5/1/2009 LARGE CELL NEUROENDOCRINE CARCINOMA William D. Travis, M.D. William D. Travis, M.D. Attending Thoracic Pathologist Attending Thoracic Pathologist Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center New York, NY New York, NY PULMONARY NE TUMORS CLASSIFICATION � LOW GRADE LOW GRADE • TYPICAL CARCINOID TYPICAL CARCINOID � INTERMEDIATE GRADE INTERMEDIATE GRADE • ATYPICAL CARCINOID ATYPICAL CARCINOID � HIGH GRADE HIGH GRADE • LARGE CELL NEUROENDOCRINE LARGE CELL NEUROENDOCRINE CARCINOMA CARCINOMA • SMALL CELL CARCINOMA SMALL CELL CARCINOMA SPECTRUM OF NE LUNG LESIONS � NE Cell hyperplasia & tumorlets (<5mm) NE Cell hyperplasia & tumorlets (<5mm) � Tumors with NE morphology Tumors with NE morphology • Typical carcinoid Typical carcinoid • Atypical carcinoid Atypical carcinoid • Large cell NE carcinoma L L Large cell NE carcinoma ll NE ll NE i i • Small cell carcinoma Small cell carcinoma � Non Non- -small cell carcinoma with NE small cell carcinoma with NE differentiation differentiation � Other tumors with NE properties Other tumors with NE properties 2004 WHO CLASSIFICATION OF LUNG AND PLEURAL TUMORS 1
5/1/2009 LUNG NE TUMOR FREQUENCY ATYPICAL CARCINOID 0.1-0.2% CARCINOID 1-2.0% LCNEC 3.0% NON-NE CARCINOMAS 75-80.0% SCLC 15-20.0% Surgically Resected SCLC 0.75-1.0% TYPICAL AND ATYPICAL CARCINOID DIAGNOSTIC CRITERIA � 1.3.7.1 TYPICAL CARCINOID 1.3.7.1 TYPICAL CARCINOID Less than 2 mitoses per 10 HPF (2 mm 2 ) and • Less than 2 mitoses per 10 HPF (2 mm ) and No foci of necrosis No foci of necrosis � 1.3.7.2 ATYPICAL CARCINOID 1.3.7.2 ATYPICAL CARCINOID 10 mitoses per 10 HPF (2 mm 2 ) • 2- -10 mitoses per 10 HPF (2 mm OR OR • Foci of necrosis Foci of necrosis � Pleomorphism, cellularity, and vascular invasion are Pleomorphism, cellularity, and vascular invasion are more subjective more subjective Travis WD, et al; Am J Surg Pathol 22:934-44, 1998 ATYPICAL CARCINOID 2
5/1/2009 2004 WHO CLASSIFICATION SMALL CELL CARCINOMA Variant Variant Co Co Combined small cell carcinoma Combined small cell carcinoma b b ed s ed s ce ce c c c c o o SCLC 2004 WHO CLASSIFICATION LARGE CELL CARCINOMA Large cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Combined large cell Combined large cell neuroendocrine carcinoma neuroendocrine carcinoma Basaloid carcinoma Basaloid carcinoma Lymphoepithelioma Lymphoepithelioma- -like carcinoma like carcinoma Clear cell carcinoma Clear cell carcinoma Rhabdoid phenotype Rhabdoid phenotype 3
5/1/2009 LARGE CELL NE CARCINOMA DIAGNOSTIC CRITERIA � NE Morphology: Organoid nesting, trabecular, NE Morphology: Organoid nesting, trabecular, palisading, rosette palisading, rosette- -like patterns like patterns Increased Mitoses (11 or more per 10 HPF or 2mm 2 ; � Increased Mitoses (11 or more per 10 HPF or 2mm ; Avg. 60) Avg. 60) � FEATURES OF A NON FEATURES OF A NON- -SMALL CELL CARCINOMA SMALL CELL CARCINOMA • Large cell size (> diameter 3 lymphocytes) Large cell size (> diameter 3 lymphocytes) • Low N/C ratio (abundant cytoplasm) Low N/C ratio (abundant cytoplasm) • Round to oval or polygonal shape Round to oval or polygonal shape • Nucleoli frequent and prominent (not every case) Nucleoli frequent and prominent (not every case) • Chromatin usually coarse or vesicular, may be finely Chromatin usually coarse or vesicular, may be finely granular granular � NE Differentiation by EM or Immunohistochemistry NE Differentiation by EM or Immunohistochemistry LCNEC LCNEC 4
5/1/2009 AE1/AE3 CD56 CGA SYN LCNEC IMMUNOHISTOCHEMISTRY 92.8 100 80 65.1 53 53 60 40 20 0 PERCENT CGA SYN CD56 Rossi G et al: J Clin Oncol 23: 8774, 2005 5
