1. health and fitness
2. disease
3. cancer

Cancer
Treatment
Reviews
Spontaneous
(1996)
22, 395-423
regression
of cancer
Rose J. Papac
Section of Medical Oncology, Yale University School
333 Cedar Street, New Haven, CT 06520, U.S.A.
of Medicine,
introduction
Spontaneous
regression of cancer is one of the most fascinating
phenomena
observed in medicine. It is generally regarded as inexplicable,
although there
are now some laboratory studies of regressed or regressing tumours, as well
as new theoretical possibilities about mechanisms.
In this review, the historical
background,
clinical features and possible mechanisms
are discussed. The
clinical aspects of the malignancies
most often reported to undergo spontaneous
regression,
namely renal cell carcinoma,
neuroblastoma,
carcinoma
of the
breast, malignant
melanoma
and leukaemias/lymphomas,
are reviewed.
The prevalent view regarding the mechanism
for spontaneous
regression is
the involvement
of immunological
factors in the host. Other mechanisms
include hormonal
changes, tumour
necrosis, trauma and changes in blood
supply. Recent. reports suggest other mechanisms
such as apoptosis
and
differentiation
to a benign tumour.
Decreased telomerase
activity has been
reported
in neuroblastomas
that regress, and hypomethylation
of DNA in
retinoblastoma
is a possibility. A role for cytokines and/or growth factors is
also discussed. The significance of spontaneous
regression is the demonstration
of endogenous
control of neoplastic growth.
Spontaneous
regression
of cancer is defined as the complete
or partial
disappearance
of malignant
tumour in the absence of therapy that is capable
of inducing anti-neoplastic
effects. Most patients ultimately relapse, so it is not
usually associated with cure of the malignant
disease.
The existence of spontaneous
regression is often questioned;
indeed, review
of the literature
reveals reported
cases which do not represent
malignant
disease, instances in which documentation
of metastases is questionable
and
some reported cases in which therapy may have played a role. In 1966, Everson
and Cole published a classic monograph
on this topic which included 176 welldocumented
cases of spontaneous
regression of cancer published from 1900
until 1964, and listed criteria for the diagnosis
(1). These are: documented
histologic
regression
of biopsy-proven
metastases;
radiologic
regression
of
0305-7372/96/060395+29
0 1996
$12.0010
395
W.B.
Saunders
Company
Ltd
396
R. J. PAPAC
presumptive
neoplastic disease; and regression of metastatic tumour following
therapy generally deemed ineffective.
The actual incidence of spontaneous
regression is unknown but clinical trials
which include an untreated
cohort of cancer patients provide some data in
several malignant diseases. There is the possibility that the phenomenon
occurs
more frequently
than can be recognized clinically. Over a 30-year interval, the
author has observed eight cases and is aware of two more. These have been
reported
briefly and are the stimulus for a review of this topic (2). Recent
literature, as a result of the advances in the biology of cancer, provides greater
insight into potential mechanisms
of spontaneous
regression.
Historical
background
Boyd suggested
that tumours
that regressed spontaneously
could be called
Saint Peregrine tumours (3). Near the end of the 13th century, Saint Peregrine,
a young priest, developed
a large bone tumour requiring amputation.
On the
night preceding surgery, he prayed intensely and, it is alleged, awoke without
any trace of the tumour. In 1345, aged 80 years, he died without recurrence of
the tumour.
Anecdotal cases of spontaneous
regression
have appeared in the medical
literature since the early 19th century (4). The first case of complete regression
of malignant
melanoma
was reported
in 1899 (5). In 1901, William Osler
published an article entitled ‘The medical aspects of carcinoma of the breast
with a note on the spontaneous
disappearance
of secondary
growths’
(6).
The second of Osler’s cases was desperately
ill, bed-ridden
with metastatic
involvement
of the spine, right eye and opposite breast. Two years later when
Osler returned from England, he noted ‘she drove a mile and a half to the
station to meet me and drove me to the station on my return’. Osler commented
that the phenomena
‘presented by these cases are among the most remarkable
which we witness in the practice of medicine..
. and illustrate the uncertainty of
prognosis and the truth of the statement that no condition, however desperate, is
quite hopeless’.
The first large series of cases of spontaneous
regression
of cancer was
reported by Rohdenberg
in 1918 (4). Of a total of 302 collected cases, only 70
were reports in which either temporary
or permanent
regression of tumour
growth was subjected to rigid scrutiny; the others could have been diagnostic
errors. The greatest number of regressions
followed
incomplete
removal of
the tumour or an acute febrile process.
The spontaneous
regression of neuroblastoma
was recognized and reported
by Cushing and Wollbach in 1927 (7). Subsequent
reports by Dargeon, Bodian,
Koop eta/. and Farber provided illustrative cases (8-l 1). Spontaneous
regression
of pulmonary
metastases
from renal cell carcinoma
was first reported
by
Bumpus in 1928 (12).
In 1966, Boyd and Everson and Cole published
monographs
on the
spontaneous
regression of cancer (1, 3). In Everson and Cole’s review of the
published cases from 1900 until 1964, cases of leukaemia and lymphoma
were
excluded due to the variability
in natural history of these diseases (1). The
SPONTANEOUS
Table
1.
Frequency
of site
Miscellaneous
Lymphoma
Leukaemia
Neuroblastoma
Retinoblastoma
Kaposi’s
sarcoma
Haemangioendothelior
Hodgkin’s
disease
Lymphosarcoma
Malignoma
of sclera
Sympathoblastoma
Osteoblastoma
Merkel’s
cell tumour
Primary
of cancer
in spontaneous
(n=211)
ma
unknown
regression,
397
1960-87
(n=564)
(n=116)
68
22
16
4
2
2
1
(n=8:)
69
6
4
4
1
(n=lO)
(n=34)
Head and neck
Adenoid
cystic
Larynx
Pharynx
Other squamous
carcinomas
10
10
10
3
1
Endocrine
Adrenal
Thyroid
(n=2)
Brain
Glioma
Astrocytoma
lntrasellar
(n=4)
tumour
with
OF CANCER
Genitourinary/breast
Hypernephroma
Breast
Testis
Bladder
Urethra
Uterus
Endometrium
Ovary
Skin
Malignant
melanoma
Bowen’s
disease
(vulva)
Basal cell carcinoma
Bowen’s
disease
(penis)
Epithelioma
68
53
41
33
7
2
2
Gastrointestinal
Colon/rectum
Stomach
Liver
Pancreas
Intestine
Reprinted
REGRESSION
permission
from
1
1
Respiratory
Lung
Bronchial
2
1
1
Soft tissue
and
Chondrosarcoma
Osteosarcoma
Sarcoma
Challis
and
Stam
(n=
carcinoma
13)
5
4
1
cell
3
(n=25)
18
7
bone
(n=5)
1
3
1
(14).
majority of cases of spontaneous
regression occurred in fourtumour
types; renal
cell carcinoma,
choriocarcinoma,
neuroblastoma
and malignant
melanoma.
Boyd reported
61 cases of spontaneous
regression,
but did not report
instances of regression in lymphomas
or leukaemias (3). The two most common
tumour types reported were retinoblastoma
and carcinoma of the breast; there
were no cases of renal cell cancer nor choriocarcinoma.
In 1974, the National Cancer Institute sponsored a conference on spontaneous
regression
of cancer which presented
a broad perspective
of the clinical
occurrence
and possible
mechanisms
(13). In addition
to solid tumours,
lymphomas
and leukaemias were included in the analysis.
In 1990, Challis and Stam published a review of cases from 1900 until 1987
(14). In comparing
frequency of regression by site of cancer from 1900 to 1965
with the period of 1966-87, lymphoma
is reported in the latter group as often
as renal cell carcinoma (Table 1). Challis and Stam comment
in particular on
the paucity of discussion in the literature regarding mechanisms.
In 1993, O’Regan and Hirshberg
published
an annotated
bibliography
of
spontaneous
regression
which encompasses
benign as well as malignant
disorders (15). It is noteworthy
that over half the cases were reported following
the review of Everson and Cole (I).
398
Fi. J. PAPAC
Table
Number
2.
