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Pathology & Laboratory Medicine

URMC / Pathology & Laboratory Medicine / Education / Case of the Month / Case 61: Vaginal Bleeding / Diagnosis

 

Diagnosis & Discussion

Diagnosis

Metastatic small cell neuroendocrine carcinoma from the uterine cervix.

Discussion

Most carcinomas of the uterine cervix are squamous cell carcinoma and small cell neuroendocrine carcinoma (SCNEC) is rare accounting for less than 5% of all malignant cervical tumors. SCNEC of the uterine cervix tends to occur in women in the fourth decade (average age 42-43 years old) and most commonly presents with vaginal bleeding. SCNEC is a highly aggressive tumor with a poor prognosis. Metastatic disease is often seen at the time of presentation with involvement of the regional lymph nodes, lung, liver, bone, and brain. Similar to squamous cell carcinoma, at this site, SCNEC is associated with high risk human papillomavirus (HPV) types 16 and 18.

There are no characteristic gross features. Histologically, SCNEC may demonstrate a nested, trabecular, or sheet-like pattern. SCNEC is composed of small cells with scant cytoplasm, hyperchromatic round to oval or spindled nuclei, and absent nucleoli. Nuclear molding, easily identifiiable mitoses, and apoptotic debris are common. There may be crush artifact and necrosis. Ancillary studies that may be performed include neuroendocrine markers such as synaptophysin, chromogranin, CD56, or INSM1. Chromogranin is the most specific neuroendocrine marker, while CD56 and synaptophysin are the most sensitive neuroendocrine markers but these lack specificity. Up to 50% of tumors may be negative for neuroendocrine markers such as synaptophysin and chromogranin; however, in one study 95% expressed INSM1. Since SCNEC is associated with HPV, p16 immunohistochemical and high risk HPV in situ hybridization stains are positive. Many of these tumors express TTF-1 and this stain has little value in excluding a pulmonary metastasis.

The histologic differential diagnosis of SCNEC of the uterine cervix includes other small round blue cell tumors such as lymphoma (positive for lymphoid markers), melanoma (positive for melanocytic markers), and Ewing family tumors (CD99 positive but negative for p16 and high risk HPV). The small cell variant of squamous cell carcinoma is also in the differential diagnosis and would express p40 or p63 diffusely; however, caution is advised because p63 may be focally expressed in some SCNEC.

In summary, SCNEC of the uterine cervix commonly presents in women in their forties with vaginal bleeding and is associated with HPV 16 and 18. These tumors are highly aggressive, often present with metastatic disease, and have a poor overall prognosis.
 

References

Kuji S, Watanabe R, Sato Y, Iwata T, et al. A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: analysis of 37 cases. Gynecologic Oncology. 2017;144:384-390.

Conner MG, Richter H, Moran CA, Hameed A, et al. Small cell carcinoma of the cervix: a clinicopathologic and immunohistochemical study of 23 cases. Ann Diagn Pathol. 2002;6:345-348.

Howitt BE, Kelly P, McCluggage WG. Pathology of neuroendocrine tumours of the female genital tract. Curr Oncol Rep. 2017;19:59.

Cohen JG, Kapp DS, Shin JY, Urban R, et al. Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010;203:347.e1-6.

Lin L, Lin Q, Liu J, Chu K, et al. Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix based on population analyses. Cancer Medicine. 2020;9:6524-6532.

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