CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
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.
BRCA1 and BRCA2 mutations, TP53 abnormalities, and immune cell infiltrates in ovarian carcinoma
The authors characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with germline or somatic mutations in BRCA1 or BRCA2, methylation of BRCA1, and normal BRCA1 or BRCA2. A total of 131 women were identified prospectively, all of whom were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma, and of these, 31 (30 percent) had germline or somatic BRCA1 or BRCA2 mutations (20 percent BRCA1 and 10 percent BRCA2; group one); 21 (20 percent) had methylation of BRCA1 (group two); and 51 (50 percent) had no BRCA loss (group three). Group four consisted of 28 cases of non-high–grade serous carcinoma, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P=.0008). Among high-grade serous carcinomas, there were no differences between groups one through three with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous tumors without mutations (P=.034; .027). TP53 expression differed between groups (P<.0001), with abnormal TP53 expression in 49 of 50 tumors from groups one and two. Wild-type TP53 expression was associated with worse outcome in high-grade serous tumors (P<.001). BRCA loss (mutation/methylation) is a common event in pelvic high-grade serous tumors (50 percent). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous tumors with germline and somatic mutations in BRCA1 or BRCA2 compared with tumors lacking BRCA abnormalities.
McAlpine JN, Porter H, Köbel M, et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol. 2012;25:740–750.
Correspondence: Dr. J. N. McAlpine at jessica.mcalpine@vch.ca
Significance of loss of ARID1A/BAF250a expression in endometriosis
Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating human SWI/SNF complexes that play an important role in controlling cell proliferation and in tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. The authors conducted a study in which they examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n=136) served as a control. Epithelial BAF250a expression was assessable in 90 of 104 (87 percent) and stromal BAF250a expression in 95 of 104 (91 percent) of the endometriosis and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n=3 of 20; 15 percent) and one deep-infiltrating endometriosis sample (n=1 of 22; five percent) but in none of the peritoneal endometriosis (n=0 of 16) and eutopic endometrium samples (n=0 of 30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (P<.0005), as well as in peritoneal (P=.003) and deep-infiltrating endometriosis (P=.02). The authors’ data demonstrate that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriosis. In addition, the authors reported that a partial loss of BAF250a expression is occurring in the form of cell clusters, indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be important in determining individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be studied further.
Samartzis EP, Samartzis N, Noske A, et al. Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation? Mod Pathol. 2012;25:885–892.
Correspondence: Dr. P. Imesch at patrick.imesch@usz.ch
Relationship between pathologic complete response and prognosis
after chemotherapy in breast cancer subtypes
The exact definition of pathologic complete response and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. The authors conducted a study in which they analyzed tumor response at surgery and its association with long-term outcome for 6,377 patients with primary breast cancer who were receiving neoadjuvant anthracycline-taxane–based chemotherapy in seven randomized trials. The authors found that disease-free survival was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n=955) compared with patients with residual ductal carcinoma in situ only (n=309), no invasive residuals in breast but involved nodes (n=186), only focal-invasive disease in the breast (n=478), and gross invasive residual disease (n=4,449; P<.001). Hazard ratios for disease-free survival comparing patients with or without pathologic complete response (pCR) were lowest when defined as no invasive and no in situ residuals (0.446) and increased when the definition included in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727). Pathologic complete response was associated with improved disease-free survival in tumors that were luminal B/human epidermal growth factor receptor 2 (HER2) negative (P=.005), HER2 positive/nonluminal (P<.001), and triple negative (P<.001) but not in luminal A (P=.39) or luminal B/HER2-positive (P=.45) breast cancer. Pathologic complete response in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis. The authors concluded that pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residuals or involved lymph nodes should not be considered as having achieved pCR. Pathologic complete response is a suitable surrogate endpoint for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors.
von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–1804.
Correspondence: Dr. Gunter von Minckwitz at gunter.vonminck witz@germanbreastgroup.de