Incidence
of spontaneous
of patients
Number
1139
571
73
91
110
3
4
5
4
4
regression
of regressions
in selected
(%)
(0.3)
(0.8)
(7)
(4.4)
(3.6)
series
of renal
cell carcinoma
Reference
Bloom
(25)
Snow
and Schellhammer
Oliver
et a/. (27)
Marcus
et al. (23)
de Riese et al. (19)
(26)
Clinical features
Collectively, from the review of O’Regan and Hirshberg, the five most common
tumours
types to undergo
spontaneous
regression
in order of number
of
reports are renal cell carcinoma,
lymphoma
and leukaemias,
neuroblastoma,
carcinoma
of the breast and melanoma
(15). The circumstances
under which
spontaneous
regression occurs differs in various neoplastic diseases, so it is
of interest to review the clinical aspects of spontaneous
regression
in these
diseases.
Renal cell carcinoma
Renal cell carcinoma
accounts
for the largest number
of patients
with
spontaneous
regression,
although
the histologic
confirmation
of metastatic
disease is in the range of 20-25% (16-18). In 1986, Kavoussi et al. reported
that 20% of all cases of spontaneous
regression of renal cell carcinoma
had
acceptable
histologic
confirmation
(16). In recent reports, there is a trend
towards better radiologic
and histologic confirmation
of metastatic
disease.
Since 1990, there have been six reports in the English literature, and of the 10
cases cited, nine met the criteria for spontaneous
regression. Five of the nine
cases had biopsies of metastases (17-23).
Merz et a/. observed ‘pseudoregression’
of pulmonary
lesions in a chest
radiograph
of a patient with renal cell carcinoma.
Computerized
tomography
(CT) demonstrated
disappearance
of the mass, presumed to be an artifact (24).
In general, the recently reported
cases have more stringent
standards
for
radiologic
diagnosis
of metastatic
disease, namely CT, magnetic
resonance
imaging (MRI) and/or lung tomograms,
as noted in a recent report from the
National Cancer Institute of cases of untreated
renal cell carcinoma
patients
who developed spontaneous
regression prior to the institution of therapy (23).
The incidence of spontaneous
regression in renal cell carcinoma is low (Table
2) (19,23, 25, 27). DeRiese et al. reported four cases of spontaneous
regression
in 110 cases of metastatic renal cell carcinoma. One of their cases was treated
with tamoxifen to complete disappearance
of tumour so that the role of therapy
is not entirely excluded; nevertheless,
the patient remained disease-free for 5
years which is a most unusual outcome for tamoxifen
treatment
of metastatic
renal cell carcinoma (19).
Males predominate
in reports of spontaneous
regression
of renal cell
SPONTANEOUS
REGRESSION
OF CANCER
399
carcinoma
by a ratio of 3:l. The duration of regressions
has ranged from 3
months to 20 years.
In over 90% of cases, pulmonary
metastases are the site of spontaneous
regression
(28). There are four reports of well-documented
regression
of
osseous lesions (22). Regression of other sites such as skin, liver, intestine and
node1 areas has also occurred.
Most frequently,
spontaneous
regression
has followed
nephrectomy,
although
regressions
are reported to occur prior to a planned nephrectomy
and in the absence of surgery for the primary tumour (1, 13, 14, 23, 28, 29). In
his review of 67 reported
cases of spontaneous
regression
of renal cell
carcinoma
(as well as two of his own cases), Fairbanks noted that 57 cases
had had nephrectomy;
five experienced
regression prior to nephrectomy
(28).
Everson and Cole noted that 22 of 31 renal cell carcinoma cases experienced
regression following
nephrectomy
(I).
There are a few instances in which regression followed radiotherapy
to the
primary tumour or to a dominant tumour site such as a large groin mass (28,
30). Vascular embolization
of the tumour
is reported to be associated with
spontaneous
regression of metastatic disease, although
it has been followed
by nephrectomy,
and the contribution
of the embolization,
as distinct from the
nephrectomy,
is unclear (31, 32). One of the cases reported by Marcus et al.
experienced
a subphrenic
abscess in the postoperative
period (23). There is a
single instance of tumour regression following
plasma infusion from a family
member who had experienced
a spontaneous
regression (33).
Post mortem examination
in patients who have demonstrated
spontaneous
regression
of pulmonary
metastases
often shows no evidence of residual
tumour.
In cases who have not had nephrectomy,
a residual renal mass,
described
as fibrotic with necrosis or some degenerating
cells resembling
tumour, is reported (34).
Malignant
melanoma
Cutaneous
melanomas
are reported to undergo spontaneous
regression in up
to 30% of cases (35-37). In thin lesions, the occurrence ranges from 29 to 67%
of patients. In a recent review of 563 primary cutaneous melanomas,
Blessing
and McLaren observed regression in 46% of thin lesions (less than 1.5mm),
32% of intermediate
(1.5-3 mm) lesions, and 9% of thick lesions, i.e. >3 mm
(37). Regression was observed more frequently
in superficial spreading lesions
and those on the trunk or lower limb. From the Sydney melanoma
unit, 28
patients with a thin primary lesion and concurrent
regional node involvement
showed regression in all 28 lesions (38). Patients with Stage I disease had over
60% incidence of regression. Of 103 patients with thin lesions followed at the
University of Illinois, 29% showed evidence of partial regression (39).
The clinical appearance
of regression is suggested
by the development
of
white, grey-white
or pink-white areas which are areas of depigmentation
(40).
Besides vitiligo,
other cutaneous
changes
associated
with regression
in
malignant
melanoma
include inflammatory
changes and dermatomyositis
(41,
42).
The histologic
appearance
of regression
has been characterized
as
400
R. .I. PAPAC
degeneration
of melanoma
cells with a dense lymphohistiocytic
infiltrate,
pigment-laden
macrophages
and, in late stages, increased vascularity
in the
papillary and reticular dermis with an atrophic epidermis (37, 38, 43). Fibrosis
in the papillary dermis is also described.
The clinical significance
of regression in a primary melanoma
is uncertain,
although some authors think it is associated with a poor outcome. Shaw et a/.
observed recurrent melanoma
in as many Stage I patients who had regression
as those without evidence of regression (38). Sondergaard
and Hou-Jensen
reviewed 496 cases of Stage I primary cutaneous
melanoma,
and found that
the IO-year survival was 95% for patients without
regression,
in contrast to
79% for patients who had experienced
regression (36). Ronan et al. observed
no metastases in a group of 73 patients without regression of a thin primary
melanoma,
while 20% of patients who developed
regression of a thin primary
melanoma
developed
fatal visceral metastatic
disease in 3-48 months (39).
Blessing and McLaren found that seven of 110 patients with thin melanomas
exhibiting regression developed metastases; this was not statistically significant
(37). Cooper and Wanebo found that thin melanomas
of the extremity were
biologically
favourable
and that foci of regression did not have any impact on
outcome (43). A study by Paladugo and Yonemoto
concluded that regressive
changes
indicated
a propensity
for metastatic
disease in thin malignant
melanomas;
this analysis included only 11 lesions with regression as compared
to 25 without
regression (44). Multiple logistic regression
analysis involving
1015 patients with primary cutaneous
melanoma
failed to identify regression
as a significant
prognostic factor (35).
Melanomas
may initially present as metastatic disease without an identifiable
primary site (45, 46). In such cases, which constitute about 5-10% of all cases
of metastatic
melanoma,
the assumption
is made that the primary site has
undergone
complete regression. Nathanson
has suggested that the criteria for
spontaneous
regression in such instances should be: (I) a clinical history of a
pigmented
lesion situated in an area drained by tumour-involved
lymph nodes;
(2) the absence of any other primary lesion; and (3) the presence of atypical
pigmented
or depigmented
change in the skin at the site of the untreated
possible primary lesion-histologic
changes in the excised site of such a
possible primary lesion which support the clinical evidence
of regression
of primary malignant
melanoma;
and (4) the absence, histologically,
or a
configuration
or primary malignant melanoma with or without the presence of
melanoma
cells in atypical distribution
in the dermis or subcutaneous
tissue
at the site of the lesion (40). In 1976, Nathanson
reported 32 such cases in the
medical literature and added one of his own experience (40). There have since
been published
more than twice the number of cases cited by Nathanson
(44-49).
