Anatomic Abstracts
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September 2009 Editors:
Intraepithelial T cells and prognosis in ovarian carcinoma
Intraepithelial tumor-infiltrating T cells have been correlated with improved outcomes in ovarian carcinoma; however, it is not known whether they are associated with disease stage, histological subtype, or BRCA mutation or expression. The authors conducted a study to deter-mine if such an association exists. The study included two case series of ovarian carcinomas: a retrospective series of 500 patients and 40 pro-spectively collected cases fully characterized for BRCA1 mutation status and expression. Intraepithelial immune cells were assessed as present or absent by immunohistochemical staining of tissue microarrays. In the retrospective case series, the presence of intraepithelial CD8+ T cells correlated with improved disease-specific survival (P=.027), whereas the presence of intraepithelial CD3+ T cells did not (P=.49). For serous ovarian carcinomas, the presence of intraepithelial CD3+ and CD8+ T cells correlated with improved disease-specific survival (P=.0016 and P≤.0001, respectively). The presence of intraepithelial CD8+ T cells was not associated with improved survival in endometrioid or clear cell carcinomas. On multivariate analysis, disease stage and CD8+ T cells were found to be independently predictive of improved disease-specific survival, whereas grade, age at surgery, and type of adjuvant treatment were not. In the prospective patient cohort, intraepithelial CD8+ T cells correlated with the presence of mutation or loss of expression of BRCA1 through promoter methylation (P=.019). The authors concluded that intraepithelial CD8+ tumor-infiltrating T cells correlate with improved clinical outcomes for all stages of ovarian cancer; this association is restricted to the serous ovarian cancer subtype and is an independent prognostic factor on multivariate analysis. The presence of intraepithelial CD8+ T cells also significantly correlates with loss of BRCA1. Clarke B, Tinker AV, Lee CH, et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009;22:393–402. Correspondence: Dr. C. B. Gilks at gilks@vch.ca
Lobules in normal breast tissue can be classified by their degree of development, which may affect their susceptibility to carcinogenesis. However, few epidemiologic studies have addressed this potential link. The authors examined the association between lobule type and subsequent breast cancer risk in a nested case-control study of benign breast disease and breast cancer within the Nurses’Health Studies (200 cases, 915 controls). Pathologists reviewed benign breast biopsy slides and classified normal terminal duct lobular units as having no type 1 lobules, mixed lobule types, or predominant type 1 and no type 3 lobules. Logistic regression analysis was used to compute odds ratios and 95 percent confidence intervals (CIs) for the association between lobule type and breast cancer risk. The authors found that women with predominant type 1 and no type 3 lobules (54 cases, 321 controls) had a decreased risk of breast cancer compared with those with no type 1 lobules or mixed lobule types (odds ratio, 0.63; 95 percent CI, 0.44–0.91), although this was attenuated after adjusting for histologic category of benign breast disease (odds ratio, 0.71; 95 percent CI, 0.49–1.02). Having predominant type 1 lobules and no type 3 lobules was associated with a similar risk reduc-tion for all categories of benign breast disease (nonproliferative: odds ratio, 0.73 [95 percent CI, 0.36–1.50]; proliferative without atypia: odds ratio, 0.80 [95 percent CI, 0.47–1.35]; and atypical hyperplasia: odds ratio, 0.61 [95 percent CI, 0.28–1.35]). The authors concluded that these results provide preliminary evidence that lobule type may be an important marker of breast cancer risk in women with benign breast disease. Baer HJ, Collins LC, Connolly JL, et al. Lobule type and subsequent breast cancer risk: results from the Nurses’ Health Studies. Cancer. 2009;115:1404–1411. Correspondence: Dr. Heather J. Baer at hbaer@partners.org
FoxP3 is a marker for immunosuppressive CD25+CD4+ regulatory T cells. These cells are thought to play a role in inducing immune toler-ance to antigens and may be selectively recruited by carcinomas. The authors investigated whether breast carcinomas had significant numbers of FoxP3-positive regulatory T cells by immunohistochemistry and if these cells were associated with other prognostic factors, such as Nottingham grade, hormone receptor immunohistochemical profile, tumor size, or lymph node metastases. Ninety-seven needle core or excisional breast biopsies with invasive breast carcinoma, diagnosed at the University of Washington, were stained with antibodies to FoxP3, estrogen receptor, and HER2/neu. The numbers of FoxP3-positive cells present within the neoplastic epithelium and immediately adjacent stroma were counted manually in three high-powered fields (HPFs, Χ400) by two independent pathologists. The average scores were then correlated with the parameters of interest. A threshold of 15 or more FoxP3-positive cells/HPF was used to define a FoxP3-positive case in some analyses. Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P=.000229). In addition, the presence of significant numbers (≥/HPF) of FoxP3-positive cells in breast carcinoma was positively associated with higher Nottingham grade (P=.00002585). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (>2.0 cm; P=.012824) and trended toward an association with estrogen receptor negativity. Interestingly, triple-negative (estrogen and progesterone receptor negative and HER2/neu neg-ative) Nottingham grade III cases were also significantly associated with high numbers of FoxP3 cells. These results indicate that regulatory T cells may play a role in inducing immune tolerance to higher grade and more aggressive breast carcinomas and are a potential therapeutic target for these cancers. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 2008;21:1527–1532. Correspondence: Dr. K. H. Allison at kallison@u.washington.edu
Different types of immunohistochemical sex cord-stromal markers have been studied in various types of ovarian sex cord-stromal tumors. However, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors as in other tumors in this spectrum of neoplasms. The authors conducted a study to determine which immunohisto-chemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor and to establish whether there are substantial differences in expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers that have known variable specificity for sex cord-stromal lineage (inhibin, cal-retinin, MART-1/melan-A, CD99, steroidogenic factor 1 [SF-1, adrenal 4-binding protein], and WT1) were performed in 127 cases of five types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). The authors found that all cases in each type of sex cord-stromal tumor expressed SF-1. All groups of tumors expressed inhibin and calretinin but with a lesser frequency (56 to 100 percent and 36 to 100 percent of cases, respectively). All types of tumors, except steroid cell tumor, expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. Only Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor showed expression of MART-1 (94 and 96 percent of cases, respectively). Fibroma/fibrothecoma was least frequently positive for several of the different markers studied. Among all tumor groups combined, inhibin and WT1 showed the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (possible range for immunohistochemical composite score, one to 12) varied between tumors: adult granulosa cell tumorinhibin (score, 10.0); Sertoli cell tumor—WT1 (score, 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)—WT1 (score, 10.4); steroid cell tumorinhibin (score, 11.2); and fibroma/fibrothecoma—WT1 (score, 8.9). The authors concluded that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each type of sex cord-stromal tumor has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors, with some exceptions—for example, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; and inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma. SF-1 is the most sensi-tive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the study’s findings relative to sensitivity and extent of expression, as well as known specificity in the literature, the most informative sex cord-stromal markers for distinguishing sex cord-stromal tumors from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1. (The exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist.) However, the utility of immunohistochemistry for diagnosing fibroma/fibrothecoma is somewhat limited. Zhao C, Vinh TN, McManus K, et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol. 2009;33:345–366. Correspondence: Dr. Chengquan Zhao at zhaoc@upmc.edu Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco. |
