1. No category

Rare tumors
Neuroendocrine tumors
Cancer of unknown primary
GIST
Dr Kocsis Judit
Neuroendocrin malignancies
Gastroenteropancreatic (GEP-NET) neuroendocrine
tumors are heterogen tumors, with different fenotype and
biologic behavior
Origin: neuroendocrine cells of intestine / pancreas
Incidence: 5.25/100 000
At any age, most common is from 5. decade
Except for appendix carcinoid (40 year)
In syndromes MEN-1 or VHL sy, NF : 15-20 years earlier
Diagnosis
If typical syndrome, histology, etc: send the patient to
center!!
Histologic confirmation (surgery-resection/biopsy,
endoscopic biopsy, UH guided liver FNAB from
metastases)
Pathology: cromogranin and synaptophysin positivity,
(NSE, CD56) pozitiviy
Importance of KI67 proliferation marker (grade)
Hormon (inzulin, glucagon, serotonin, gastrin) content
detection of tumor doesn’t correlate with function
Diagnostic workup, imaging
Serum cromogranin A
In carcinoid: urine 5-HIAA
Gold standard imaging test: somatostatin
scintigraphy
New standard (soon): Ga-DOTA-TOC/-NOC/-TATE
PET
PET CT, CT, MRI
Changes in the new 2010 WHO classification
GEP-NET WHO classification
(2010)
• Well differentiated NET (malignant behaviour)
Ki67 index*
- G1 low grade
<2%
- G2 intermedier grade
3-19%
- G3 high
grade
>20%
• Poorly differentiated neuroendocrin carcinoma: NEC
- G4 high grade, malignant behaviour >20%
*% of positive cells from 100
A GEP_NET classification according to origin and
function
Intestinal NETs (carcinoid, 50%)
1, with carcinoid syndrome (30% of carcinoids) flushing,
diarrhea,endocardial fibrosis, wheezing caused by release of
serotonin predominantly from liver metastases
2, without carcinoid syndrome (70% of carcinoids)
Pancreatic neuroendocrin tumors (PETs) (∼30% )
Nonfunctioning (45%–60% of PETs)
Functioning (40%–55% of PETs)
Funtcionally active PNETs
Gastrinoma, excessive gastrin production, Zollinger–Ellison
•
Insulinoma, excessive insulin production, hypoglycemia syndrome
• Glucagonoma, excessive glucagons production, glucagonoma
syndrome
• VIPoma, excessive production of vasoactive intestinal peptide (VIP),
Watery diarrhea, hypokalemia–achlorhydria syndrome
• PPoma, excessive PP production, (generally classified as
nonfunctioning PETs)
• Somatostatinoma, excessive somatostatin production
• CRHoma, excessive corticotropin-releasing hormones production
• Calcitoninoma, excessive calcitonin production
• GHRHoma, excessive growth hormone-releasing hormone
production
• Neurotensinoma, excessive neurotensin production
• ACTHoma, excessive production of adrenocorticotropic hormone
• GRFoma, excessive production of growth hormone-releasing factor
• Parathyroid hormon related peptide tumor
•carcinoid tumor ≠
carcinoid syndrome
Carcinoid syndrome
• Basicly overproduction of serotonin and other
neurohormons , consequent paraneoplastic syndrome
• Mainly if multiple liver metastases
• Gonadal carcinoid rarely
• Altogether in 4-5%- of carcinoid tumors
• Main symptoms:
– Flushing – caracteristicly without sweating, or with it
Diarrhoea
– Bronchoconstriction, dyspnea
– Right sided heart symptoms, changes, endocardial
fibrosis (cardiomyopathy)
Patient with GEP-NET
Possible complains/symptoms
Flush
-(arc)kipirulás (átm.)
-sweating
-cardiorespiratoric
failure
-hypotension
Rash
-diabetes
-muscle mass decrease
-weight loss
Severe
diarrhoea
-dehidration
-hypokalaemia
-acid loss
Hypoglycemia
Peptic ulcer
Clinical presentation
Heterogen, depends on:
• Histology type
• Anatomic localization
• Secretogen ability
Somatostatin receptor scintigraphy
Treatment I.
Surgical resection whenever possible
Localised disease:
intestinal carcinoid: resection, regional (retorperit)
lymphadenectomy
Pancreas: resection if possible + lymphadencetomy
(except for: G3 NEC)
Advanced: resection is beneficial + try metastasectomy
also!
Importance of cytoreduction (if >70% can be removed)
Treatment II.
Locoregional interventions
TACE (transcatheter arteric embolization)
TAE (transcatheter arteric embolization)
HAI (hepatic artery infiltration)
RFA (radiofrequency ablation)
SIRT (selective internal radiotherapy)
Radioembolisation
 Treatment of liver metastases with 30-35 mm
diameter 90Y-conjugated microspheres.
