LUNG CANCER PATHOLOGY: UPDATE ON NEUROENDOCRINE LUNG TUMORS
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1 LUNG CANCER PATHOLOGY: UPDATE ON NEUROENDOCRINE LUNG TUMORS William D. Travis, M.D. Attending Thoracic Pathologist Memorial Sloan Kettering Cancer Center New York, NY
2 PULMONARY NE TUMORS CLASSIFICATION LOW GRADE TYPICAL CARCINOID INTERMEDIATE GRADE ATYPICAL CARCINOID HIGH GRADE LARGE CELL NEUROENDOCRINE CARCINOMA SMALL CELL CARCINOMA
3 LUNG NE TUMOR FREQUENCY ATYPICAL CARCINOID % CARCINOID 1-2.0% LCNEC 3.0% NON-NE CARCINOMAS % SCLC %
4 NE TUMORS: CLINICAL FEATURES: JAPANESE REGISTRY TC AC LCNEC SCLC AGE: Mean (Range) yr SEX: % M 52 (17-83) (38-73) (40-84) (17-88) 79.7 PARANEO- PLASTIC % % SMOKERS Asamura H et al: J Clin Oncol 24: 70,
5 CARCINOID: ORGANOID NESTING
6 TYPICAL AND ATYPICAL CARCINOID DIAGNOSTIC CRITERIA TYPICAL CARCINOID Less than 2 mitoses per 10 HPF (2 mm 2 ) and No foci of necrosis ATYPICAL CARCINOID 2-10 mitoses per 10 HPF (2 mm 2 ) OR Foci of necrosis Pleomorphism, cellularity, and vascular invasion are more subjective Travis WD, et al; Am J Surg Pathol 22:934-44, 1998
7 ATYPICAL CARCINOID
8 TYPICAL VS ATYPICAL CARCINOID SURVIVAL 100% 80% 60% 40% 20% 0% PERCENT SURVIVAL NE6/23/94 TC=33; AC=65 P<.001 TIME (YEARS) TC AC
9 IASLC CARCINOID CASES BY DETAILED PATHOLOGIC STAGE 100% 80% 60% 6th Edition Pathological Stage Carcinoid IA IB IIA IIB IIIA IIIB Deaths / N 27 / / 66 7 / 18 6 / 21 5 / 12 0 / 7 5-Year Estimate 92% 95% 65% 71% 64% 100% 100% 80% 60% IASLC Proposed Path Stage Carcinoid IA IB IIA IIB IIIA IV Deaths / N 27 / / / 37 3 / 18 5 / 13 1 / 1 5-Year Estimate 92% 94% 74% 83% 67% 0% 40% 40% 20% 20% 0% Years After Surgery 0% Years After Surgery IASLC DATA: Problem in both IASLC proposed and UICC6: Survival for IIB is better than IIA: Why? Multiple same lobe nodules (n=7) 100% survival; Within 2 cm of carina (n=2); >3cm (n=2); visceral pleural invasion (n=1); unknown T factors (n=7)
10 TNM FOR LUNG CARCINOIDS TNM is a useful predictor of survival N and M factors are strong predictors of survival T factor details are limited in both IASLC and SEER databases T factors that need more detailed evaluation: Size Multiple nodules (ipsilateral same/separate lobe vs contralateral) < 2 cm distal to carina Atelectasis Pleural invasion Cannot assess typical vs atypical carcinoid in these datasets Need for International Registry for Pulmonary NE Tumors Brompton Hospital; London, December 13-14, 14, 2007 Travis WD, et al: JTO 3:1213, 2008
11 2004 WHO CLASSIFICATION LARGE CELL CARCINOMA Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma Basaloid carcinoma Lymphoepithelioma-like like carcinoma Clear cell carcinoma Rhabdoid phenotype
12 LARGE CELL NE CARCINOMA DIAGNOSTIC CRITERIA NE Morphology: Organoid nesting, trabecular, palisading, rosette-like patterns Increased Mitoses (11 or more per 10 HPF or 2mm 2 ; Avg. 60) FEATURES OF A NON-SMALL CELL CARCINOMA Large cell size (> diameter 3 lymphocytes) Low N/C ratio (abundant cytoplasm) Round to oval or polygonal shape Nucleoli frequent and prominent (not every case) Chromatin usually coarse or vesicular, may be finely granular NE Differentiation by EM or Immunohistochemistry
13 LCNEC
14 LCNEC
15 LCNEC
16 AE1/AE3 CD56
17 CGA SYN
18 TTF-1 Ki-67
19 LCNEC IMMUNOHISTOCHEMISTRY PERCENT CGA SYN CD56 Rossi G et al: J Clin Oncol 23: 8774, 2005
20 LCNEC: NCC Research Institute, Tokyo 87 cases (3.1% resected lung cancers) Sex:77M (89%); 10F; Mean age 68 yr (37-82) Smoking: 98%; No paraneoplastic syndrome 5-yr survival overall: 57% Stage 1: 67%; II:75%; III:45%;IV:0% Stage I LCNEC:67%; PD NSCLC:88%, LCC:92% (p=0.003) No difference between Stage I SCLC and LCNEC Takei H et al: J Thorac Cardiovasc Surg 24:285, 2002
21 LCNEC: CHEMOTHERAPY ADJUVANT SETTING Platinum & Etoposide (44mo) vs Gemcitabine & Taxanes (12 mo) vs No chemotherapy (12 mo) P< Rossi G et al: J Clin Oncol 23: 8774, 2005
22 LCNEC: CHEMOTHERAPY METASTATIC SETTING Platinum & Etoposide (51mo) vs Gemcitabine & Taxanes (21 mo) P< Rossi G et al: J Clin Oncol 23: 8774, 2005
