Small Cell Carcinoma of the Lung

Epidemiology and Etiology:

• Highly correlated with smoking history (>98% in smokers)

Common Sites:

• Central location more common
• 65% present as perihilar mass
• rarely endobronchial (although may constrict bronchus from external compression)

Gross features:

• extensive lymph node mets commonly
• white-tan
• soft
• friable
• extensive necrosis
• extrinsic compression of bronchus with advanced disease

Histologic features:

• peribronchial location with infiltration of bronchial submucosa and peribronchial tissue
• diffuse sheets usually
• may see rosettes, peripheral palisading, organoid nesting, streams, ribbons
• rarely tubules or ductules
• Small,round, oval, fusiform, and spindle-shaped cells
• Usually diameter of 2 or 3 lymphocytes
• Scant cytoplasm
• High n:c ratio is useful to discriminate from LCNEC
• Poorly defined cell borders
• Finely granular nuclear chromatin
• absent or inconspicuous nucleoli
• Nuclear molding is prominent
• Crush artifact is common – think small cell if you see crush on biopsy
• High mitotic count
• Numerous apoptotic bodies
• Necrosis is common and often extensive
• Basophilic staining of vascular walls (DNA) (Azzopardi effect) in necrotic areas
• All are high-grade
• combined small cell lung carcinoma:
• mixed with non-small cell histology
• >10% required for combined small cell carcinoma with LCNEC
• No minimum percentage for adeno or squamous components
• chemotherapy effects:
• mixtures of large cell, squamous, giant cell, or adenocarcinoma (15-45%)

Immunophenotype:

Marker:	Sensitivity:	Specificity:
Chromogranin A	Most (May be focal / weak)
Synaptophysin	Most
CD56 (Leu-7) (NCAM) (neural cell adhesion molecule)	Most sensitive	Less specific than other NE markers Uncommonly can be positive in basaloid squamous
BCL2	90%
Pankeratin (AE1/AE3)	99%
TTF-1	Up to 90-95% (esp. less specific clone)	Usually absent in typical carcinoids, present in LCNEC usually
AE1/AE3 CAM5.2 MNF116 (small perinuclear dots or diffuse cytoplasmic)		Not
HMWK cocktail (neg) (CK1, CK5, CK10, CK14) (34BE12 is CK14?)	“Always”
GFAP		Not
Napsin A (neg)	Consistently
CD117 (c-kit)
Ki-67 > 50% (65-80%) (may reach 100%)		Ewing family tumours are less mitotically active than SCLC
CD99 (neg)		Majority of Ewing Family Tumours have diffuse membranous expression of CD99 and usually lack keratin expression
CK20 (neg)		Merkel cell is CK20+/CK7-/TTF1-
P63 (neg)
P40 (neg)

• no stain reliably separates small cell CA from non-small cell CA or LCNEC (light microscopy is best)
• < 10% of SCLC can be completely unreactive or only very focally reactive for NE markers

Molecular features:

• similar to LCNEC
• Modal chromosome numbers typically in the triploid range (4)
• Losses:
• 3p (90%) (4)
• 3p25-26 (4)
• 3p24 (4)
• 3p21.3 (4)
• 3p14.2 (4)
• 3p12 (4)
• candidate tumour suppressor genes:
1. Beta-retinoic acid receptor gene (4)
2. Protein-tyrosine phosphatase-gamma gene (4)
3. Semaphorin IV and A(V) gene (4)
4. VHL (4)
5. FHIT (4)
6. RASSF1 (4)
• 17p (4)
• 17p13 (4)
1. candidate TSGs:
1. TP53 (4)
• 5q (90%) (4)
• 5q13-21 (4)
1. candidate tumour suppressor genes:
1. p85alpha regulatory unit of phosphatidylinositol-3 kinase gene (4)
2. APC (4)
• Chromosome 13 (4)
• 13q (90%) (4)
• Candidate TSGs:
1. RB1 (13q14) (4)
• 4q (60-70%) (4)
• 10q (60-70%) (4)
• 10q24-26 (4)
1. potential TSGs:
1. PTEN/MMAC1 – known deleted/mutated in multiple malignancies
1. Not seen in NSCLCs
• 16q (60-70%) (4)
• Gains:
• 3q (60-70%) (4)
• 5p (60-70%) (4)
• 8q (40%) (4)
• 19q (40%) (4)
• Amplifications:
• MYC amplifications (8q21-23) (30%)
• not usually seen in NSCLC ( < 10%)
1. MYCC amplification is seen in both SCLC and NSCLC (5)
• also MYCL1 (1p32) (4)– limited to SCLC (5)
• also MYCN (2p23) (4) – limited to SCLC (5)
• 6q21 (5)
• 19q13.1
• Genes overexpressed:
• E2F1 (downstream of RB)
• Genes underexpressed:
• 14-3-3sigma (hypermethylation) (frequent in SCLC) (6)
• RB alterations (loss of Rb expression) (80-100%) (>90%) (6)
• Much higher frequencies than in NSCLC, except large cell with neuroendocrine features (6)
• p16 and cyclin D1 expression are normal in most
• P53 mutation (50-80%)
• Both RB and p53 alterations are present in virtually all SCLCs (6)
• bcl2/bax
• Intense BCL2 expression on immuno
• LOH 5q (frequent in early stage SCLC)
• Infrequent in non-metastatic NSCLC
• Gene not identified
• APC gene mutations
• Component of the wnt pathway (up to 5%)
• Changes common to all lung carcinomas

Other features:

• EM shows dense-core neurosecretory granules, 100nm in diameter (66%)
• Paraneoplastic syndromes common

References:

• Robbins 2005
• Travis WD. Pathology of Lung Cancer. Clinics in Chest Medicine 2002; 23(1): 65-81.
• WHO Lung books 2004, 2015
• (4) Balsara BR, Testa JR. Chromosomal imbalances in human lung cancer. Oncogene (2002); 21: 6877-83.
• (5) Zunyan D et al. A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. Human Molecular Genetics (2003); 12(7): 791-801.
• (6) Osada H and Takahashi T. Genetic alterations of multiple tumour suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene (2002); 21: 7421-34.