Regression of metastatic
lesions from malignant
melanoma
is uncommon;
the majority of cases involve nodal or subcutaneous
deposits (48, 49). From
eight different series of patients which involved 4541 cases with metastatic
melanoma,
Nathanson found 0.22% had spontaneous
regression, although in
individual reports, it varied from 0.08 to 0.71% (40). Visceral deposits are rarely
reported to undergo
regression.
When this develops,
regression
has most
SPONTANEOUS
REGRESSION
OF CANCER
401
frequently
been reported
in pulmonary
metastases;
other sites include liver,
brain, intestines and even osseous lesions (40, 50).
Regression of ocular melanomas
is rarely reported, but histological changes
are similarto those described for cutaneous melanomas (51,521. The occurrence
of regression of metastatic lesions from an ocular primary melanoma
is about
10% (40).
The majority of patients who developed
regression of primary melanoma
are men; in regression involving metastatic disease, there is an almost equal
representation
of the sexes (46, 47, 49). Nathanson
suggested that about 40%
of patients who had spontaneous
regression of metastatic disease would be
cured (40). This was based upon the proportion
of patients free of disease or
dead of other causes at 5 years follow-up.
The phenomenon
of late recurrence
in malignant melanoma suggests that a better definition of cure would be death
without disease. In the author’s experience, a dramatic instance of spontaneous
regression
of metastatic
melanoma
was of 8 years duration
with relapse
followed by death. Similar cases of spontaneous
regression followed by relapse
at intervals from 6 to 12 years following
spontaneous
regression are reported
(47, 50). Few cases have had autopsy confirmation
of disappearance
of
metastases.
There have been several clinical settings in which regression of malignant
melanoma
have occurred (1,401. For the majority of cases, regression has been
linked to a surgical procedure to the primary or a metastatic lesion. In some
instances, infection in proximity to the tumour has been noted. Irradiation of
a metastatic site remote from the regression lesion has been cited as a possible
factor. Several instances
of spontaneous
regression
developed
following
termination
of pregnancy.
Regression
has been observed following
blood
transfusion,
plasma infusion from a patient who had had a spontaneous
regression, and following
anti-rabies vaccine.
Neuroblastoma
Neuroblastoma
is cited as a tumour
with well-documented
occurrence
of
spontaneous
regression, although there is considerable
debate regarding the
actual incidence. Evans et a/. found an 8% incidence (53). Mass screening data
from a Danish survey found 2% of cases of neuroblastoma
had well-documented
spontaneous
regression (54). However, the incidence may well be higher since
the survey found an increased incidence from 1943 until 1980with an unchanged
mortality
rate. Moreover, the incidental finding of neuroblastoma
at autopsy
in infants is much more frequent than the clinical detection (54).
The patients likely to develop spontaneous
regression of neuroblastoma
are
predominantly
infants (53-55). In Evans et al.‘s review of this topic, 65% of the
cases were less than 6 months of age when the diagnosis was established
(53). The clinical presentation
of patients who have developed
spontaneous
regression is mainly Stages II and IVS (53, 55, 56). Stage II patients often have
a partial resection of the tumour which may be followed by regression of the
residual disease. Stage IVS is of interest since this was described to identify
patients who had disseminated
disease but a favourable prognosis (57). Patients
typically have involvement
of the skin, liver and bone marrow, and are frequently
402
R. J. PAPAC
under the age of 1 year. Recent reports suggest that Stage IVS is a more
heterogenous
disease than generally recognized (58). The site of the primary
tumour
does not seem to be a significant
factor, although
the size may be
important
since the regressions in Stage II seem associated with little residual
tumour,
and the IVS cases of regression
have had small primary tumours.
Regression rarely develops in patients with osseous metastases.
Biologic features of the tumour have been examined to provide data which
may assist in determining
whether
it is possible
to define a type of
neuroblastoma
which
will
undergo
spontaneous
regression.
N-myc
amplification,
expression
of the TRK gene, DNA ploidy, the presence of
chromosome
Ip abnormalities,
the numbers of argyrophilic
nucleolar organizer
regions, serum neuron-specific
enolase and ferritin levels have had prognostic
importance
(59-62). There is not a consistent pattern of these biologic features
that describes patients who experience spontaneous
regression, although the
lack of N-myc gene expression
or amplification
is considered
favourable,
as
are high levels of expression
of the TRK gene, a low ferritin and serum
neuron-specific
enolase, and a hyperdiploid
karyotype. A consistent pattern of
argyrophilic
nucleolar organizer regions, determined
by a silver colloid tissue
staining
procedure,
is reported
to suggest a prediliction
for spontaneous
regression.
The histologic
findings
in regression
of neuroblastoma
include
total
disappearance
of the tumour,
a fibrotic
scar on maturation
to a benign
ganglioneuroma,
an observation
described by Cushing and Wollbach (7). In
the review by Everson and Cole of 29 cases, five showed
maturation
to
ganglioneuroma
(1). A subsequent
case report described a patient who had
subcutaneous
nodules which were biopsied serially. At 4.5 months of age,
neuroblastoma
was present; biopsies at 16, 36 and 76 months of age showed
ganglioneuroma
and, in some areas, only fibrotic scar. At 3 years of age, there
was a persistent left suprarenal mass which was removed, showing no viable
tumour
but central necrosis and calcification,
demonstrating
a spectrum
of
histologic findings in the same patient (63). There are reports in which waxing
and waning of palpable tumour without therapy are documented
with ultimate
biopsy evidence of transformation
to ganglioneuroma
(53, 63).
Survivals of patients who have had spontaneous
regression vary but are
generally
of long duration
(53, 54, 64). In a recent study of Stage IVS
neuroblastoma,
eight of 18 patients without
life-threatening
symptoms
were
followed
until disease progression
developed
(60). Eight patients developed
spontaneous
regression
without
treatment
and of these eight, one patient
relapsed 10 months later and died despite therapy. The other seven cases were
alive at follow-up
ranging from 26 to 76 months. While relapse may develop
following
spontaneous
regression, it is considered
a rare development
(63).
Carcinoma
of the breast
In the anecdotal reports of spontaneous
regression in the 19th century, breast
cancer was cited (4). One involved a patient whose breast cancer showed
change relative to the onset of menses, and another patient whose tumour
decreased at the menopause.
In the review of Everson and Cole, there were
SPONTANEOUS
Table
Number
3.
Incidence
of spontaneous
of patients
140
31
83
Number
18 (12.9)
5 (16.3)
19 (23)
REGRESSION
OF CANCER
regression
in low-grade
of regressions
(%)
403
lymphomas
Reference
Gattiker
et al. (70)
Mead et al. (7 1)
Horning
et al. (72)
only six cases of breast carcinoma (1). Lewison observed 12 cases of partial or
temporary
regressions
of breast cancer over a 25-year period (65). In 1982,
Ross et al. reported follow-up of a striking instance of spontaneous
regression
of breast carcinoma,
and reviewed all reports published in English since 1900
(66). Only 13 met the criteria of Everson and Cole (1). By 1987, Challis and
Stam found a total of 22 reported cases (14).
The spontaneous
regression is most frequently
related to onset of menses
or to menopause,
and in some cases to development
of ovarian metastases
(1, 66). Regression
of lung metastases
occurred
in one case following
mastectomy
(67). It is of interest that Ross et al. noted that 11 of the 13 cases
were pre-menopausal
when the spontaneous
remission occurred (66).
Spontaneous
regression has involved primary breast tumours which were
untreated and observed to regress, metastatic lung, subcutaneous
and osseous
lesions, malignant
pleural effusions
and ascites (I, 6, 65-68). Regression
involving
an untreated
primary breast carcinoma
has been reported
for a
duration
of 17 years (68). In most cases, spontaneous
regression
of breast
cancer is followed by relapse of the disease (65).
Haematoiogic
malignancies
The haematologic
malignancies,
although
cited by Rohdenberg,
were not
included in several subsequent compilations
of cases of spontaneous
regression
(I, 3, 4). In 1976, Wiernik tabulated
the cases of lymphoma,
leukaemia and
plasma cell dyscrasias, and presented an analysis of clinical features (69). In
the 1990 review of Challis and Stam, lymphomas
were as frequently
reported
as cases of renal cell carcinoma (I 4). There were 53 cases of leukaemia, a number
exceeding that of neuroblastoma
and breast carcinoma.
