A.Sadeghipour M.D. Associate Professor of Pathology and Lab. Medicine - PowerPoint Presentation

1. A.Sadeghipour M.D.Associate Professor of Pathology and Lab. MedicineIran University of Medical sciencesThe Pathologic classification of Neuroendocrine Tumors

2. WhyNeuroendocrine Tumors?

3. 50%OF THE NEUROENDOCRINE TUMORSARE DIAGNOSED WHEN IN ADVANCED STAGES

4. Incidence of NETs isRapidly Increasing

5. Complexities of Organ Specific Classification of NETs Could Lead to Confusion inDiagnosis and Management

6. Neuroendocrine TumorsOverview of the PresentationDefinition and historyEpidemiological aspectsClinical presentationParaclinical diagnosis ImmunohistochemistryPathological classification, staging and gradingRole of Pathologist in multidisciplinary approach to diagnosis and management

7. Neuroendocrine TumorsDefinitionNeoplasms originating from the neuroendocrine cell system characterized by cytoplasmic neurosecretory granulesEnterochromaffin Cell

8. EmbryologyEmbryologic data have now refuted the neural crest origin of most neuroendocrine cells.Neural crest origin Endodermal originadrenal medulla extra-adrenal paragangliacells of the myenteric plexus sympathetic gangliathe thyroid C cellsPeptide- and amine-producing cells of the bronchopulmonary tract andGastroenteropancreatic axis

9. Cells of Origin

10. Neuroendocrine TumorsEpidemiological Aspects

11. NETs arise from cells which produce and secrete hormonesMost NETs are slow growing and malignant, with metastatic potentialCommon sites of origin are:GI tractLungsPancreas 11 NETs

12. Incidence of Neuroendocrine Tumors Is Increasing2.0001.003.004.005.006.0001002003004005006005.25Year74767880828486889092949698000204Incidence of all malignant neoplasmsIncidence of neuroendocrine tumorsIncidence of NETs per 100,000Incidence of all malignant neoplasms per 100,000The incidence and prevalence of NETs has increased approximately 500% over the past 30 years (better diagnosis?)Source: US SEER database. Adapted with permission from Yao JC, et al. J Clin Oncol. 2008 26:3063-3072.

13. 13NETs Are the Second Most Prevalent Type of GI Malignancy in the US2x more prevalent than pancreatic cancer1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004. 2. Modlin IM, Lye KD, Kidd M. Cancer. 2003;97(4):934-959.]2x more prevalent than pancreatic cancer[[Colorectal1Stomach1Pancreas1Esophagus1Hepatobiliary1GEP-NET2100, 000Prevalence in SEER Database1,100, 0001,200, 0000

14. NETNeuroendocrine tumours (NETs) are derived from cells that have the unique ability to synthesise, store and secrete a variety of metabolically active substances, peptides and amines, which can cause distinct clinical syndromes.

15. Tumours regarded as NETs on the basis of the immunohistochemical expression of markers of NE differentiation Endocrine-Related Cancer (2010) 17 R173–R193CgA-positive neuroendocrine tumours byimmunohistochemistryAnterior pituitary tumoursNFPAPRLoma (CgB positive)GHACTHTSHFSH/LHParathyroid tumoursMedullary thyroid carcinomaMerkel cell tumourNeuroendocrine gastroenteropancreatic tumours(GEP tumours)Carcinoids (foregut, midgut and hindgut)ECL-omaNon-functioning pancreatic neuroendocrine tumoursGastrinomaInsulinomaVIP-omaGlucagonomaSomatostatinomaPhaeochromocytomaParagangliomaNeuroblastoma and ganglioneuromaSmall/large cell lung carcinoma

16. Neuroendocrine TumorsClinical PresentationsAsymptomatic cases (50%)Initial clinical symptoms are often non-specific and variableCarcinoid syndrome (symptoms mistaken with other more common problems)Most NETs are non-secretory and their clinical presentation before metastasis is non-specific

17. Clinical presentation of GI NETs varies widelyOften discovered incidentallySymptoms due to:Mechanical bulkFibrosisSecretion of various hormonesSerotonin is most common substance secreted from GI NETSerotonin release can cause carcinoid syndrome17GI NETsClinical PresentationSerotonin-producing GI NET (ileum)

