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.
Assessing IHC biomarkers for basal-like breast cancer against a gene-expression profile gold standard
Gene-expression profiling of breast cancer delineates a particularly aggressive subtype referred to as basal-like. This subtype comprises approximately 15 percent of all breast cancers and afflicts younger women. It is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) or EGFR, are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature. A parallel comparison of 46 proposed immunohistochemical biomarkers of basal-like breast cancer was performed against a gene-expression profile gold standard on a tissue microarray containing 42 basal-like and 80 nonbasal-like breast cancer cases. Ki67 and PPH3 were the most sensitive biomarkers (both 92 percent) positively expressed in the basal-like subtype, whereas CK14, IMP3, and NGFR were the most specific (100 percent). Among the biomarkers surveyed, loss of INPP4B (a negative regulator of phosphatidylinositol signaling) was 61 percent sensitive and 99 percent specific with the highest odds ratio (OR) at 108, indicating the strongest association with basal-like breast cancer. Expression of nestin, a common marker of neural progenitor cells that is also associated with the triple-negative/basal-like phenotype and poor breast cancer prognosis, possessed the second highest OR at 29 among the 46 biomarkers surveyed, as well as 54 percent sensitivity and 96 percent specificity. As a positively expressed biomarker, nestin possesses technical advantages over INPP4B that makes it a more ideal biomarker for identifying basal-like breast cancer. The comprehensive immunohistochemical biomarker survey presented in this study is a necessary step for determining a surrogate immunopanel that best defines basal-like breast cancer in a practical and clinically accessible manner.
Won JR, Gao D, Chow C, et al. A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard. Mod Pathol. 2013;26:1438–1450.
Correspondence: Dr. T. O. Nielsen at torsten@mail.ubc.ca
Influence of sampling modality on predictive value of grading in adult soft tissue extremity sarcomas
Histologic grade is one of the best predictors of outcome in adult soft tissue sarcomas. Current grading systems were validated on resection specimens; however, there has been a trend toward the use of biopsies to diagnose these tumors. The authors conducted a study to determine whether the grade of an extremity soft tissue sarcoma determined on tissue obtained by core needle biopsy or incisional biopsy is predictive of metastasis- or disease-free survival and whether either sampling modality is superior. A total of 103 core needle biopsies and 107 incisional biopsies of nonmetastatic spindle cell sarcomas of the extremities were retrieved from the archives. All cases had a minimum two-year followup. Patient data and outcome and tumor characteristics were recorded. Tumors were reviewed and evaluated using the French Federation of Cancer Centers Sarcoma Group grading system. Kaplan-Meier survival curves were generated to correlate tumor grade with metastasis- and disease-free survival for both groups. The authors found that patient and tumor characteristics were similar between groups, except that more tumors were grade 3 and superficial in the incisional biopsy group. Grade determined on core needle biopsy was not predictive of metastasis-free survival (P=0.59) or disease-free survival (P=0.50). In contrast, grade determined on incisional biopsy was predictive of both metastasis-free survival (P<0.001) and disease-free survival (P=0.001). The authors concluded that biopsy, particularly core needle biopsy, represents a convenient diagnostic tool, particularly in the context of neoadjuvant therapy. However, based on these results, incisional biopsy is recommended if grading is to be used to predict prognosis in spindle cell soft tissue sarcomas of the extremities.
Khoja H, Griffin A, Dickson B, et al. Sampling modality influences the predictive value of grading in adult soft tissue extremity sarcomas. Arch Pathol Lab Med. 2013;137:1774–1779.
Correspondence: Dr. Rita Kandel at rkandel@mtsinai.on.ca
ARID1A expression and PI3K-Akt pathway alterations, TP53, and microsatellite instability in endometrial carcinogenesis
The switch/sucrose nonfermentable subunit ARID1A (AT-rich interactive domain 1A gene) has been postulated as a novel tumor suppressor of gynecologic cancer and a driver gene in endometrial carcinogenesis. However, its relationship to established molecular alterations in endometrioid endometrial cancer (EEC) is unknown. The authors analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry), and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), they included a Lynch syndrome set. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in 31 percent (40 of 130) of the EEC cases. No loss of expression of the other subunits of the switch/sucrose nonfermentable complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P=0.0004). In contrast with the Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14 percent) of the Lynch syndrome set, compared with 24 cases (75 percent; P<0.0001) of the sporadic microsatellite-unstable tumors, showed loss of ARID1A. These observations suggest that ARID1A is a causative and not a target gene of microsatellite instability by playing a role in the epigenetic silencing of the MLH1 gene in endometrial cancer.
Bosse T, Ter Haar NT, Seeber LM, et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod Pathol. 2013;26:1525–1535.
Correspondence: Dr. T. Bosse at t.bosse@lumc.nl