Other haematologic
malignancies,
namely multiple myeloma,
Waldenstrom’s
macroglobulinemia
and myelodysplastic
syndromes,
are reported
to undergo
spontaneous
remission, but the majority of cases of remissions of haematologic
malignancy
are lymphoma
and leukaemia cases (69).
Malignant
lymphoma.
Since 1980, three series of low-grade lymphomas
have
documented
the incidence of spontaneous
regression
in these lymphomas
(Table 3) (70-72). Gattiker eta/. observed 18 of 140 patients who had regressions
associated with either no treatment
or no treatment
for 4 or more years in
association with stable disease that then regressed (70). Of these, 4.7% were
complete regressions. In a randomized trial of low-grade lymphomas
in which
patients with no treatment were compared to those with therapy, spontaneous
regression was noted by Mead et al. in five of 31 patients who were untreated;
404
R. J. PAPAC
two had complete remissions (71). Horning and Rosenberg reported that 23%
of low-grade
lymphomas
in a Stanford
series developed
spontaneous
regression
(72). In the low-grade
lymphomas,
untreated
cases have been
observed to demonstrate
fluctuations
in nodal size and/or organomegaly.
The duration of spontaneous
regression reported by Mead et al. ranged from
13 to 36+ months; in the retrospective
review of Gattiker et al., the median
duration
of regression
in 11 patients who had either complete
or partial
regression was 1.2 years with a range of 2 months to 12 years (70, 71). Of the
five patients who had complete regressions, all but one relapsed. The survival
of patients who experienced
regressions was significantly
longer than that of
patients without
such regression.
In the Stanford
experience,
the median
duration
of regression varied from 4 to 72+ months with median duration
from 6 to 15 months, depending
upon the histology (72). The sample size in
the follicular, mixed and small lymphocytic
types is very small (three cases in
each group). It is noteworthy
that only six of the 19 patients with regression in
this series showed subsequent
disease progression,
and of these, only three
required therapy.
The disease sites which demonstrated
spontaneous
regression in low-grade
lymphomas
include both peripheral and visceral nodal masses, skin lesions,
liver, spleen, pleural effusion and ascites (70-72). In two cases, there was
disappearance
of peripheral blood and bone marrow lymphocytosis.
Histologic features of cases who had spontaneous
regression were assessed
in five patients by Strickler et al. and compared
to six patients with the
same type of lymphoma
who had progressive
disease (73). In patients with
spontaneous
regression, there were significantly
more T-helper cells in the host
infiltrate
than in the control patients. Otherwise
there were no significant
differences
in cytotoxic/suppressor
T-cells, macrophages,
or other lymphoid
populations
determined
by immunophenotyping.
In high-grade
lymphomas,
the occurrence
of spontaneous
regression
is
reported less frequently
(70). There are a number of isolated case reports of
large cell diffuse lymphoma
that are quite typical of the disease, namely
involvement
of peripheral and visceral nodal areas with hepatosplenomegaly
and an aggressive clinical course (74-76). Spontaneous
regression has generally
developed in the setting of a febrile illness. In one patient, remission developed
twice upon treatment
with vitamin C in high dosage with a survival of 17 years
from diagnosis (77).
The occurrence of spontaneous
regression in high-grade lymphomas
is noted
in several histologic types and also in specific disease sites. From a study of
41 patients with Ki-1 positive large cell lymphoma,
three adults develped
spontaneous
regression of 9,27 and 120 months duration (78). In two instances,
regression
involved
cutaneous
lesions; in the third patient, nodal disease
regressed. Several case reports of spontaneous
regression of this lymphoma
have also been reported; one in a paediatric patient and another in a patient
with AIDS (79-81).
Burkitt’s lymphoma
has been reported to undergo spontaneous
regression
(82-84).
Burkitt and Kyalwazi observed
four cases; two were complete
regressions
and two were partial (82). One of the latter received medication
from a witch doctor. One of Burkitt’s cases was included in a review by Ziegler
SPONTANEOUS
REGRESSION
OF CANCER
405
who added two additional cases (83). One remission was noted to be of 8 years
duration, and two cases experienced a 1 year remission. One remission followed
measles rash and measles vaccine. In a recent case report of Burkitt’s lymphoma,
remission developed
in association with herpes zoster infection (84).
Other instances of regression of high-grade
lymphoma
include a small noncleaved cell, non-Burkitt’s
lymphoma
involving tonsil and cervical nodes in a
12-year-old
boy following
biopsy with a 3-year follow-up
(85). Similarly,
regression of diffuse large cell lymphoma
involving the tonsillar region and
left neck occurred in a 54-year-old woman prior to the institution
of treatment
(74). This regression persisted for up to 4 years on follow-up.
Cases of gastric lymphoma,
large cell type, are reported in which endoscopic
biopsy revealed the diagnosis, and subsequent
gastric resection showed no
evidence of tumour (86). The only therapy was the administration
of the H-2
histamine antagonist cimetidine, suggesting that the eradication of Helicobacter
pylori was not a factor in these regressions.
Several reports of spontaneous
regression of intra-cerebral
lymphoma include
instances of CT scan evidence of change in size of masses that ultimately
progressed and, on biopsy or at autopsy, were found to be lymphoma
(87, 88).
The regressions
are generally of l-4 months duration and partial in extent.
Whether these represent true regression or changes due to associated necrosis,
infarction
or haemorrhage
is unclear. These cases were not in AIDS-related
lymphomas.
There are, however, several cases of regression of lymphomas
occurring in AIDS patients (80, 89-91). In these cases, infections were present
at the time of spontaneous
regression. Other instances of regression of highgrade lymphoma
have included
angiocentric
cutaneous
T-cell lymphoma
(characterized
by immunophenotyping)
with a complete
regression
after
therapy was declined (92).
Adult T-cell leukaemia/lymphoma
is another aggressive
disease that has
shown spontaneous
regression (93-95). In the cases cited, the diagnosis has
been well established
by immunophenotyping,
and in two instances by study
of HTLV-1 proviral DNA. In a series from Japan of 82 patients, three (3.7%)
experienced
spontaneous
regression of 3, 12 and 72 months duration (94). An
interesting feature of this report was the gene analysis of HTLV-1 proviral DNA
and T-cell receptor re-arrangement
studies. In one patient, the monoclonal
integrated
band of HTLV-1 proviral DNA and re-arranged
band of TCT-P gene
were at the same positions before regression and after recurrence; in the other
patient, they were at different positions before regression and after recurrence.
The development
of spontaneous
regression in lymphoma
is sometimes
of
long duration and has most frequently
followed a febrile illness, sometimes a
viral infection, and occasionally
has developed after biopsy (69).
Leukaemia.
Spontaneous
remission of both chronic and acute leukaemias has
been described (69). Reports prior to the past three decades often do not meet
either the standards for diagnosis or for remission of the diseases. Nevertheless,
there appear to be some common
clinical findings
in the occurrence
of
remissions in these diseases.
In chronic lymphocytic
leukaemia, the incidence of spontaneous
regression
is about 1% (96-98). Wiernik observed that one-third of the cases were associated
406
R. J. PAPAC
with a new primary carcinoma
(69). In more recent reports, this has not
been noted. A more frequent association
has been viral infection antedating
spontaneous
regression (97, 98).
The development
of spontaneous
regression
in chronic
lymphocytic
leukaemia
has been characterized
as a gradual
clinical improvement
in
adenopathy,
hepatosplenomegaly
and peripheral
blood findings
(96). The
documentation
of bone marrow remission was not present in all cases despite
normalization
of other features, so that a partial remission ensued. In some
instances, clonal remission developed
from 9 months to 1.6 years following
the clinical remission (96, 98). T-cell subsets also became normal in some but
not all patients (99). The duration of reported remissions ranges from 1 to over
11 years.