18. Symptoms of carcinoid syndrome include:GI NETsCarcinoid SyndromeRapid heart beatHypotensionDiarrheaFlushingHeart diseaseWheezingCarcinoid syndrome is associated with metastatic disease

19. Natural History of Neuroendocrine Tumours19Vinik A, et al. Pancreas. 2009 Nov;38(8):876-89123456789Time, yearsPrimary tumour growthMetastasesFlushingDiarrheaDeathVague abdominal symptomsEstimated time to diagnosis: 5 to 7 years***Symptoms of carcinoid syndrome

20. Nonspecific Symptoms Are Commonto Multiple DiagnosesMenopauseIrritable Bowel SyndromeFunctional Bowel DiseaseAnxietyNeurosisFood AllergyAsthmaAlcoholismThyrotoxicosisPeptic UlcerNETSymptoms • Sweating • Flushing• Diarrhea• Intermittent abdominal pain• Hypoglycemia • Confusion• Bronchoconstriction• Dyspepsia • GI bleeding• Cardiac disease20Aggarwal G, et al. Cleve Clin J Med. 2008;75(12):849-855.

21. Spectrum of paraneoplastic humoral syndromes secondary to NETs

22. Functional NETs: Secrete active substances , peptides and amineNon-Functional NETs: Mass effect

23. Neuroendocrine TumorsPathological classificationStaging/Grading

24. NETs have been traditionally classified as foregut, midgut, or hindgut, depending on site of originReplaced by new tumor-based classification method developed by World Health Organization (WHO)24ClassificationTraditional Method

25. WHO classification defines NETs by degree of tumor differentiation, with specific clinicopathological featuresThe WHO classification system is based on the following criteria:Biological behavior (malignancy)MetastasesKi-67 indexAngioinvasionTumor sizeHistological differentiation Hormonal syndrome25Classification World Health Organization Method

26. WHO Classification 2000The nomenclature used in this classification is considers the following factors:Histomorphology (degree of differentiation)Presence / absence of local invasion / metastasis (Stage)Proliferation index (grade)

27. WHO Classification 2000Well differentiated endocrine tumors - low grade malignancyWell differentiated endocrine carcinomasPoorly differentiated endocrine carcinomas - small cell carcinomasMixed exocrine and endocrine carcinomas Tumor-like lesions

28. WHO Classification

29. WHO Classification 2000

30. Well differentiated neuroendocrine tumor grade 1

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32. WHO Classification 2000

33. Neuroendocrine tumor grade 2 RadioGraphics March 2002 vol. 22 no. 2 351-365

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35. WHO Classification 2000

36. Small cellneuroendocrine carcinoma grade 3Cesar A. Moran etal.Am J Clin Pathology, 2009; 131: 206-221.

37. Cesar A. Moran etal.Am J Clin Pathology, 2009; 131: 206-221. Large cellneuroendocrine carcinomaGrade 3

38. WHO Classification 2010: NeuroendocrineNeoplasms of the Digestive SystemWorking principles “Neuroendocrine” defines the peptide hormoneproducing tumors and share neural-endocrine markers“Neuroendocrine neoplasm” includes well- and poorly differentiated tumorsPremise: All neuroendocrine neoplasms have a malignant potential This premise has an influence on the incidence data because NENs that were regarded as benign and not considered in the incidence data (eg, SEERS data) now have to be included

39. WHO Classification 2010: NeuroendocrineNeoplasms of the Digestive SystemMain criteria determining the malignant potential–Tumor histopathologyo Well differentiatedo Poorly differentiated–Proliferative activity G1, G2, G3–Site, size, infiltration/invasion, metastasis (TNM)o Esophagus, stomach, duodenum, ileum, appendix, colorectum,pancreas

40. Neuroendocrine Neoplasms: NENs of the Gastroenteropancreatic (GEP) SystemBosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

41. Neuroendocrine Neoplasms: NENs of the Gastroenteropancreatic (GEP) SystemBosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

