Name of journal: World Journal of Clinical Cases esps manuscript no: 12344 Columns: Review Adenoid cystic carcinoma of breast: Recent advances



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Name of journal: World Journal of Clinical Cases

ESPS Manuscript NO: 12344

Columns: Review
Adenoid cystic carcinoma of breast: Recent advances
Miyai K et al. Adenoid cystic carcinoma of the breast
Kosuke Miyai, Mary R Schwartz, Mukul K Divatia, Rose C Anton, Yong Wook Park, Alberto G Ayala, Jae Y Ro
Kosuke Miyai, Mary R Schwartz, Mukul K Divatia, Rose C Anton, Alberto G Ayala, Jae Y Ro, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX 77030, United States
Kosuke Miyai, Department of Basic Pathology, National Defense Medical College, Saitama 359-0042, Japan
Yong Wook Park, Department of Pathology, Hanyang University, Guri Hospital, 153 Gyeongchun-ro, Guri, Gyeonggi-do 471-701, South Korea
Author contributions: All the authors contributed to this work.
Correspondence to: Jae Y Ro, MD, PhD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, 6565 Fannin Street, Suite M227, Houston, TX 77030, United States. jaero@houstonmethodist.org
Telephone: +1-713-4412263 Fax: +1-713-7931603
Received: July 3, 2014 Revised: September 3, 2014

Accepted: September 18, 2014



Published online:
Abstract

Adenoid cystic carcinoma (ACC) of the breast is a rare, special subtype of breast cancer characterized by the presence of a dual cell population of luminal and basaloid cells arranged in specific growth patterns. Most breast cancers with triple-negative, basal-like breast features (i.e. tumors that are devoid of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 expression, and express basal cell markers) are generally high-grade tumors with an aggressive clinical course. Conversely, while ACCs also display a triple-negative, basal-like phenotype, they are usually low-grade and exhibit an indolent clinical behavior. Many discoveries regarding the molecular and genetic features of the ACC, including a specific chromosomal translocation t (6; 9) that results in a MYB-NFIB fusion gene, have been made in recent years. This comprehensive review provides our experience with the ACC of the breast, as well as an overview of clinical, histopathological, and molecular genetic features.


© 2014 Baishideng Publishing Group Inc. All rights reserved.
Key words: Adenoid cystic carcinoma; Breast; Triple-negative and basal-like phenotype; Histology; Molecular genetic features
Core tip: Adenoid cystic carcinoma (ACC) of the breast is a rare, special subtype of breast cancer characterized by the presence of luminal and basaloid cells arranged in specific growth patterns. Although ACCs display a triple-negative, basal-like phenotype, these tumors are usually low-grade and exhibit an indolent clinical behavior. Many discoveries regarding the molecular genetic features of the ACC, including a specific chromosomal translocation t (6; 9) that results in a MYB-NFIB fusion gene, have been made in recent years. This review provides our experience with ACCs, as well as an overview of its clinical, histopathological, and molecular genetic features.
Miyai K, Schwartz MR, Divatia MK, Anton RC, Park YW, Ayala AG, Ro JY. Adenoid cystic carcinoma of breast: Recent advances. World J Clin Cases 2014; In press
INTRODUCTION

Invasive breast carcinoma comprises a heterogeneous group of tumors with various clinical, morphologic, and molecular genetic features[1,2]. According to the 2012 World Health Organization classification, invasive ductal carcinoma of no special type (NST) is the most common histologic type, accounting for up to 75% of all invasive breast carcinomas[3]. The remainder of the invasive cancers represents at least 18 different special and rare histomorphologic subtypes, including adenoid cystic carcinoma (ACC), a salivary gland-type of breast carcinoma[3].

A characteristic histologic pattern of ACC of the breast includes both epithelial and myoepithelial components and resembles a well-known tumor of the salivary gland origin known by the same name. However, patients diagnosed with ACC of the breast have a better prognosis that those who are diagnosed with ACC of the salivary gland[4-6]. ACC of the breast belongs to the basal-like subgroup of breast cancers[7-9]. Based on extensive molecular and genetic profiling studies, basal-like tumors are most often hormone receptor [estrogen receptor (ER) and progesterone receptor (PR)] negative, do not express human epidermal growth factor receptor 2 (Her2), but express one or more basal/myoepithelial cell markers [e.g., cytokeratins (CKs) 5, 5/6, 14, and 17][10]. Unlike other triple-negative breast cancers that are associated with poor prognosis, ACC has an overall excellent prognosis[11]. Because of these distinct clinicopathologic features that set it apart from the other triple-negative breast cancers, an understanding of ACC of the breast is essential for surgical pathologists, breast surgeons, and oncologists. This review will focus on ACC of the breast and will outline important updates in its epidemiology, clinical features, histomorphologic/immunohistochemical characteristics, molecular genetic features, and prognosis/treatment. In addition, we will address our team’s experience with this clinical entity.
EPIDEMIOLOGY

