Neuroendocrine Differentiation in Primary Rectal Cancer: Immune Histology with Prognostic Impact?

Abstract

Background: The aim of this study was to determine the incidence and prognostic significance of neuroendocrine differentiation in primary rectal cancer with special reference to ki-67 staining index. Methods: Formalin-fixed and paraffin-embedded tissue sections of 94 rectal carcinomas were used for immunohistochemical analysis of chromogranin A (CgA), synatophysin (Syn) and neuron-specific enolase (NSE). Inclusion criteria were sporadic rectal adenocarcinoma resected curatively by total mesorectal excision, adjuvant radiochemotherapy in UICC stages II and III, and complete intrainstitutional follow-up. Results of immunohistochemistry were correlated with clinical and histopathologic data. End points of analysis were tumor progression and 5-year survival. Statistics included univariate and multivariate analysis. Results: Of 94 rectal carcinomas studied, 20% (19/94) were CgA-positive, 7% (7/94) were Syn-positive, and 3% (3/94) were NSE-positive. No expression of neuroendocrine markers was documented in 72% (68/94). There was no carcinoma which expressed all three markers, and only 3% (3/94) showed a combination of at least two markers. Neither for Syn nor for NSE any significant association with clinical or histopathological variables could be found. Expression of CgA significantly correlated with age and differentiation (p = 0.03). Within a mean follow-up of 50 months, tumor progression occurred in 14 patients (15.4%): 2 patients had local recurrences (isolated), 4 had local and distant recurrence and 8 had metachronous distant metastases without local recurrence. Only UICC stage and preoperative CEA serum level were significantly associated with tumor progression, whereas the neuroendocrine markers failed to show any correlation. Focusing solely on distant recurrence, the incidence of metachronous distant metastases was significantly associated with UICC stage, depth of invasion, preoperative CEA serum level, and CgA expression (23.5% in CgA-positive vs. 5.9% in CgA-negative tumors, p = 0.02). The neuroendocrine markers did not show any relation with survival prognosis. Correlated to ki-67 expression, 89.5% (17/19) of CgA-positive tumors showed a concurrent high ki-67 expression of more than 40% of cells (staining index > 0.4). Conclusions: The expression of the neuroendocrine marker CgA seems to have a prognostic impact in primary rectal cancer for the incidence of metachronous distant recurrence. It seems that the increased proliferation (assessed by ki-67 staining index) could play a role in curatively resected rectal cancer.