 High dose radioactivity in liver mets.
 Very expensive
Treatment III.
Systemic treatment
Functioning NET:somatostatin analog therapy
(interferon)
Intestinalis G1and G2 NETs: somatostatin analog
therapy
PNET: everolimus (mTOR inhibitor),sunitinib (TKI)
ill. pazopanib
G3 NEC: not! (chemotherapy)
Treatment III.
Systemic treatment (KT)
Chemotherapy is not advised: classic carcinoid (G1)
Advised: metastatic NET G2 and NEC G3
Irresecable disease, progressive liver mets, pancreas
G1/G2 NET
streptozotocin + 5-fluorouracil (5-FU)/doxorubicin
Temozolomide (+ capecitabine)
But: NEC G3 with liver mets: cisplatin + etoposid
Treatment IV
Somatostatin receptor targeted radiotherapy
Somatostatin analog – radioizotop conjugate
111In
(Indium) is good for diagnosis but not for therapy.
Therapy
1, β-emitter 90Yttrium
2, β+γ emitter 177Lutecium90Y-DOTATOC
in larger tumors, 177Lu-DOTATATE in
smaller tumors
Effectivity in well differentiated NETs
Metastatic
disease
Early phase
Surgery
Systemic treatment
Neo-adjuvant
treatment
Multidisciplinar approach
Adjuvant
Palliatíve
Summary of treatment options for localised and metastatic NET
Role os SSA in treatment
Well differentiated
neuroendokrin tumor
(Ki-67<2%)
Well differentiated
poorly differentiated
neuroendokrin carcinoma neuroendokrin carcinoma
(Ki-67 3-20%)
(Ki-67 >20%)
Surgery, intervention radiology
Somatostatin-analóg
interferon
sunitinib
everolimus
+ combination
doxorubicin
streptozotocin
temozolamid
capecitabin
bevacizumab
tünetekre
Somatostatin –analóg
+ cisplatin + etopozid
temozolamid
+ capecitabin
bevacizumab
tünetekre
somatostatinanalóg
Endoradiotherapy:
szomatosztatin peptid radionuklid kezelés (90YDOTATOC, 177Lu-DOTATATE); 131I-MIBG
Kjell Öberg, 2011
+
Somatostatinanalogs
Ala Gly Cys Lys Asn Phe
Phe
S
Trp
S
Lys
SS-14
• -Octreotide
(sc, infúzió)
-Sandostatin LAR (im. havonta)
Cys Ser Thr Phe Thr
Octreotide
• Lanreotide
-PR (mély sc 7, 10, 14 naponta)
-Somatuline Autogel (mély sc
havonta)
DPhe
Cys Phe
S
DTrp
S
Lys
Thr(ol)
Cys Thr
DβNAI
Cys Tyr
S
DTrp
S
Lys
Lanreotide
• Pasireotide - Som230 (sc)
Injekciók közötti intervallumok
adott esetben növelhetőek
Thr
Cys Val
Phg
DTrp
Pro
SOM230
Phe
Tyr
(Bzl)
Lys
SS-analógok → neuroendokrin szekréció redukálása
Neurotensin
PP
VIP
Motilin
6000
Plazma Peptid koncentráció (pg/mL)
SSA: funkcionáló
tumorok többségét
kontrollálja
Kezdeti dózis
5000
4000
3000
2000
1000
A magas keringő peptidszint
hozzájárul a karcinoid
betegség tüneteihez
0
Nap 1
2
3
Kezelés előtt
4
5
6
7
8
9
Octreotide
kezelés
10
Octreotide mérsékli a
neurohormonok szekrécióját
11
12
→ tünetek
javulnak
Carcinoid crisis
treatment:
a) Octreotide bolus, 300 (100-500) μg sc./ iv.
b) Octreotide infusion or 4-6x/die sc.
Prophylactic:
a) 2 days 3-4 x 200-250 μg octreotid sc.
b) before interventions 1-2 hours 200-250 μg
octreotid
Gastric carcinoid tumor (type 2) regression
after 1 year sc. octreotide
GLUCAGONOMA SS-analog treatment
Before
After
Cancer of unknown primary tumor
(CUP)
Definition, incidence
(CUP = cancer of unknown primary)
Heterogen group of metastatic tumors, when the origin
(primary) of tumor can not be detected by standard
diagnostic tests
(physical exam., lab, occult blood test, IHC, X-ray, CT,
mammography (MR, PET)).
3-5 %- of all malignancies
7.-8. most common malignancy
Majority of primery tumor can not be detected in vivo
CUP Biology
 Biologic behaviour is less known than in the case of known primary tumors
 More involved field, early dissemination, lack of primary tumor (regression?, dormant
tumor?), unpredictable metastatic spread, agressivity
 Metastatic disease could arise without primary tumor growth (organ specific
transformation of circulating tumor cells, onkogen induction)
 Prognosis usually worse
 But: There is a small, heterogen subgroup, where prognosis is much better,
long term survival is possible, even cure sometimes!
