
Keratoacanthomas can be successfully removed by laser ablation272. Initial
curettage or shave excision may simplify the procedure and improve the cure
rates233. If any doubt exists after initial biopsy, then tumours should be treated as
SCC293.
K
O
V
E
R
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
79
10. PREVENTION
10.
PREVENTION (INCLUDING
CHEMOPREVENTION)
PREVENTION
D
E
Exposure to sunlight is strongly associated with the development of nonmelanocytic skin cancer. Within Australia3 and other countries such as the USA294,
the incidence of non-melanocytic skin cancer is highest in areas of low latitude
(ie closest to the equator) and it occurs more frequently on parts of the body
that are habitually exposed to sunlight295. In particular, squamous cell carcinoma
(SCC) rarely occurs on parts of the body that are not habitually exposed295. SCC
and the other main type of non-melanocytic skin cancer, basal cell carcinoma
(BCC), appear to differ in their relationship to sun exposure. SCC is related to
total lifetime exposure to the sun, but not to the pattern of exposure
(intermittent exposure versus more continuous exposure as occurs in outdoor
workers)296,13,39. Outdoor workers appear to have the highest risk. In contrast,
recreational and intermittent exposure may be more closely related to BCC than
the total amount of exposure, with indoor workers possibly having higher risk
than outdoor workers296,13,12,297.
K
O
V
E
R
A randomised trial of adults in Queensland showed that sunscreens reduced the
risk of SCC, but not BCC298. Two randomised trials of sunscreens showed that
they reduced the prevalence of solar keratoses, which are closely related to
SCC207,299.
Studies of immigrants to Australia indicate that sun exposure during childhood
and adolescence is very important in causing both BCC18 and SCC29. There is also
more direct evidence of the importance of exposure early in life for SCC 29. These
findings indicate that particular emphasis should be placed on protection from
excessive sunlight exposure in childhood and adolescence. However, skin cancer
itself is rare before puberty and there may be a long latent period, usually many
years, from the initiating sun exposure to the time a skin cancer (especially an
SCC) becomes clinically apparent. Furthermore, while childhood sun exposure is
very important in the development of skin cancer, exposure in adult life is also
important. Therefore, everyone should be advised to use sun protection
measures throughout their life. This is considered advisable despite lack of
conclusive evidence of reduced incidence of skin cancer resulting from current
sun avoidance practice.
The Cancer Council Australia does not distinguish between melanoma and nonmelanoma in its recommendations on prevention of skin cancer, which relate to
sun protection. It recommends avoiding the sun in the middle of the day, staying
in the shade whenever possible, wearing a wide brimmed hat and clothing to
cover exposed skin, and using sunscreen. These strategies are discussed in more
detail below.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
81
10. PREVENTION
The most effective strategy to prevent skin cancer is to avoid exposure to
ultraviolet radiation (UV) from the sun and to plan outdoor activities before
10am and after 2pm (before 11am and after 3pm Daylight Saving Time). Sixty
per cent of the day’s harmful UV occurs between these hours. Skin will burn
more quickly around midday than earlier or later in the day.
In addition:
Hats and clothing
D
E
Always encourage the wearing of broad-brimmed or legionnaire hats (those
which cover face, neck and ears reduce the UV exposure to the face and eyes)
and comfortable clothing that protects the arms, legs, body and neck from the
sun. Choose closely woven fabrics that can’t be seen through when held up to
the light. (The Australian Standards Association has a system for the rating of the
protection factors of fabrics to help consumers select fabrics with a high
protection factor rating, if they want300.)
K
O
Shade
Seek shade. Whenever possible, choose activities which can be conducted in or
moved to shady areas. But it is possible to get burnt in the shade by reflected
UV rays so use clothing and sunscreen as well.
V
E
R
Sunscreen
Use sunscreen. Apply a sunscreen of SPF15 or greater to all exposed areas of
skin as the last line of defence. All recommended sunscreens should be broad
spectrum with protection extending as far as possible into the UVA range.
Sunscreen should not be relied on as the only form of protection. Apply 20
minutes before going outside and reapply at least every two hours. For specific
circumstances such as swimming, a water-resistant sunscreen should be
selected301. (The Australian Standards Association permits labelling of the sun
protection factor of a sunscreen up to 30+301.)
Sunscreens should not be used to extend the duration of sun exposure, such as
prolonging sunbathing. Using sunscreen to extend exposure to the sun may
increase the risk of developing melanoma.
Sunglasses
Wear sunglasses. There are a wide range of sunglasses available which are
effective and inexpensive—check the label to make sure they meet the
Australian Standard AS 1067.
Window glass
Three millimetre window glass is equivalent to SPF 14 sunscreen in filtering
UVB. It does not filter UVA.
Advice should be given regarding the potential risk of UV damage from sunbeds,
tanning booths and tanning lamps4.
82
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
10. PREVENTION
Guidelines
Level of
Evidence
Refs
Use broad spectrum sunscreens with an SPF of 15
or greater as an adjunct to sun avoidance and other
sun protective measures.
*
Squamous cell carcinoma; there is no evidence for BCC.
II*
298, 299
Use clothing, where possible, as the primary means
of photoprotection.
III
295
Recommendations
•
•
•
•
•
D
E
Stay in the shade whenever possible during daylight hours
Avoid the sun in the middle of the day (ie during the two hours either side
of solar noon)
Wear a broad brimmed hat when outdoors
Provide children with appropriate sun protection for outdoor activities
Advise against the use of sunbeds, tanning booths and tanning lamps
K
O
V
E
R
CHEMOPREVENTION
Synthetic retinoids
Organ transplantation
Both cardiac and renal transplant recipients have been shown to have a greatly
increased risk for the development of non-melanoma skin cancer. This has been
shown to affect 25% of Australian renal transplant recipients by 5 years and 44%
by 9 years post transplantation302. The most dramatic increase in incidence occurs
in squamous cell carcinoma though there is also an increase for basal cell
carcinoma303. A greater proportion of the squamous cell carcinomas occurring in
this context show aggressive growth patterns and poor prognostic features304,305.
Aggressive squamous cell carcinomas contribute to substantial numbers of deaths
in the Australian organ transplant population. Human papilloma virus infection is
more common in the transplant population and prolific warts may develop. High
frequencies are seen of the human papilloma virus Types 5 and 8 that are
associated with cutaneous malignancies in the condition epidermodysplasia
verruciformis303. These may play an aetiological role in the development of
squamous cell carcinomas. UV exposure is also an important risk factor in this
population.
Four studies of retinoid chemoprophylaxis of skin cancer have been undertaken
in renal transplant recipients. All have shown a significant reduction in rates of
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
83
10. PREVENTION
squamous cell carcinomas during treatment306,307,230,308. In one study patients were
observed following cessation of retinoid chemoprophylaxis and skin cancer
suppression was not maintained, suggesting that these agents act at a late stage
in tumour development.
