Large Cell Carcinoma

Large cell undifferentiated carcinoma

Large cell anaplastic carcinoma

Epidemiology and Etiology:

• 2.3% of all lung CA (has gone down from 10% in 1990s)
• 60 years mean
• Males mostly
• Diagnosis requires a thoroughly sampled, resected tumour
• Many tumours previously classified as large cell carcinoma by 2004 WHO classification are now classified as solid adenocarcinoma or non-keratinizing squamous cell carcinoma, based on IHC and mucin stains.
• Basaloid carcinoma is now considered under squamous cell carcinoma
• Large cell neuroendocrine carcinoma is no longer considered under large cell carcinoma (it is under neuroendocrine tumours now)
• Lymphoepithelioma-like carcinoma is now under other and unclassified carcinomas
• Clear cell is no longer considered a histological subtype, but should be recorded as cytological feature even with small proportions present
• Rhabdoid is no longer considered a histological subtype, but should be recorded as cytological feature even with small proportions present
• Etiology similar to other lung cancers such as adenocarcinoma

Common sites:

• periphery of lung usually

Gross features:

• large
• necrotic
• cavitation rarely

Histologic features:

• sheets, nests
• cohesive typically
• undifferentiated (diagnosis of exclusion)
• lacks features of small cell, glandular, or squamous differentiation (in any part, by definition)
• cytoplasmic secretory products (mucin stain)
• note that these differentiated carcinomas may have areas of large cell carcinoma
• cytological samples may provide subtle morphological differentiation that is not apparent in resection specimens in the absence of immunostains
• large polygonal cells
• high-grade, overtly malignant cytological features:
• large vesicular nuclei with prominent nucleoli
• rhabdoid maybe (should be documented as a percentage of the total tumour (prognostically significant)
• voluminous cytoplasm
• eccentrically placed nuclei
• massive nucleoli
• ovoid perinuclear inclusions maybe, especially by Romanowsky stain
• brightly eosinophilic structures, possibly megamitochondria by Romanowsky stain
• less cohesion
• note that rhabdoid cells may be distinguished from rhabdomyosarcomaotous differentiation (evidence of carcinosarcoma) by CK+ and desmin neg, myogenin neg.
• moderate amount of cytoplasm
• necrosis frequent
• basaloid carcinoma variant:
• lymphoepithelial-like carcinoma variant:
• large cell carcinoma with rhabdoid phenotype variant:
• clear cell carcinoma variant:

Immunophenotype:

Marker:	Sensitivity:	Specificity:
TTF-1 (neg or unclear)
Napsin A (neg or unclear)
P40 (neg or unclear)
P63 (4A4) (neg or unclear)
CK5/6 (or CK5) (neg or unclear)
CD56 (neg)
Synaptophysin (neg)
Chromogranin (neg)
CK7	Typically positive	Typically positive in nearly all resected morphologically undifferentiated adenoCAs (by IHC) / Also positive frequently in p40-positive / TTF-1 neg undifferentiated squamous cell CAs

• TTF-1 and p40 are viewed as the most useful
• Diagnosis of large cell carcinoma is only made when IHC for differentiation markers is negative, unclear, or not available
• 3 subtypes of Large cell carcinoma based on IHC:
• Large cell carcinoma with null immunohistochemical features:
• Positive for cytokeratins
• Negative for lineage-specific markers and mucin
• Large cell carcinoma with unclear immunohistochemistry features:
• Positive for cytokeratins
• Unclear immunoprofiles and negative for mucin
• See table 1.20 in WHO 2015 (p. 83)
• Large cell carcinoma with no stains available:
• No IHC or mucin staining available
• Most TTF1/p40 double negative LCC are thought to be adenocarcinomas based on molecular / microRNA studies
• Neuroendocrine markers do not need to be undertaken routinely in morphologically undifferentiated NSCCs

Molecular features:

• Changes seen in all lung carcinomas
• KRAS mutations (similar to solid-pattern adenoCA)

Other features:

• EM – commonly squamous or adenocarcinoma features
• Grade 4 by definition
• Poor prognosis

References:

• Travis et al. (eds.) WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart (2015)
• Travis WD. Pathology of Lung Cancer. Clinics in Chest Medicine 2002; 23(1): 65-81.