Highly proliferative anal neuroendocrine carcinoma: molecular and clinical features of a rare, recurrent case in complete remission

Abstract

Background: Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood.

Case presentation: At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%.

Conclusions: For the first time, we report the detection of HPV45 in a case of ANEC. To our belief, PIK3CA mutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or the PIK3CA mutation may have contributed to the favorable outcome.

Keywords: Anal neuroendocrine carcinoma; Case report; HPV; Mutation; PIK3CA; Remission.

Fig. 1

Imaging of the lower abdominal cavity and pelvic region visualizing one of the local recurrences as well as the radiological evidence of complete remission after the final round of surgery. Left columns depict conventional computerized tomography (CT) scans and right columns visualize the positron emission tomography with fluorodeoxyglucose (PET F18 FDG) findings. Top row: White arrowhead highlights one of the local recurrences, a right-sided subcutaneous inguinal lymph node metastasis. Bottom row: No remaining tumor tissue is evident after the fourth and final round of surgery. Left side is marked by the letter “L”

Fig. 2

Photomicrographs of routine stained and immunohistochemical preparations of the small cell anal neuroendocrine carcinoma (ANEC). All images are magnified × 400 unless otherwise specified. a. Routine hematoxylin-eosin stain of the primary ANEC. The tumor is shown with solid growth and a monotonous appearance with only mild atypia. Note the squamous cell epithelium of the anal canal to the left. b. Routine hematoxylin-eosin stain highlighting the prominent nuclear molding, a feature of the small cell phenotype. c. Routine hematoxylin-eosin stain displaying a regional lymph node metastasis of the ANEC. Magnification ×100. d-g. Immunohistochemical analyses of the primary ANEC, displaying widespread immunoreactivity towards chromogranin A (d), synaptophysin (e), P16 (f) and a Ki-67 index of 80% (g). h. Regional, subcutaneous metastasis two years later displaying absent chromogranin A immunoreactivity. The same tumor was consistently positive for synaptophysin (data not shown). j. Same subcutaneous recurrence with a Ki-67 index of 90%