Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma.
BACKGROUND
Approximately 10-20% of nonsmall cell lung carcinomas (NSCLC) show neuroendocrine (NE) differentiation, as evaluated by panendocrine markers or ultrastructural evidence of dense-core secretory granules. However, little is known regarding the prevalence and clinical implications of NE differentiation in patients with Stage I NSCLC.


METHODS
The authors analyzed 220 consecutive patients with Stage I NSCLC (pT1-T2N0M0) among 2100 patients with primary lung carcinoma who underwent surgical treatment between 1987 and 1993. Using light microscopy and immunohistochemical staining for synaptophysin, chromogranin A, and respiratory tract-related hormones, 28 NSCLC specimens with NE differentiation (NSCLC-ND) and 11 large cell neuroendocrine carcinoma (LCNEC) specimens were identified.


RESULTS
The 28 NSCLC-ND specimens included 15 adenocarcinomas and 13 squamous cell carcinomas. Neoplastic cells with NE features never exceeded 20% in NSCLC-ND specimens, whereas neoplastic cells amounted to 20-90% in LCNEC specimens. NSCLC-ND specimens with > 5% NE-differentiated tumor cells showed increased Ki-67 labeling index (P = 0.007) and invasive phenotype, as evaluated by fascin immunoreactivity (P = 0.021). Patients with adenocarcinoma, but not with squamous cell carcinoma, who had > 5% NE-differentiated cells had a worse clinical course compared with patients who had ordinary NSCLC, with reduced overall survival (P = 0.017) and disease free survival (P = 0.049). In multivariate analysis, NE differentiation > 5% neoplastic cells in patients with adenocarcinoma independently predicted a poorer prognosis (hazard ratio, 2.61; 95% confidence interval, 0.99-6.85). Hormone production was restricted to chromogranin positive NSCLC-ND but did not affect prognosis.


CONCLUSIONS
Stage I adenocarcinomas with >or= 5% NE tumor cells are clinically aggressive tumors, similar to LCNEC. Hormone production identifies a more fully developed neuroendocrine phenotype but is not relevant to prognosis. The identification of NE-differentiated cells in patients with NSCLC may have clinical relevance.
Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy. giuseppe.pelosi@ieo.it
Giuseppe
G
Pelosi
Felice
F
Pasini
Angelica
A
Sonzogni
Fausto
F
Maffini
Patrick
P
Maisonneuve
Antonio
A
Iannucci
Alberto
A
Terzi
Giovanni
G
De Manzoni
Enrica
E
Bresaola
Giuseppe
G
Viale
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation; D053379:Chromogranin A; D002864:Chromogranins; D018572:Disease-Free Survival; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis; D016708:Synaptophysin
C498543:CHMP3 protein, human; D053379:Chromogranin A; D002864:Chromogranins; D056827:Endosomal Sorting Complexes Required for Transport; D006728:Hormones; D009419:Nerve Tissue Proteins; D016708:Synaptophysin