Because of the need for long term therapy it is recommended that retinoids be
instituted only when patients begin to suffer from numbers of squamous cell
carcinomas that are causing significant morbidity or threatening life. The long
term benefits must be weighed against the short and long term adverse effects of
retinoids. The major long term adverse effect is calcification of tendons and
ligaments and spinal hyperostoses309.
Xeroderma pigmentosum
D
E
A trial using isotretinoin in 7 patients showed a 63% reduction in skin cancers
compared with the 2 year period before treatment310.
K
O
Naevoid basal cell carcinoma syndrome
Several trials of retinoids have demonstrated effective chemoprophylaxis of basal
cell carcinoma in this context120, 311,312.
Betacarotene supplementation
V
E
R
Two trials of betacarotene in the chemoprevention of skin cancer have failed to
demonstrate a beneficial effect120,313,298.
84
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
1 1 . M E TA S TA S I S
11.
F RO M N O N - M E L A N O M A S K I N C A N C E R
M E TA S TA S I S F R O M N O N - M E L A N O M A
SKIN CANCER
BASAL
CELL CARCINOMA
Lymph node metastases
D
E
Basal cell carcinomas rarely metastasise to lymph nodes. Most commonly the
patient has a long history extending over many years of multiple recurrences or
an uncontrolled primary lesion. Other factors including a history of prior
radiotherapy, large primary tumours and head and neck lesions have also been
noted314,315.
K
O
Regional control can usually be achieved with lymphadenctomy. Post operative
radiotherapy may be indicated for patients with a high risk of recurrence ie.
extensive disease, multiple involved nodes, extra capsular extension, close/
involved surgical margins316,317. Radiotherapy alone is a reasonable alternative to
surgery for the poor operative candidate or the patient with inoperable disease
requiring palliation. Survival after development of regional disease is short due
mainly to failure to control the primary lesion.
V
E
R
Distant disease
Metastatic disease from BCC is an extraordinarily rare event. Lung and bone are
the commonest sites. Reported experience with only a handful of patients
indicate that cisplatin based regimens appear to be the most effective. Response
rates of up to 83% have been reported with a median duration among
responders of 24 months318. Radiotherapy may be useful in palliation of distant
metastases.
Chemotherapy
(i)
(ii)
Systemic treatment:
Rarely systemic chemotherapy is used in metastatic basal cell carcinoma
or for locally advanced disease. Most regimens include cisplatin. Only
small groups of patients have been reported with response rates up to 83%
with 37% being complete responses319,320,321,322,323,324,325.
Local treatment:
Local chemotherapy has been employed in the treatment of basal cell
carcinoma. Most commonly reported is the topical application of 5flourouracil creams326,118,327,255. Intralesional 5-FU with epinephrine injectable
gel has also been used. More recently, electro-chemotherapy which
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
85
1 1 . M E TA S TA S I S
F RO M N O N - M E L A N O M A S K I N C A N C E R
involves intralesional bleomycin and electric pulses locally has achieved
response rates approaching 100%328.
Guidelines
Level of
Evidence
Refs
III
319, 320,
321, 322,
323, 324,
325
Response rates have been reported of up to 83%
with 37% being complete.
Intralesional 5-FU with epinephrine injectable gel has
also been used. More recently, electro-chemotherapy
which involves intralesional bleomycin and electric pulses
locally has achieved response rates approaching 100%.
SQUAMOUS
K
O
CELL CARCINOMA
Lymph node metastases
V
E
R
D
E
III
118, 255,
326,327,
328
The incidence of lymph node metastases from SCC occurring in sun effected skin
is very low (less than 1%) but may be considerably higher in certain situations
including49,329:
1.
SCC occurring at sites of mucosal-squamous cell junction including lip,
anus and vulva
2.
Immuno-suppression
3.
Previous radiotherapy
4.
SCCs arising in chronically inflamed/irritated lesions.
Primary lesions located in the head and neck, in particular the lip and ear, are
responsible for the majority of lymph node metastases from SCC.
Among patients developing regional recurrence, specific tumour factors related
to the development of regional recurrence include49:
1.
Tumor Size. SCC greater than 2cm are twice as likely as smaller lesions to
develop regional recurrence.
2.
Tumor Site. Lesions located on the ear and lip have a higher rate of local
recurrence than cutaneous SCC elsewhere.
3.
Tumor Grade. Poorly differentiated SCC have double the recurrence rate of
well differentiated lesions.
4.
Tumor Thickness. SCC greater than 4mm in thickness recur three times
more commonly than thinner lesions.
5.
Recurrent SCC. Recurrent lesions are twice as likely to recur.
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
1 1 . M E TA S TA S I S
6.
F RO M N O N - M E L A N O M A S K I N C A N C E R
Peri-neural Invasion. The most serious predictor of regional recurrence
with up to 50% developing regional recurrence.
The time to development of regional disease is short, usually within 12–24
months after initial treatment of the primary lesion.
Key point:
•
Regional lymph node spread of SCC is uncommon but is
often associated with metastasis to distant sites and a
poor outcome.
D
E
Any clinical suspicion of node metastases warrants investigation by CT scanning
+ ultrasound. The diagnosis of nodal metastases should be confirmed by fine
needle aspiration cytology (FNAC). Occasionally image guided FNAC or core
biopsy may be necessary. Open incision biopsy of a suspicious lymph node for
diagnosis is not advised: it potentially increases the risk of dermal lymphatic
involvement, compromises further management, reduces the efficacy of
subsequent lymphadenectomy and usually requires an avoidable general
anesthetic330.
K
O
V
E
R
Guideline
Clinically suspected lymph node metastases should
be confirmed by fine needle aspiration cytology
(under radiological guidance if required). Open
surgical biopsy should be avoided.
Level of
Evidence
Refs
IV
330
Although cutaneous SCC is the obvious primary for a regional lymph node
metastases, this is not always the case, especially in the head and neck the
commonest site of regional metastases. Patients may have had numerous
previous skin cancers of the head and neck and may also be at increased risk for
other upper aero-digestive tract mucosal primary SCCs as the source of the SCC
nodal metastasis. A thorough examination of the upper aero-digestive tract by an
experienced clinician is necessary if any doubt as to the site of the primary
lesion exists.
Guideline
The treatment of metastatic disease to lymph nodes
is primarily surgical.
Level of
Evidence
Refs
IV
49, 117,
329, 331
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87
1 1 . M E TA S TA S I S
F RO M N O N - M E L A N O M A S K I N C A N C E R
Given the complexity of treatment for patients with regional metastases specialist
referral is indicated. Lymphadenectomy for disease in the axilla or groin is
straightforward. Occasionally lymph node metastases occur at unusual sites
including the epitrochlear region and popliteal fossa. For cervical lymph nodes
most authorities recommend a selective neck dissection. The extent of the
lymphadenectomy is determined by the site of the primary lesion and the
involved node(s) and the extent of the disease. Generally the accessory nerve
and sternomastoid muscle can be preserved which reduces the morbidity of the
procedure.