Postmortem (autopsy) analysis
Adenocarcinoma
Pancreas (22%)
Lung (20%)
RCC 5%
Colon, prostata 3 %
Urothelial, ovarian, nasopharyngeal carcinoma, adrenal gland,
thyroid 2-2 %
In 23 % autopsy failed to find primary
Evaluation of the patient with CUP
Physical examination ( head-neck region, axillary and inguinal lymph node region, thyroid, breast,
abdomen, testicular examination, rectal and pelvic exam.)
Lab (hematology, urine, stool occult blood, renal and liver function)
Basic radiology: chest, abdominal, pelvic CT
But: avoid unnecessary further examinations (eg. endoscopies) without suspition!
Endoscopy: only in the case of appropriate symptom, complain, lab finding
PET: detects primary tumor in 25-50 (+ staging)
But: accuracy is 45% in head-neck cancer
Tumor markers: not routin (not useful for differentiation)
Except for: germ cell tumor markers (AFP, βHCG) in extragonadal germ cell tumor
and serum PSA
Differenciálás a citokeratin markerek alapján ismeretlen
eredetű carcinomák esetén
CK7 / CK20
CK7 +/ CK20+
--
Urothelium
daganatok;
- petefészek
- mucinosus rák;
- hasnyálmirigyrák;
- epeúti rák;
CK7+ / CK20 -
CK7 - / CK20+
CK7 - / CK20 -
- tüdőrák;
- emlőrák;
- paizsmirigyrák;
- endometrium rák;
- méhnyakrák;
- nyálmirigy rákok;
- epeúti rák;
- hasnyálmirigyrák;
- colorectalis rákok;
- Merkel-sejtes rák;
- májsejtrák;
- vesesejtes rák;
- prosztatarák;
-laphám- és
-kissejtes
-tüdőrák;
fej-nyaki rákok;
Classification according to histology
 -well and intermediate differentiated
adenocarcinoma (50%)
 -poorly differentiated carcinoma (including poorly diff.
adenocarcinoma)(30%)
 -squamous cell carcinoma (15%)
 -undifferentiated tumor (5%) -neuroendocrin differentiated carcinoma,
lymphoma, germ cell tumor , melanoma, sarcoma, embryonal cell cc
Favorable clinicopathologic entities
 -Midline poorly differentiated carinoma (extragonadal germ cell tumor);
 -Peritoneal papillary adenocarcinoma in women;
 -Female patient with axillary lymph node metastases (adenocarcinoma);
 -Squamous cell cancer lymph node metastases in cervical region;
 -Poorly differentiated neuroendocrine carcinoma;
 -Osteoblastic bone metastases with elevated PSA in men;
 -Isolated inguinal lymph node squamous cell metastases;
 -Monolocalised, small, potentially resectable metastases;
Treatment of favorable
subgroup
Treatment is same as for known primary
tumors with the same histology (equivalent
tumor) and the same stage
prognosis is similar
Unfavorable clinicopathologic
entities
 Adenocarcinoma metastases in liver or other organs
 Non-papillary malignant ascites (adenocarcinoma)
 Multiple cerebral metastases (adenocarcinoma or squamous cc)
 Multiple lung/pleura metastases (adenocarcinoma)
 Multiple bone metastases (adenocarcinoma)
Treatment of unfavorable group
Realistic aim: decrease symptoms and maintain quality of life
-Survival improvement is minimal
 Systemic treatment or best supportive care
-Low toxicity, well tolerated, relatively convenient
chemotherapy first line
-Second line treatment : only in selected cases
-Most common combinations: 3 weekly paclitaxel+carboplatin,
cisplatin+gemcitabine, or cisplatin+etoposid.
GIST
Gastrointestinal stroma tumor
Patology, epidemiology
Most common sarcoma of GI tract
Origin: precursors of intestinal Cajal cells
Stomach and small intestine
1.5/100000/year
95% CD117/KIT pozitivity (IHC)
Exon 9 and 11 mutations (KIT activation mutation)
Localised disease
Only curative treatment option: resection,R0
Prognostic factors:
Size of primary tumor
Mitotic rate (mitózis/50 hpf)
Presence of cKIT mutations
Treatment of advanced disease
Surgery is not preferred
Systhemic treatment: imatinib mesylat
(Glivec) 400 mg /die
Progression: 800 mg/die
cKIT Exon 9 mutation: 800 mg initial dose
Imatinib rezistence/intolerance: sunitinib
Adjuvant therapy
In high risk patients adjuvant Glivec therapy
is indicated to decrease relapse rate