Squamous Cell Carcinoma of the LUNG (SqCC)

Epidemiology and Etiology:

• Closely correlated with smoking history (>98% in smokers)
• Arises most often in segmental bronchi with involvement of lobar and mainstem bronchus by extension

Common sites:

• Central location (65%) – in continuity with segmental or subsegmental bronchi
• Commonly obstruct the airway with atelectasis of distal lung

Gross features:

• Gray-white
• Firm
• Necrosis or central cavititation common

Histologic features:

• Keratinization
• Squamous pearls
• Individual cells with markedly eosinophilic dense cytoplasm
• Intercellular bridges
• Papillary type
• clear cell type
• small cell type
• basaloid types

Immunophenotype:

Marker:	Sensitivity:	Specificity:
p40	Uncommonly completely absent	More specific than p63
p63		Positive in up to 30% of adenocarcinoma
CK5	Most
CK 5/6	Most
P40		Most specific marker for squamous CA
34BetaE12	Most	Frequently diffusely positive in solid pattern adenocarcinoma
CEA	Most
35BetaH11 (low-molecular weight keratin)	Many
TTF-1 (neg)	Most Rarely weak/focal expression in non-keratinizing SqCA Should be negative in keratinizing SqCA
CK7 (neg)	Positive in up to 30%	Urothelial CA is more often positive (not great to distinguish the two)
Desmocollin 3	Lower sensitivity than p40	Fairly specific
GATA3 (neg)	Most	Urothelial CA is more often positive
Uroplakin 3 (neg)	Most	Urothelial CA is more often positive
CK20 (neg)	Most	Urothelial CA is more often positive

• For distinguishing primary lung SqCA from mets, p53 and p16 may be helpful
• Biopsy:
• Cases positive for a squamous marker (i.e. p40 or p63) with at least moderate, diffuse staining, and a negative adenocarcinoma marker and/or mucin stains should be classified as NSCC, favour squamous cell carcinoma
• If an adenocarcinoma marker such as TTF-1 is positive, the tumour should be classified as NSCC, favour adenocarcinoma, regardless of any expression of squamous markers.
• If SqCC marker (i.e. p40, p63, and/or CK5/6) is positive, and ADC marker / mucin neg, then can call NSCC< favor SqCC
• Resection:
• If TTF-1 is negative (not focal or diffuse) then SqCC diagnosis can be made with diffuse positivity for any one of the following: p63, p40, CK5, CK5/6
• Non-keratinizing squamous cell carcinoma should show diffuse positive staining for p40
• The presence of intracellular mucin in a few cells does not exclude tumours from this category

Molecular features:

• For distinguishing primary lung SqCA from met, TP53 mutation, loss of heterozygosity involving microsatellite markers, or HPV testing / genotyping may be helpful
• Gene expression profile:
• High expression:
1. keratins (5, 6, 13, 14, 16, 16, 19)
2. collagen VII alpha 1
3. galectin 7
4. ataxia-telangiectasia group D-associated protein
5. s100 calcium binding protein A2
6. bullous pemphigoid antigen 1
7. p63 (found in 3q26-29 region)
1. other genes in this area also overexpressed:
1. claudin 1
2. phosphatidylinositol glycan class X
3. discs large homologue 1
2. regardless of CNAs present or not
• P53 mutations
• Highest frequency of all lung cancers
• APC gene mutations
• Component of the wnt pathway (up to 5%)
• TP63 overexpression / amplification:
• Not in other histologic types
• encodes for p63 protein, a member of the p53 family
• plays a role in squamous differentiation
• may be required for development of squamous metaplasia and SCC
• 3q
• Only region of genome consistently shown to differ between SCC and AC is 3q26-29 (1, ref in 1) 3q24-qter (CGH) (4)
• 3q26-27 amplified in 25-40% of SqCA and only very rarely in AdCA (3)
• This region is amplified in SCC (50-85%) and 25-30% of AC (1) (2)
• Located at 180 to 199Mb on chromosome 3 (3q26-29)
• PIK3CA is at 3q26 – potentially relevant (2) (4)
• Either near diploid or hyperdiploid-aneuploid with mean chromosome numbers in the triploid range
• Aneuploidy is a bad prognostic marker
• Multitude of cytogenetic alterations are characteristic
• Amplifications of telomeric 3q region
• Most characteristic cytogenetically for SCC phenotype
• Gain of 3q24qter in majority of SCC and minority of adenocarcinomas
• Alterations associated with metastatic phenotype:
• Deletions of 3p12-p14, 4p15-p16, 8p22-p23, 10q, 21q
• Overrepresentation of 1q21-q25, 8q11-q25
• Other frequent deletions:
• 3p (larger segments of allelic loss than most adenocarcinomas and preneoplastic/preinvasive lesions)
1. FHIT (fragile histidine triad) gene deletion or methylation
• 4q, 5q, 8p, 9p, 10q, 11p, 13q, 17p, 18q, 21q
• Frequent overrepresentations:
• 5p, 8q, 11q13, 12p
• Changes common to all lung carcinomas

Other features:

• somewhat better prognosis stage for stage than adenocarcinoma
• metastasize outside of the thorax late compared to other lung cancers
• hypercalcemia (almost pathognomic – rarely seen in other lung cancers)
• SCC histology predicts for life-threatening hemorrhage with bevacizumab treatment

References:

• Robbins 2005
• Travis WD. Pathology of Lung Cancer. Clinics in Chest Medicine 2002; 23(1): 65-81.
• WHO blue book 2004
•  (1) Tonon G et al. High-resolution genomic profiles of human lung cancer. PNAS (2005); 102(27): 9625-30.
• (2) Balsara BR, Testa JR. Chromosomal imbalances in human lung cancer. Oncogene (2002); 21: 6877-83.
• (3) 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.