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Anatomic Pathology Selected Abstracts, 6/14

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Anatomic pathology abstracts editors: Michael Cibull, MD, professor of pathology, University of Kentucky, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.

Utility of triple antibody cocktail intraurothelial neoplasm-3 and AMACR
in urothelial CIS and reactive urothelial atypia

Urothelial carcinoma in situ (CIS) is a prognostically and therapeutically significant lesion with considerable morphologic overlap with reactive conditions, especially in the setting of prior therapy. Various markers, including CK20, CD44s, and p53, have been used as an adjunct in making this distinction. However, the utility of these markers in the post-treatment scenario is not fully established. The tumor-associated marker α-methy-lacyl-CoA racemase (AMACR) is expressed in a subset of high-grade urothelial carcinomas but has not been studied in CIS. Therefore, the authors conducted a study to evaluate the immunoreactivity of CK20, CD44s, and p53 as a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3) in distinguishing CIS from its mimics and to compare its utility with AMACR in the diagnosis of CIS. The study involved 135 specimens—seven benign ureters and 128 bladder biopsies (28 reactive, 33 post-therapy reactive, 43 CIS, 24 CIS post-therapy). Immunostaining for p53 (brown, nuclear), CD44s (brown, membranous), and CK20 (red, cytoplasmic and membranous) was performed as a cocktail, and the staining pattern was further classified as malignant (full-thickness CK20 and/or full-thickness p53 with CD44s negativity), reactive/benign (CK20 limited to the umbrella cell layer, p53 negative, and CD44s positivity ranging from basal to full thickness), or indeterminate (CK20 and p53 positive but not full thickness and/or CD44s positive). AMACR staining was performed in 50 cases. Cytoplasmic staining for AMACR was graded as negative (absent to weak focal staining [fewer than five percent of cells]) and positive (five percent or greater). The IUN-3–malignant pattern was observed in 84 percent of cases of CIS without a history of prior therapy and 71 percent of cases of CIS with a history of prior therapy. Cases with post-therapy reactive atypia showed an IUN-3–reactive pattern in 84 percent of cases and IUN-3–indeterminate pattern in 16 percent of cases. The IUN-3–malignant pattern was not identified in any cases. Benign and reactive urothelium, with and without a history of therapy, showed an IUN-3–reactive pattern and negative AMACR staining in all cases. AMACR positivity was observed in 78 percent of nontreated CIS cases and 50 percent of CIS post-therapy cases. In these cases, the IUN-3 cocktail showed an IUN-3–malignant pattern in 83 percent of untreated CIS cases and 88 percent of CIS post-therapy cases. The authors concluded that AMACR positivity is a potentially useful marker of CIS. However, the IUN-3–malignant pattern is a more reliable indicator of CIS compared with AMACR, especially in the post-treatment setting. The simultaneous evaluation of all three markers—p53, CD44s, and CK20—in a single slide in the form of a cocktail is advantageous, especially with small biopsy specimens.

Aron M, Luthringer DJ, McKenney JK, et al. Utility of a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3-CK20/CK44s/p53) and α-methylacyl-CoA racemase (AMACR) in the distinction of urothelial carcinoma in situ (CIS) and reactive urothelial atypia. Am J Surg Pathol. 2013;37:1815–1823.

Correspondence information not provided.

Use of cervical mucus to screen for gynecological malignancies

High-grade malignancies are the leading cause of death from gynecological tumors. Unfortunately, no efficient screening method is available for these tumors. The authors reported the results of a pilot study based on the frequency of TP53 mutations in these cancers. Mucus from the cervix of 32 hysterectomy specimens with no grossly visible cervical or serosal involvement were included in the study. TP53 exons 5–9 mutations were screened for mutations using single-strand conformation polymorphism (SSCP). Immunostain for p53 protein was performed in all fallopian tubes and in a sample from the tumors that were identified prospectively. Thirty-two cases, including 19 malignant and 13 benign, were included. P53 immunostain was positive in only five of the cases—three high-grade malignant tumors and two precancerous lesions (serous tubal intraepithelial lesion or p53 signature) in the fallopian tubes. A TP53 mutation band pattern was detected by SSCP in two of three and two of two cases, respectively. Twenty-seven cases were negative for p53 immunostain, four of which were positive for TP53 mutation by SSCP, including three low-grade malignancies. The authors concluded that the results of this study provide evidence that DNA from precursor lesions of high-grade ovarian, fallopian tube, and endometrial carcinomas can be detected in cervical mucus. Additional studies using different markers in a preoperative setting and large-scale screening studies will determine the utility of using cervical mucus to screen for gynecological malignancies.

Lamzabi I, Buckingham L, Gebrekiristos M, et al. Use of cervical mucus to screen for gynecological malignancies: a pilot study. Mod Pathol. 2013;26:1508–1513.

Correspondence: Dr. I. Lamzabi at ihab_lamzabi@rush.edu

Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma

Loss of PTEN (phosphatase and tensin homolog) expression and microsatellite instability are two of the more common molecular alterations in endometrial carcinoma. Controversy surrounds whether there is a relationship between these molecular mechanisms. Therefore, a cohort of 187 pure endometrioid and nonendometrioid endometrial carcinomas, carefully characterized as to clinical and pathological features, was examined by the authors for PTEN sequence abnormalities and the immunohistochemical expression of PTEN and the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. MLH1 methylation analysis was performed when tumors had loss of MLH1 protein. Mismatch repair protein loss was more frequent in endometrioid carcinomas compared with nonendometrioid carcinomas, a difference primarily attributable to the presence of MLH1 methylation in a greater proportion of endometrioid tumors. Among the nonendometrioid group, mixed endometrioid/nonendometrioid carcinomas were the histotype that most commonly had loss of mismatch repair protein. In endometrioid tumors, the frequency or PTEN loss measured by immunohistochemistry and mutation did not differ significantly between the mismatch repair protein intact or mismatch repair protein loss groups, suggesting that PTEN loss is independent of mismatch protein repair status in this group. However, in nonendometrioid carcinomas, intact positive PTEN immunohistochemical expression and wild-type PTEN were highly associated with retained positive expression of mismatch repair proteins in the tumor. Of relevance to screening endometrial cancers for Lynch syndrome is that an initial PTEN immunohistochemistry determination may be able to replace the use of four mismatch repair immunohistochemical markers in 63 percent of patients with nonendometrioid endometrial carcinoma. Therefore, PTEN immunohistochemistry, combined with tumor histotype, is a useful adjunct in the clinical evaluation of endometrial carcinomas for Lynch syndrome.

Djordjevic B, Barkoh BA, Luthra R, et al. Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas. Mod Pathol. 2013;26:1401–1412.

Correspondence: Dr. R. R. Broaddus at rbroaddus@mdanderson.org

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