Large Cell Neuroendocrine Carcinoma of the Cervix Associated with Adenocarcinoma In Situ: Evidence of a Common Origin

To the Editor: Large cell neuroendocrine carcinoma (LCNEC) is a rare aggressive cervical neoplasm, considerably rarer than the well-recognized small cell neuroendocrine carcinoma of the cervix. It is histologically similar to the more common LCNEC of the lung. In the largest series to date (1), Gilks et al. reported 12 cases, and were able to find only 24 previously reported nonsmall cell neuroendocrine carcinomas of the cervix. Of the 12 reported cases in their series, 8 showed adjacent adenocarcinoma in situ. We recently encountered a case of a LCNEC of the cervix with coexisting adenocarcinoma in situ. The latter showed neuroendocrine features by immunohistochemistry, a finding that suggests a common origin of the lesions. A 35-year-old female, G2P2002 presented with a history of two mildly abnormal Pap smears, ASCUS, and subsequent AGUS. Examination revealed a 5.0 cm polypoid lesion protruding from the os that was clinically confined to the cervix. The lesion was removed in the office. The patient was referred to a gynecologic oncologist, and a colposcopically directed biopsy was negative. The patient was treated with two cycles of chemotherapy with carboplatin, taxol, and etoposide and then underwent radical hysterectomy with pelvic and paraaortic lymphadenectomy. Histology of the polypoid lesion revealed a tumor with a trabecular pattern and extensive geographic necrosis (Fig. 1A). The tumor cells had abundant cytoplasm, large nuclei, and prominent nucleoli. There were more than 30 mitoses per 10 high-power fields. The cells were focally positive for mucin, and were positive for keratin and chromogranin on immunohistochemistry. A diagnosis of LCNEC was made. The uterus in the radical hysterectomy specimen was grossly unremarkable and weighed 105 grams. The cervix was submitted entirely for microscopic examination. No residual LCNEC was seen microscopically in cervix, vaginal cuff, or parametria, and the pelvic and paraaortic lymph nodes were negative. Multiple foci of adenocarcinoma in situ were noted in the cervix (Fig. 2A). Immunohistochemistry revealed positivity for chromogranin in these foci (Fig. 2B).FIG. 1.: A) Large cell neuroendocrine carcinoma of the cervix showing a trabecular pattern and geographic necrosis. B) The tumor cells have moderate to abundant cytoplasm and there are numerous mitotic figures.Figure 1: ContinuedFIG. 2.: A) Adenocarcinoma in situ in the hysterectomy specimen. B) The cells of the adenocarcinoma in situ are immunoreactive for chromogranin.In the uterine cervix, neuroendocrine carcinomas are uncommon, particularly those composed of large cells (1). A recent College of American Pathologists workshop has adopted a standardized terminology that has been in use for histologically similar lung neoplasms (2) that includes small (oat) cell carcinomas, typical carcinoid tumors, atypical carcinoid tumors, and LCNECs. The last three are distinguished by the degree of mitotic activity, nuclear atypia, and necrosis. LCNECs of the uterine cervix are aggressive tumors, with a similarly poor prognosis to that of small cell neuroendocrine carcinoma of the cervix (1). Adenocarcinomatous differentiation in association with neuroendocrine carcinomas has been described in the cervix, endometrium, and ovary (1). Eight of Gilks' (1) 12 cases of LCNEC of the uterine cervix had coexisting adenocarcinoma in situ, and in 3 cases, an invasive adenocarcinoma component was present. Savargaonkar et al. (3) suggest that neuroendocrine differentiation is not rare in invasive glandular lesions of the cervix. Neuroendocrine carcinomas have been postulated to arise from cervical glandular reserve cells (4), as well as from cervical endocrine cells (5). The high frequency of in situ and invasive adenocarcinoma with LCNECs of the cervix suggests divergent differentiation rather than synchronous carcinomas. The strong chromogranin staining pattern in both the LCNEC and adenocarcinoma in situ in our case also suggests they are of common origin. Shijun Cui, M.D. Pierre Lespinasse, M.D. Bernadette Cracchiolo, M.D., M.P.H. Jahir Sama, M.D. Michael S. Kreitzer, M.D. Debra S. Heller, M.D