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April 2011

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

HER2 immunohistochemistry in breast core needle biopsies HER2 immunohistochemistry in breast core needle biopsies

Core needle biopsies are widely used to determine human epidermal growth factor receptor 2 (HER2) status in breast cancer. Publications have reported false-positive rates of up to 20 percent on core needle biopsies (CNBs) if immunohistochemistry (IHC) is compared with fluorescence in situ hybridization (FISH). To clarify whether confirmation of IHC positivity by FISH is generally required, the authors analyzed the reliability of IHC positivity on CNBs versus surgical specimens in a multi-institutional study. Five pathologic laboratories contributed to the study by performing IHC on 500 CNBs and the corresponding surgical specimens overall. If IHC revealed a score of 2+ or 3+, HER2 status was confirmed by FISH in a central laboratory. The authors compared their evaluation to Food and Drug Administration-approved scoring criteria and recently published American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) guidelines. They found that CNBs scored 3+ revealed five false-positive results if the scoring followed FDA criteria (five of 40; 12.5 percent) and two false-positives if it followed ASCO-CAP cri-teria (two of 33; 6.1 percent). IHC was falsely negative in only one CNB. By contrast, IHC on surgical specimens revealed five false-negative results but only one false-positive result (one of 35; 2.9 percent) if scored following FDA-approved criteria. With the aid of the ASCO-CAP criteria, false-positive IHC results were obtained at only one of the five participating institutions. The authors concluded that IHC scores of 3+ on CNBs proved to be reliable in four of the five participating institutions if scoring followed the ASCO-CAP criteria. Therefore, it is possible to determine HER2 status in breast cancer on CNBs using the common strategy to screen all cases by IHC and retest only scores of 2+ by FISH. Prerequisites are quality assurance and application of the new ASCO-CAP criteria.

Lebeau A, Turzynski A, Braun S, et al. Reliability of human epidermal growth factor receptor 2 immunohistochemistry in breast core needle biopsies. J Clin Oncol. 2010:10;28(20):3264–3270.

Correspondence: A. Lebeau at a.lebeau@uke.de
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Molecular profiling of invasive breast cancer Molecular profiling of invasive breast cancer

Several oncogenes and tumor-suppressor genes have been implicated in the development, progression, and response to therapy of invasive breast cancer. The phenotypic uniqueness, and therefore the heterogeneity of clinical behavior, of patients’ tumors may be traceable to these genes’ underlying variations in gene copy number. To obtain a more complete view of gene copy number changes and their relationship to phenotype, the authors analyzed 20 breast cancer-related genes in 104 invasive breast cancers using multiplex ligation-dependent probe amplification (MLPA). They identified MYC gene amplification in 48 percent of patients, PRDM14 in 34 percent, topoisomerase IIα (TOP2A) in 32 percent, ADAM9 in 32 percent, HER2 in 28 percent, cyclin D1 (CCND1) in 26 percent, EMSY in 25 percent, IKBKB in 21 percent, AURKA in 17 percent, FGFR1 in 17 percent, estrogen receptor-α (ESR1) in 16 percent, CCNE1 in 12 percent, and EGFR in nine percent of patients. A significant correlation was found between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1, and HER2 were negatively associated with estrogen receptor status, whereas FGFR1, ADAM9, IKBKB, and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC, and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors, and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1, and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1, 20 percent) and FGFR1 (10 percent). The authors concluded that MLPA analysis with this breast cancer “kit” allowed them to simultaneously assess copy numbers of 20 important breast cancer genes. This provided an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and, thereby, data on the potential importance of these genes in breast cancer.

Moelans CB, de Weger RA, Monsuur HN, et al. Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod Pathol. 2010;23:1029–1039.

Correspondence: Dr. C. B. Moelans at cmoelans@umcutrecht.nl
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Biomarkers as objective standards in diagnosis of cervical biopsies Biomarkers as objective standards in diagnosis of cervical biopsies

Histopathologic diagnosis of cervical biopsies determines the clinical management of patients with an ab-normal cervical cancer screening test, yet it is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce the diagnostic variability of cervical biopsy evaluations, but systematic, rigorous evaluations of their potential clinical utility are lacking. To address the diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, the authors conducted a community-based and population-based evaluation. They used 1,455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a 14-month period. Thin sections of each biopsy from 1,451 of 1,455 (99.7 percent) biopsies underwent evaluation of immunohistochemical stains for the three biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by three pathologists. P16 immunostaining, using the strongest staining as the cutpoint, was 86.7 percent sensitive and 82.8 percent specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2[+]) diagnoses. The performance of p16(INK4a) was more sensitive (P<0.001), less specific (P<0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity, 68.9 percent; specificity, 97.2 percent). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis, but its performance at all staining intensities was inferior to p16 immuno-staining and did not increase the accuracy of CIN2(+) diagnoses when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. The authors determined that L1 immunostaining is not useful in distinguishing between CIN and non-CIN. They concluded that immunohistochemical staining for p16 is a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+).

Galgano MT, Castle PE, Atkins KA, et al. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 2010;34(8):1077–1087.