5/1/2009 TTF-1 Ki-67 COMBINED LCNEC & ADENOCA MSKCC: 86 LCNEC HISTOLOGY Type Type Number (%) Number (%) Pure LCNEC Pure LCNEC 68 (79%) 68 (79%) Combined LCNEC/Adenoca Combined LCNEC/Adenoca 15 (19%) 15 (19%) Combined LCNEC/Squamous Combined LCNEC/Squamous 2 (2%) 2 (2%) Combined LCNEC/Giant Cell Combined LCNEC/Giant Cell 1 (1%) 1 (1%) Total Total 86 86 6
5/1/2009 MSKCC: 86 LCNEC HISTOLOGY Type Type Number (%) Number (%) Surgically Resected Specimens: Pure LCNEC Pure LCNEC 68 (79%) 68 (79%) Combined LCNEC/Adenoca Combined LCNEC/Adenoca 80% – Pure LCNEC 15 (19%) 15 (19%) Combined LCNEC/Squamous Combined LCNEC/Squamous 2 (2%) 2 (2%) 20% – Combined LCNEC Combined LCNEC/Giant Cell Combined LCNEC/Giant Cell 1 (1%) 1 (1%) Total Total 86 86 SCLC VS LCNEC: DDX FEATURE FEATURE SCLC SCLC LCNEC/LCC LCNEC/LCC Cell Size Cell Size Smaller (< 3 small resting Smaller (< 3 small resting Larger Larger lymphocytes) lymphocytes) N/C Ratio N/C Ratio Higher Higher Lower Lower Nuclear Chromatin Nuclear Chromatin Finely granular, uniform Finely granular, uniform Coarsely granular, vesicular, Coarsely granular, vesicular, Less uniform Less uniform Nucleoli Nucleoli Absent or faint Absent or faint Often (not always) present, Often (not always) present, may be prominent or faint may be prominent or faint Nuclear molding Nuclear molding Characteristic Characteristic Uncharacteristic Uncharacteristic Fusiform shape Fusiform shape Common Common Uncommon Uncommon Polygonal shape with ample Polygonal shape with ample Uncharacteristic Uncharacteristic Characteristic Characteristic pink cytoplasm pink cytoplasm Nuclear smear Nuclear smear Common Common Uncommon Uncommon Basophilic staining of stroma Basophilic staining of stroma Occasional Occasional Rare Rare and vesssels and vesssels SMALL LARGE CELL CELL CARCINOMA NEUROENDOCRINE CARCINOMA 7
5/1/2009 NE TUMORS: Ki-67 TC AC LCNEC SCLC SPECTRUM OF NE DIFFERENTIATION LARGE CELL CARCINOMA DIAGNOSIS NE MORPHOLOGY NE IHC OR EM LCNEC YES YES LC WITH NE- YES NO MORPHOLOGY LCC-NE NO YES DIFFERENTIATION LCC (NON-NE) NO NO LUNG 515 NE TUMORS: AFIP, GRENOBLE, MANCHESTER: SURVIVAL 5 yr TC: 97% C 9 % AC: 51.6% LCNEC: 15.5% SCLC: 12.2% 515 Cases: TC-92; AC-128, LCNEC – 154, SCLC – 141; p<0.0001 8
5/1/2009 SURVIVAL STAGE I NE TUMORS 5 yr TC: 98% C 9 % AC: 73.7% LCNEC: 25.3% SCLC: 20.1% Travis W et al, unpublished AFIP data LARGE CELL NEUROENDOCRINE CARCINOMA 3-year Surv; N Stg 1: 40.1%;54 Stg 2: 19.0%; 21 Stg 3: 23.6%;24 Stg 4:12.1%;11 P<0.001; Tot:110 Travis W et al, unpublished AFIP data MSKCC 367 NE TUMORS: OVERALL SURVIVAL p<0.001 Survival: 5 & 10 yr TC (n=190): 99 & 91% AC ( AC (n-29): 87 & 31% 29) 87 & 31% LCNEC (n=86):42 & 21% SCLC (n=62): 34 & 22% Roh MS et al, unpublished data 9
5/1/2009 MSKCC SCLC VS LCNEC: OVERALL SURVIVAL p=NS SCLC: N=60 5 YR: 34% LCNEC: N=87 5 YR: 42% Roh MS et al, unpublished data MSKCC: SCLC AND LCNEC BY AGE LCNEC: Mean:63 yr, Median:63 yr SCLC: Mean:67 yr, Median:69 yr RANGE: 43-80 yr RANGE: 40-86 yr MSKCC: SCLC AND LCNEC BY AGE AGE: SCLC OLDER SCLC OLDER THAN LCNEC; P=0.010 SCLC: Mean:67 yr, Median:69 yr LCNEC: Mean:63 yr, Median:63 yr RANGE: 43-80 yr RANGE: 40-86 yr 10
5/1/2009 MSKCC: LCNEC AND SCLC BY SEX 50 47 45 40 ents 39 35 35 Number of Patie 31 31 30 25 Male Female 20 15 10 5 0 LCNEC SCLC Roh MS et al; unpublished data MSKCC: LCNEC AND SCLC BY SEX 50 47 45 40 ents 39 High grade NE carcinomas: Significantly High grade NE carcinomas: Significantly g g g g g g y y Number of Patie 35 35 31 31 more males than carcinoids (p=0.003) more males than carcinoids (p=0.003) 30 Male 25 Female 20 15 10 5 0 LCNEC SCLC Roh MS et al; unpublished data MSKCC: LCNEC AND SCLC BY SMOKING HISTORY 70 69 60 ents 50 50 Number of Patie 48 48 40 Never Former 30 Current 20 15 10 7 5 1 0 LCNEC SCLC Roh MS et al; unpublished data 11
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