23 PULMONARY NE TUMORS 5-yr Survival TC: 87% AC: 56% LCNEC: 27% SCLC: 9% Asamura H et al: J Clin Oncol 24: 70, 2006
24 NONSMALL CELL CARCINOMA WITH NE DIFFERENTIATION (NSCLC-NED) LIGHT MICROSCOPY Ordinary squamous cell, adenocarcinoma, or large cell ca No morphologic NE features ELECTRON MICROSCOPY NE Granules in 5-10% 5 of NSCLC IMMUNOHISTOCHEMISTRY Positive NE markers in 10-20% of NSCLC Definition varies: EM: dense core granules IHC: Antibodies, % staining, # of pos Ab (1 VS 2)
25 NONSMALL CELL CARCINOMA WITH NE DIFFERENTIATION (NSCLC-NED) SURVIVAL Worse (Berendsen( 89, Pujol 93, Hiroshima 2002, Pelosi G 2003) Better (Carles( 93, Schleusener 96, Harada 2002) Not significant (Skov 91, Graziano 93, Linnoila 94, Graziano 94), Gajra A 2002) RESPONSE TO CHEMOTHERAPY Increased (Graziano 89, Linnoila 89) Not increased (Neal 86, Carles 93, Schleusener 96, Gajra A 2002)
26 2004 WHO CLASSIFICATION SMALL CELL CARCINOMA Variant Combined small cell carcinoma
27 SCLC
28 COMBINED SCLC & ADENOCA
29 COMBINED SCLC & SQUAMOUS CELL CA
30 SMALL CELL CARCINOMA IMMUNOHISTOCHEMISTRY KERATIN CD56 CHROMO- GANIN A TTF-1
31 SCLC: CRUSH ARTIFACT
32 SCLC: CYTOLOGY
33 SCLC VS LCNEC: DDX FEATURE Cell Size N/C Ratio SCLC Smaller (< 3 small resting lymphocytes) Higher LCNEC/LCC Larger Lower Nuclear Chromatin Nucleoli Nuclear molding Finely granular, uniform Absent or faint Characteristic Coarsely granular, vesicular, Less uniform Often (not always) present, may be prominent or faint Uncharacteristic Fusiform shape Common Uncommon Polygonal shape with ample pink cytoplasm Nuclear smear Uncharacteristic Common Characteristic Uncommon Basophilic staining of stroma and vesssels Occasional Rare
34 SMALL CELL CARCINOMA LARGE CELL NEUROENDOCRINE CARCINOMA
35 LUNG NE TUMORS: SURVIVAL 5 yr TC: 97% AC: 51.6% LCNEC: 15.5% SCLC: 12.2% 515 Cases: TC-92; AC-128, LCNEC 154, SCLC 141; p<0.0001
36 SURVIVAL STAGE I NE TUMORS 5 yr TC: 98% AC: 73.7% LCNEC: 25.3% SCLC: 20.1%
37 408 MSKCC NE LUNG TUMORS SURGICAL CASES ( )
38 Competing Risks (probability of Survival, accounting for death from other causes)
39 PULMONARY NE TUMORS TREATMENT HISTOLOGY SURGERY CHEMO- THERAPY RADIATION TC Primary approach Not proven Not proven AC Primary approach Not proven Not proven LCNEC If resectable Probably needed Effective locally SCLC Controversial Primary approach Effective locally
40 NE LUNG TUMORS No No No No Rare Rare No No Yes Yes Yes Yes No No Yes Yes MEN I MEN I Mutation Mutation Syndrome Syndrome Yes Yes Yes Yes No No No No Histologic Histologic heterogeneity heterogeneity Yes Yes Yes Yes Yes Yes No No Necrosis Necrosis >11 >11 (median (median-80) 80) >11 >11 (median (median-70) 70) <2 <2 Mitoses per Mitoses per 2mm 2mm 2 SCLC SCLC LCNEC LCNEC AC AC TC TC
41 p53 IHC, LOH AND MUTATIONS NE LUNG TUMORS PERCENT OF CASES TC AC LCNEC SCLC IHC LOH MUT Onuki N, et al: Cancer 85:600, 1999
42 GENE PROFILING: NE TUMORS He P, et al: Hum Pathol 35: 1196, 2004
43 PULMONARY NE TUMORS CLASSIFICATION LOW GRADE TYPICAL CARCINOID INTERMEDIATE GRADE ATYPICAL CARCINOID HIGH GRADE LARGE CELL NEUROENDOCRINE CARCINOMA SMALL CELL CARCINOMA
44 INTERNATIONAL REGISTRY OF NE LUNG TUMORS Will collect TC with metastases AC LCNEC Resected SCLC Tissue archive (slides, blocks, frozen tissue) Pathology panel consensus review Clinical Data: Therapy & Response? National Registries Exist in Spain and Japan Encourage Collaboration
45 INTERNATIONAL NE LUNG TUMOR REGISTRY OVERALL GOALS To develop collaborations that allow for combining data on rare NE tumors to answer difficult questions that none of us can answer by ourselves To encourage existing (Japan, Spain) and the development of new national registries of pulmonary NE tumors To establish an international consensus and a worldwide uniform approach to diagnosis (2004 WHO classification) To develop a tissue network for study of molecular changes with hope of identifying molecular therapeutic targets
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