Intestinal-type Endocervical Adenocarcinoma In Situ

Abstract

Conventional endocervical adenocarcinoma in situ (cAIS) is typically strongly and diffusely positive for p16 with a high Ki67 index consistent with its frequent association with high-risk human papillomavirus (HPV) infection. The intestinal variant (iAIS) is less common, and its relationship to HPV infection has not been thoroughly examined. This study compares the clinicopathologic features, frequency of HPV infection, and expression of CDX2 and surrogate biomarkers of HPV infection (p16, Ki67) in cAIS with those of iAIS. A total of 86 cases with a diagnosis of AIS (49 iAIS, 37 cAIS) were identified from our multi-institutional files. Of these, 13 iAIS and 20 cAIS cases had slides and tissue available for histopathologic review, immunohistochemical analysis, and molecular tests. All 86 cases were used to evaluate clinical parameters; however, HPV DNA analysis and immunohistochemical analysis for p16, MIB-1, CDX2, and p53 were performed only on those cases with available slides or paraffin blocks. The average age at diagnosis was significantly higher in iAIS compared with that in cAIS (44.5 vs. 32.6 y) (P=0.0001). All 20 cAIS cases showed moderate to strong and diffuse p16 staining; however, only 9/13 iAIS cases showed this degree of p16 staining, whereas 4/13 (31%) iAIS cases showed weak and patchy distribution (P<0.02). Only 6/9 (67%) iAIS cases were positive for either HPV type 18 (5) or 33 (1), in contrast to 11/11 conventional cAIS (P=0.04). Similarly, 12/14 cAIS, but only 5/13 iAIS, cases showed a high Ki67 proliferative index. CDX2 was positive in all iAIS cases, whereas p53 was negative. Most iAIS cases are positive for high-risk HPV and show moderate to strong and diffuse p16 staining; however, a subset of iAIS shows variable staining with p16 and Ki67, is not associated with HPV, and occurs in a distinctly older age group suggesting an alternative pathogenesis. Awareness that iAIS can show variable staining for p16 and Ki67 is important when resolving problematic endocervical lesions, particularly in small biopsies with unusual p16 staining patterns.

International Endocervical Adenocarcinoma Criteria and Classification (IECC)

“…An additional 19% contained gastric-type adenocarcinoma in situ, 26 some of which demonstrated intestinal differentiation. 49 It should be emphasized that intestinal differentiation, predominantly but not exclusively in the form of goblet cells, can be observed in in-situ and invasive adenocarcinomas of both HPVA and NHPVA types, and is therefore not diagnostically informative.…”

Retrospective analysis of cytology and high‐risk HPV testing in 1067 endocervical adenocarcinomas and precursor lesions

“…AIS, a precancerous lesion of EAC, is invariably associated with hrHPV infection with rare exceptions 19,20 . Patients with AIS were diagnosed at the mean age of 35–40 years, 6–13 years younger than that with EAC 21–24 .…”

Dataset for the Reporting of Carcinoma of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

“…p16 and/or HPV testing are considered desirable (not essential) criteria, as the morphologic features usually allow accurate differentiation. The ubiquitous use of and reliance on p16 immunohistochemistry to diagnose cervical ACA may cause diagnostic problems for HPV-independent tumors, since these typically do not exhibit the diffuse strong immunoreactivity characteristic of HPVassociated tumors (see the Ancillary studies section) (40,41). Invasive stratified mucin-producing carcinoma is the invasive counterpart of stratified mucinproducing intraepithelial lesion (SMILE) and a variant of HPV-associated ACA characterized by solid nests of tumor cells with mucin vacuoles scattered throughout the entire thickness of the nests; the term invasive SMILE can also be used.…”