D
E
Post-operative radiotherapy is recommended for patients with a high risk of
recurrence including332,333,334:
•
Parotid node metastases
•
⊕ 3 nodes positive in the neck
•
⊕ 4 nodes positive in the axilla or groin
•
Significant extra nodal extension
•
Close or involved surgical margins
•
Skin infiltration
•
Recurrent nodal metastases, salvaged surgically
•
Node metastases in unusual sites, viz posterior triangle neck / SCF /
occipital nodes (from primary cutaneous SCC of posterior scalp, upper
trunk), epitrochlear and popliteal nodes
•
node metastases accompanied by local relapse.
K
O
V
E
R
For patients with extensive disease, eg very large nodes, multiple nodes, bilateral
nodes and involvement of overlying skin or fixation of nodes, multimodality
treatment is indicated. In these instances, or if any doubt exists on the extent or
integration of treatment, pre-operative assessment and opinion from a
multidisciplinary team is recommended. A head and neck surgeon, reconstructive
surgeon, dental oncologist, surgical oncologist, radiation oncologist and medical
oncologist may need to be involved in complex cases.
Recurrence of nodal disease is associated with a very poor prognosis. While no
randomised trials exist to support the role of post-operative RT in cutaneous
SCC, evidence extrapolated from mucosal related metastatic SCC is strongly
supportive.
Curative RT alone for nodal metastases is indicated if lymphadenectomy is not
possible due to the patient being unfit for surgery or refusing surgery. Salvage
surgery is sometimes possible if complete or durable control is not achieved with
RT alone. Palliative RT is appropriate for inoperable, advanced regional
metastases to treat pain, stave off skin ulceration, and reduce bleeding. It is
unlikely to prolong survival.
Survival after lymph node metastasis is poor with only one third surviving 5
years. Half of these patients die of uncontrolled regional disease without distant
metastases. For patients with regional spread from SCC of the lip, survival may
be twice as high.329
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
1 1 . M E TA S TA S I S
F RO M N O N - M E L A N O M A S K I N C A N C E R
Dermal lymphatic spread (in transit metastases)
This is a very uncommon condition and may be seen in association with regional
spread and or locally recurrent disease. Wide surgical excision is indicated
followed by adjuvant radiotherapy. Further recurrence is not uncommon331.
Perineural spread
Perineural spread may be incidental or symptomatic. Incidental implies early
spread is asymptomatic and is recognised only after complete pathological
examination of the specimen. No further intervention is indicated if the lesion
has been completely excised. Radiotherapy treatment recommendations are
found in the Chapters on surgery and RT for SCC. (Chapters 6 & 7)
D
E
Symptomatic perineural spread is late or established spread of SCC away from
the primary SCC site along an involved nerve and carries a very poor prognosis.
The vast majority occur in head and neck cutaneous SCC.
K
O
Surgical resection of the involved nerve, which is usually followed by adjuvant
radiotherapy, is appropriate. Alternatively, high dose RT with palliative or
curative intent covering the entire course of the nerve back to its origin from the
CNS is acceptable. Treatment invariably causes major morbidity. Relief of
symptoms occurs in >50% of cases with variable durability.
V
E
R
Metastatic squamous cell carcinoma
Distant metastases from SCC are uncommon49,329. They rarely precede the
development of regional metastases or occur in isolation from regional
metastasis. The time to occurrence after presentation with the original primary
lesion is short, usually within 2 years. The commonest sites of spread are the
lung and liver but bone and brain may also be involved. Radiotherapy is
effective in controlling symptoms and delaying local progression of disease.
Cisplatin based chemotherapy protocols appear to be the most effective but
other agents with some efficacy include 5-flurouracil, bleomycin and
vindesine334,322,325. Survival despite treatment is poor with few patients surviving
more than 2 years. Specialist referral is indicated.
Chemotherapy
(i)
Systemic treatment:
Systemic chemotherapy has been used for metastatic squamous cell
carcinoma of the skin. It can be used alone or as part of multimodality
therapy. Most regimens are based on cisplatin with the most commonly
reported phase II studies using cisplatin and doxorubicin319,320,321,322,323.
Other drugs include methotrexate, 5-fluorouracil, bleomycin and
vindesine324,325,326,118. Objective response rates of > 80% have been reported
with complete response rates of around 30%.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
89
1 1 . M E TA S TA S I S
(ii)
F RO M N O N - M E L A N O M A S K I N C A N C E R
Local treatment:
Local chemotherapy has been used in the treatment of metastatic
squamous cell carcinoma. Small studies have investigated intra lesional
cisplatin with epinephrine or 5-fluorouracil with epinephrine gels327, 255.
Topical 5-fourouracil has activity in squamous cell carcinoma in small
series252,328,335,336.
Guidelines
Most regimens are based on cisplatin with the
most commonly reported phase II studies using
cisplatin and doxorubicin. Other drugs include
methotrexate, 5-fluorouracil, bleomycin and
vindesine. Objective response rates of > 80% have
been reported with complete response rates of
around 30%. Patients should be considered for
referral to a suitable cancer specialist centre for
multidisciplinary care.
Level of
Evidence
Refs
III
118, 319,
320, 321,
322, 323,
324, 325,
326
III
252, 255,
327 , 328,
335, 336
K
O
Small studies have investigated intra lesional cisplatin
with epinephrine or 5-fluorouracil with epinephrine
gels. Topical 5-fluorouracil has activity in squamous cell
carcinoma in small series.
V
E
R
90
D
E
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
12. FOLLOW
12.
UP
F O L L OW U P
No study has assessed the possible benefit from regular medical review for
patients who have been treated for a non melanoma skin cancer in comparison
with observation by the patient themselves.
D
E
There are three reasons to undertake follow-up for such patients:
DETECTION
O F F U R T H E R P R I M A RY T U M O U R S
Many studies attest to the higher incidence of subsequent non-melanoma skin
cancers in patients who have been treated for one337. It is likely that these will
be detected earlier by regular medical follow-up thereby minimising the
morbidity associated with the disease and its treatment.
K
O
At each follow-up visit all of the skin surface that has been chronically or
intermittently sun exposed should be examined. Good lighting is important.
The frequency and duration of follow-up should be varied according to risk
factors for further primary tumours. Patients in special risk groups such as organ
transplant recipients may require three monthly follow-up by a specialist. For
others annual follow-up by their general practitioner may be sufficient.
V
E
R
LOCAL
P E R S I S T E N C E O F T H E P R E V I O U S LY T R E AT E D
T U M O U R 62,104,338,339,337
Follow-up after treatment for a primary tumour for local persistence (clinical
local recurrence) of the primary tumour should be considered if:
(a)
A treatment modality has been used that is associated with a high rate of
locally persistent disease.
(b) There is uncertainty about the completeness of removal with previous
surgery.
(c)
The primary tumour has clinical and/or histological features that are
associated with high risk of locally persistent disease.
