Editors: Michael Cibull, MD, professor emeritus, University of Kentucky College of Medicine, 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.
Reproducibility of residual cancer burden for assessing breast cancer after neoadjuvant chemotherapy
The residual cancer burden index was developed to quantify residual disease ranging from pathological complete response to extensive residual disease. The authors conducted a study to evaluate inter-pathologist reproducibility in the residual cancer burden index score and category and in their long-term prognostic utility. Five pathologists independently reviewed pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial. The size of tumor bed, average percent overall tumor cellularity, average percent of in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist. Residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for agreement in residual cancer burden score among pathologists was 0.931 (95 percent confidence interval [CI], 0.908–0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95 percent CI, 0.539–0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient, 0.980; 95 percent CI, 0.954–0.992) than the primary component (overall correlation coefficient, 0.795; 95 percent CI, 0.716–0.853). At a median follow-up of 12 years, residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient, 0.995; 95 percent CI, 0.989–0.998). The authors concluded that residual cancer burden assessment is highly reproducible, with reproducible long-term prognostic significance.
Peintinger F, Sinn B, Hatzis C, et al. Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy. Mod Pathol. 2015;28(7):913–920.
Correspondence: Dr. W. F. Symmans at email@example.com
Cervical and anorectal squamocolumnar junctions and HPV-related cancer risk
Human papillomavirus infection causes cancers and their precursors (high-grade squamous intraepithelial lesions) near cervical and anal squamocolumnar junctions. Recently described cervical squamocolumnar junction cells are putative residual embryonic cells near the cervical transformation zone. These cells appear multipotential and share an identical immunophenotype (strongly CK7 positive) with more than 90 percent of high-grade squamous intraepithelial lesions and cervical carcinomas. However, because the number of new cervical cancers discovered worldwide annually is 17-fold that of anal cancer, the authors posed the hypothesis that this difference in cancer risk reflects the differences in the transition zones at the two sites. They studied the microanatomy of the normal anal transformation zone (n=37) and the topography and immunophenotype of anal squamous neoplasms (n=97). A discrete anal transition zone was composed of multilayered CK7-positive/p63-negative superficial columnar cells and an uninterrupted layer of CK7-negative/p63-positive basal cells. The CK7-negative/p63-positive basal cells were continuous with the basal cells of the mature squamous epithelium, and they were identical in appearance. This was in contrast to the cervical squamocolumnar junction, which harbored a single-layered CK7-positive/p63-negative squamocolumnar junction cell population. Of the 97 anal intraepithelial neoplasia/squamous cell carcinomas evaluated, only 27 percent (26 of 97) appeared to originate near the anal transition zone, and only 23 percent (22 of 97) were CK7 positive. Therefore, this study reveals two fundamental differences between the anus and cervix: The anal transition zone does not harbor a single monolayer of residual undifferentiated embryonic cells, and the dominant tumor immunophenotype is in keeping with an origin in metaplastic (CK7-negative) squamous rather than squamocolumnar junction (CK7-positive) epithelium. The implication is that, at birth, the embryonic cells in the anal transition zone have already begun to differentiate, presenting a metaplasia that—similar to vaginal and vulvar epithelium—is less prone to HPV-directed carcinogenesis. This, in turn, underscores the link between cancer risk and a very small and discrete population of vulnerable squamocolumnar junction cells in the cervix.
Yang EJ, Quick MC, Hanamornroongruang S, et al. Microanatomy of the cervical and anorectal squamocolumnar junctions: a proposed model for anatomical differences in HPV-related cancer risk. Mod Pathol. 2015;28:994–1000.
Correspondence: Dr. C. P. Crum at firstname.lastname@example.org
Study of episomal papillomavirus infection of placenta and pregnancy complications
Viral infections are known to adversely affect pregnancy, but scant attention has been given to human papillomavirus infection relative to pregnancy. The authors conducted a study to determine the molecular and histopathological features of placental human papillomavirus (HPV) infection in association with pregnancy complications, such as fetal growth restriction, prematurity, pre-eclampsia, and diabetes. They selected 339 placentae based on the presence or absence of pregnancy complications. Five independent methods were used to identify HPV in the placenta, namely, immunohistochemistry for L1 viral capsid, in situ hybridization to high-risk HPV DNA, PCR, Western blotting, and transmission electron microscopy. Pregnancy complications and uterine cervical smear screening results were correlated with placental HPV histopathology. In the study, which was deliberately biased towards complications, HPV was found in the decidua of 75 percent (253 of 339) of placentae and was statistically associated with histological acute chorioamnionitis (P<.05). In 14 percent (35 of 253) of the HPV-positive cases, HPV L1 immunoreactivity also occurred in the villous trophoblast, where it was associated with a lymphohistiocytic villitis (HPV-LHV) and was exclusively of high-risk HPV type. HPV-LHV was significantly associated with fetal growth restriction, preterm delivery, and pre-eclampsia (all P<.05). All cases of pre-eclampsia (20 of 20) in the cohort had high-risk placental HPV. An additional 55 cases (22 percent; 55 of 253) of HPV-positive placentae had minimal villous trophoblast HPV L1 immunoreactivity, but a sclerosing pauci-immune villitis, statistically associated with diabetes (49.1 percent; 27 of 55; P<.05). For women with placental HPV, 33 percent (69 of 207) had an HPV-related positive smear result before pregnancy compared with 9.4 percent (eight of 85) of women with HPV-negative placentae (P=.0001). These findings support the need for additional investigations to determine if vaccination of women and men will improve pregnancy outcomes.
Slatter TL, Hung NG, Clow WM, et al. A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications. Mod Pathol. 2015;28:1369–1382.
Correspondence: Dr. N. Hung at email@example.com
Role of BAP1 expression in diagnosis of mesothelioma in effusion cytology
Although most mesotheliomas present with pleural effusions, whether mesothelioma can be diagnosed with confidence in effusion cytology is controversial. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA1-associated protein (BAP1) is a tumor-suppressor gene that shows biallelic inactivation in approximately half of all mesotheliomas. The authors investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. Forty-three of 75 (57 percent) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, eight cases demonstrated negative staining for BAP1. On follow-up, six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months. Two were lost to follow-up immediately and mesothelioma could not be excluded. Only five of 100 consecutive benign effusions were interpreted as BAP1 negative. One of those patients died soon after and mesothelioma could not be excluded. On unblinded review, the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells, suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. Forty-seven effusions with adenocarcinoma were BAP1 positive. The authors concluded that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. They cautioned that interpreting BAP1 immunohistochemistry on cell blocks may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. They also noted that BAP1 loss is not a sensitive test because it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.
Andrici J, Sheen A, Sioson L, et al. Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology. Mod Pathol. 2015;28:1360–1368.
Correspondence: Dr. A. J. Gill at firstname.lastname@example.org