Correspondence: Dr. Mark H. Stoler at mhs2e@virginia.edu
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Detecting lymphovascular invasion in lymph node-positive patients with primary operable breast cancer Detecting lymphovascular invasion in lymph node-positive patients with primary operable breast cancer

Lymphovascular invasion is a widely recognized prognostic factor in lymph node-negative breast cancer. However, data about its prognostic significance in lymph node-positive patients are limited and controversial. From 931 patients operated on and monitored at the authors’ institution for an invasive breast carcinoma between 1989 and 1992, 374 lymph node-positive breast cancers were diagnosed, and all were entered in the authors’ study (median followup, 126 months). The authors found that lymphovascular invasion (LVI) was present in 46 percent of tumors and was associated with age of 40 years or less (P=0.02), high histological grade (P=0.01), and negative estrogen receptor status (P=0.032), but not with tumor size, number of involved lymph nodes, or HER2/neu status. LVI was an independent prognostic factor for distant metastases (P=0.002). Furthermore, in HER2/neu-negative/hormone receptor-positive tumors (n=287), the number of independent prognostic factors (LVI, age, histological grade, number of involved lymph nodes, and tumor size) was associated with a five-year metastasis-free survival rate ranging from 100 percent if no factors (n=25) were present, to 89 percent plus or minus two percent if one or two factors (n=186) were present, to 67 percent plus or minus six percent if three to five factors (n=76) were present (P<0.001). The authors concluded that LVI is an independent prognostic factor in lymph node-positive breast cancer and merits further prospective investigation as a decision tool in adjuvant chemotherapy.

Ragage F, Debled M, MacGrogan G, et al. Is it useful to detect lymphovascular invasion in lymph node-positive patients with primary operable breast cancer? Cancer. 2010;116(13):3093–3101.

Correspondence: Dr. Marc Debled at debled@bergonie.org
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Determining HER2/neu gene amplification status in cytologic breast cancer specimens using automated SISH Determining HER2/neu gene amplification status in cytologic breast cancer specimens using automated SISH

Silver-enhanced in situ hybridization is an emerging tool for determining HER2/neu amplification status in breast cancer. SISH is technically comparable to fluorescence in situ hybridization (FISH) but does not need to be interpreted with a fluorescence microscope. Although recent studies of histologic evaluations of SISH are promising, the authors evaluated its performance on 71 cytologic breast cancer specimens with the new combined HER2/Chr17 probe. HER2/neu status, as routinely determined by FISH, was available for all patients. The authors found it easy to evaluate SISH signals in cytologic cell blocks and smear specimens in most cases. Small numbers of tumor cells and difficulties in identifying tumor cells in lymphocyte-rich backgrounds were limiting factors. HER2/neu status, as determined by HER2/Chr17 SISH, was basically identical to the results of the corresponding FISH. The discrepancies were primarily due to the heterogeneity of HER2/neu amplification in the tumor tissue. Interobserver agreement for the SISH evaluation was high (kappa value, 0.972). The authors concluded that HER2/Chr17 SISH is a useful and accurate method for evaluating HER2/neu gene amplification status in cytologic breast cancer specimens, particularly in metastatic breast cancer lesions. The advantages of signal permanency and bright-field microscopic result interpretation make this technique an attractive alternative to the FISH-based gold standard.

Fritzsche FR, Bode PK, Moch H, et al. Determination of the HER2/neu gene amplification status in cytologic breast cancer specimens using automated silver-enhanced in-situ hybridization (SISH). Am J Surg Pathol. 2010;34(8):1180–1185.

Correspondence: Dr. Florian Rudolf Fritzsche at florian.fritzsche@usz.ch or florian.fritzsche@ludwigh.ox.ac.uk
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Histopathologic features of various cutaneous CD34+ spindle cell neop-lasms Histopathologic features of various cutaneous CD34+ spindle cell neop-lasms

Spindle cell lipoma, dermatofibrosarcoma protuberans, and solitary fibrous tumors are cutaneous CD34+ spindle cell tumors that may exhibit histopathologic and immunophenotypic overlap. The authors sought ways to reliably distinguish between these lesions, even in small or superficial biopsies. They examined 10 morphologic characteristics in a group of five spindle cell lipomas (SCLs), six cutaneous solitary fibrous tumors (SFTs), and 12 dermatofibrosarcoma protuberans (DFSPs). The authors found that SFTs and DFSPs exhibited extensive histopathologic overlap in small or partial biopsies. However, adnexal entrapment, which the authors defined as a diffuse proliferation of tumor cells around pilosebaceous and eccrine structures with minimal disruption or expansion of the dermis, was seen in 10 of the 12 DFSPs and none of the SFTs or SCLs. Even when only superficial portions of a lesion were present, adnexal entrapment was identifiable. The authors reported that SCL posed little diagnostic difficulty, in part because excisional biopsies were performed in all cases of SCL. They concluded that careful attention to these histopathologic features allows pathologists to reliably distinguish between these tumors.

Wood L, Fountaine TJ, Rosamilia L, et al. Cutaneous CD34+ spindle cell neoplasms: histopathologic features distinguish spindle cell lipoma, solitary fibrous tumor, and dermatofibrosarcoma protuberans. Am J Dermatopathol. 2010;32(8):764–768.

Correspondence e-mail not provided.
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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.