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Neuroendocrine Tumor Classification and Diagnostic Criteria: Evolution and Challenges

This presentation explores the historical evolution and problems with neuroendocrine tumor classification, highlighting diagnostic criteria such as clinical, morphological, hormonal, Ki67, and gene expression factors. It covers the complexities in identifying benign, malignant, and clinically aggressive tumors, discusses the WHO classification changes over the years, and addresses the challenge of fitting the classification system into clinical practice. Specific tumor types like medullary thyroid carcinoma and pheochromocytoma are emphasized. The focus is on understanding the various criteria used for classification and their implications for treatment and prognosis.

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Neuroendocrine Tumor Classification and Diagnostic Criteria: Evolution and Challenges

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  1. Tumori neuroendocrini Il ruolo dell’anatomia patologica M. Papotti, M. VolanteUniversità di Torino Corso AME Milano, 25 maggio 2007

  2. Caro Mauro, …. Riguardo alla tua relazione, considerato il titolo, avremmo piacere che tu affrontassi nel tempo che hai a disposizione 20 min la classificazione del neuroendocrino, i limiti della citologia in rapporto alle scelte terapeutiche, il discorso dei recettori e della loro utilità in pratica clinica. considera che sarà un corso AME (…) con un taglio decisamente pratico e questo anche per quanto riguarda l'anatomia patologica. Invito del dr R. Cozzi

  3. Different diagnostic criteria and classification for • Medullary thyroid carcinoma • Pheochromocytoma/Paraganglioma • Parathyroid adenoma/carcinoma • Pituitary adenoma/carcinoma

  4. neuroendocrine tumor classificationMENU - History, Definition & Glossary - Pathological classification  pure NE tumors  mixed NE/exocrine tumors - Further characterisation

  5. History 1907 “carcinoid” term Oberndorfer 1930 carcinoid syndrome Cassidy 1940/50 “helle zellen” Feyrter 1952 serotonin discovery Erspamer & Asero 1963 fore-, mid-, hind-gut carcinoids Williams & Sandler 1965/70 APUD concept Pearse 1980 diffuse NE system WHO 1994 “neuroendocrine tumor” replaces carcinoid Capella et al 2000 classification of endocrine tumors WHO Solcia et al

  6. History 1907 “Karzinoid” term SiegfriedOberndorfer 6 ileal tumors, slowly growing, no metastases

  7. NE TUMORS Glossary & Synonyms • carcinoid, malignant carcinoid • apudoma • islet cell tumor • adenoma / microadenoma vs carcinoma • Kultchisky cell tumor / carcinoma • endocrine carcinoma • endocrine neoplasm • hormone…-oma (insulinoma, gastrinoma,..) • pancreatic (A/B/D/PP)-cell tumor

  8. Neuroendocrine tumor classificationMENU - History, Definition & Glossary -Pathological classification pure NE tumors  mixed NE/exocrine tumors - Further characterisation

  9. THE BENIGN THE MALIGNANT THE CLINICALLY AGGRESSIVE Clinical Morphological Hormonal Ki67 Gene expression WHICH CLASSIFICATION CRITERION ????

  10. Clinical Morphological Hormonal Ki67 Gene expression Incidence, Localisation, Endocrine function, Symptoms, Treatment, Behavior, Survival

  11. Clinical Morphological Hormonal Ki67 Gene expression insulinoma Macro 1 cm • Single or multiple • Well demarcated or invasive • Size 0.5-15 cm. • Cystic appearance • Lymph node mets • Distant mets Gastric micro-carcinoids

  12. Micro Tumor architecture

  13. Clinical Morphological Hormonal Ki67 Gene expression THE BENIGN THE MALIGNANT THE CLINICALLY AGGRESSIVE Gross features and structure are not enough for the purpose of identifying homogeneous groups with clinical relevance