42. GradeLung and Thymus(WHO)GEP-NETs(ENETS)GEP-NETs(WHO 2010)Lung and Thymus(Moran et al)Pancreas(Hochwald et al)Low GradeCarcinoid tumorNeuroendocrinetumor, grade 1 (G1)Neuroendocrineneoplasm, grade 1Neuroendocrinecarcinoma, grade 1Well-differentiatedpancreatic endocrineneoplasm, low gradeIntermediate GradeAtypical carcinoidtumorNeuroendocrinetumor, grade 2 (G2)Neuroendocrineneoplasm, grade 2Neuroendocrinecarcinoma, grade 2Well-differentiatedpancreatic endocrineneoplasm,intermediate gradeHigh Grade Small cell carcinomaNeuroendocrinecarcinoma, grade 3(G3), small cellcarcinomaNeuroendocrinecarcinoma, grade 3,small cell carcinomaNeuroendocrinecarcinoma, grade 3,small cell carcinomaPoorly differentiatedpancreatic endocrinecarcinoma, smallcell carcinomaLarge cellneuroendocrinecarcinomaNeuroendocrinecarcinoma grade 3(G3), large cellneuroendocrineNeuroendocrinecarcinoma, grade 3,large cellneuroendocrinecarcinomaNeuroendocrinecarcinoma, grade 3,large cellneuroendocrinecarcinomaPoorly differentiatedpancreatic endocrinecarcinoma, largecell neuroendocrinecarcinomaSystems of Nomenclature for Neuroendocrine Tumors(Pancreas & Volume 39, Number 6, August 2010)The grade of the tumor MUST be included in the pathology report, along with a reference to the specific grading system being used. Unqualifiedterms such as neuroendocrine tumor or neuroendocrine carcinoma without reference to grade do not provide adequate pathology information.

43. Diagnostic Standards for NENsMandatory:Histopathology―well or poorly differentiatedExpression of neuroendocrine markers synaptophysin and chromogranin AProliferative activity: G1–G3Stage: pTNM (ENETs 2007 and UICC 2009)

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45. Differentiated Stem Cell Origin of GEP-NENs

46. Expression of neuroendocrine markers

47. NE-Cells

48. Neuroendocrine TumorsIHC for DiagnosisCytosolic (NSE, PGP 9.5)Related to secretory granules (chromogrnins)Related to synaptic vesicles (synaptophysin, VMAT)Intermediate filaments (NF, High molecular weight CK)Adhesion molecules (N-CAM)

49. IHC Markers in Diagnosis of NETs

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51. Exceptions Regarding the Staining Specificity of Markers of Neuroendocrine Cells• Chromogranin A may be negative in– Somatostatin-positive duodenal NET– Rectal NET– Paragangliomas• Synaptophysin may be positive in– Adrenal cortex tumors– Solid-pseudopapillary neoplasms of the pancreas

52. Proliferative activity: G1–G3

53. WHO Classification and Grading (2010)for GEP-NEN• Well-differentiated neuroendocrine tumor (NEN)(malignant behavior)– G1 – low grade <2%– G2 – intermediate grade 3%–19%o Information on individual value should be provided– G3 – high grade >20%• Poorly differentiated neuroendocrine carcinoma(NEC)– G3 – high-grade malignant behavior >20 %

54. GradeLung and Thymus(WHO)GEP-NETs(ENETs,WHO)Lung and Thymus(Moran et al)Pancreas(Hochwald et al)Low Grade<2 mitoses / 10 hpfAND no necrosis<2 mitoses / 10 hpfAND <3% Ki67 index<3 mitoses / 10 hpfAND no necrosis<2 mitoses / 50 hpfAND no necrosisIntermediate Grade2-10 mitoses / 10 hpfOR foci of necrosis2-20 mitoses / 10 hpfOR 3%-20% Ki67 index4-10 mitoses / 10 hpfOR foci of necrosis2-50 mitoses / 50 hpfOR foci of necrosisHigh Grade>10 mitoses / 10 hpf>20 mitoses / 10 hpfOR >20% Ki67 index>10 mitoses / 10 hpf,Necrosis present>50 mitoses / 50 hpfGrading Systems for Neuroendocrine TumorsPancreas . Volume 39, Number 6, August 2010

55. Gradin Proposal for GEP NETsENTS and AJCC

56. TNM Classification of GEP-NENsSite-specific TNM staging of NETs of the gastroenteropancreatic system (stomach, duodenum, ileum, appendix, colorectum, pancreas)ENETS: 2006/2007 Rindi, Klöppel, Ahlman, ..... Wiedenmann. TNM staging of foregut, midgut and hindgut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Archiv. 2006;449:395-401, and 2007;451:757-762.UICC: 2009 Sobin, Gospdarowicz, Wittekind. TNM Classification of Malignant Tumours. Wiley- Blackwell. 7th Edition; 2009.

