Neuroendocrine neoplasms of the lung M Papotti, L Righi, & M Volante University of Turin at San Luigi Hospital TORINO
NETs OF THE LUNG Menu - Spectrum of NE lung tumors - CARCINOID TUMORS - SCLC /LCNEC - Combined NE and non-ne carcinomas - Mechanisms driving NE differentiation - Predictive markers of response to therapy
SPECTRUM OF LUNG NETs typical carcinoid atypical carcinoid Small or Large cell NE carcinoma rare very rare common rare Most benign Malignant 2004
TC AC LCNEC SCLC -Different & separate subtypes in the WHO -Different epidemiology and pathology -Different therapy & clinical behavior -Different Authors.. LB WOOLNER WD TRAVIS TC AC LCNEC J AZZOPARDI SCLC among others
SPECTRUM OF PULMONARY NETs typical carcinoid atypical carcinoid Small or Large cell NE carcinoma rare very rare common rare Most benign (low grade) Malignant
DIAGNOSIS of CARCINOIDS No major diagnostic problems for the typical typical carcinoid (surgical specimen) TC
DIAGNOSIS of CARCINOIDS TC SCLC AC Difficulties in identifying the intermediate entities 1972 at Mayo -Hypercellularity & disorganised structure -Nuclear pleomorphism -Mitotic count>5-10/10hpf -Necrosis Arrigoni, Woolner et al 1972
SPECTRUM OF LUNG NE TUMORS TC AC SCLC Different survival 2-9 mitoses or necrosis Ki67
20 years later.. SPECTRUM OF LUNG NE TUMORS TC AC LCNEC SCLC <2 mitoses 2-9 mitoses >10 mitoses small cells no necrosis or necrosis (necrosis) (necrosis) Significantly different survival MITOSES p<0.0001 Significantly different survival p<0.0001 NO significantly Travis et al 1991 & 1998 different survival
SPECTRUM OF PULMONARY NETs Well differentiated Poorly differentiated typical carcinoid atypical carcinoid Small or Large cell NE carcinoma rare very rare common rare Most benign Malignant
LCNEC: HISTORY Travis WD, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell NE carcinoma. AJSP 1991;15:529-53 NE differentiated Travis WD, et al. Survival analysis of 200 pulmonary NE tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. AJSP 1998;22:934-44
LCNEC morphology - Organoid growth - Large cells - Extensive necrosis - Atypias & nucleoli - High mitotic index CgA Ki67
LCNEC: diagnostic challange. Mitotic count & necrosis as crucial criteria N Where was LCNEC born from? See blue circle Atypical carcinoid Anaplastic LCC >10 mitoses NE differentiated cell intermediate cell type SCLC oat cell
HISTORY OF SCLC
No major diagnostic problems for the classical oat cell type -solid growth of small cells -3 lymphocytes in size -finely granular chromatin dark nucleus
SCLC CGA SYN -DNA crush artifacts: (Azzopardi s phenomenon) -extensive necrosis -high mitotic count TTF1
DISTINGUISHING SCLC FROM LCNEC: does it matter? Significant indicators for differential dx: organoid growth, tumor cell size, N/C ratio, nuclear molding, rosette formation, prominent nucleoli Sun, Pathol Int 2009 However, large degree of overlap exists: eg: cell size chromatin texture immunoprofile Hiroshima, Modern Pathol 2006
In addition: - Similar behavior & survival. - Similar therapy of LCNEC and SCLC Asamura et al JCO 24, 70-76, 2006 DISTINGUISHING SCLC FROM LCNEC: does it matter? NO!!!!!!!!!!!!