ACC is an uncommon subtype of invasive breast carcinoma and accounts for less than 0.1% of all primary carcinomas of the breast[3,12,13]. Recently, several independent studies based on large patient cohorts have provided more insight into its epidemiology and clinical characteristics[11,14-20]. These information in the recent (i.e. 2010-) studies is summarized in Table 1. For example, the reported age distribution for patients diagnosed with ACC of the breast ranges from 38 to 81 years (with a median age of 60 years; Table 1) and is similar to that seen in other invasive breast cancer cases[3]. Moreover, a previous case series of 338 patients with ACC of the breast conducted over a 30-year period identified its age-adjusted incidence ratio (AAIR) to be 0.92 per 1 million person-years. The AAIR remained constant during the 30-year period was 39% lower in African-Americans than in Caucasian-Americans[11]. Most cases are in females, but occasional cases have been reported in male patients[21,22].


CLINICAL FEATURES

The ACC of the breast can affect the left and right breasts equally and tumors arise irrespective of the breast quadrants. However, in about 50 percent of patients, lesions are found in a subareolar region[23]. Pain or tenderness described in a minority of cases has not been correlated with histologically-confirmed perineural invasion[24]. Mammographically, these tumors may appear as asymmetric densities or irregular masses. Sonographically, they appear as well-defined, irregular, heterogeneous, or hypoechoic masses. Nonetheless, the radiographic findings are non-specific and can be misdiagnosed as benign lesions[13,25]. Subsequently, it could be challenging for a radiologist to make the correct diagnosis of carcinoma without histologic confirmation[25]. Lastly, although most patients present with a solitary tumor, a few cases of multifocal ACC of the breast have also been reported[26,27].


HISTOMORPHOLOGIC/IMMUNOHISTOCHEMICAL CHARACTERISTICS

The mean size of ACC usually range of the breast is 3.0 cm (range, 0.7 to 12.0 cm)[28]. Most cases are macroscopically well-circumscribed. Occasionally, pink, tan, or gray microcysts are evident[28]. ACC usually presents as a localized disease of pathological T stage I or II (Table 1).

The histology of ACC of the breast is similar to that of their salivary gland counterparts. A variety of microscopic patterns detected in the ACC of the salivary glands may also be present in the ACC of the breast. A tumor typically consists of a dual-cell population of luminal and myoepithelial-basal cells which may be arranged in one or more of three architectural patterns: tubular-trabecular, cribriform, and solid-basaloid (Figure 1)[3]. There are two types of structures lined by these two different types of cells: true glandular spaces and pseudolumina. Luminal cells, characterized by round nuclei and eosinophilic cytoplasm, surround true gland lumina containing periodic acid-Schiff (PAS)-positive neutral mucin. Immunohistochemically, the luminal cells are positive for CK7, CK8/18, epithelial membrane antigen (EMA), and CD117 (c-Kit)[2,29-31]. On the other hand, the myoepithelial-basal cells exhibit central oval nuclei and scant cytoplasm, and form pseudolumina, which result from intraluminal invaginations of the stroma. The myoepithelial-basal cells are immunoreactive for basal cytokeratins (CK5, CK5/6, CK14, CK17) (Figure 2), myoepithelial markers (p63, actin, calponin, S-100 protein), vimentin, and epidermal growth factor receptor (EGFR)[2,29-32]. Kasami et al[33] reported that the polarity of the different types of cells could be demonstrated by immunohistochemistry: myoepithelial-basal cells usually express laminin, fibronectin, basal lamina related proteins, and type IV collagen, whereas the luminal cells express proteins related to cell polarization and epithelial differentiation, including fodrin, E-cadherin, and -catenin. The authors suggest that this preserved cell polarity and segregated cell differentiation could explain the lack of metastatic capacity observed in this tumor type. Other reports describe areas of squamous differentiation and even rare sebaceous differentiation in ACC of the breast[34,35].

In a way akin to the ACC of the salivary gland, ACCs of the breast are graded according to the proportion of solid growth: tumors with either cribriform or tubular-trabecular pattern and without solid elements are considered grade I, tumors with ≤ 30% of solid growth are classified as grade II, and tumors having more than 30% solid growth are designated grade III[4,36]. Ro et al[4] reported that tumors with a solid pattern (grade II and III) had a tendency to be larger than those without a solid pattern (grade I), and that grade II and III tumors were more likely to develop recurrences. In their series, three patients who developed metastatic ACC had grade II or III lesions. Furthermore, Shin et al[37] reported 9 cases of the solid (basaloid) variant of breast ACC in which the tumor cells tend to be larger, with hyperchromatic nuclei showing moderate to marked atypia, pleomorphism, and increased mitotic activity. This solid variant of ACC was associated with an aggressive clinical course. However, it is important to note that the histological grade defined by this system was not correlated to the disease outcomes observed in two other studies[34,38]. The most recent American Joint Committee on Cancer staging manual (7th edition) recommends that Nottingham histologic grading be provided uniformly for all breast carcinomas[39]. Based on this grading scheme, most ACCs would belong to the histologic grade 1 (3 + 1 + 1) or histologic grade 2 (3 + 2 + 1).

