Clear Cell Adenocarcinoma In Situ as a Potential Precursor Lesion for Sporadic Invasive Endocervical Clear Cell Adenocarcinoma

To the Editor:

We present this clinico-pathologic summary as it may shed some light on the existence of a precursor to invasive cervical clear cell carcinoma. A healthy 14-yr-old patient, without a history of hormonal therapy or intrauterine diethyl-stilbestrol exposure, underwent Pap smear and human papillomavirus (HPV) testing after reporting recent sexual intercourse. The high-risk HPV test was negative; however, the Pap smear showed atypical glandular cells favoring adenocarcinoma; follow-up colposcopy and biopsy were recommended. Microscopically, the biopsy’s surface squamous epithelium was normal, but variably sized neoplastic glands infiltrated cervical stroma with an accompanying desmoplastic and inflammatory infiltrate. The cells had clear cytoplasm, some with a hobnail appearance, pleomorphic, and hypercromatic nuclei and rare mitotic figures. Cells expressed Napsin A, CK7, and PAX8 (Fig. 1) and they were negative for p16, high-risk HPV, ER, PR, Racemase, CD10, WT1, CDX2, TFF1, Calretinin, GATA3, and PDL1. p53 showed a wild-type expression pattern, staining for PMS2 and MSH6 was intact, and Ki-67 marked ~40% of tumor cells. The morphology and immunohistochemical profile supported a diagnosis of clear cell adenocarcinoma (CCC). A subsequent loop electrosurgical excision of the transformation zone was performed and additional tumor was found with a similar morphology, 5 mm in horizontal extend and invading to a depth of 2 mm (2018 FIGO stage IA1). Non-neoplastic endocervical glands beneath the squamous metaplastic surface were focally partly replaced by cells with clear cytoplasm and atypical nuclei (Fig. 1). No lymph-vascular invasion was identified. Radiologic evaluation showed no uterine corpus or adnexal mass. The final diagnosis was sporadic endocervical HPV-independent invasive CCC associated with in situ adenocarcinoma of clear cell type. The patient is disease free 6 mo after the initial diagnosis.

FIG. 1: Superficial gland beneath the squamous epithelium presents squamous metaplasia pushed up by the atypical lining epithelium, with cytoplasmic clearing and similar degree of cytologic atypia as the invasive component (A); the invasive component is represented by multiple glands of various sizes and shapes lined by atypical cells that are infiltrating the cervical stroma presenting desmoplasia and inflammatory infitrate (B); Napsin A is positive in the infiltrauive component but negative in normal endocervical gland (C); original epithelium of endocervical glands with squamous metaplasia, partially or completelly replaced by atypical epithelium with clear cytoplasm and hypercromatic nuclei, consistent with clear cell adenocarcinoma in situ (D, E).

According to the 2020 World Health Organization (WHO) classification and International Endocervical Adenocarcinoma Criteria and Classification (IECC) of tumors of female genital tract, endocervical adenocarcinomas are either HPV-associated or independent, with CCC belonging to the later category ^1,2. To date, little information has been published about HPV-independent precursor lesions other than those found in association with gastric-type adenocarcinoma ³. “Atypical cervical ectropion” was initially proposed as a precursor lesion ^4–7, but a recent small study suggested that CCCs might originate in tubo-endometrioid metaplasia, a theory originally proposed by Robboy and collegues ^8,9. However, given the considerable frequency of tubo-endometrioid metaplasia and the rarity of CCC, we think other mechanisms must account for these observations. Our case demonstrates that clear cell carcinoma in situ is a likely precursor to invasive clear cell carcinoma, similar to “endometrial serous intraepithelial carcinoma” and “serous tubal intraepithelial carcinoma” ¹. We suspect that this precursor may be inapparent or obliterated by invasive carcinoma in many cases. In summary, we describe a possible precursor to invasive cervical CCC in an otherwise healthy 14-yr-old patient.