Insufficient evidence of endocervical origin in germline BRCA1 and MSH2 -associated tumors

To the Editor:

We read with interest a recent article ¹ in which two cases of apparent non–human papillomavirus (HPV)–related endocervical adenocarcinomas associated with germline BRCA1 and MSH2 mutations, respectively, were described. Although germline and somatic analyses confirmed that the patients are carriers of BRCA1 and MSH2 germline mutations and that the tumors were pathogenetically underpinned by these respective abnormalities, there is a lack of evidence that the neoplasms are actually endocervical in origin.

The first case presented by Carnevali et al. ¹ is of a 63-year-old woman with germline BRCA1 mutation and apparent endocervical serous carcinoma. Although “papillary serous carcinomas” of the cervix have been described, modern studies have elucidated several important points regarding these neoplasms and have ultimately concluded that there is insufficient evidence that this entity truly exists. Accordingly, the International Endocervical Adeno-carcinoma Criteria and Classification, ² adopted as the 2020 World Health Organization classification, ³ removed endocervical serous carcinoma as a distinct neoplasm. When the diagnosis is considered, it is mandatory to exclude mimics including HPV-associated adenocarcinoma, clear cell carcinoma, mesonephric carcinoma, and drop metastases from the adnexa or corpus. The latter possibility is particularly relevant in the case described by Carnevali et al., ¹ as they report “p53 signatures” involving the right fimbria and immunohistochemical WT-1 positivity in the cervical tumor. Taken together, there is a lack of compelling evidence that the tumor is endocervical in origin. Rather, it much more likely represents a drop metastasis from the adnexa (particular in the context of a BRCA1 patient).

The second presented case of an apparent endocervical adenocarcinoma with mixed histologic features in a 31-year-old patient with Lynch syndrome raises similar issues. As with the first case, details regarding specimen processing are not provided. Given the rendered diagnosis, a diligent microscopic assessment of the entire lower uterine segment and endometrium to rule out an (overwhelmingly more likely) endometrial primary is mandatory. The described tumor shows the typical hallmarks of a mismatch repair deficient endometrial neoplasm, including heterogeneous morphology and abundant tumor-infiltrating lymphocytes. As indicated by the authors, endometrial carcinomas in the context of Lynch syndrome often arise in the lower uterine segment, and it is well known that these may simulate an endocervical primary. As a case in point, the patient’s sister developed what was described as two separate endometrioid carcinomas involving the cervix and endometrium. The tumors were deemed to be unrelated given differences in morphology and discordant expression of estrogen and progesterone receptors. However, rather than two separate tumors, these findings are entirely in keeping with cervical involvement of a morphologically heterogeneous mismatch repair–deficient endometrial carcinoma.

Overall, the conclusion that primary adenocarcinomas of the endocervix (outside of gastric type endocervical adenocarcinoma) may be associated with an underlying hereditary cancer syndrome is not supported by the cases presented by Carnevali et al., ¹ or elsewhere in the literature. It is critical to note that in cases of non–HPV-related adenocarcinomas involving the endocervix, diligent care must be taken to exclude tumors that may otherwise involve the cervix, particularly those of endometrial origin and drop metastases from the adnexa.