Small cell carcinoma of the lung

Definition

A malignant epithelial tumour composed of small cells with scant cytoplasm, finely granular nuclear chromatin and inconspicuous nucleoli. There is nuclear moulding and a high mitotic count.

Combined small cell carcinoma consists of small cell carcinoma in conjunction with a non-small cell component, commonly squamous cell carcinoma, adenocarcinoma or large cell carcinoma, less often sarcomatoid carcinoma.

Epidemiology

Small cell carcinoma accounts for about 20% of primary lung carcinomas. There is a strong associated with cigarette smoking, with a relative risk of 18.3 for heavy smokers¹.

Clinical features

Hoarseness and vocal cord palsy are more common, stridor and haemoptysis less common, than for squamous cell carcinoma. Clinical symptoms are often attributable to distant metastases. Paraneoplastic effects are common.

Radiology

Hilar and mediastinal masses are often seen due to metastases at presentation, while the primary tumour is not radiographically apparent.

Histopathology

There is commonly no clear architecture, but there may be nesting trabeculae, peripheral palisading or rosette formation. Cells are small with scant cytoplasm and round to spindle nuclei, with fine chromatin and lacking conspicuous nucleoli. Nuclear moulding is common. Crush artefact is common. Larger specimens tend to show larger nuclei with some giant cells and more prominent nucleoli¹². The mitotic rate is usually over 60 /10 HPF. The Azzopardi effect is seen, consisting of encrustation of blood vessels with nuclear basophilic material. Paranuclear blue inclusions (paranuclear cytoplasmic blue inclusions, 1 to 4 microns in diameter, indenting the nucleus, seen in air dried smears stained with Romanowsky type stains) may be useful in the cytological diagnosis of small cell carcinoma,although they are also seen in other small round cell tumours of childhood¹⁶.

Combined small cell carcinoma includes a non-small cell component. Since scattered large cells are common in small cell carcinoma, if this component is large cell carcinoma, it has been proposed that must comprise at least 10% of the tumour¹².

Immunohistochemistry

See immunohistochemistry of malignant epithelial tumours of lung.

	CD56	positive
	chromogranin	positive
	synaptophysin	positive
	positivity for at least one neuroendocrine marker	>90% of cases
	TTF-1	90%
	cytokeratins	variable, often punctate
	EMA	positive6
	BerEP4	positive6
	Retinoblastoma protein	0/40 (contrasts with retention of nuclear staining in both typical and atypical carcinoid tumours of lung)2, 6/29 (cf 30/48 non-neuroendocrine lung carcinomas)7
	Transcription factor E2F1	24/265
	MIC2	2/33 (in the two positive cases, staining was less strong than is typically seen in PNET)10
	pax-5	22/30 (17 of 23 in lung, 2 of 3 in bladder, 2 of 3 metastatic to lymph nodes and 1 of 1 case in colon: 2 diffuse strong, 12 diffuse moderate, 6 diffuse weak, 2 focal moderate)18

Cytogenetics and molecular genetics

Loss of heterozygocity is common on 3p¹⁷ in small cell carcinoma of lung. LOH at the MEN1 gene locus occurs in the spectrum of neuroendocrine tumours of lung¹³. The patterns of p53 gene mutations were different between atypical carcinoid and high grade neuroendocrine tumours of lung¹³. Loss of expression due to hypermethylation appears to be more common in small cell and large cell lung carcinoma than in other types¹⁴. Caspase-8 expression is lost in neuroendocrine tumours of the lung but not in non-small cell carcinomas¹⁵.

Ultrastructure

Differential diagnosis

• Lymphoid infiltrates: positive for CD45, negative for cytokeratins, TTF-1 and neuroendocrine markers.

  • inflammatory

  • lymphomas

• Other neuroendocrine tumours

  • carcinoid tumours show a much lower mitotic count, less apoptosis and less necrosis. They show nuclear staining for the retinoblastoma protein².

  • To distinguish small cell carcinoma from large cell neuroendocrine carcinoma, a cut of in nuclear size of three times the size of the nucleus of a lymphocyte has been proposed. However, a morphometric study showed a considerable overlap in this parameter¹¹.

• Other "small round blue cell tumours"

  • PNET: lower mitotic count, is also positive for CD99^8,10 but negative for TTF-1 and cytokeratins

  • metastatic Merkel cell carcinoma is positive for CK20^3,4 but negative for CK7 and TTF-1⁴

• Other primary and metastatic non-small cell carcinomas

  • Small cell variant of squamous cell carcinoma: immunohistochemistry is invaluable.

Management

Treatment is by chemotherapy⁹. Resection is appropriate for a few low stage tumours.

Prognosis

Widespread dissemination makes the TNM staging inappropriate and small cell carcinoma is staged as limited versus extensive disease. Adverse prognostic markers include extensive stage, poor performance status, elevated serum LDH or alkaline phosphatase and low plasma soduim.

References

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

¹ Khuder SA Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer 2001; 31:139-48

² Cagle PT, el-Naggar AK, Xu HJ, et al. Differential retinoblastoma protein expression in neuroendocrine tumors of the lung. Potential diagnostic implications. Am J Pathol 1997; 150:393-400

³ Chan JK, Suster S, Wenig BM, et al. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am J Surg Pathol 1997; 21:226-34

⁴ Cheuk W, Kwan MY, Suster S, et al. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med 2001; 125:228-31.

⁵ 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

⁶ Guinee DG, Jr., Fishback NF, Koss MN, et al. The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 1994; 102:406-14

⁷ Gouyer V, Gazzeri S, Brambilla E, et al. Loss of heterozygosity at the RB locus correlates with loss of RB protein in primary malignant neuro-endocrine lung carcinomas. Int J Cancer 1994; 58:818-24

⁸ Halliday BE, Slagel DD, Elsheikh TE, et al. Diagnostic utility of MIC-2 immunocytochemical staining in the differential diagnosis of small blue cell tumors. Diagn Cytopathol 1998; 19:410-6

⁹ Johnson DH Management of small cell lung cancer: current state of the art. Chest 1999; 116:525S-530S

¹⁰ Lumadue JA, Askin FB,Perlman EJ MIC2 analysis of small cell carcinoma. Am J Clin Pathol 1994; 102:692-4

¹¹ Marchevsky AM, Gal AA, Shah S, et al. Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms. Am J Clin Pathol 2001; 116:466-72

¹² Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002; 26:1184-97

¹³ Onuki N, Wistuba, II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999; 85:600-7

¹⁴ Osada H, Tatematsu Y, Yatabe Y, et al. Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers. Oncogene 2002; 21:2418-24

¹⁵ Shivapurkar N, Toyooka S, Eby MT, et al. Differential inactivation of caspase-8 in lung cancers. Cancer Biol Ther 2002; 1:65-9

¹⁶ Walker WP, Wittchow RJ, Bottles K, et al. Paranuclear blue inclusions in small cell undifferentiated carcinoma: a diagnostically useful finding demonstrated in fine-needle aspiration biopsy smears. Diagn Cytopathol 1994; 10:212-5

¹⁷ Zabarovsky ER, Lerman MI,Minna JD Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002; 21:6915-35

¹⁸ Dong HY, Liu W, Cohen P, et al. B-cell specific activation protein encoded by the PAX-5 gene is commonly expressed in merkel cell carcinoma and small cell carcinomas. Am J Surg Pathol 2005; 29:687-92

This page last revised 19.8.2005.

©SMUHT/PW Bishop