In chronic myelogenous
leukaemia
(CML), there are several reports of
spontaneous
remission (100-104). One case report is clearly consistent with
a spontaneous
remission,
since the patient was untreated
and developed
cytogenetic
regression with a marked decrease in the number of Philadelphia
chromosome
positive metaphases
(from 100 to 37%) over a g-year follow-up
period, and also demonstrated
complete disappearance
of an associated trisomy
8 abnormality
(103). In two cases, reported
as spontaneous
regressions,
disappearance
of the Philadelphia
chromosome
followed
therapy
with
busulphan in one case and with hydroxyurea
in the other patient, neither having
been treated to marrow hypoplasia (101, 104). This is a most unusual outcome
with these treatments;
hence, it is possible that these cases could represent
spontaneous
regression but the effect of treatment
cannot be discounted.
Cases of acute leukaemia
reported
by Southam
et al. in 1951 to have
spontaneous
regression were generally preceded by bacterial infection (105).
Collected from the literature were 57 cases, not all of whom had bone marrow
documentation.
Clinical observation
included the occurrence of remissions in
patients who were leucopenic
as well as those who had severe pyogenic
infections. In some instances, the transfusion
of blood products was implicated
in the genesis of spontaneous
remission. The remissions were generally brief,
from 4 weeks to 4 months.
In childhood
acute lymphoblastic
leukaemia, Diamond and Luhby reviewed
300 cases and found spontaneous
remission in 4.5% of patients, all of whom
had preceding cytopenias
and severe infection (106). Remissions of infantile
acute leukaemia are described although
there is difficulty in establishing
the
diagnosis of leukaemia in infants (107). Demonstration
of an abnormal karyotype
or immunophenotype
has been useful. There are reports of infantile acute
leukaemia with a leukaemic blood picture, no therapy, spontaneous
remission
and later relapse (108, 109).
There are very few cases of spontaneous
remission in acute lymphoblastic
leukaemia
in adults (69, 105). One report includes a 57-year-old
man and
another a 22-year-old
woman
who developed
remission without
cytotoxic
treatment.
Remissions without therapy are described in acute T-cell leukaemia/
lymphoma
(93-95).
One patient
with
prolymphocytic
leukaemia
who
experienced
spontaneous
remission has been reported (110).
In adult acute myeloid leukaemia, Wiernik found five cases who entered
remission without specific therapy (69). Common features were severe bacterial
SPONTANEOUS
REGRESSION
OF CANCER
407
infection and brief duration of remission, the longest being 5 months. Following
this, there have been additional
reports of at least 12 cases of spontaneous
regression in acute myeloid leukaemia, generally brief in duration, the median
being 4 months (111-116).
Interestingly,
three of these cases had acute promyelocytic
leukaemia (112,
113, 115). Cytogenetic
studies were done in eight cases; in three, there were
no abnormalities
(114-116). Two cases had documented
cytogenetic as well as
haematologic
remission. In all but four cases, the initial course was complicated
by severe pyogenic infection. In one patient, acute promyelocytic
leukaemia
was diagnosed
at 32 weeks of pregnancy
(115). The patient underwent
Caesarean
section and, within hours, her platelet count which had been
30,00Ocu/mm
rose to 121,000cu/mm
and remained
normal. Bone marrow
examination
showed complete remission 12 days later.
There are four reported
instances of remission
without
relapse of acute
leukaemia (2, 11 I). One of these cases bears a remarkable similarity to a patient
whom the present author has followed.
Enck reported
a 28-year-old
man
admitted with a diagnosis of acute promyelocytic
leukaemia, clinical evidence
of bleeding and without haematologic
improvement
after 6 weeks of therapy
(112). He was admitted febrile in a near terminal state, anti-leukaemia
therapy
was discontinued,
he was treated for infection and improved dramatically
with
normalization
of the bone marrow. He was alive and well 8 years later. The
patient from the present author’s study, a 52-year-old
male, was admitted
febrile without documented
infection, cytopenic with 90% myeloid blasts in the
marrow, and received prednisone and 6-mercaptopurine.
He was initially treated
with 50 mg qid, but inadvertently
this was changed to 50 mg qd after 2 weeks.
He entered complete remission within 10 days and has not relapsed in 24 years
(2).
In these leukaemia patients, the dose and duration of treatment were unlikely
to result in sustained remission
of 8 and 24 years. Spontaneous
remission
seems likely, although
the possibility
exists that the anti-leukaemic
agents
exerted effectiveness
through some anomalous
mechanism.
Miscellaneous
tumours
Choriocarcinoma,
seldom reported in the past few decades, was one of the
most frequently
reported tumours to undergo spontaneous
regression in the
review of Everson and Cole (1). With the advent of curative therapy for this
tumour type, it is unlikely that any patient would remain untreated. Spontaneous
regression is of interest from several points of view. The tumour is regarded
as a grafted neoplasm in the host since it arises from placental tissue; regression
may have an immunological
basis (117). The very high incidence of total
regression
of the primary tumour
in the presence of metastatic
disease is
remarkable.
Boyd’s review, as well as subsequent
reports, suggests that retinoblastoma
is among the tumours most frequently noted to develop spontaneous
regression
(3). Most often this has occurred with bilateral tumours, following enucleation
of one eye (118).
It is noteworthy
that Everson and Cole’s review listed relatively few of
R. J. PAPAC
408
Table
4.
Mechanisms
suggested
basis for spontaneous
of cancer
Immunological
mechanisms
Hormonal
mechanisms
Elimination
of a carcinogen
Induction
of differentiation
Tumour
necrosis
Angiogenesis
inhibition
Psychologic
mechanisms
Oncogenes,
growth
factors,
Apoptosis
Epigenetic
mechanisms
as the
regression
cytokines
the commonly
occurring
tumours,
such as lung, breast,
prostate
and
gastrointestinal
tumours,
among
those reported
to develop
spontaneous
regression (1). In fact, the frequently reported tumours to regress spontaneously
were relatively uncommon
tumours. In the review by Challis and Lamb, there
are increased numbers of some of the common tumour types, mainly lung and
gastrointestinal
(14). However, there is still a disproportionate
occurrence of
reports of spontaneous
regressions in rare tumours such as Merkel cell tumour,
hepatocellular
carcinoma,
non-AIDS-related
Kaposi’s sarcoma and adrenal
cortical carcinoma
(118-126). Almost every type of cancer has been reported
to undergo spontaneous
regression (14, 15).
Mechanisms.
Most reports of spontaneous
regression describe the occurrence
but do not provide a discussion regarding possible causative mechanisms.
In
the review of Everson and Cole, and in subsequent
articles, Cole referred to
immunological
mechanisms
as the most important
factor in spontaneous
regression (I, 127, 128). This is a generally prevalent view, although there is
now an expanded
list of potential
mechanisms
(Table 4). Other causative
factors cited by Everson and Cole include operative trauma, hormones and the
elimination
of a carcinogen (I).
In their tabulation
of cases, Challis and Stam found that subsequent
reports
listed maturation
and differentiation
of tumours,
necrosis and psychological
factors as mechanisms
of spontaneous
regression (14). Stoll, in a discussion
of new insights into spontaneous
regression,
suggested
that natural factors
and chemical agents could induce regression (118). The specific natural factors
cited were oncogenes,
growth factors and cytokines. The chemical agents
mentioned
by Stall include methotrexate
in choriocarcinoma,
and compounds
capable of inducing
differentiation
such as retinoids,
interferon,
and some
dietary components.
In view of current knowledge
of the biology of neoplasia,
additional
mechanisms
proposed
as the basis for spontaneous
regression
include epigenetic changes and induction of apoptosis.
While most discussions of causative factors in spontaneous
regression are
speculative,
recent literature
includes some laboratory
studies of regressed
lesions as well as comparison
of cellular infiltrates
from regressed
and
proliferative
lesions (73, 129). A discussion of the suggested mechanisms
and
supportive
data follows.
SPONTANEOUS
Immunological
REGRESSION
OF CANCER
409
mechanisms
Immunologic
factors almost
certainly
play a role in some instances
of
spontaneous
regression of tumours (118,130). The increased incidence of some
tumours in immunosuppressed
individuals, and regression following
reduction
of immunosuppressive
agents, suggests a role for immunologic
factors (131).
Examples of this phenomenon
are the occurrence of lymphoma
in transplant
patients
and in AIDS cases, the regression
of Kaposi’s sarcoma
when
corticosteroid
therapy was withdrawn,
and the reversibility
of lymphomas
developing
with
methotrexate
therapy
for rheumatoid
arthritis
when
methotrexate
was stopped (118, 124, 132).