Phenotypically, both luminal and myoepithelial-basaloid cells in ACC of the breast are generally negative for ER, PR, and Her2 proteins (Table 2 and Figure 3)[11,14,40-43]. The immunohistochemical profile of ACC of the breast fits well within that of triple-negative breast cancers with basal-like features. In one study, ER and PR expression was detected in 46% and 36% of ACC cases, respectively[5]. Although this cohort was one of the larger series of ACCs reported to date (n = 28), the cases were collected from different institutions and did not undergo a central review for the diagnosis. Subsequently, it cannot be rule out that a substantial number of these cases were actually invasive cribriform carcinomas with ER and PR immunoreactivity. In addition, it should be noted that in the latter study, dextran-coated charcoal assay was used to assess expression for ER and PR instead of the now more widely used immunohistochemistry. Since normal breast lobules and ducts are often entrapped within the bulk of tumor tissues, it may lead to false positive results of the dextran-coated charcoal assay.

There have been several case reports suggesting an association between ACC of the breast and various benign lesions including microglandular adenosis, tubular adenosis, adenomyoepithelioma, and fibroadenoma[44-48]. Acs et al[44] suggested that ACC of the breast may develop in a background of and in continuity with microglandular adenosis. Following this hypothesis, their group described a morphological spectrum of lesions with a trend of progression, encompassing microglandular adenosis, “atypical microglandular adenosis” (also described as “ACC in situ”), and invasive ACC[44]. Da Silva et al[45] reported a morphological characterization of tubular adenosis arising concurrently with ACC in the breast, although the comparative genomic hybridization (CGH) analysis performed on these two lesions failed to provide evidence of molecular evolution from tubular adenosis to ACC. Importantly, breast that harbors the ACC can rarely also contain other types of carcinoma, as was shown in a case where the ACC of the breast coexisted with an invasive ductal carcinoma of NST[49,50].



ACC of the breast that exhibits a cribriform/tubular pattern should be distinguished from the invasive cribriform/tubular carcinomas or a benign condition termed collagenous spherulosis[51,52]. This is especially important when a pathologist is provided with tiny tissue specimens obtained by core needle biopsies[36]. Invasive cribriform/tubular carcinomas are characterized by the hyper-proliferation of a single type of neoplastic cells (i.e. luminal cell) only, which is contrast to the dual cell types observed in ACC. Moreover, cribriform/tubular carcinomas are generally immunoreactive for ER and PR, whereas ACCs are negative for both[53]. In addition, limited evidence exists of c-Kit and/or p63 immunoreactivity in ACCs of the breast (positive for both), compared to the invasive cribriform/tubular carcinomas that are negative for both markers[40]. In collagenous spherulosis, collagenous spherules are irregular, mostly observed at the periphery of the lesions, and no mucosubstance is detected within lumens. Immunohistochemically, ACCs are c-Kit (+), calponin (-), and smooth muscle myosin (-), whereas the collagenous spherulosis lesions are c-Kit (-), calponin (+), and smooth muscle myosin (+), which may help to differentiate between these two types of lesions[54]. The differential diagnosis of the solid (basaloid) variant of ACC includes small cell carcinoma (neuroendocrine carcinoma), solid papillary carcinoma, metaplastic carcinoma, and malignant lymphoma[37]. Although an extensive and careful search for a more typical cribriform pattern of ACC should be performed, immunohistochemistry can also be helpful to distinguish these tumors from ACC.
MOLECULAR GENETIC FEATURES

