Increased endocrine cells in treated rectal adenocarcinomas: A possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy
The presence of focal endocrine cells in colorectal adenocarcinoma is a relatively common phenomenon. However, endocrine differentiation in treated adenocarcinomas of the gastrointestinal tract has received little attention. We noted striking numbers of cells with endocrine morphology and phenotype in the residual tumor of six randomly encountered cases of rectal adenocarcinoma that were subjected to neoadjuvant therapy. All six cases had a substantial treatment response (> or =50%). To validate our initial observation and to explore its clinicopathologic significance, further morphologic and immunohistochemical studies were performed on 53 cases of rectal adenocarcinomas treated with preoperative radiation with (33 cases) or without (20 cases) chemotherapy. Pretreatment biopsies from 20 of the 53 cases and 79 resection specimens of rectal adenocarcinoma that received no neoadjuvant therapy were used as controls. Chromogranin positivity was identified in the posttreatment resection specimens in 36 of the 53 study cases (67.9%). Twenty of the 36 showed positive staining in > or =20% of the residual tumor cells. The chromogranin-positive cells in these cases often formed cords or nests. On hematoxylin and eosin sections these cells had markedly eosinophilic cytoplasm and round and uniform or sometimes pleomorphic nuclei with an often dense chromatin pattern. The proportion of chromogranin-positive cells was significantly associated with the extent of treatment response (p = 0.0005). Tumors treated with both chemotherapy and radiotherapy were more likely to have abundant chromogranin-positive cells compared with tumors treated with radiotherapy alone (p = 0.0004). In contrast, only 30% of the pretreatment biopsies and 17.7% of the control resection specimens of untreated rectal carcinomas showed chromogranin-positive cells, predominantly arranged as scattered individual positive cells, constituting <10% of the tumor. No significant correlation was observed between pretreatment and posttreatment specimens with regard to chromogranin positivity (p = 1.0). Ten of 15 patients (66.7%) whose resection specimens showed positive chromogranin staining failed to demonstrate any chromogranin positivity in their pretreatment biopsy specimens. In addition, groups or nests of chromogranin-positive cells noted in posttreatment specimens showed a very low Ki67 labeling index (<5%) but showed a frequency of abnormal p53 protein expression comparable with that observed in tumor foci resembling conventional adenocarcinoma (66.7% vs 62.5%). Our findings demonstrate that there is an increased frequency and density of cells with an endocrine phenotype in rectal adenocarcinomas that were subjected to neoadjuvant therapy and that the extent of endocrine cells appears proportional to the degree of treatment response. The possible mechanism for the increased endocrine cells in treated rectal adenocarcinomas may be related to induction of endocrine differentiation in tumor cells by cytotoxic insult.