In the observed regressions of renal cell carcinoma and malignant melanoma,
immune mechanisms
are often invoked as the mechanism
of regression (40,
118). In both tumours,
regressions
have occurred following
plasma infusion
from patients who have experienced
a regression,
suggesting
that humoral
factors may play a role (33, 127). Also, in both tumour types, cytokines, namely
interferon
and interleukin
2 (IL-21, exert antitumour
effects (133, 134). IL-2 is
presumed
to activate T-lymphocytes,
natural killer (NK) cells, lymphocyteactivated killer cells (LAK) and tumour infiltrating
lymphocyte
(TIL) cells as a
mechanism
of action; interferons
are capable of multiple immunomodulatory
effects involving monocytes,
macrophages
and B-cells, as well as induction of
IL-2 receptors (135, 136).
In a patient with renal cell carcinoma, in whom biopsy-proven
lung metastases
showed complete
resolution
without treatment,
assays of LAK activity, and
mixed lymphocyte
cytotoxicity, were obtained (18). These immune parameters
were within the normal range. While specific immunologic
factors are not yet
identified in the regression of renal cell carcinoma, the effects of nephrectomy
are attributed to immune mechanisms,
assuming that removal of bulk tumour
enables or stimulates the body’s immune system to control residual disease
(118, 127).
In melanoma
there is evidence for immune-mediated
host responses in
spontaneous
regression.
Tefany
et al. reported
immunocytochemical
comparisons
between regressing and non-regressing
melanomas
(129). These
indicate increased helper T-cells with increased expression of the IL-2 receptor
infiltrating the regressing primary melanoma without changes in T-suppressor
cells. A number of leucocyte antigens have been assessed including antigenpresenting
cells and leukocyte adhesion
molecules,
but no difference
was
observed
in regressing
as compared
to non-regressing
lesions. Melanoma
tumour associated antigens, such as GD3, glycoprotein
75 antigen, glycoprotein
110 and GD2, were expressed at a higher percentage in regressing lesions, but
not to a significant level.
Mackensen eta/. characterized
lymphocytes
of a regressive melanoma lesion,
demonstrating
amplification
of cytotoxic
T-lymphocytes
that were reactive
against the autologous
tumour
(137). From the lymphocytes
infiltrating
the
regressive melanoma
lesion, a series of lymphocyte
clones were analysed for
the T-cell receptor gene expression. A unique cell expressing a VP 13.1/J6 1.1
gene segment was found expressed in the cloned cells. When compared to the
uncultured
tumour tissue, the specific cytotoxic T-lymphocytes
were selected
and amplified
in vivo at the lesion site.
410
R. J. PAPAC
In melanoma
patients with regional nodal metastases, several studies have
shown suppressor T-cell activity against induction of cytotoxic T-cells in lymph
nodes containing
metastases (38, 138). It is suggested that migration of helper
T-cells from these lymph nodes may boost cytotoxic T-cell responses at the
primary regressing melanoma
site.
These studies in melanoma
are consistent with a cell-mediated
antitumour
effect and suggest that an effector T-cell has contributed
to the regression. The
effector cell may be a cytokine secreting cell. Cytokines per se have not been
cited in the spontaneous
regression of melanoma,
although there is evidence
that interleukin 6 (IL-6) may function as an antagonist
or agonist in melanoma
growth (139). The expression of IL-8 by melanoma
cells is also demonstrated
to influence the biologic behaviour of melanoma
(140).
The role of immunologic
factors in regressions
observed
in basal cell
carcinoma has been reported recently (141). lmmunocytochemical
comparison
of proliferative
and regressive lesions was carried out. The regressive lesions
showed increased numbers of helper T-cells, increased expression of the IL-2
receptor and no change in T-suppressor cells. These results are similar to those
reported in cutaneous melanomas
with regression.
Experimental
evidence for an immune
mechanism
in the spontaneous
regression of neuroblastoma
is suggested by Bolande, who reported maternal
pregnancy serum possessed an IgM natural antibody binding to neuroblastoma
cells and capable of amplifying
the response to the lytic action of serum
complement
(142). Arguments
against the immunologic
mechanism
are the
observation
that neuroblastoma
is not observed in immunodeficient
states,
and the fact that the role of immune
mechanisms
is not well established
in
childhood malignancies
(143).
In the spontaneous
regression of choriocarcinoma,
immune mechanisms
are
considered to be significant since the neoplasm may be regarded as a grafted
tumour whose regression may represent graft rejection (117).
There are four reported
cases of small cell lung carcinoma
in whom
spontaneous
regression occurred in association with neuropathy,
which was
associated in three of the four cases with antineuronal
antibodies
(144, 145).
Two cases had anti-Hu and atypical antineuronal
antibody. One case had only
anti-Hu antibody. The autoantibodies
reactive with neurons are also reactive
with small cell lung carcinoma,
suggesting
that the regression
is possibly
antibody or cell mediated.
The spontaneous
regression in cases in lymphoma
and leukaemia is often
attributed
to immune
mechanisms
(69, 118). Characteristics
of the cellular
infiltrate in a regressed lymphoma
are similar to those noted in regressed
cutaneous
tumours
(73, 129). Since the occurrence
of regressions
in these
conditions is often in the setting of febrile illnesses, bacterial or viral, cytokines
associated with host responses to infections could mediate the regressions.
Coley’s toxin which contained
bacterial
endotoxin
was associated
with
occasional instances of tumour
regression
(146). It is possible that tumour
necrosis factor, which is cytotoxic for some tumour
cells, is an important
cytokine for instances of fever-related
regressions (147).
The regression-of
low-grade
gastric mucosa-associated
lymphoid
tumour
(MALT) lymphomas
with eradication of Helicobacter pylori suggests that these
SPONTANEOUS
REGRESSION
OF CANCER
411
lymphomas
represent a response to an antigenic stimulus from the H. pylori
(148). It is conceivable
that other lymphomas
might be antigen-driven,
and
regress following
dimunition
in antigen exposure or the development
of an
anti body.
Hormonal
mechanisms
Hormonal mechanisms are most likely the mediators of spontaneous
regression
in breast carcinoma
(1, 65, 66). The evidence
is circumstantial
since the
regressions have developed
mainly at the time of menopause,
but also at the
onset of menses or with the development
of ovarian metastases, presumed to
induce an endogenous
oophorectomy.
There are several cases of complete
remissions
of malignant
melanoma
reported during pregnancy
and following
delivery (I, 40). Some melanoma
cells express hormonal
receptors which led to some clinical therapeutic
trials
of hormonal therapy which were generally disappointing
(149-151).
There are three case reports of remission
of acute leukaemia
following
termination
of pregnancy (15,152,153).
The mechanism of regression is unclear
but it is suggested
that the leukaemic cells may have expressed hormonal
receptors, so that with hormonal
alterations
at the termination
of pregnancy,
the leukaemia regressed (118). Oestrogen receptors have been found in some
human myeloid leukaemia cell lines, and oestrogen,
with colony stimulating
factor, has been demonstrated
to have stimulatory
effects on growth of some
leukaemia cell lines (154).
Five cases of regression of metastases from ovarian carcinoma
following
oophorectomy
are cited by Everson and Cole (I). There are also rare instances
of regression of metastases of sarcomas with termination
of pregnancy (I).
Elimination
of a carcinogen
The elimination
of a carcinogen
is suggested
in instances of bladder cancer
when transplantation
of the ureters resulted in regression of the bladder tumour
(1). It has been postulated that a carcinogen present in the urine was eliminated.
To date, the carcinogen
has not been identified.
However, in instances of pre-invasive
lesions such as those noted in the
bronchial
tree of heavy smokers,
cessation
of smoking
has led to the
disappearance
of pre-invasive changes (I 18).
Induction
of differentiation
Differentiation,
a mechanism by which malignant cells develop a non-malignant
phenotype,
is postuled
to occur in several types of neoplastic
disease.
Retinoblastoma,
neuroblastoma,
choriocarcinoma,
embryonal
cell carcinoma
of the testis and leukaemia are malignancies
in which differentiation
is possibly
a major factor in spontaneous
regression (118, 155).