  14. CLASSIFICATION PROBLEMS 1994 2000

  15. 2000 WHO CLASSIFICATION • Introduces terms tumor/carcinoma (vs carcinoid) ….LUNG EXCLUDED • Replaces neuroendocrine with endocrine • Incorporates hormonally active tumors • (morpho-functional approach) • Recognizes mixed exo-endocrine tumors • Incorporates information on tumor grade • Introduces criteria of malignancy (angioinvasion, Ki67 pancreas, only)

  16. Microscopic features of malignancy • Depth of invasion • Size of tumor • Angioinvasion • High grade cellular atypia GI NETS

  17. 3 TIE SYSTEM for GI NETs

  18. PANCREATIC NETs Microscopic features of malignancy • Invasion of surrounding tissues • Size of tumor (>6 cm is suspected) • High grade cellular atypia • Focal or diffuse necrosis • High mitotic index • Blood or lymph vessel & nerve invasion • Ki67 > 2%

  19. 3 TIE SYSTEM for pancreatic NETs

  20. Does this system fit with the clinical practice? Is it easily applicable? E. Bajetta, L. Catena, G. Procopio, E. Bichisao, L. Ferrari, S. Della Torre, S. De Dosso, S. Iacobelli, R. Buzzoni, L. Mariani and J. Rosai Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? Ann Oncol 2005 16:1374 Problem of other non-carcinoid NETs (eg malignant pheochromocytoma, MTC, parathyroid carcinoma, Merkel cell carcinoma, etc…)

  21. Does this system fit with the clinical practice? Is it easily applicable? • Benign vs uncertain behaviour in well differentiated pancreatic NETs • Appendiceal NETs (small & invasive?) • Mixed endocrine – exocrine tumors • Use morphology or Ki67 first? • The new TNM system for foregut NETs • Extra GEP: pulmonary NETs  especially intermediate grades

  22. BENIGN vs UNCERTAIN BEHAVIOR Benign Uncertain Extrapancreatic growth no no Angioinvasion no yes Size >=2 cm no yes Mitoses >2 /10HPF no yes Ki67 >2% no yes

  23. Resembles WD NET (benign), but in general: size >3 cm, mitoses >2, Ki67 >5% butabove all: unequivocal signs of malignancy must be present LOCAL INVASION LYMPHNODE LIVER

  24. FOREGUT NET CLASSIFICATION Recent proposal of a staging system for fore-gut NETs and improvement of grading system using mitoses + Ki67

  25. SPECTRUM OF PULMONARY NETS TC SCLC Difficulties in identifying the intermediate entities AC LCNEC

  26. SPECTRUM OF PULMONARY NETS TC AC SCLC Indolent clinical behavior Aggressive clinical behavior Significantly different survival Arrigoni et al 1972

  27. SPECTRUM OF PULMONARY NETS TC AC LCNEC SCLC <2 mitoses 3-10 mitoses >10 mitoses small cells no necrosis or necrosis (necrosis) (necrosis) Significantly different survival p<0.0001 Significantly different survival p<0.0001 NO significantly different survival Travis et al Am J Surg Pathol 22,934,1998

  28. SPECTRUM OF PULMONARY NETS TC AC LCNEC SCLC TC AC LCNEC SCLC NO significantly different survival Asamura et al JCO 24:70,2006

  29. Degree of differentiation WELL DIFF. POORLY DIFF. LUNG SMALL CELL/ LARGE CELL NE CARCINOMA TYPICAL CARCINOID ATYPICAL CARCINOID MEEC WELL DIFF. NE TUMOR benign/borderline WELL DIFF. NE CARCINOMA POORLY DIFF. NE CARCINOMA (small/large cell) GEP LOW GRADE HIGH GRADE Biological behaviour

  30. Neuroendocrine tumor classificationMENU - History, Definition & Glossary -Pathological classification  pure NE tumors mixed NE/exocrine tumors - Further characterisation

  31. 2000 WHO CLASSIFICATION CATEGORIES RECOGNIZED • 1 well differentiated endocrine tumor • 2 well differentiated endocrine carcinoma • 3 poorly differentiated endocrine carcinoma • 4 mixed exocrine-endocrine tumor • (5 tumor-like lesions)

