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.