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.
GATA3: a multispecific but potentially useful marker in surgical pathology
The transcription factor GATA3 is important for differentiating breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested that it may be useful in evaluating carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. The authors conducted a study in which they examined normal developing and adult tissues and 2,040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology. They used monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed more strongly in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in more than 90 percent of primary and metastatic ductal and lobular carcinomas of the breast, urothelial and cutaneous basal cell carcinomas, and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than gross cystic disease fluid protein. Among squamous cell carcinomas, the expression was highest in the skin (81 percent) and lower in cervical (33 percent), laryngeal (16 percent), and pulmonary tumors (12 percent). Common positivity was found in skin adnexal tumors (100 percent), mesothelioma (58 percent), salivary gland (43 percent), and pancreatic (37 percent) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was less than 10 percent. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51 percent), whereas oncocytomas were positive in 17 percent of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. The authors concluded that GATA3 is a useful marker for characterizing not only mammary and urothelial carcinomas but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.
Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38:13–22.
Correspondence: Dr. Markku Miettinen at miettinenmm@mail.nih.gov
Chromophobe hepatocellular carcinoma with abrupt anaplasia
Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separating hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognoses, or therapeutic responses. To identify potential subtypes, two pathologists conducted a study in which they independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided the cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm; abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology); and scattered microscopic pseudocysts, which the authors designate as chromophobe hepatocellular carcinoma with abrupt anaplasia. Thirteen cases were identified (six percent of all hepatocellular carcinomas), comprising six men and seven women who were an average age of 61 years. Six cases occurred in cirrhotic livers. Serum alfa-fetoprotein was elevated in six out of 10 (60 percent) cases. A variety of underlying liver diseases were noted, but cases were enrichment for chronic hepatitis B (P=0.006). Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately eight percent of unselected hepatocellular carcinomas. In contrast, 11 of 12 (92 percent) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. The authors propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.
Wood LD, Heaphy CM, Daniel HD, et al. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod Pathol. 2013;26:1586–1593.
Correspondence: Dr. M. S. Torbenson at mtorben@jhmi.edu
Standard HER2 testing of endometrial serous carcinoma—experience at a large academic center
HER2 overexpression or amplification, or both, has been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, considerable variation exists in the reported rates of HER2 overexpression and amplification, likely, at least in part, resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, there are no established guidelines for HER2 testing in endometrial carcinoma. A study was conducted in which 108 endometrial carcinoma cases—85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component—were identified over a four-year period at a large academic center. All H&E and HER2 immunohistochemical slides were reviewed, and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to FDA criteria and breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients’ medical records. Thirty-eight (35 percent) cases showed HER2 overexpression or gene amplification, or both, 20 (53 percent) of which had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five (13 percent) of the HER2-positive cases demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75 percent (39 of 52) when using the FDA criteria, compared with 81 percent (42 of 52) by the ASCO/CAP scoring system. The authors concluded that in this large comprehensive study, 35 percent of endometrial serous carcinomas harbor HER2 protein overexpression or gene amplification, or both, over half of which demonstrate significant heterogeneity of protein expression. The breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended due to the significant heterogeneity of HER2 protein expression.
Buza N, English DP, Santin AD, et al. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Mod Pathol. 2013;12:1605–1612.
Correspondence: Dr. N. Buza at natalia.buza@yale.edu
Discontinuous foci of cancer in a single core of prostatic biopsy
Prostate biopsy reports orient urologists in outlining a patient’s treatment options. Discontinuous involvement of a core by multiple foci of cancer is not infrequent; however, there is no consensus as to which method of quantification should be the standard. The authors used two distinct approaches to quantify the length of cancer foci in the prostate biopsy and compared the results to prostatectomy parameters. All patients with matched prostate biopsy and prostatectomy treated by the same medical team between 2006 and 2010 were included consecutively in the study. Tumor extent in the prostate biopsy was estimated by multiple approaches, and the length was measured in millimeters. The subset of cases with discontinuous foci of cancer in a single core was initially reported by adding each foci and ignoring the benign intervening prostatic tissue, which was designated as additive quantification (AQ). On slide review, these foci were reassessed as a single focus and measured by linear quantification (LQ). Prostatectomies were partially embedded according to the International Society of Urological Pathology recommendations, and the percentage of tumor was evaluated with graphic precision. Mean percentage of the tumor in prostatectomy (%RP) and in the prostate biopsy were arbitrarily classified as limited (less than six percent) and nonlimited (six percent or more). Prostate biopsy parameters were then correlated with %RP and margin status. All methods of quantification of the tumor in the prostate biopsy obtained excellent correlation with %RP. Linear and additive quantification diverged in 14 of 38 patients, with a mean total length of cancer of 5.8 mm more than the length obtained by LQ in the same population, accurately upgrading six of 14 cases to nonlimited. This subset (LQ>AQ) was more often seen in prostate biopsy with significantly more positive cores (P=0.003) of predominantly Gleason score 7 and associated with positive surgical margins in prostatectomy (P=0.034) independent of %RP (21 versus 19 percent in the margin-negative cases). However, in the subset of prostate biopsy in which the tumor infiltration was continuous (AQ=AL), positive margins were associated with tumor extent (31 versus six percent in margin-negative cases). Discontinuous foci of cancer in a single core were most often seen in prostate biopsy sampling nonlimited disease, and this event was associated with positive surgical margins. Linear quantification of cancer improved the performance of the prostate biopsy in predicting prostatectomy tumor extent relative to the traditional millimetric sum. The authors concluded that their findings support the idea that discontinuous foci may represent undersampling of a larger irregular nodule; however, this study is based on routine reports and does not directly access tumor biology.
Schultz L, Maluf CE, da Silva RC, et al. Discontinuous foci of cancer in a single core of prostatic biopsy: when it occurs and performance of quantification methods in a private-practice setting. Am J Surg Pathol. 2013;37:1831–1836.
Correspondence: Luciana Schultz at lu_schultz@yahoo.com.br