The development
of ganglioblastoma,
a benign tumour, is noted in a minority
of cases of regressed neuroblastoma
(7,53). In tissue cultures of neuroblastoma
cells, differentiation
can be induced with exposure to nerve growth factor,
412
R. J. PAPAC
serum-free
media, cyclic nucleotides,
retinoic acid and some cytotoxic agents
(53, 118).
In embryonal
carcinoma and teratocarcinoma
of the testis, differentiation
to
a mature
teratoma
has generally
developed
following
treatment
with
chemotherapy,
radiotherapy
or both (156). A case report of a patient with
pulmonary
metastases
who refused therapy
and developed
spontaneous
regression describes the finding of a mature teratoma in the testicular site of
the original primary tumour (157). Spontaneous
regression of primary testicular
tumours
is presumed
in cases with metastatic disease in whom the primary
site cannot be identified and intra-abdominal
metastases are evident. Cultured
human teratocarcinoma
cells provide
in vitro demonstration
of extensive
capability to differentiate
into several cellular lineages (158).
In choriocarcinoma,
Friedman
and
Skehan
reported
morphological
differentiation
of human choriocarcinoma
cells in culture by methotrexate
(159).
The mechanism
of the differentiating
effect is felt related to possible depletion
of several different folate co-factors or differential
sensitivity of varied target
sites. It is possible that differentiation
by depletion of folate co-factors could
occur in instances of spontaneous
regression.
In the acute leukaemias, laboratory studies support induction of differentiation
as a mechanism
of spontaneous
regression.
A wide variety of compounds,
including
vitamins,
steroid hormones
and cytotoxic agents in low dosage,
demonstrate
the capability of inducing differentiation
in vitro (160). The effects
of trans-retinoic
acid in acute promyelocytic
leukaemia are an example of in
viva differentiation
(155). Laboratory
studies indicate that the suppression
of
the leukaemic phenotype
with differentiation
does not restore all the normal
controls, a finding that may be the basis for the generally brief duration of
spontaneous
remissions in acute leukaemia (160).
The potential for spontaneous
regression
by differentiation
of lymphoma
cells is suggested by a case report of a patient with follicular lymphoma
who
developed
a febrile illness with high IL-6 serum levels, following
autologous
bone marrow
transplant
and IL-3 therapy
(161). The patient
developed
plasmacytosis
and paraproteinaemia.
Immunophenotyping,
cytogenetics
and
Southern
blotting
indicated a clonal relationship
of the plasma cells to the
original
lymphoma.
This was interpreted
as evidence that the malignant
lymphoma
cells were stimulated
by IL-3 and IL-6 to become terminally
differentiated
plasma cells.
Turnout- necrosis
and angiogenesis
inhibition
Compromise
of the blood supply to a tumour or necrosis of tumour tissue is
listed as a mechanism
for spontaneous
regression. The regressions following
surgery or irradiation to a tumour site could be related to this mechanism
(14).
The survival of tumours
is dependent
not only on an adequate blood supply
but on the production
of new vessels. Angiogenesis
as an essential component
of the neoplastic process is a focused area of research (162). A number of
cytokines are known to inhibit this process, namely TNF CI and transforming
growth factor fi which could play a role in spontaneous
regressions (163).
SPONTANEOUS
Psychologic
REGRESSION
OF CANCER
413
mechanisms
Psychological
mechanisms
in spontaneous
regression are generally regarded
with sceptisism since the phenomenon
lends itself to misuse by faith healers.
Psychological
methods
are reported
by several authors but corroborating
studies are lacking (164-166). While psychological
interventions
benefit many
cancer patients,
these techniques
do not induce regression
of cancer in
reproducible
fashion.
Psycho-neuro-immunological
mechanisms
are suggested
by some authors
on the basis of interactions
between immune, endocrine and nervous systems
(165, 167). The finding of opioid receptors on macrophages
and lymphocytes
suggests that psychological
factors could influence the immune system and
modify
cancer
growth
through
the cell-mediated
reactions
involving
macrophages
and T-lymphocytes
(167, 168). While there may be some links in
these processes, it is now a remote and highly theoretical
construct.
Oncogenes
and growth
factors
In human neoplasia, the expression
of oncogenes, the inactivation,
mutation
or loss of suppressor
genes and the function of growth factors are regarded
as central to the neoplastic state (169-172). The expression of certain genes
promotes cell survival which is enhanced by trophic growth factors. Genes for
suppression
of malignancy,
as well as inhibitory growth factors, have roles in
regulation of cell growth and differentiation
(171, 172).
Study of chronic myeloid leukaemia (CML) cells in vitro indicates that the
balance of stimulatory
and inhibitory factors is shifted, as compared to normal
haematopoietic
cells (173). In normal
haematopoiesis,
two endogenous
inhibitors, transforming
growth factor p (TGF /I) and macrophage
inflammatory
protein-la
(MIPa), maintain primitive cells in a reversible state. In cells of CML,
the primitive cells have a selective unresponsiveness
to MlPcl such that the
fusion gene BCL-ABL is affecting only some of the pathways involved in the
complex signalling for cell cycle control of haematopoiesis.
The demonstration
of retention
of some control provides further emphasis for the concept of
existence of mechanisms
for reversal of the malignant
phenotype.
While there are no specific examples to document the role of inhibitory growth
factors in spontaneous
regression nor for change in oncogene expression, these
possibilities have been cited (169, 170). In CML, expressing BCL-ABL augments
sensitivity
of haematopoietic
cells to growth-factor
mediated
signals of
differentiation,
suggesting that CML progenitors could be eliminated in response
to haemopoietic
growth factors (174). Additionally,
as noted earlier, remission
in acute leukaemias has been associated at times with viral infections. Recent
studies indicate that in association
with viral infection,
interferon
CI exerts
myelosuppressive
effects indirectly mediated
by inhibition
of the paracrine
production
of haemopoietic
growth factors (175). An indirect effect of growth
factors
in spontaneous
regression
was suggested
in a case report of
spontaneous
regression in metastatic lung cancer following
myxedema
coma
(176). The authors note that the hypothyroid
state has been associated with
reduced rates of neoplastic
growth.
The thyroid hormone
(T3) is a potent
414
R. J. PAPAC
stimulator
of growth
factors, notably epidermal
growth
factor (frequently
expressed in lung cancer), nerve growth factor and insulin-like growth factor.
Presumably,
severe deficiency of the hormone
by altering autocrine
growth
factors could influence programmed
cell death, apoptosis.
Apoprosis
A mechanism
which has received attention
for spontaneous
regression
in
recent literature is the occurrence of apoptosis or programmed
cell death (177).
In tumouregenesis,
the protein expressed by the BCL-2 gene, as well as other
proteins and environmental
factors, inhibits programmed
cell death (177, 178).
A developmental
time switch for activation of apoptosis has been proposed
by Pritchard
and Hickman
as the basis for spontaneous
regression
in
neuroblastoma
(143). Biological variation in time of apoptosis could explain
the regression. This mechanism
is amenable to investigation
by measurements
of DNA fragmentation
and in situ end labelling.
In regression of renal cell carcinoma,
Pansera has suggested that apoptosis
occurs as a re-expression
of embryonic
cell death, a normal occurrence
in
embryogenesis
of the kidney (179). During kidney development,
the pronephros
and mesonephros
regress completely
so that these regressive phenomena
are
instances of cell death during development.
Re-expression
of cell death in
renal cell carcinoma
may be a manifestation
of embryonic
characteristics,
as
sometimes
seen in neoplasia.
The role of apoptosis in spontaneous
remission of a mantle zone lymphoma
is described in a recent report by Kaufman et al. (180). An untreated
patient
experienced
15 cycles of remission and disease activity. At stages of the disease
when remission was present, analysis of the peripheral
blood lymphocytes
showed a small population
of lymphocytes,
IgM and CD5+. During relapse,
two B-cell clones with differently re-arranged heavy chain genes were detected.
