Large cell carcinoma of the lung

Definition

An undifferentiated carcinoma lacking squamous, glandular or small cell features.

Epidemiology

Large cell carcinoma accounts for about 9% of primary lung carcinomas, of which about one third are large cell neuroendocrine carcinomas. All subtypes occur predominantly in smokers, except for lymphoepithelioma-like carcinoma⁷, which is most common in among the Chinese^2,4,6.

Clinical features

A case associated with Eaton-Lambert syndrome has been reported⁸.

Radiology

Apart from basaloid carcinoma, most large cell carcinomas occur peripherally within the lung⁴.

Histopathology

These tumours are poorly differentiated and lack squamous, glandular or small cell components.

Variants:

• Large cell neuroendocrine carcinoma (LCNEC)¹⁹: the neuroendocrine differentiation is suggested by organoid nesting, trabecular growth, rosetting or perilobular palisading. Cells are moderately large with abundant cytoplasm. Nucleoli are prominent. Mitotic rates exceed 11/10 HPF. Necrosis is common.

• Combined large cell neuroendocrine carcinoma: a LCNEC combined with adenocarcinoma, squamous cell carcinoma or sarcomatoid carcinoma. If a small cell component is present, the tumour is classified as a combined small cell carcinoma.

• Basaloid carcinoma¹: there is a solid or trabecular pattern with peripheral palisading. Nuclear moulding is absent. The mitotic rate exceeds 15/10HPF. Squamous differentiation is lacking. Comedo necrosis is common.

• Lymphoepithelioma-like carcinoma^2,4,7: resembles that seen in the nasopharynx. It shows a syncytial growth pattern. Cells are large with large prominent nucleoli. Some cases show squamoid or glandular differentiation²⁰. There is a marked lymphocytic infiltrate composed of mature lymphocytes, plasma cells and histiocytes, with some eosinophils and neutrophils. There may be intra-epithelial infiltration within small bronchi⁴. Rarely, there is amyloid intra-tumoral deposition⁴. Rare in the West, it is relatively common in China. Chinese^6,20 but not Western cases are associated with EBV infection⁴.

• Clear cell carcinoma: the cells are large with clear or foamy cytoplasm, variably containing glycogen. Clear cell tumours showing focal squamous or glandular differentiation should be classified as such¹².

• Large cell carcinoma with rhabdoid phenotype: at least 10% of cells must be of rhabdoid type with eosinophilic cytoplasmic globules^3,5. These tumours frequently show neuroendocrine differentiation³.

Immunohistochemistry

See immunohistochemistry of malignant epithelial tumours of lung.

Large cell neuroendocrine carcinoma:

	CD56	usually positive
	Chromogranin	usually positive
	Synaptophysin	usually positive
	Definite positivity with one neuroendocrine marker is sufficient to establish the diagnosis of LCNEC
	TTF-1	50% of cases
	CK14	negative
	CK20	negative
	Transcription factor E2F1	5/1022

Basaloid carcinoma: Neuroendocrine markers are negative (in 10% of cases, one marker is positive in less than 20% of tumour cells). TTF-1 is negative.

Large cell carcinoma with rhabdoid phenotype: the cytoplasmic globules are positive for vimentin and cytokeratin³.

Differential diagnosis

• Poorly differentiated squamous cell carcinoma. If a basaloid carcinoma includes a squamous component, it is to be regarded as a variant of squamous carcinoma.

• Solid type adenocarcinoma

• Atypical carcinoid: mitotic count less than 10/10 HPF

• Basaloid carcinoma: small cell carcinoma

• Lymphoepithelioma-like carcinoma: inflammatory pseudotumour, lymphoma, primary lymphoid hyperplasia.

• Clear cell carcinoma: metastatic metastatic clear cell renal, thymic, thyroid or salivary gland carcinoma, clear cell variants of squamous cell carcinoma or adenocarcinoma.

• Monotonous sheets of large cells resembling immunoblasts: DLBCL; LCA and cytokeratins differentiate. It has been suggested that large cell carcinomas of this morphology are aggressive¹³.

Prognosis

As for other non-small cell carcinomas of lung, dependent on performance status and TNM staging. The prognosis is worse than for other non small cell carcinomas¹⁸. Lymphoepithelioma-like carcinoma has a better prognosis⁷. Basaloid carcinoma is reported to have a prognosis inferior to that of poorly differentiated squamous cell carcinoma¹⁵.

