CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Shaomin Hu, MD, PhD, gastrointestinal/liver pathology fellow, University of Chicago; and S. Emily Bachert, MD, pathology resident, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington.
Keratin 17: a sensitive and specific biomarker of urothelial neoplasia
October 2019—There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for detecting urothelial tumors. The authors conducted a study to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and urine cytology specimens. The authors evaluated K17 expression using IHC in formalin-fixed, paraffin-embedded tissue specimens of nonpapillary invasive urothelial carcinoma (UC; classical histological cases), high-grade papillary UC (PUC-HG), low-grade papillary UC (PUC-LG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive versus negative based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on detecting K17 in any urothelial cells. Mann–Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17-positive tumor cells was 70 percent (range, 20–90 percent) in PUNLMP, 30 percent (range, 5–100 percent) in PUC-LG, 20 percent (range, 1–100 percent) in PUC-HG, and 35 percent (range, 5–100 percent) in UC, but staining was rarely detected (range, 0–10 percent) in normal urothelial mucosa. Defining cases in which K17 was detected in 10 percent or more of cells were considered positive. The sensitivity of K17 in biopsies was 89 percent (95 percent confidence interval [CI], 80–96 percent) and the specificity was 88 percent (95 percent CI, 70–95 percent) to distinguish PUC-LG, PUC-HG, and UC from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100 percent and specificity of 96 percent for urothelial carcinoma in 112 selected urine specimens. Therefore, the authors concluded that K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be investigated further as a novel biomarker for the cytologic diagnosis of urine specimens.
Babu S, Mockler DC, Roa-Peña L, et al. Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia. Mod Pathol. 2019;32(5):717–724.
Correspondence: Dr. L. F. Escobar-Hoyos at luisa.escobarhoyos@stonybrookmedicine.edu or Dr. K. R. Shroyer at kenneth.shroyer@stonybrookmedicine.edu
Micropapillary cervical adenocarcinoma: a clinicopathologic study of 44 cases
Micropapillary adenocarcinoma has been reported as an aggressive variant of adenocarcinoma in several organs, where it is associated with poor clinical outcome. The authors conducted a study of the clinicopathologic features and outcomes of cervical adenocarcinomas with a micropapillary component (micropapillary cervical adenocarcinomas), which was the largest reported study of these neoplasms. The study comprised 44 cervical adenocarcinomas of usual (human papillomavirus related) type (84 percent); mucinous, not otherwise specified (4.5 percent); gastric type (4.5 percent); endometrioid (4.5 percent); and adenosquamous carcinoma (two percent). The micropapillary component comprised more than 50 percent of the neoplasm in 34 (77 percent) cases (group one) and 10 to 50 percent in 10 (23 percent) cases (group two). Lymph node metastasis was present in 41 of 44 (93 percent) cases, and the nodal tumor typically retained a prominent micropapillary morphology. Follow-up ranged from seven to 123 months (mean, 65.9 months). Seventeen of 44 (38.6 percent) patients had no evidence of disease on follow-up, while six of 44 (13.6 percent) were alive with disease and 21 of 44 (47.7 percent) died of disease. No survival differences between group one and group two were found. Lymph node metastasis (P = .0015), lymphovascular space invasion (P = .002), parametrial involvement (P = .03), and depth of stromal invasion (P = .045) were related to tumor recurrence on univariate analysis. On multivariate analysis, lymph node metastasis (P = .001) and extent of lymphovascular space invasion (P = .027) were significant independent predictors of tumor recurrence. The study showed that a micropapillary component in cervical adenocarcinoma may be associated with aggressive behavior and that a micropapillary architecture may occur within a variety of cervical adenocarcinoma types.
Alvarado-Cabrero I, McCluggage WG, Estevez-Castro R, et al. Micropapillary cervical adenocarcinoma: a clinicopathologic study of 44 cases. Am J Surg Pathol. 2019;43(6):802–809.