57. Comparability of ENETS 2006/2007 With UICC/AJCC 2009 TNM Classifications

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61. Mixed Adenoneuroendocrine Carcinoma (MANEC)MANECs have a carcinoma phenotype that is recognizable as both adenocarcinoma and neuroendocrine carcinoma – Each component exceeds at least 30% of all neoplastic cells – Both components should be gradedThe identification in adenocarcinomas of scattered neuroendocrine cells (<30%) does not qualify for MANEC

62. Neuroendocrine TumorsLaboratory MarkersUrine 5 HIAABiogenic amine elevated 25-50 folds in GEP NETsSerum NSE: Glycolytic enzyme useful to detect advanced NETsSerum chromogranin A: Diagnostic and prognostic marker85% sensitivity and 95% specificity for diagnosisSerum level correlates with tumor burden1. Oberg K, Stridsberg M. Adv Med Biol. 2000;482:329-337, 2. Taupenot L, Harper KL, O’Connor DT. N Engl J Med. 2003;348:1134-1149, 3. Ardill JE, Erikkson B. Endocr Relat Cancer. 2003;10:459-462.

63. Low CgA≤5000 g/LCgA Levels have Prognostic ValueLevels are indicative of tumor burden1An increase from baseline signals disease progressionA decrease from baseline may indicate a response to treatment2An independent predictor of survival outcome3,45 year survival based on CgA level3,41. Ericksson B, Öberg K, Stridsberg M. Digestion. 2000; 62(suppl 1):33-38. 2. Jenson EH, Kvols L, McLoughlin JM, et al. Ann Surg Oncol. 2007;14(2):780–785. 3. Ardill JES, Ericksson B. Endocrine Rel Cancer. 2003; 10:459-462. 4. Tiensuu Janson EM, Öberg KE, Bailliér’s Clin Gasteroenterol. 1996; 1094:589-601.806040200Survival PercentageHigh CgA>5000 g/L

64. Sensitivity and Specificity of CgADifferential Diagnoses of high and low CgAFalse positive resultsChronic atrophic gastritisProton pump inhibitorsRenal insufficiencyHeart failureCertain states of osmotic diarrheaFalse negative resultsIn poorly differentiated tumorsPatients with SSA treatment

65. 107 cases (41 pre-operative samples)Role of IHC in Targeted TherapyCorrelation of Octreotide Scintigraphy with sstr IHCVolante M. et al Mod Pathol. 2007 Nov;20(11):1172-82. Correlation with:Scintigraphy (107 cases)77%Therapeutic response (28 cases)75%

66. The issue of functionality of NETsFunctioning NETs are defined based on the presence of clinical symptoms due to excess hormone secretionTerms reflecting the clinical syndromes may be applied to these NETs, such as insulinoma, glucagonoma, and gastrinoma.the biologic behavior of most functioning NETs is still defined by the grade and stage of the tumor (although the clinical consequences of the hormone hypersecretion can be significant)

67. The functional status of the tumor is defined by the clinical findings,not by the pathologic appearance or immunohistochemicalprofile

68. Thus The pathologic diagnosis of functioning NETsshould be the same as for analogous nonfunctioning NETs of the same anatomic site

69. Standardization of Pathology ReportCould be Very Helpful

70. Recommendations for ReportingUse the minimum pathology data set schemaUse the exact terms proposed in the classification system you are usingIndicate the classification/grading/staging system used for preparation of the reportTry to stress on the similarities of different classification systems Give the synonyms of the name of a particular tumor when applicableIndicate the result of Ki67 and/or mitotic count in the report

71. Multidisciplinary Approach in the Management of NETsNETManagementPathologistSurgeonEndocrinologistNuclear Medicine Specialist Radiation OncologistGastroenterologist Nurse Medical Oncologist

72. Thank You