Rare tumors Neuroendocrine tumors Cancer of unknown primary GIST Dr Kocsis Judit

Neuroendokrin 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)

Possible complains/symptoms 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 Májmetastasisok kezelése 30-35 mm átmérőjű 90Y-kapcsolt gyanta mikroszférákkal. Nagy dózisú radioaktivitás a májáttétekben. A vizsgálat előtt 99Tc-makroalbumin vizsgálat a tüdő-shunt vizsgálatára és angiographia a vaszkuláris anatómiára. Nagyon drága.

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 analóg – radioizotóp konjugátum A 111In diagnosztikára alkalmas, de terápiára nem. Terápiában 1, β-sugárzó 90Yttrium 2, β+γ sugárzó 177Lutécium- 90Y-DOTATOC nagyobb, 177Lu-DOTATATE kisebb tumorméret esetén javasolt Elsősorban a jól differenciált daganatok esetében hatékony

Neo-adjuvant treatment Metastatic disease Early phase Surgery Systemic treatment Neo-adjuvant treatment Adjuvant Palliatíve Multidisciplinar approach

Well differentiated neuroendokrin tumor (Ki-67<2%) Summary of treatment options for localised and metastatic NET Role os SSA in treatment Well differentiated neuroendokrin tumor (Ki-67<2%) Well differentiated neuroendokrin carcinoma (Ki-67 3-20%) poorly differentiated neuroendokrin carcinoma (Ki-67 >20%) Surgery, intervention radiology Somatostatin-analóg interferon sunitinib everolimus + combination doxorubicin + streptozotocin temozolamid + capecitabin bevacizumab tünetekre Somatostatin –analóg cisplatin + etopozid tünetekre somatostatinanalóg Endoradiotherapy: szomatosztatin peptid radionuklid kezelés (90Y-DOTATOC, 177Lu-DOTATATE); 131I-MIBG   Kjell Öberg, 2011

Somatostatin-analogs Ala Gly Cys Lys Asn Phe Trp Thr Ser S SS-14 Somatostatin-analogs -Octreotide (sc, infúzió) -Sandostatin LAR (im. havonta) Lanreotide -PR (mély sc 7, 10, 14 naponta) -Somatuline Autogel (mély sc havonta) Pasireotide - Som230 (sc) Phe DTrp Lys Thr Cys S DPhe Thr(ol) Octreotide Tyr DTrp Lys Val Cys S DβNAI Thr Lanreotide Injekciók közötti intervallumok adott esetben növelhetőek DTrp Lys Phe Tyr (Bzl) Phg Pro SOM230 24

SS-analógok → neuroendokrin szekréció redukálása Neurotensin VIP PP Motilin 6000 5000 4000 3000 2000 1000 SSA: funkcionáló tumorok többségét kontrollálja Kezdeti dózis Plazma Peptid koncentráció (pg/mL) Slide 2.5. Sandostatin® Reduces Neuroendocrine Secretions Sandostatin® reduces the secretion of neurohormones that contribute to the symptoms of carcinoid disease, leading to improved symptomatology. Octreotide mérsékli a neurohormonok szekrécióját → tünetek javulnak A magas keringő peptidszint hozzájárul a karcinoid betegség tüneteihez Nap 1 2 3 4 5 6 7 8 9 10 11 12 Kezelés előtt Octreotide kezelés Reference 1. Maton PN, O’Dorisio TM, Howe BA, et al. Effect of a long-acting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med. 1985;312:17-21. 25

Carcinoid crisis treatment: a) Octreotide bolusban, 300 (100-500) μg sc./ iv. b) Octreotide infúzió vagy napi 4-6x 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

CK7 / CK20 CK7 +/ CK20+ CK7+ / CK20 - CK7 - / CK20+ CK7 - / CK20 - Urothelium daganatok; petefészek mucinosus rák; - hasnyálmirigyrák; - epeúti rák; - tüdőrák; - emlőrák; - paizsmirigyrák; - endometrium rák; - méhnyakrák; - nyálmirigy rákok; - colorectalis rákok; - Merkel-sejtes rák; - májsejtrák; - vesesejtes rák; - prosztatarák; laphám- és kissejtes tüdőrák; fej-nyaki rákok; Differenciálás a citokeratin markerek alapján ismeretlen eredetű carcinomák esetén

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.

Gastrointestinal stroma tumor 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