The prognostic significance of neuroendocrine differentiation remains uncertain^9,10. It has been proposed that large cell neuroendocrine carcinoma ¹⁴ or large cell carcinoma with large cell neuroendocrine features (these include neuroendocrine carcinoma, large cell carcinoma with neuroendocrine differentiation, large cell carcinoma with neuroendocrine morphology)¹¹ are more aggressive than is classical large cell carcinoma. Accurately staged stage I large cell carcinoma with neuroendocrine differentiation may have a relatively good prognosis²¹. Combined small cell carcinoma / large cell carcinoma has an inferior survival compared to pure large cell carcinoma¹⁶.

Lung tumours with a rhabdoid phenotype show aggressive behaviour and poor prognosis⁵, particularly if the proportion of rhabdoid cells exceeds 10%¹⁷.

References

⁰Tumours of the Lung, Pleura, Thymus and Heart. WHO Classification of Tumours. IARC Press 2004.

¹Brambilla E, Moro D, Veale D, et al. Basal cell (basaloid) carcinoma of the lung: a new morphologic and phenotypic entity with separate prognostic significance. Hum Pathol 1992; 23:993-1003

²Castro CY, Ostrowski ML, Barrios R, et al. Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature. Hum Pathol 2001; 32:863-72

³Cavazza A, Colby TV, Tsokos M, et al. Lung tumors with a rhabdoid phenotype. Am J Clin Pathol 1996; 105:182-8

⁴Chan JK, Hui PK, Tsang WY, et al. Primary lymphoepithelioma-like carcinoma of the lung. A clinicopathologic study of 11 cases. Cancer 1995; 76:413-22

⁵Chetty R, Bhana B, Batitang S, et al. Lung carcinomas composed of rhabdoid cells. Eur J Surg Oncol 1997; 23:432-4

⁶Chang YL, Wu CT, Shih JY, et al. New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol 2002; 26:715-23

⁷Chen FF, Yan JJ, Lai WW, et al. Epstein-Barr virus-associated nonsmall cell lung carcinoma: undifferentiated "lymphoepithelioma-like" carcinoma as a distinct entity with better prognosis. Cancer 1998; 82:2334-42

⁸Demirer T, Ravits J,Aboulafia D Myasthenic (Eaton-Lambert) syndrome associated with pulmonary large-cell neuroendocrine carcinoma. South Med J 1994; 87:1186-9

⁹Gajra A, Tatum AH, Newman N, et al. The predictive value of neuroendocrine markers and p53 for response to chemotherapy and survival in patients with advanced non-small cell lung cancer. Lung Cancer 2002; 36:159-65

¹⁰Graziano SL, Mazid R, Newman N, et al. The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer. J Clin Oncol 1989; 7:1398-406

¹¹Iyoda A, Hiroshima K, Toyozaki T, et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001; 91:1992-2000

¹²Katzenstein AL, Prioleau PG,Askin FB The histologic spectrum and significance of clear-cell change in lung carcinoma. Cancer 1980; 45:943-7

¹³Matsui K, Kitagawa M, Wakaki K, et al. Lung carcinoma mimicking malignant lymphoma: report of three cases. Acta Pathol Jpn 1993; 43:608-14

¹⁴Mazieres J, Daste G, Molinier L, et al. Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases. Lung Cancer 2002; 37:287-92

¹⁵Moro D, Brichon PY, Brambilla E, et al. Basaloid bronchial carcinoma. A histologic group with a poor prognosis. Cancer 1994; 73:2734-9

¹⁶Ruffini E, Rena O, Oliaro A, et al. Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance. Eur J Cardiothorac Surg 2002; 22:701-7

¹⁷Shimazaki H, Aida S, Sato M, et al. Lung carcinoma with rhabdoid cells: a clinicopathological study and survival analysis of 14 cases. Histopathology 2001; 38:425-34.

¹⁸Takei H, Asamura H, Maeshima A, et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases. J Thorac Cardiovasc Surg 2002; 124:285-92

¹⁹Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991; 15:529-53

²⁰Wong MP, Chung LP, Yuen ST, et al. In situ detection of Epstein-Barr virus in non-small cell lung carcinomas. J Pathol 1995; 177:233-40

²¹Zacharias J, Nicholson AG, Ladas GP, et al. Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection. Ann Thorac Surg 2003; 75:348-52

²² Eymin B, Gazzeri S, Brambilla C, et al. Distinct pattern of E2F1 expression in human lung tumours: E2F1 is upregulated in small cell lung carcinoma. Oncogene 2001; 20:1678-87

This page last revised 29.3.2005.

©SMUHT/PW Bishop