  32. CGA Exocrine Endocrine

  33. NE differentiation in colon cancer 1995 CGA mucin

  34. …..ANY BIOLOGICAL and/or CLINICAL SIGNIFICANCE?? pure non-NE ca. non-NE ca. focal NE BREAST and COLORECTAL CANCERS NO Non-NE carcinomas with NE differentiation Y/N ? NSCLC STOMACH & PROSTATE CANCERS YES Breast (WHO2004) Lung (WHO2004) GI tract (WHO2003) Prostate (WHO2003)

  35. >5% NE+ cells

  36. Am J Surg Pathol August 2006 LCNEC of the stomach are significantly more aggressive than conventional ADC. ADC-NED have also a worse prognosis than conventional ADC (borderline significance)

  37. Reduced survival of CGA+ cases CGA increase during progression

  38. CASE REPORT April 2007 July 1996 Nov 1997 Oct 1999 May 2000 Rectal polyp, cancerised Local recurrence Pelvic recurrence Stable disease Rectum resection Radical Surgery FNAB ADC stage B1 • ChTx 1: 5-FU + folic acid (6x) • RT: 50 Grey • ChTx 2: oxaliplatin + 5-FU + folic acid (12x) CgA CgA CgA Oncologia Prof Dogliotti dr Tampellini ChTx 1 RT ChTx 2

  39. pure NE tum. pure non-NE ca. NE tum. non-NE ca. mixed (intermingled) mixed (collision) focal non-NE focal NE 0% 30% 100% non-NE NE 100% 30% 0% Mixed NE/non-NE carcinomas WDET - TC WDEC - AC PDEC – SCLC/LCNEC Non-NE carcinomas with NE differentiation Breast (WHO2004) Lung (WHO2004) GI tract (WHO2003) Prostate (WHO2003) WHO 2000 Endocrine WHO 2004 lung WHO 2000 Endocrine tumors

  40. Degree of differentiation WELL DIFF. POORLY DIFF. LUNG SMALL CELL/ LARGE CELL NE CARCINOMA TYPICAL CARCINOID ATYPICAL CARCINOID Mixed Endo-Exocrine Ca WELL DIFF. NE TUMOR benign/borderline WELL DIFF. NE CARCINOMA POORLY DIFF. NE CARCINOMA (small/large cell) GEP LOW GRADE HIGH GRADE Biological behaviour

  41. HOW TO BREAK THE ARROW? TYPICAL CARCINOID LUNG LUNG WELL DIFF. NE TUMOR benign/borderline ATYPICAL CARCINOID GEP MEEC SMALL CELL/ LARGE CELL NE CARCINOMA WELL DIFF. NE CARCINOMA POORLY DIFF. NE CARCINOMA (small/large cell) Light microscopy + ……?? GEP

  42. Neuroendocrine tumor classificationMENU - History, Definition & Glossary - Pathological classification pure NE tumors mixed NE/exocrine tumors - Further characterisation

  43. Further characterisation • hormonal • Ki 67 • receptors • molecular THE BENIGN THE MALIGNANT THE CLINICALLY AGGRESSIVE

  44. Chromogranins Synaptophysin N-CAM Cytoker. 34bE12 NSE, VMAT PGP9.5 Neurofilaments MARKERS SSTR2 Hormones: calcitonin, bombesin, insulin, glucagon, somatostatin, gastrin, PP, VIP, ACTH, serotonin, … NEW: ghrelin, cortistatin, obestatin, secretagogin[Virch Arch 449, 402, Oct 2006] CGA

  45. Further characterisation • Ki 67 proliferation index LOW HIGH

  46. KI-67: DIAGNOSTIC USE 2000

  47. KI-67: PROGNOSTIC USE OS KI-67 in WD NE carcinoma P = 0.017 Prognostic value if groups are homogeneous (eg all WDCA or PDCA). Otherwise possible bias due to tumor differentiation TTP P = 0.043 Brizzi et al, 2007 (submitted)

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