Neuroendocrine Differentiation in Endocrine and Nonendocrine Lung Carcinomas

Abstract

Bronchial carcinoids and small cell lung cancer (SCLC) are currently recognized as neuroendocrine (NE) neoplasms. However, non-SCLC (NSCLC) may also express NE properties. Paraffin-embedded sections of a comprehensive panel of 113 lung carcinomas were analyzed for the expression of three general markers common to all NE cells, namely, chromogranin A, Leu-7 and neuron-specific enolase (NSE), five specific NE secretory products, and four other tumor markers by immunohistochemistry using the sensitive avidin-biotinylated peroxidase technique. The authors were able to demonstrate the following: (1) most, but not all carcinoids and SCLCs expressed multiple NE markers in a high percentage of tumor cells; (2) up to a half of NSCLC cases contained small subpopulations of cells expressing NE in a high percentage of tumor cells; (2) up to half of NSCLC cases contained small subpopulations of cells expressing NE markers; and (3) occasional NSCLCs showed staining patterns indistinguishable from SCLC. Specifically, 7 of 77 NSCLCs expressed four or more NE markers. NE markers in NSCLCs were more commonly expressed in adenocarcinomas and large cell carcinomas and rarely in squamous cell carcinomas. For comparison, the mean number of NE markers expressed by all cases of NSCLC was 1.5, carcinoids 6.0, and SCLCs 3.8. Individual "marker counts" were not useful in categorizing lung tumors as carcinoids and SCLC versus NSCLC. Instead, 95% of the tumors were correctly classified, applying a statistical model created from staining indices of the three general NE markers (chromogranin A, Leu-7, NSE) and three other tumor markers (carcinoembryonic antigen, keratin, vimentin). Because NSCLCs with NE features might have different clinical characteristics than other NSCLCs, immunohistochemistry provides an effective manner to identify this biologically interesting subset of NSCLCs in routine paraffin sections.

Neuroendocrine differentiation and clinical behaviour in non-small cell lung tumours

“…Similar findings have been reported by others (Bergh et al, 1985;Said et al, 1985;Rode et al, 1985;Dhillon et al, 1985;Linnoila et al, 1988b;Graziano et al, 1989). The detection of CK-BB immunoreactivity in 67% of SCLC and 14% of squamous cell tumours compares well with previous radioimmunoassay data (Ruberry et al, 1983).…”

“…The detection of CK-BB immunoreactivity in 67% of SCLC and 14% of squamous cell tumours compares well with previous radioimmunoassay data (Ruberry et al, 1983). While several studies have failed to detect bombesin like immunoreactivity in NSCLC using immunohistochemistry Hamid et al, 1987), a recent study by Linnoila et al, 1988b, reported the immunohistochemical detection of bombesin like immunoreactivity in 13% of NSCLC. In the present study, 8% of NSCLC tumours showed bombesin like immunoreactivity.…”

“…These include L-dopa decarboxylase (Baylin et al, 1980;Berger et al, 1981;Gazdar et al, 1988a), peptide hormones including calcitonin (Berger et al, 1981) and gastrin releasing peptide (Yamaguchi et al, 1985) and neurone specific enolase (NSE) (Bergh et al, 1985;Said et al, 1985;Rode et al, 1985;Dhillon et al, 1985;Linnoila et al, 1988b;Graziano et al, 1989). Although elevated levels of neuroendocrine (NE) markers have been detected in NSCLC tumours, the expression of more than one NE marker, though common in small cell lung cancer (SCLC) occurs much less frequently in NSCLC (Berger et al, 1981).…”

“…Although elevated levels of neuroendocrine (NE) markers have been detected in NSCLC tumours, the expression of more than one NE marker, though common in small cell lung cancer (SCLC) occurs much less frequently in NSCLC (Berger et al, 1981). Recent immunohistochemical studies have shown the presence of multiple NE markers in 10-20% of NSCLC (Gazdar, 1986;Linnoila et al, 1988b;Berendsen et al, 1989). The occurrence of NE differentiation in NSCLC tumours is significant not only because it suggests that the major forms of lung cancer represent a continuum of differentiation within a common cell lineage, but also because the response of neuroendocrine NSCLC (NE-NSCLC) to chemotherapy has been shown to be similar to that of SCLC.…”

Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours

“…As expected, the incidence of their mRNAs was higher among SCLCs, which exhibit a neuroendocrine phenotype (Linnoila et al, 1988), than among adenocarcinomas and squamous cell carcinomas ( Figure 1 and Table 1). These data support the proposed use of PCI and PC2 as discriminatory indicators of neuroendocrine differentiation of neoplastic tissues (Creemers et al, 1992;Scopi et al, 1995) We did not observe any correlation between the differentiation or the metastatic character of the primary tumours and the pattern or the level of convertase expression.…”