(d) The tumour has been treated at a site where extensive locally persistent
disease would be difficult to treat.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
91
12. FOLLOW
E A R LY
UP
D E T E C T I O N O F M E TA S TA T I C D I S E A S E
Published studies suggest that frequency of metastatic disease from primary
squamous cell carcinoma of the skin may be as much as 1–2%, although this is
likely to be the upper limit for the vast majority of tumours. The rate is higher
from lip and ear49,340. Metastasis from squamous cell carcinoma generally presents
in the regional lymph nodes. It has been suggested that six monthly follow-up
for a two year period would be sufficient for most squamous cell carcinomas.
Tumours with factors that increase the risk of metastatic disease (eg large volume
lesions, lip lesions, transplant recipients) should be considered for more frequent
follow-up over a longer period. At each follow-up visit the patient should be
examined by the doctor, palpating both regional and distant lymph node sites in
addition to examining the skin for local persistence of the primary tumour and
further primary tumours.
K
O
D
E
Following treatment of a primary tumour all patients should receive counselling
about their risk for further primary tumours, local persistence of their previous
primary tumour and for metastatic disease. As much as possible these risks
should be quantified. The patient should be advised about ways in which these
problems might present and how they should go about assessing themselves for
these possible eventualities.
V
E
R
Conclusion and Guideline
There are no data available as yet to underpin a
recommendation on the frequency or nature of
follow up after the treatment of primary cutaneous
non-melanoma skin cancer.
92
Level of
Evidence
Refs
O
Nil
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
13. WHO
13.
T R E AT S
&
P RO B L E M S TO R E F E R
W H O T R E AT S A N D P R O B L E M S TO
REFER
I N T RO D U C T I O N
D
E
The pivotal position occupied by general practitioners (GPs) in the Australian
health scene accounts for the fact that they diagnose and manage most
suspicious skin lesions in Australia, particularly in rural areas341,342. Morbidity
studies highlight the very high incidence of NMSC in Australia and thus the
significantly high workload and decision making for skin cancer management by
the general practitioner343. Raasch and others raise questions about the current
practice of ‘excising suspicious skin lesions as informal screening for skin
cancer’343,344.
K
O
A recent study in the Townsville area of Queensland which addressed this issue
confirmed the general understanding that excision biopsy is the standard
preferred management for clinically diagnosed NMSC and the lesions that were
diagnosed as clinically benign were not excised or biopsied343. The study also
found that there was a relatively high proportion of correct clinical diagnoses for
NMSC.
V
E
R
It is sobering to realise that NMSC is responsible for the death of 200 Australians
each year30. Difficulty in managing many of these tumours is ‘due to atypical or
unusual presentations as well as a poor understanding of their histological
variants’ 345. This highlights the importance of appropriate training and skills
acquisition for the GP. As Marks points out, with this background GPs should be
able to treat a large proportion of skin cancers.
TO
T R E AT O R T O R E F E R
The decision influencing treatment depends on many factors including the
experience and skills of the doctor of first contact, geographical location, local
facilities including availability of radiotherapy and in particular available
specialists whether surgeons or operative dermatologists.
The actual decision to refer for specialist management can be difficult346.
However rural GPs especially those in remote areas may proceed directly to
excision biopsy with confidence in their own skills while GPs in busy city
practices are inclined to refer to specialists trained in skin surgery.
The most appropriate practitioner to manage the uncomplicated small tumours is
the adequately trained GP who can simply remove most of these by an elliptical
excision with a 3 mm margin. Early presentation and diagnosis facilitates the
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
93
13. WHO
T R E AT S
&
P RO B L E M S TO R E F E R
process and the more experience that the GP acquires, which largely comes
from hands on treatment, the better the management process. It should be
emphasised that there is a wide variation in skills, training and confidence of
GPs with some, particularly rural GPs or those with surgical training in hospitals,
possessing skills to manage more complex skin tumours. The treating GP should
have an appropriate treatment room with adequate sterilisation facilities, correct
instruments and good lighting.
GPs should be prepared to excise most tumours at first contact because it makes
economic sense. They should also be able to learn and undertake basic skin
biopsy techniques (punch and shave) to establish a diagnosis.
D
E
GPs should also be aware of the variety of treatment modalities for NMSC
including surgical excision, cryotherapy, curettage and radiotherapy. Each
management decision has to be tailored to the particular lesion in that individual
patient but generally simple surgical excision with primary closure is the
treatment of choice for most skin cancers.
K
O
Cryotherapy is a useful and relatively simple option in appropriately trained GPs
for the treatment of low risk superficial BCCs, but histological diagnosis is
essential before such destructive forms of therapy347. Obvious or suspected solar
keratoses are an exception.
A review of Health Insurance Commission data on services provided for excision
of skin tumours reveals that along with specialists such as dermatologists and
plastic surgeons, Australian GPs excise a substantial proportion of these lesions
on the face and body, not just tumours less than 10 mm, but also including those
10–20 mm in size.
V
E
R
GPs need to be aware of the limitations of their skills and should be prepared to
refer to an appropriate specialist.
P RO B L E M
AREAS REQUIRING EXPERIENCE AND CARE
The education of GPs on the management of NMSC should include basic
information on the anatomical pitfalls awaiting surgical excision. The following
summarises potential or real problem areas345,346.
•
The face—for cosmetic reasons
•
The face—for potential nerve damage eg temporal branch of facial nerve
•
The lips and helix of the ear—because of malignant potential
•
The eyelids
•
The inner-canthus of the eye with close proximity to the nasolacrimal duct
•
Mid sternomastoid muscle area where the accessory nerve is superficial
•
Fingers where functional impairment may be a concern
•
Lower limb below knee where healing, especially in the elderly, will be a
problem
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Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
13. WHO
P RO B L E M S
T R E AT S
&
P RO B L E M S TO R E F E R
TO R E F E R 346,347
There are specific lesions where it is appropriate to refer to a specialist and this
may apply to the experienced GP. In many instances it is comforting for both the
patient and their GP to have a technically difficult problem managed by a
specialist.
Referral should be considered for:
•
uncertainty of diagnosis
•
any doubts about appropriate treatment
•
tumours larger than 1cm
•
multiple tumours
•
recurrent tumours, despite treatment
•
incompletely excised tumours especially when complete excision may be
difficult
•
recommended treatment beyond the skills of the practitioner
•
anticipation of difficulty with technique or anatomy where an appropriate
specialist should be consulted
•
squamous cell carcinomas on the lips and ears
•
infiltrating or scar-like morphoeic BCCs, particularly those on the nose or
around the nasal labial fold—as there may be a problem in determining
the tumour’s extent and depth
•
cosmetic concerns such as lesions of the upper chest and upper arms
where keloid scarring is a potential problem
•
areas where palpable regional lymph nodes suggestive of metastatic
spread of squamous cell carcinoma viz head & neck, axilla and groin
•
large lesions which may require complicated methods of closure such as
grafts and flaps—where the GP is inexperienced in these techniques
•
when the GP will be unavailable for regular follow up especially for an
SCC
K
O
V
E
R
D
E
Key point:
•
Operative specialists should be given the opportunity to
deal with the lesion in its entirety.
