Low-grade Neuroendocrine Tumor of the Cervix: Report of 3 Cases of a Rare Neoplasm With Review of the Literature

Abstract

Neuroendocrine neoplasms are uncommon in the cervix with almost all representing neuroendocrine carcinomas (NECs), either small cell or large cell type. Cervical low-grade neuroendocrine tumors (NETs) are extremely rare with few recent reports using contemporary modern diagnostic criteria. We report 3 cases of cervical NET in patients aged 32 to 57 yr and undertake a review of the literature. The first case was a pure grade 2 NET with pelvic lymph node metastasis (FIGO stage IIIC1). In the second case, a grade 1 NET was associated with high-grade squamous intraepithelial lesion, adenocarcinoma in situ and human papillomavirus (HPV)-associated adenocarcinoma and was FIGO stage IA1. The third patient underwent chemoradiotherapy following a biopsy diagnosis of a high-grade NEC which was radiologically FIGO stage IIIC1 and salvage hysterectomy revealed residual tumor with features of a grade 1 NET. In all cases, the NET was diffusely positive with at least 2 of the neuroendocrine markers chromogranin, synaptophysin, and CD56. The first tumor was p16 negative and the third exhibited block-type immunoreactivity. Molecular tests revealed high risk HPV types 18 and 51 in the third case but no HPV in the first case. p16 immunohistochemistry and HPV molecular testing was not available in the second case. The patients remain disease free with follow-up ranging from 2 to 8 yr. Since a combination of NET and NEC is extremely rare at all sites due to a different pathogenesis, we speculate that in the third case, the NET developed out of the NEC as a "maturation" phenomenon secondary to chemoradiotherapy.

Figure 1

Case 1. Medium power showing tumour involving the stroma between normal endocervical glands (A). On high-power, the tumour is composed of bland epithelioid and spindle cells, in areas forming pseudorosettes (B). Tumour within lymphovascular space (C). Lymph node metastasis (D).

Figure 2

Case 1. Immunohistochemistry showing negative staining with p16 (A) and diffuse staining with chromogranin (B) and synaptophysin (C). The Ki67 proliferation index is 3% (D).

Figure 3

Case 2. Medium power showing low grade NET (top right) and AIS (lower left) (A). High power of low-grade NET component showing nested and corded arrangements of bland cells (B). Immunohistochemistry showing diffuse staining with chromogranin in the low-grade NET (C). There is focal positive staining with chromogranin in the AIS component (D).

Figure 4

Case 3. SCNEC in original biopsy showing diffuse arrangement of cells with scant cytoplasm (A). Immunohistochemistry showing diffuse block-type staining with p16 (B) and diffuse staining with chromogranin (C). The Ki67 proliferation index is in excess of 90% (D).

Figure 5

Case 3. Tumour in hysterectomy specimen showing diffuse arrangement of bland cells with spindle cell nuclei (A). Immunohistochemistry showing diffuse block-type staining with p16 (B) and diffuse staining with chromogranin (C). The Ki67 proliferation index is low (1.3%) (D).