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Intestinal-type Endocervical Adenocarcinoma In Situ: An Immunophenotypically Distinct Subset of AIS Affecting Older Women

Howitt, Brooke E. MD; Herfs, Michael PhD; Brister, Kathriel MD; Oliva, Esther MD; Longtine, Janina MD; Hecht, Jonathan L. MD, PhD; Nucci, Marisa R. MD

The American Journal of Surgical Pathology: May 2013 - Volume 37 - Issue 5 - p 625–633
doi: 10.1097/PAS.0b013e318285be00
Original Articles

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.

*Department of Pathology, Brigham and Women’s Hospital, Division of Women’s and Perinatal Pathology

Department of Pathology, Beth Israel Deaconess Medical Center

§Department of Pathology, Massachusetts General Hospital, Boston, MA

Department of Pathology, University of Liege, Liege, Belgium

Presented in part at the 100th Annual Meeting of the United States and Canadian Academy of Pathology, San Antonio, TX, 2011.

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Marisa R. Nucci, MD, Department of Pathology, Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail:

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