Although complete excision of a skin cancer with a narrow margin may not
effect outcome it is better to avoid two procedures for the one lesion.
The first opportunity for treatment is the best opportunity to achieve cure.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
95
13. WHO
T R E AT S
&
P RO B L E M S TO R E F E R
Follow up
All patients treated for NMSC whether by the GP or specialist require follow-up
for evidence of recurrence, metastasis and/or any new primary skin cancers. The
patient’s GP is ideally placed for such review and can liaise with any treating
specialist regarding particular concerns.
Opportunistic screening
D
E
Screening for NMSC should be considered during the general examination of
patients presenting with another medical problem or for a routine examination.
Although the majority of cancers appear on sun exposed areas where they are
most clearly visible it is important to keep in mind that a significant number of
NMSCs occur on the trunk and limbs hence the relevance of a total body
cutaneous examination not only in those at greater risk (family history, past
personal history and skin type) but in all patients. Such an examination should
be a feature of the annual check-up.
K
O
Education of GPs
All graduating doctors should have had the opportunity to become familiar with
skin disorders in particular malignant skin tumours. This of course is the
responsibility of those in medical schools who are responsible for the
curriculum. A good undergraduate foundation complemented in particular by
clinical exposure to patients in dermatology clinics or general practice seems to
be imperative.
V
E
R
Vertical integration of this education with substantial postgraduate education and
training in the general practice training program is important to achieve a well
informed practitioner. Diagnostic and management skills should be assessable
during this program.
Education of the patient
One of the important health promotion and educative tasks of the GP is
education of their patients about prevention and management of skin cancer.
Video programs, wall charts and patient education material in the waiting room
is one method, as well as opportunistic education of patients through preventive
advice348. Clear explanation of the tumour, management plan and reason for any
referral is simple good sensible medical care.
Summary
The patient’s general practitioner is the first to be confronted with a suspicious skin
lesion. Hence the importance of providing optimal training from undergraduate
through to graduate for GPs with a heavy emphasis on recognition of skin cancer.
Correct diagnosis and appropriate management are linked343.
96
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
13. WHO
T R E AT S
&
P RO B L E M S TO R E F E R
For most clinically obvious or suspicious NMSCs the best management is
excision with a 3mm margin followed by primary closure and then histological
confirmation.
It is imperative that GPs be aware of their limitations and refer where
appropriate. Such guidelines for referral to a specialist with training in skin
surgery and other treatment modalities are presented in this paper.
Key points:
D
E
•
GPs play a pivotal role in the early detection and
management of NMSC.
•
Uncomplicated small tumours are best removed by an
elliptical excision with a 3mm margin.
•
The first opportunity for treatment is the best strategy to
achieve cure.
•
Caution should be used in the management of NMSCs on
the face, including the ears.
•
It is important to be aware of guidelines for referral.
•
Specialists should be given the opportunity to deal with a
problematic lesion in its entirety.
K
O
V
E
R
•
Opportunistic screening with a total body cutaneous
examination on all patients should be practised.
•
Young patients with sun damaged skin need regular
review.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
97
13. WHO
T R E AT S
&
P RO B L E M S TO R E F E R
Tumour features that indicate a high risk (after R Rosen345)
Table 1
Basal cell carcinoma
Recurrent
Incompletely excised
Larger than 2cm
Poorly defined
Morphoeic, infiltrating
Micronodular, perineural
Special sites:
Nose
Eyelids
Temple
Pre and post auriculae
K
O
Lower legs
Squamous cell carcinoma
Recurrent
Incompletely excised
Larger than 2cm
V
E
R
Deeper than 6 mm
Primary mucosal SCC
Poorly differentiated SCC
Perineural
98
D
E
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
See suspicious skin lesion
Body site,
problem
Biopsy
Uncomplicated
Refer
Not refer
Not refer
Not monitor
Monitor
D
E
* Tumour >1cm, 'recurrent tumours', incompletely excised tumours, recommended treatment beyond skills of GP,
anticipated difficulty with technique or anatomy, suggestion of metastases, follow-up uncertain or unavailable.
No NMSC
Missed NMSC
No NMSC
Delayed
treatment
No NMSC
Early detection
Adequate
&
Not monitor
Monitor
Not biopsy
K
O
Not excise
Monitor
8. Prevention
Treat
Inadequate/
complications
T R E AT S
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
Figure 1 Pathway for management of NMSC—GP focus (courtesy of B Raasch 343)
Not NMSC
Skills,
location,
facilities,
experience
Suspect NMSC
Excise
V
E
R
Complicated*
Refer
POSSIBLE
OUTCOMES
13. WHO
P RO B L E M S TO R E F E R
99
14. ECONOMICS
14.
O F T H E P U B L I C H E A LT H P R O B L E M
E C O N O M I C S O F T H E P U B L I C H E A LT H
P R O B L E M D U E TO N O N - M E L A N O M A
SKIN CANCER IN AUSTRALIA
NMSC is by far the most common malignant neoplasm in Australia, with an
incidence of 282,825 cases in 1996349(Table 4.2). However, many of these cases are
amenable to cure and hence not life-threatening. For this reason, the public
health problems of NMSC measured in terms of disability-adjusted life-years
(DALYs) is not as large as the incidence of the disease would suggest. The
estimates of the public health problem in Australia in terms of DALYs constructed
by Mathers, Vos and Stevenson349 (Table 5.3) show the rank of the DALY disease load
for males is 71 out of 75 leading causes of the public health problems, while for
females it fails to rank in the top 75 leading causes.
K
O
1 (Table 2)
D
E
Mathers et al
estimate that the total direct cost of NMSC in Australia in
1993–94 was $232.3 million. This is considerably larger than an earlier estimate
of the annual direct cost of NMSC of $50 million although the authors of the
1985 study stress that they believe it is a minimum estimate350. These estimates
suggest a small to moderate disease liability arising from NMSC when viewed in
the context of the total health system costs for disease and injury in 1993–94 of
$31,397 million351 (Table 6.20).
V
E
R
Mathers et al1 (Table 11) estimate that the treatment cost per case of NMSC in
Australia is $750. This figure is within the range of treatment costs for basal cell
carcinoma in an Australian study by Shiell250. Four treatment endpoints are
identified in that study (treatment costs in parentheses): simple excision with
primary closure ($216); excision with simple skin graft for small lesions
performed in the surgeon’s own rooms ($520); excision with extensive skin graft
for large lesions ($773); and treatment with interferon alfa-2b ($1,388).
PREVENTION
Carter, Marks and Hill2 report the potential cost-effectiveness of a national
primary prevention program for skin cancer in Australia, based on the SunSmart
campaign in Victoria. Their analysis is based on a 20-year national health
promotion campaign with time lags of 5 and 15 years before any reductions in
deaths from melanoma and NMSC respectively occur. While the cost per life-year
saved is quite low when only the costs of the campaign to government are
included in the cost of the program ($1,360 per life-year with no cost offsets for
treatment cost savings), it is considerably higher when private costs for
sunscreen and hats are included ($25,134 per life-year). Avoidance of deaths
from melanoma constitutes the major source of health benefits in this analysis.