MIXED SMALL AND LARGE CELL CAs: does it matter? Same case, but = cell size xs S M L XL
SPECTRUM OF LUNG NE TUMORS TC AC LCNEC SCLC TC AC LCNEC SCLC NO significantly different survival
NET DIAGNOSIS No major diagnostic problems for the two entities at the extremes of the spectrum at least in histological material TC SCLC? Peripheral, size 11 mm
necrosis
Mitoses 3 mit 2 mit 4 mit 5 mit
WHERE DOES THIS TUMOR STAND IN THE SPECTRUM? TC AC LCNEC SCLC Diagnostic work up: Structure: organoid + diffuse Cytology: small cell type (mostly) + spindle Diagnostic criteria: high grade (by mitoses) Tentative diagnosis: High grade NE carcinoma
WHAT ELSE????? SPECTRUM OF PULMONARY NETs typical carcinoid atypical carcinoid Small or Large cell NE carcinoma rare very rare common rare Most benign Malignant + Combined small/large cell NE and adeno- or squamous carcinoma + Conventional adenocarcinoma with NE differentiation
pure NE tum. NE tum. focal non-ne combined (intermingled) combined (collision) non-ne ca. focal NE pure non-ne ca. 0% NE 100% 30% non-ne 100% 30% 0% Combined LCNEC & squamous ca CgA HMW CK
Q3: What do mixed tumors look like? SEPARATE FRUITS SINGLE FRUITS NEARBY FRUIT SALAD FRUIT SALAD SEPARATE TUMORS COLLISION TUMORS COMBINED (COMPOSITE) MIXED TUMOR What about this condition? (ie cherries + very few strawberries) courtesy dr Volante Conventional ADC with focal NE differentiation
Unfortunately, the identification of a NE component is largely depending on the selected method & marker 12.5% + by CgA IHC 37.5% + by CgA RTPCR
HMW cytokeratins: useful non-ne marker Combined SCLC & squamous ca mixed (collision) CgA HMW CK
COMBINED LUNG CARCINOMAS CgA SCLC + Squamous ca 7 cases studied Am J Clin Pathol 131, 376, 2009 HMW CK
Q3: What do mixed tumors look like? pure NE tum. NE tum. focal non-ne mixed (intermingled) mixed (collision) non-ne ca. focal NE pure non-ne ca. 0% 100% NE 30% 50% Combined SCLC/LCNEC GEP MANEC non-ne 100% 30% 0%
Conventional NSCLC with focal NE differentiation pure NE tum. NE tum. focal non-ne combined (intermingled) combined (collision) non-ne ca. focal NE pure non-ne ca. 0% NE 100% 30% 100% non- NE 30% 0%
NE DIFFERENTIATION in NSCLC PATHOLOGIST: Present in up to 25% of NSCLC, depending on the method used to assess NE phenotype ONCOLOGIST: Define the clinical significance, if any!! NO BREAST and COLORECTAL CANCERS Y/N? NSCLC YES STOMACH & PROSTATE CANCERS
YES Prognostic significance NO >5% NE cells Ionescu, Gown. NSCLC with NE differentiation-an entity of no clinical or prognostic significance. AJSP 2007;31:26 yrs OS Segawa et al. IHC detection of NE differentiation in non-smallcell lung cancer and its clinical implications. J Cancer Res Clin Oncol. 2009 Jan 17
NETs OF THE LUNG Menu - Spectrum of NE lung tumors - CARCINOID TUMORS - SCLC /LCNEC - Combined NE and non-ne carcinomas - Mechanisms driving NE differentiation - Predictive markers of response to therapy
WHO DRIVES NE DIFFERENTIATION? Role of hash-1? Human homologue-1 of achaete-scute gene from Drosophila Family of basic helixloop-helix (bhlh) transcription factors (Johnson et al., Nature 1990) Critical role in normal development of peripheral nerves (Lo & Anberson, Neuron 1995) and endodermal endocrine cells (Guillemot et al. Cell.1993)
hash-1 in human NE tumors: Medullary thyroid carcinoma (Ball, PNAS 1993) Neuroblastoma (Rostomlily, Cancer Res 1997) Gastrointestinal NE ca (Takashi, Cancer Res 2005) Small Cell Carcinoma of the lung (Hirotaka, Cancer Res 2005; Borges, Nature 1997) SCLC NSCLC In SCLC, ASCL1 gene modulates tumor-initiating capacity by directly regulating stem cell marker genes (CD133 and ALDH1A1). Jiang et al. Cancer Res. 2009;69:845
By in situ hybridisation By immunohistochemistry hash-1 CgA TC SCLC LCNEC
hash-1 in NE differ prostate & lung ca In combined lung cancers, hash1 is mostly expressed in the NE component, both in chromogranin positive and negative cells CgA Mod Pathol 2008 hash1 transfected NSCLC cell lines express hash1 de novo and NE markers in parallel. H522 cells hash-1 hash1 Rapa et al manuscript in preparation CgA
SUMMARY TC AC LCNEC SCLC Menu - Spectrum of NE lung tumors - CARCINOID TUMORS - SCLC /LCNEC - Combined NE and non-ne carcinomas - Mechanisms driving NE differentiation
Thank you!! Susanna Cappia Marco Volante Luisella Righi Ida Rapa Valentina Monica Eleonora Duregon Arianna Votta Jessica Giorcelli Gaia Gatti University of Turin at San Luigi Hospital
HISTOLOGICAL TYPES WHO 1981: A- oat cell, B- intermediate cells (round or spindled) C- combined with a NSCLC histotype IASLC 1988 : A- oat cell, B- mixed small & large cell, C- combined small & non-small cell lung carcinoma