Correspondence: Dr. Isabel Alvarado-Cabrero at keme2.tijax12@gmail.com
Use of NKX2.2 IHC in distinguishing Ewing sarcoma from cytomorphologic mimics
Ewing sarcoma is a round cell sarcoma that can be challenging to diagnose using cytologic material given its significant overlap with numerous mesenchymal, epithelial, and lymphoid cytomorphologic mimics. The authors conducted a study to assess the utility of the novel marker NKX2.2 in diagnosing Ewing sarcoma (ES) using such material and its ability to distinguish ES from its mimics. NKX2.2 IHC was performed on cell blocks from 107 fine-needle aspirations, and nuclear expression was scored semiquantitatively for extent and intensity. The study cohort included ES (n =10), well-differentiated neuroendocrine tumor (n = 20), melanoma (n =11), Merkel cell carcinoma (n =10), small cell carcinoma (n =10), alveolar rhabdomyosarcoma (n = 2), spindle cell/sclerosing rhabdomyosarcoma (n = 2), synovial sarcoma (n = 12), solitary fibrous tumor (n = 2), chronic lymphocytic leukemia (n =10), lymphoblastic lymphoma (n =11), adenoid cystic carcinoma (n = 6), and CIC-rearranged sarcoma (n =1). The results indicated that NKX2.2 had high sensitivity (100 percent) and moderate specificity (85 percent) for the diagnosis of ES using cytologic material. NKX2.2 expression also was present in a subset of mesenchymal and epithelial mimics. Staining was most commonly observed in small cell carcinoma (80 percent) and well-differentiated neuroendocrine tumor (45 percent). Among mesenchymal mimics, 42 percent exhibited NKX2.2 expression. NKX2.2 staining was absent in melanoma, adenoid cystic carcinoma, and lymphoproliferative neoplasms. The authors concluded that NKX2.2 is a highly sensitive but only moderately specific marker for ES. Neuroendocrine neoplasms exhibit variable NKX2.2 expression and remain a potential diagnostic pitfall. Therefore, NKX2.2 expression should be interpreted in the context of an appropriate IHC panel, and often with confirmatory molecular testing, to accurately diagnose ES.
Russell-Goldman E, Hornick JL, Qian X, et al. NKX2.2 immunohistochemistry in the distinction of Ewing sarcoma from cytomorphologic mimics: Diagnostic utility and pitfalls. Cancer Cytopathol. 2018;126(11):942–949.
Correspondence: Dr. Vickie Y. Jo at vjo@bwh.harvard.edu
Minimal microsatellite shift in MSI-high endometrial cancer: a pitfall in interpretation
Mismatch-repair deficiency testing plays a critical role in identifying probands in Lynch syndrome families and triaging patients with high-stage or recurrent solid malignancies for checkpoint inhibitor (pembrolizumab) immunotherapy. The authors compared microsatellite shift patterns of microsatellite instability (MSI) PCR analysis at five National Cancer Institute-recommended loci between microsatellite instability MSI-high endometrial carcinoma (n = 50) and MSI-high colorectal cancer (n =19). The endometrial cancer cohort included 45 endometrioid, one serous, and four clear cell carcinomas. Overall, 52 percent (26 of 50) of MSI-high endometrial cancers showed minimal microsatellite shift (defined as a one- to three-nucleotide repeat shift at an involved locus) observed at one or more loci. Among MSI-high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21 of 21; 100 percent), D17S250 (10 of 11; 91 percent), D5S346 (11 of 12; 92 percent), BAT25 (nine of 12; 75 percent), and BAT26 (eight of 21; 38 percent). Noticeably, 11 of the 26 (42 percent) cases showed only minimal shift. Among MSI-high endometrial cancers with minimal microsatellite shift, 65 percent (17 of 26) had combined MLH1 and PMS2 loss, eight percent (two of 26) had combined MSH2 and MSH6 loss, 12 percent (three of 26) had MSH6 loss, and 15 percent (four of 26) had loss of PMS2 by IHC. In contrast, only 16 percent (three of 19) had minimal microsatellite shift seen in the colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 14 percent (seven of 50) of MSI-high endometrial carcinomas showed isolated loss of MSH6, in contrast to seven percent (one of 15) of MSI-high colorectal carcinomas. The authors concluded that MSI-high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. MSI-high endometrial cancers also have more frequent loss of MSH6. The ability to recognize minimal microsatellite shift is crucial in interpreting microsatellite instability PCR data for endometrial carcinoma.
Wu X, Snir O, Rottmann D, et al. Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation. Mod Pathol. 2019;32(5):650–658.