Anatomic Pathology Selected Abstracts, 2/13

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Determining HER2 status on breast core-needle biopsies

Preoperative breast cancer diagnosis on core biopsies has become a standard of care in many countries. Controversy surrounds the accuracy of HER2 testing on biopsies as compared with surgical specimens, and few data exist concerning the use of emerging technologies, such as bright-field in situ hybridization, in such a setting. A French multicenter, cross-sectional, histopathological study assessed the concordance of HER2 status determined by immunohistochemistry and silver or chromogenic in situ hybridization (SISH and CISH, respectively) on core-needle biopsies with HER2 status determined by fluorescence in situ hybridization (FISH) performed on surgical specimens. The concordance between biopsy and operative results was also assessed for each method. The authors studied 260 breast tumors from 24 centers between April 2003 and August 2009. Excellent concordance (k, 0.92–0.97) was shown between immunohistochemistry and FISH, with low discordance rates (two to four percent) and high specificity (97 to 98 percent) and sensitivity values (95 to 99 percent), with no significant difference according to the immunohistochemistry interpretation guidelines used. The correlation between SISH and CISH on biopsies and FISH on surgical samples was strong (k, 0.96 and 0.94, respectively), with no significant difference between false-negative rates or sensitivity and specificity values (two and five percent, 99 and 96 percent, and 98 and 98 percent, respectively). Whatever the evaluation technique, excellent concordance between biopsies and surgical specimens was observed (k ³ 0.97; discordance rates between one and two percent), with high sensitivity (98 to 99 percent) and specificity (98 to 100 percent). Based on these results, when FISH cannot be used, SISH or CISH, or both, could be proposed as an alternative method to determine HER2 status and to confirm ambiguous immunohistochemistry results, either for preoperative percutaneous biopsies or surgical specimens. CISH and SISH could also be used for quality controls and immunohistochemistry calibration.

Arnould L, Roger P, Macgrogan G, et al. Accuracy of HER2 status determination on breast core-needle biopsies (immunohistochemistry, FISH, CISH and SISH vs. FISH). Mod Pathol. 2012;25:675–682.
Correspondence: Dr. L. Arnould at larnould@dijon.fnclcc.fr

Use of MiTF in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor

The overlapping histopathologic features of cellular neurothekeoma and plexiform fibrohistiocytic tumor, when both are predominantly composed of histiocytoid cells, make it difficult to distinguish between these entities. Some have suggested that they are related. No prior study has offered a reliable immunohistochemical panel to differentiate these entities. The authors conducted a study in which they retrieved skin biopsies diagnosed in the timeframe of 2004 to 2010 as cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT) and obtained the accompanying pathology reports. Each case was reviewed by at least two dermatopathologists and two soft tissue pathologists to confirm the diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). The authors found that, histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and consistently negative in PFHT. The authors concluded that CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Fox MD, Billings SD, Gleason BC, et al. Expression of MiTF may be helpful in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen. Am J Dermatopathol. 2012;34(2):157–160.
Correspondence: Dr. Thomas Cibull at tcibull@northshore.org

A study of genetic heterogeneity in HER2/neu testing by FISH

Amplification of the ERBB2 oncogene encoding HER2/neu protein (HER2) is of predictive and prognostic importance in breast carcinoma. Fluorescence in situ hybridization (FISH) is a widely accepted method for determining HER2 amplification status. A HER2-amplified tumor is defined as having a ratio of HER2 signals to chromosome 17 centromeric probe signals (HER2/CEP17 ratio) exceeding 2.2. However, the presence of scattered cells demonstrating HER2 amplification is of unclear significance. A 2009 panel guideline defined a tumor with genetic heterogeneity as having at least five percent but fewer than 50 percent of (non-clustered) tumor nuclei with a ratio greater than 2.2. The authors conducted a study to examine the statistical distribution of breast tumors tested by FISH for HER2 amplification after implementation of this 2009 guideline. They identified 2,522 consecutive breast carcinoma cases (2009–2011) tested for HER2 amplification. All cases were tested by FISH using a standard clinical protocol, adhering to established guidelines. For each case, data on cell counts were retrieved electronically. Each tumor was compared with a theoretical normal distribution by quantile-quantile analysis. Of 2,522 FISH tests for HER2, 1,900 (75 percent) were non-amplified, 394 (16 percent) were amplified, and 228 (nine percent) were HER2 equivocal. A total of 666 (26 percent) had genetic heterogeneity. Among these genetically heterogeneous cases, the ratio was non-amplified in 430 (64.5 percent), amplified in 24 (four percent), and equivocal in 212 (31.5 percent). The amplified subpopulation in genetically heterogeneous tumors was larger if the overall ratio was close to 2.2. However, the percentage of nuclei greater than 2.2 in a genetically heterogeneous tumor was not informative of the underlying tumor-cell distribution. The authors concluded that the proportion of HER2-amplified nuclei within a tumor does not contribute information independent of the HER2/CEP17 ratio. Reassessment of the definition of genetic heterogeneity in HER2 testing is warranted.

Chang MC, Malowany JI, Mazurkiewicz J, et al. ‘Genetic heterogeneity’ in HER2/neu testing by fluorescence in situ hybridization: a study of 2522 cases. Mod Pathol. 2012;25:683–688.
Correspondence: Dr. M. C. Chang at mchang2@mtsinai.on.ca