Elsevier

Human Pathology

Volume 85, March 2019, Pages 221-227
Human Pathology

Original contribution
A combination of GATA3 and SOX10 is useful for the diagnosis of metastatic triple-negative breast cancer

https://doi.org/10.1016/j.humpath.2018.11.005Get rights and content

Highlights

  • SOX10 is a sensitive and stable lineage marker of both primary and metastatic triple-negative breast cancer.

  • SOX10 is a useful breast lineage marker in the triple-negative subset of breast cancers in which standard breast lineage marker sensitivity is reduced.

  • SOX10 is complementary to GATA3 as a lineage marker because it labels a different subset of breast cancer.

  • A panel of both GATA3 and SOX10 is recommended for confirming a breast site of origin in triple-negative breast cancer metastases.

Summary

In metastatic breast cancer (MBC), it can be difficult to establish the origin if the primary tumor is triple negative or if there is a loss of biomarker expression. SOX10 expression has been reported in primary triple-negative breast cancer but is poorly studied in metastatic lesions. In this study, the diagnostic utility of a panel of SOX10, GATA3, and androgen receptor (AR) in MBC negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was evaluated and compared with the expression of these markers in the matched primary breast cancer. In a series of 57 triple-negative MBCs, 82% were positive for GATA3, 58% for SOX10, and 25% for AR. Nearly all MBCs (95%) were positive for either GATA3 or SOX10, with 46% dual positive and 5% of cases negative for both markers. Most GATA3-negative MBC cases were SOX10 positive (70%). AR expression was only seen in GATA3-positive MBC (25%) and was significantly more frequent in SOX10-negative MBC (48%) versus SOX10-positive MBC (9%; P = .001). Concordance for GATA3, SOX10, and AR between the primary and metastasis was 89%, 88%, and 80%, respectively. Although GATA3 is a more sensitive lineage marker than SOX10 in MBC, SOX10 is a useful adjunct because it is positive in most GATA3-negative breast metastases. Using both GATA3 and SOX10 is recommended for confirming breast as the site of origin in metastases that lack estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, whereas the addition of AR is not helpful.

Introduction

Breast cancer metastases are commonly encountered in clinical practice owing to the high prevalence of this disease and the high frequency that these lesions are surgically biopsied. Breast cancer is one of the most common cancers in the United States. Based on National Cancer Institute/Surveillance, Epidemiology, and End Results reporting, in 2016 new breast cancer diagnoses exceeded 266 000, with more than 40 000 breast cancer deaths reported [1]. The most significant cause of breast cancer mortality is due to metastatic progression. Risks for the development of metastases are related to several factors including primary tumor size, histologic grade, lymph node involvement, and tumor biology/biomarker status [2], [3]. Breast cancer patients have a high likelihood of developing metastases, especially if diagnosed at an early age [4]. Accurate diagnosis of breast cancer metastases is critically important to facilitate clinical therapeutic decision making. Per current guidelines, those patients with clinically suspected breast cancer metastases who are surgically appropriate and have accessible lesions should be offered biopsy for confirmation of disease process, and for the reassessment of breast biomarkers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [5]. The diagnostic distinction of a suspected metastatic breast cancer (MBC) from a nonbreast malignancy is a very relevant clinical consideration. Published studies indicate that women who are diagnosed as having a primary breast cancer (PBC) have a relatively higher risk of developing a second nonbreast malignancy compared with women from the general population. This risk is highest within the first 10 years after the PBC diagnosis and in younger premenopausal patients [6].

The confirmation of a breast primary site of origin of a metastatic lesion is generally straightforward if (1) the patient has an established history of breast cancer, (2) histologic slides from the prior PBC are available to re-review for morphologic comparison to metastasis, (3) the metastasis shows stable expression of both breast lineage markers and biomarkers (ER/PR/HER2). However, in clinical practice, these favorable diagnostic conditions may not be present. It can be difficult to establish the origin of a putative breast metastasis if the primary tumor is either triple negative for breast biomarkers (ER/PR/HER2) or if there is a loss of biomarker expression in the metastasis. Likewise, the histologic slides from the prior PBC may not be practically available for re-review. In addition, a metastasis may represent the initial clinical presentation from an occult PBC.

It is important to note that the sensitivity of standard breast lineage markers is dependent on tumor subtype, with the lowest sensitivity observed in grade 3, ER-negative, and metaplastic breast cancers [7]. High-grade and triple-negative breast cancer (TNBC) can pose a diagnostic challenge because they may display both nonspecific histomorphologic features and immunophenotypic staining profiles. TNBC and basal-like breast cancers often do not show positivity for established standard breast lineage markers such as mammaglobin (17%-24%) and GCDFP-15 (0-5%) [8]. The reduced sensitivity of most breast lineage markers including GATA3 in TNBC can complicate the diagnosis of MBC [9]. In addition, the potential for loss of biomarker expression in MBC imposes a further diagnostic challenge, as ER/PR/HER2 status is not infrequently discordant between the primary and metastatic lesion [10].

The availability of more sensitive breast lineage markers that can reliably identify metastatic breast carcinoma that is triple negative for ER, PR, and HER2 would be of high clinical utility. Labeling of TNBC by SOX10 and androgen receptor (AR) has been recently described in primary TNBC. However, there are few publications that have examined their performance in MBC. Furthermore, no studies have directly compared the sensitivity of SOX10 with the standard breast lineage marker GATA3, specifically in the most clinically challenging context of working up metastatic TNBC. An assessment of the stability and concordance of these lineage markers between the primary and matched metastatic lesion is also lacking.

In this investigation, we evaluated the diagnostic utility of a panel of SOX10, GATA3, and AR in MBC that is negative for ER, PR, and HER2 and compared the expression of these markers with matched PBC.

Section snippets

Case selection

After institutional review board approval, we conducted a retrospective search of the pathology database at our institution to identify MBC diagnosed from 2013 to 2017, which lacked expression of ER, PR, and HER2, and for which we had an available in-house PBC specimen. Outside consult cases were excluded. Clinicopathological data from the electronic medical record and pathology reports were collected. For PBC, this included specimen type (core needle biopsy and/or excision specimen), patient

Results

A total of 898 in-house MBC specimens were identified in our database during the search period. Cases in which no prior in-house PBC cases were reviewed in our institution were excluded (n = 635). Of 263 MBC cases with matched in-house PBC specimens, 72 (27%) of the MBC cases were triple negative for ER, PR, and HER2. Of the 72 triple-negative MBC cases, 57 had adequate/available MBC tissue available and were included in the series. Of these 57 cases, 44 had adequate/available PBC tissue for

Discussion

In our study, we demonstrate that SOX10 is a sensitive lineage marker for both primary and metastatic TNBC and will label approximately two-thirds of these tumors. Our analysis indicates that SOX10 expression is stable between primary and metastatic lesions, and it showed the highest level of concordance compared with GATA3 and AR. The primary reason that SOX10 is useful is because it is sensitive in the subset of breast cancers (TNBC) in which standard breast lineage marker sensitivity is

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    Competing interest: The authors declare that there is no conflict of interest regarding the publication of this article.

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