Smith and McGhan352 also discuss the costs of treatment of potentially malignant
skin lesions and the benefits of prevention in the US context. However, no
formal economic evaluation is undertaken.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
101
15. QUESTIONS &
15.
C O N C E R N S T H AT M I G H T A R I S E D U R I N G C O N S U LTAT I O N
Q U E S T I O N S A N D C O N C E R N S T H AT
M AY A R I S E D U R I N G C O N S U LTAT I O N
Non-melanoma skin cancers are so common in this country that all of us, health
carers included, are at least potential consumers. It may be useful, therefore, to
give some consideration to the perspective of consumers. By doing this
practitioners may be stimulated to think about all the queries and concerns they,
and their lay friends, would have as consumers, and become better prepared to
deal with such matters if they should arise, or if they ought to be raised, during a
consultation or when speaking to an audience on the subject of skin cancers.
This, in turn, should help towards achieving the objectives of these Guidelines,
namely, to promote optimal care of these conditions and to meet the
requirements of consumers.
K
O
D
E
The concerns of consumers, or potential consumers, are about the causes of skin
cancer; the likelihood of getting it and how to prevent it; how to detect it and
what to do about it; the effects, side-effects, effectiveness and cost of treatment;
and after-effects, subsequent care and prognosis. In fact all the same topics as
practitioners and care-providers are concerned about—and which these
Guidelines deal with—but slanted away from the ultra-technical, specialised and
statistical aspects of the subject towards what is personal, practical and
understandable by the laity, and not only for curious or affected subjects
themselves, but also for their children and other family members and friends in
the community.
V
E
R
Consumers would like their doctors and other service providers to be aware of
all their possible concerns and to be prepared to address them, respectfully and
sincerely, even if they seem trivial or even silly or inappropriate. Furthermore,
bearing in mind that they might not think of all the relevant questions at the time
of the consultation, or be a bit too nervous or scared to ask them, or hesitant
and embarrassed because they speak English poorly, they would like the
practitioners, in their best ‘client oriented’ mode, to raise ones which might be
relevant.
What follows could be regarded as a checklist, far from complete, of concerns
which people have. They are loosely categorised and abbreviated: key words,
thought-provokers, pointers towards topics of concern. Which concerns will, or
should, be addressed in any consultation, and in what order, will, of course, be
uniquely trimmed to each situation.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
103
15. QUESTIONS &
SPECIFIC
C O N C E R N S T H AT M I G H T A R I S E D U R I N G C O N S U LTAT I O N
TO P I C S
Susceptibility
I realise there are different types of skin cancers. Tell me about them. Looking at
me now, and at my inheritance and upbringing, what are the chances that I, or
members of my family might develop skin cancers? Is the likelihood greater than
average? Or less? For what reasons?
D
E
I have heard that being of Celtic or Anglo-Saxon origin and having fair sensitive
skin as well as increasing age increases the risk of skin cancer. So, I wonder
about me and my own particular type of skin, its colour and hairiness and
whether my dark spots, freckles or other noticeable marks are suspect. What
about hair colour? Is it true that people with red hair and freckles are especially
at risk?
K
O
What about such factors as the geographical areas in which I have lived, my
exposure to sunlight, and the times I got sun burnt, especially way back when I
was a youngster? Am I put at risk by my present occupation, or by my smoking,
or by my habit of not wearing long sleeves and a hat? What about old scars or
grazes? Also, I have plastered many things on my skin over the years, and still
do—such as oils, soap, lotions, perfumes, sprays and so on; could any of these
do harm?
V
E
R
Prevention
Looking towards the future. I have gained some information, but tell me more
about the known causes of skin cancer and what I can do to prevent or at least
reduce the chance of getting it?
Tell me about sunshine, ultra-violet rays and any other important factors. How
can I best protect myself from the sun? What are the bad seasons of the year,
times of day, and geographical places? Is it true that even cloudy days, reflected
sun and wind can be harmful? Am I safe in deep shade or under shadecloth, or
behind glass in a car or in the house? Do my jobs or my recreational activities
put me unduly at risk?
What benefit might be expected from various fabrics, colours and styles in
clothing, swimwear and hats? What chemicals should, or should not, be put on
skin—thinking of skin care products, cosmetics, soaps, tanning lotions, hair
sprays and dyes?
What about food and drugs by mouth, and the cleaning agents and pesticides
and paints and other things I use in the home and outside? What protects and
what harms?
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15. QUESTIONS &
C O N C E R N S T H AT M I G H T A R I S E D U R I N G C O N S U LTAT I O N
Diagnostic pointers
What should I be on the lookout for? How do I detect and assess anything which
might be cancerous and warrant consultation? I’m thinking of my children as well
as me.
Are there any sensations, such as itch, pain or numbness that I should take
notice of and report? What might I see or feel? What are the important areas I
should inspect and how often and what about the scalp, ears, nose, genitals and
other tricky sites?
D
E
As for spots already on my skin, what should I watch out for? Changes in colour,
size, shape, thickness, bleeding, discharge? Is there a place for photography
which I have read about? I realise, of course, but need reminding, that it is
unwise to feel or prod too much or pick at any spots or sores and wise to seek
expert advice.
K
O
Consulting
When should I, or my family member, make an appointment to be seen? By
whom? How often?
Are routine checkups at certain ages advisable? If I suspect a problem should I
visit my general practitioner or go straight to a dermatologist? Would
pharmacists, nurses or naturopaths be able to help me? What about general
surgeons and plastic surgeons: how, when and for what purposes should they
come into the picture?
V
E
R
How much are these consultations and investigations likely to cost me, taking
Medicare into account and any private insurance and possible eligibility for
Veterans Affairs assistance and Workers Compensation?
If I find a suspicious skin spot or lump how urgently should it be attended to?
Treatment
What can be done, should be done, or should not be done, by me or by whom?
If treatment is to be considered I would like to know the options and all about
them.
Can I be convinced that my general practitioner will advise me well, treat my
cancers well (if we both opt for him or her to carry out treatment at this stage),
and refer me, if and when appropriate, to someone else who can competently
deal with it?
Is there any way in which I can treat myself, or at least assist in the treatment?
Or things I should not do, perhaps exercise, shaving or using certain soaps or
creams?
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
105
15. QUESTIONS &
C O N C E R N S T H AT M I G H T A R I S E D U R I N G C O N S U LTAT I O N
Please tell me all about freezing, biopsy, excision and any other medical or
surgical procedures that may be on the cards and what they may mean to me by
way of preparation (including whether I should stop my medications),
hospitalisation, complications, time off work, after-care and cost. Please take into
account my frailties and my living arrangements.
Progress/Watchfulness
What next? What might I expect and what should I do in the future?
D
E
What do I need to watch and do immediately post-treatment? Might I need visits
to be arranged from a community nurse or a home helper?