Spontaneous
apoptosis was detected by DNA fragmentation
of cultured cells
obtained during relapse of the disease. Viability of cells from the acute disease
phase was low with 50% of cells non-viable
in 16 h as compared
to 90% of
cells viable at 3 days during remission. In this case, no molecular alterations
were detected in BCL-2 gene nor ~53, a tumour suppressor gene that functions
as an inducer of apoptosis and which can be a regulator of BCL-2. The authors
suggest that the neoplastic cells, in response to loss of a T-cell-mediated
survival
signal or cytokine-mediated
regulation,
underwent
apoptosis
followed
by
clinical remission.
Epigeneric
mechanisms
Epigenetic change may play a role in the spontaneous
regression
of some
retinoblastoma
tumours (181). Abnormalities
of DNA methylation
are associated
with the incipient stages of tumour development.
The abnormalities
include
overall genomic
hypomethylation,
regional hypermethylation
and increased
capability for hypermethylation
(182). Regional hypermethylation
may involve
CpG islands which are cytosine-guanine
rich regions of the genome found in
the promoter area of many genes, normally free of methylation,
except for the
SPONTANEOUS
REGRESSION
OF CANCER
415
genes involved in X-inactivation
or gene imprinting
(183). Greger et a/., using
methylation-sensitive
restriction
enzymes and a cloned DNA probe for the
unmethylated
CpG island at the 5’ end of the retinoblastoma
gene (a tumour
suppressor
gene), obtained
evidence of hypermethylation
of this gene in a
sporadic
retinoblastoma
tumour
(181). There were, however,
two sites of
the CpG island not methylated,
possibly reflecting demethylation.
Since the
maintenance
methylase
does not replicate methylation
patterns during DNA
synthesis with absolute fidelity, it is surmised that loss of methylation
could
lead to re-activation
of the retinoblastoma
gene and suppression
of tumour
growth. There is no evidence for inactivation
of the retinoblastoma
gene by
hypermethylation,
but there
is a tentative
suggestion
that
loss of
hypermethylation
may be involved in the spontaneous
regression
of some
retinoblastomas.
Telomerase,
a ribonucleoprotein
polymerase,
functions
to maintain
the
essential genetic elements of telomeres, the eukaryotic ends of chromosomes
(184). With successive replications, telomere shortening
develops in senescent
aging with suppression
of telomerase
activity (185). Activation of telomerase,
however, is regarded as essential to cell immortalization
and most cancers. In
a survey of 12 tumour tissue types, 90 of 101 were positive for telomerase
activity (186). Some adjacent tissues also demonstrated
positivity, suggesting
involvement
not evident by pathologic
examination.
A recent study of telomerase activity in neuroblastoma
is of particular interest.
Yokoyama et a/. studied 79 untreated cases and found that 16 cases with high
telomerase
activity had a poor prognosis, and 60 patients with low levels had
a favourable
outcome
(187). Those patients whose tumours
did not show
telomerase
activity underwent
spontaneous
regression, suggesting
repression
of telomerase
activity as a possible mechanism for regression.
Discussion
Observations
of spontaneous
regression of cancer are, as described by Osler,
one of the most remarkable
phenomena
observed in medicine (6). There is
hope that elucidating
the mechanism
could lead to replication of the process
and a better method of treating cancer.
With regard to the occurrence of spontaneous
regression, the observation
of
waxing and waning
of tumour
growth,
particularly
in neuroblastoma
and
lymphomas,
suggests that it may not be an uncommon
phenomenon
in some
tumours.
Indeed, the reports of a 23% incidence in low-grade
lymphomas
supports this (72).
The rather disproportionate
occurrence
of spontaneous
regression
in
uncommon
tumours suggests that these tumours may be uncommon
because
regression
develops frequently,
perhaps when these tumours
are clinically
unrecognized.
A corollary of this consideration
is that the commonly
occurring
tumours are those with much less capability of spontaneous
regression; hence
their frequent occurrence.
From review of the clinical features of spontaneous
regression, there seems
to be a prediliction
for regression to develop frequently
in some sites, notably
416
R. J. PAPAC
lung and in cutaneous
sites, whether the tumour is a primary skin neoplasm
or a secondary cutaneous
deposit, as in lymphoma
and neuroblastoma.
The
site predilection
in regression of tumours suggests that micro-environmental
factors play a role in the regression.
While there are studies indicative of
involvement
of immunologic
mechanisms
in the process in cutaneous tumours,
growth factors are probably
significant
as well. In melanoma
growth,
IL-6
clearly plays a role; it has not been assessed in regressive lesions.
Treatment of the primary tumour by surgery or radiation has been associated
with regression in three of the four most common tumour types reported to
undergo
spontaneous
regression.
The mechanism
by which regression
of
metastatic lesions disappear following
removal of a primary tumour is unclear.
This is generally attributed to ‘host factors’ considered to be immune-mediated
(1,141. Treatment of the primary tumour, however, is not essential for regression
to develop, suggesting
that reduction in cell numbers or tumour mass is not
crucial to the process of spontaneous
regression. It is possible that cytokines
and/or
autocrine
growth
factors,
produced
by the primary
tumour
and
promoting
proliferation
and metastases,
could be depleted or reduced with
removal of the primary neoplasm with consequent
re-establishment
of growth
controls and spontaneous
regression of metastatic deposits.
Ultimately
in cases of spontaneous
regression,
the tumour
is no longer
evident, suggesting that either apoptosis or differentiation
to a benign neoplasm
occurs. Apoptosis
is well documented
in the case report of a mantle cell
lymphoma
demonstrating
cycles of spontaneous
regression;
Pritchard and
Hickman suggest apoptosis
as a possible mechanism
in the spontaneous
regression of neuroblastoma
(143, 180). Differentiation
to a benign neoplasm
is documented
to occur in patients with neuroblastoma
and testicular germ
cell tumours;
it certainly seems a possible mechanism
in acute leukaemias.
An intriguing
issue in spontaneous
regression
is whether
a common
mechanism is essential forthe processto occur orwhether
multiple mechanisms
lead to spontaneous
regression.
Immunologic
factors and hormonal
changes
are clinically significant
in the occurrence
of spontaneous
remissions,
and
would seem either directly or indirectly to promote the process. Dietary factors,
cytokines and/or growth factors conceivably could play a role in differentiation.
The discovery of endogenous
inhibitors
of angiogenesis
offers yet another
possible contributing
factor in the process of spontaneous
regression.
The
epigenetic phenomena,
demethylation
and telomerase inactivation or inhibition
are of particular interest since these could be determined
in regressing tumours.
Endeavours to study spontaneous
regression with histologic or immunologic
analyses is a comparatively
recent development.
The most comprehensive
studies are in cutaneous
melanoma
and in lymphoma.
The studies
in
retinoblastoma
and neuroblastoma
are of exceptional
interest, and provide an
impetus for further work to verify and confirm the data.
A single mechanism
for spontaneous
regression
remains
a possibility,
however. Variability in expression of the malignant phenotype
may be assumed
in some settings. An example is noted in the patients who have prolonged
remissions of malignant
disease, followed by relapse, observed particularly in
patients with carcinoma arising in breast, kidney, occasionally
melanoma
as
well as lymphomas.
Molecular biology provides evidence of occult disease in
SPONTANEOUS
REGRESSION
OF CANCER
417
instances in which relapse or clinically evident disease does not develop.
Suppression
of the malignant
phenotype
may occur as a consequence
of
modifiers intrinsic to the host (genetic, immunologic,
angiogenesis
inhibitors,
etc.) or external agents (differentiating
agents).
Reversibility
of the malignant
process in spontaneous
regression
could,
therefore,
evolve
from
several
initiating
events-but
the ultimate
reestablishment
of controls could involve a single crucial process. Perhaps, as
suggested by Thomas, ‘In the end, when all the basic facts are in . . . it will turn
out that all forms of cancer, in whatever organs and of whatever cell types, are
a single disease, caused by a single central controlling mechanism gone wrong’
(188).
The significance
of spontaneous
regression
of cancer is that it provides
evidence for the existence of endogenous
control of neoplastic growth. Perhaps
efforts to define and apply methods of re-establishing
or strengthening
growth
control could yield greater benefits in the quest for effective methods of cancer
treatment.
Acknowledgements
The interest and encouragement
of Dr. Mary Keohane-Pelliccia,
C. Hirshberg
and Dr. J. J. Fischer in the preparation
of this manuscript is deeply appreciated.
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