Can I then expect this to be the end of the problem, or is it likely to come back
in the same place? Will there by any disfigurement? Is it likely to spread
elsewhere? How would I know if this happens and what might the outcome of
that be? Are there any tests that can be done to check for cure?
K
O
Do these cancers ever regress without treatment? Do they become more, or less,
frequent with advancing age? What measures should I take to prevent or deter
the problem developing in the future and in other areas?
When, how often and for how long should I attend my general practitioner or
specialist for review?
V
E
R
IN
GENERAL
Consumers want expertise, information, answers to questions, advice, shared
decision-making, actions to be taken on the basis of informed consent and
coordination and continuity of care. They place high value on being treated with
respect and patience, non-discrimination, privacy, confidentiality and, where
needed, emotional support, involvement of family and friends and access to
interpreters.
Attention to these concerns and desires of consumers can contribute to them
becoming cooperative, compliant, satisfied people, rather than reluctant, critical,
disgruntled patients—a happy outcome for the practitioner as well as the
consumer. However, consumers may need to be made aware that health-care
providers, too, have their own personal and professional concerns and desires,
that knowledge of skin cancers and resources for the provision of services are
limited and that probabilities and not certainties are generally the rule in matters
of health, especially in regard to predictions, the actual outcome of treatment
and prognosis.
It may also be helpful to consumers, and potential consumers, in this area of
health to refer them to one or other of the agencies linked to The Cancer
Council Australia, or even to provide them with appropriate pamphlets and other
material available from those sources.
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APPENDIX 1
APPENDIX 1
I N T E R N AT I O N A L U N I O N A G A I N S T C A N C E R ( U I C C ) T N M —
C L A S S I F I C AT I O N O F M A L I G N A N T T U M O U R S
Fifth Edition
1997 ed.
Carcinoma of the Skin
(excluding eyelid, vulva, and penis)
(ICD-O C44.0, 2-9, C63.2)
K
O
Rules for classification
D
E
The classification applies only to carcinomas. There should be histological
confirmation of the disease and division of cases by histological type.
The following are the procedures for assessing T, N, and M categories:
T categories
Physical examination
N categories
Physical examination and imaging
M categories
Physical examination and imaging
V
E
R
Regional Lymph Nodes
The regional lymph nodes are those appropriate to the site of the primary
tumour.
TNM Clinical Classification
T
TX
T0
Tis
T1
T2
T3
T4
Primary tumour
Primary tumour cannot be assessed
No evidence of primary tumour
Carcinoma in situ
Tumour 2cm or less in greatest dimension
Tumour more than 2cm but not more than 5cm in greatest
dimension
Tumour more than 5cm in greatest dimension
Tumour invades deep extradermal structures, ie cartilage, skeletal
muscle or bone
Notes: In the case of multiple simultaneous tumours, the tumour with the highest
T category is classified and the number of separate tumours is indicated in
parentheses, eg T2(5).
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
107
APPENDIX 1
N—Regional lymph nodes
NX
N0
N1
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis
M—Distant metastasis
MX
M0
M1
Distant metastasis cannot be assessed
No distant metastasis
Distant metastasis
pTNM Pathological classification
D
E
The pT, pN, and pM categories correspond to the T, N, and M categories.
K
O
pN0 Histological examination of a regional lymphadenectomy specimen will
ordinarily include 6 or more lymph nodes.
G Histopathological Grading
GX
G1
G2
G3
G4
Grade of differentiation cannot be assessed
Well differentiated
Moderately differentiated
Poorly differentiated
Undifferentiated
V
E
R
Stage grouping
Stage 0
Stage I
Stage II
Stage III
Stage IV
Tis
T1
T2
T3
T4
Any T
Any T
N0
N0
N0
N0
N0
N1
Any N
M0
M0
M0
M0
M0
M0
M1
S U M M A RY
Skin Carcinoma
T1
<2cm
T2
>2 to 5cm
T3
>5cm
T4
Deep extradermal structures (cartilage, skeletal muscle, bone)
N1
Regional
108
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
APPENDIX 2
APPENDIX 2
SOURCES
FOR
C A N C E R I N F O R M AT I O N
D
E
For information relating to cancer, contact the Cancer Information
Service (Cancer Helpline) 13 11 20
The Cancer Council ACT
159 Maribyrnong Avenue
KALEEN ACT 2617
Tel: (02) 6262 2222
Fax: (02) 6262 2223
Email: [email protected]
Website: www.cancer.org.au/act
Executive Officer: Joan Bartlett
The Cancer Council New South Wales
153 Dowling Street
WOOLLOOMOOLOO NSW 2011
Tel: (02) 9334 1900
Fax: (02) 9358 1452
Email: [email protected]
Website: www.cancercouncil.com.au
CEO: Dr Andrew Penman
V
E
R
K
O
The Cancer Council Northern Territory
Shop 3 Casi House
Vanderlin Drive
CASUARINA, NT 0810
Tel: (08) 8927 4888
Fax: (08) 8927 4990
Email: [email protected]
Website: www.cancercouncilnt.
citysearch.com.au
Executive Director: Brian McCarthy
The Cancer Council Tasmania
140 Bathurst Street
HOBART TAS 7000
Tel: (03) 6233 2030
Fax: (03) 6233 2123
Email: [email protected]
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
109
APPENDIX 2
Website: www.cancer.org.au/tas Executive
Director: Lawson Ride
The Cancer Council Victoria
1 Rathdowne Street
CARLTON VIC 3053
Tel: (03) 9635 5000
Fax: (03) 9635 5270
Email: [email protected]
Website: www.cancervic.org.au
Director: Professor David Hill
The Cancer Council South Australia
202 Greenhill Road
EASTWOOD SA 5063
Tel: (08) 8291 4111
Fax: (08) 8291 4122
Email: [email protected]
Website: www.cancersa.org.au
Executive Director: Assoc. Prof. Kerry Kirke AM
Cancer Foundation of WA
46 Ventnor Avenue
West Perth WA 6005
Tel: (08) 9212 4333
Fax: (08) 9212 4334
Email: [email protected]
Website: www.cancerwa.asn.au
Acting CEO: Phillip Schmaal
V
E
R
K
O
D
E
Queensland Cancer Fund
553 Gregory Terrace
FORTITUDE VALLEY QLD 4006
Tel: (07) 3258 2200
Fax: (07) 3257 1306
Email: [email protected]
Website: www.qldcancer.com.au
Exec. Director: Graeme Brien AM
110
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
APPENDIX 3
APPENDIX 3
M E M B E R S O F T H E AC N M A N AG E M E N T
C A N C E R W O R K I N G P A RT Y
OF
NON-MELANOMA SKIN
D
E
Professor Robin Marks AM
Dermatology (Chairman)
Dr Jill Ainslie
Radiotherapy
Dr Philip Bekhor
Dermatology
Professor Adele Green
Epidemiology
K
O
Mr Michael Henderson
Dr Dudley Hill
A/Professor John Kelly
A/Professor Steven Kossard
Mr Allan MacLeod
V
E
R
Professor John Murtagh AM
A/Professor Ian Olver
Dr Robert Sinclair
Ms Margaret Staples
Professor David Weedon AO
Surgical Oncology
Dermatology
Dermatology
Dermatopathology
Plastic Surgery
General Practice
Medical Oncology
Dermatology
Epidemiology
Pathology
Emeritus Professor Malcolm Whyte AO Consumer
Emeritus Professor Tom Reeve AC CBE Executive Officer, Australian Cancer
Network (Convenor)
Special thanks to:
James R.G. Butler, PhD
Senior Fellow (Health Economics) & Deputy Director
National Centre for Epidemiology and Population Health (NCEPH)
The Australian National University, Canberra
for his contribution of the Economic chapter to these Guidelines.
and
Mrs Christine Vuletich, who has shown infinite patience in responding to all
requests in preparation, alteration and finalising the manuscript.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
111
A B B R E V I AT I O N S
A B B R E V I AT I O N S
BCC
Basal cell carcinoma
C
Curettage
DFTC
Double freeze-thaw cycle
HPU
Human papilloma virus
HTT
Halo thaw time
IEC
Intra-epidermal squamous cell carcinoma (Bowen’s disease)
KA
Keratoacanthoma
M
Margin treated beyond clinically visible tumour
mm
Millimetres
NMSC
Non-melanoma skin cancer
OST
Open spray technique with liquid nitrogen
PDT
Photodynamic therapy
RT
Radiotherapy
S
Shave excision
V
E
R
K
O
SCC
Squamous cell carcinoma
SFTC
Single freeze-thaw cycle
SK
Solar keratosis
SPF
Sun protection factor
TCN
Themocouple needle
TTT
Total thaw time
UVA
Ultraviolet radiation (320–400 nm)
UVB
Ultraviolet radiation (290–320 nm)
XP
Xeroferma pigmentosum
D
E
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
113
G L O S S A RY
G L O S S A RY
Basosquamous or Meta typical
Terms used for basaloid tumour which show evidence of squamatisation.
These tumours should be viewed as equivalent to squamous cell
carcinoma.
D
E
Bowen’s disease
A well-demarcated erythematous scaling plaque that histologically
demonstrates full thickness intraepidermal keratinocyte dysplasia.
Bowenoid solar keratosis—see chapter 4
A pathological description of a solar keratosis which shows full thickness
keratinocyte dysplasia, rather than just keratinocyte dysplasia at the basal
layer of the epidermis.
K
O
Brachytherapy
A method of giving high dose radiotherapy to a localised area by placing
the source of the radiation close to the lesion being treated.
V
E
R
Chemoprophylaxis
The use of pharmacological products to prevent disease, in this case, skin
cancer.
Cryotherapy
The use of very low temperature to treat skin cancer and related
dysplasias. Liquid nitrogen is used most commonly, having a temperature
of –190º C.
Curettage
The use of a sharp curette to remove skin cancer or related dysplasias
from the skin under local anaesthetic.
Deep radiotherapy
Radiotherapy that penetrates deeply through the skin and affects tissues
below it.
Desmoplasia
Tumours which induce sclerotic and extensive fibrous stroma that may be
mistaken for a scar. The tumours often present as infiltrative cords of cells that
may have ill defined boundaries and are prone to recurrence. Both squamous
cell carcinoma and basal cell carcinoma may produce this pattern.
Diathermy treatment
The use of a direct current electrical apparatus to ablate skin cancer and
related dysplasias.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
115
G L O S S A RY
Electrodessication
Use of diathermy treatment to ablate skin cancer and related dysplasias.
Fine needle aspiration cytology
The use of a fine needle to biopsy a tumour or lymph node to obtain cells
for cytological confirmation of diagnosis.
Imiquimod
An immune response modifier that induces cytokines related to cell
mediated immune responses including interferon-α (IFN-α), IFN-γ, and
interleukin.
D
E
Interferon
A naturally occurring cytokine having antiviral, antimicrobial, anti-tumour
and immuno-modulatory actions.
K
O
Laser therapy
The use of laser technology to ablate skin cancer and related dysplasias.
Megavoltage
The use of very high voltage electric current to create high energy
radiotherapy that can be deeply penetrating through tissues.
V
E
R
Melanocyte stimulating hormone
Melanocyte stimulating hormone is derived from the pituitary gland and
keratinocytes amongst other cells and is capable of stimulating melanin
production by melanocytes to increase pigmentation.
Micronodular
A histopathological term describing a growth pattern of basal cell
carcinoma in the dermis.
Mohs’ surgery
Surgery where microscopic confirmation of complete tumour clearance is
achieved at the time of the operation with a pathologist using a specialised
sectioning technique to examine microscopically the tissue removed to
confirm complete tumour clearance. Once this is confirmed, the wound is
closed.
Morphoeic
Morphoeic means scar like and is a term used to describe one of the
clinical variants of BCC.
p53 gene
A tumour suppressor gene. Abnormalities of this gene leading to
dysfunctional P53 protein have been demonstrated in cancers of many
different types, including non-melanoma skin cancer.
116
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
G L O S S A RY
Perineural
Perineural applies to the invasion of a tumour along, but not in, a nerve.
Photodynamic therapy
The use of light, plus a photo-absorbent porphyrin related chemical, to
destroy skin cancer and related dysplasias.
Poorly differentiated
Tumours in which products of differentiation such as keratin, desmosomal
attachments or glandular differentiation are poorly expressed.
Immunohistochemistry techniques for keratin subsets are often used to
identify such tumours.
D
E
Radiotherapy
Radiotherapy (RT) is the use of ionising radiation to treat cancer and allied
disease.
K
O
Solar keratosis
A solar keratosis is clinically an erythematous scaling lesion in the heavily
light exposed areas of skin that histologically has keratinocyte dysplasia at
the basal layer of the epidermis.
SPF 14
SPF stands for Sun Protection Factor, a laboratory derived rating system of
sunscreens active in the UVB range. The SPF number is the multiple by
which a dose of ultraviolet radiation which causes minimal erythema in
human skin needs to be increased to cause minimal erythema in the same
person when the tested sunscreen has been applied to their skin prior to
exposure. For example, when an SPF 14 sunscreen is correctly applied in
the laboratory, the dose of radiation necessary to cause minimal erythema
through the sunscreen is 14 times the dose required to produce minimal
erythema in the skin without any screen applied.
V
E
R
Superficial radiotherapy
Superficial applies to radiotherapy that is absorbed and has its major effect
within the skin and not the tissues deeper to it.
UV
UV (ultraviolet) is the solar spectrum reaching the Earth’s surface in the
wavelength range of 290–400nm.
UVA
Ultraviolet radiation in the wavelengths 320–400nm.
UVB
Ultraviolet radiation in the wavelengths 290–320nm.
Non-Melanoma Skin Cancer: Guidelines for treatment and management in Australia
117
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