Microarray-based gene expression profiling studies have been performed in common types of breast cancer, such as the invasive ductal and lobular carcinomas[7-9]. However, most of these studies did not focus on special types of breast cancer, and consequently, there is only limited transcriptomic data on the ACC features. A recent molecular subtype analysis using a single sample predictor (i.e. centroid) performed on 4 ACCs revealed that two of the samples were classified as basal-like, while the other two were shown to exhibit the normal breast-like phenotype. Based on this divergence in the results, they could be an artifact of sample representation, perhaps caused by the contamination with normal tissues[55]. In fact, molecular subtype assignment following hierarchical clustering showed that all four ACCs consistently displayed a basal-like phenotype, and all of them clustered with one of the five subgroups of the triple-negative breast cancers. In another study that utilized the immunohistochemical staining analysis and microarray-based gene expression profiling for a series of 113 tumors that belonged to 11 special histologic types of breast cancer (including 4 ACCs), Weigelt et al[43] reported that the ACC, medullary carcinoma, and metaplastic carcinoma were highly similar in their immunohistochemical and gene expression profile. However, ACCs did not intermingle with medullary and metaplastic carcinomas in the hierarchical clustering, but formed a separate group. Another study, an array-based CGH analysis of 59 breast cancers that belonged to 10 special histologic special types established that while medullary and metaplastic carcinomas displayed complex genomes, ACCs consistently exhibited simpler patterns of gene copy number aberrations[56]. In line with these results, a recent CGH analysis study revealed that ACC of the breast manifested significantly lower frequencies of genetic instability and lower copy number alterations than the histologic grade-matched basal-like and invasive ductal carcinomas of NST[29]. At the genomic level, the ACC is substantially different from the other basal-like breast cancers. Studies show that it rarely harbors genomic aberrations associated with basal-like invasive ducal carcinomas of NST, such as gains of 1q, 6p, 8q, and 10p, and losses of 4p, 5q, and 10q[29,57,58]. Furthermore, aneuploidy is reported in fewer than 10% of cases with ACC of the breast[5]. Together, these findings illustrate the heterogeneity of triple-negative, basal-like breast cancers. Although the majority of these tumors are high grade cancers with high levels of genetic instability and an aggressive clinical course (e.g., grade 3 invasive ductal carcinoma of NST, medullary carcinoma, and metaplastic carcinoma), there is also a subgroup of low grade tumors with low frequencies of genetic instability and an indolent clinical behavior (e.g., ACC and secretory carcinoma)[10,41,43,59-61]. Thus, we emphasize that based solely on molecular subtyping and without a proper histologic classification, ACCs, which have an indolent clinical behavior, would be classified as a triple-negative, clinically aggressive tumors. Therefore, information regarding the histologic type of triple-negative breast cancers should be included in histopathology reports and taken into account for clinical decision making.

Although studies using next-generation sequencing (NGS) for a whole exome or microRNA expression profiling for ACC of the salivary gland have been recently reported[62-65], there has been few studies using NGS for ACC of the breast. In one study utilizing microRNA expression profiling for each two cases of ACC of the salivary gland and breast, Kiss et al[65] reported that the let-7b was overexpressed in ACC of the salivary gland, while decreased in ACC of the breast. In addition, the miR-24 was decreased in salivary gland-derived but overexpressed in breast-derived adenoid cystic carcinomas.

Similar to ACCs of the salivary gland, ACCs of the breast are characterized by the t(6; 9) (q22-23; p23-24) chromosomal translocation, which generates fusion transcripts involving the oncogene MYB and the transcription factor gene NFIB. Several previous studies reported that this chromosomal translocation is present in over 90% of ACC cases and is a key ACC oncogenic mechanism[29,66,67]. The MYB-NFIB fusion protein retains the DNA-binding and transactivation domains of a wild-type MYB, and is therefore expected to activate MYB target genes[29,66]. MYB is a leucine zipper transcription factor that plays an important role in the control of cell proliferation, apoptosis, and differentiation[68,69], while its target genes include BCL2 and GRP78/BIP, which are essential for cell survival[70]. MYB is a direct target of EG signaling and is highly expressed not only in ACCs, but also in cell lines of ER-positive breast cancers[71,72]. Recently, one study reported that 67% (8/12 cases) of dermal cylindroma displayed the t (6; 9) and MYB-NFIB fusion transcripts and that the composition of these chimeric transcripts was identical to that seen in ACC[73].

Approximately 7% of the breast cancer cases are related to hereditary condition and caused by mutations in the BRCA1 and BRCA2 genes[3]. Although medullary and metaplastic breast carcinomas, with which ACC shares immunohistochemical and molecular findings, show a frequent promotor methylation of BRCA1 gene, ACC of the breast usually retains normal BRCA1 gene function[2,29]. To our knowledge, BRCA2 gene status has not been investigated in ACCs of the breast.

As we had indicated previously, ACCs of the breast typically do not express the full-length ER- (ER-66) and PR[11,14,39-42]. However, several studies had shown that the ACC, apocrine carcinoma, and triple-negative breast cancer of NST exhibited a frequent membranous/cytoplasmic immunoreactivity for ER-36, a novel ER-66 splice variant implicated in membrane-initiated estrogen signaling[74-76]. In the experimental cell models of breast cancer, ER-36 was shown to transduce the membrane-initiated steroid signaling cascade, and served as a dominant-negative modulator of ER-66 mediated transcription activity[75]. In addition, ER-36 was reported to be related to non-genomic ER activities, in which activation of the mitogen-activated protein kinase (MAP/K/ERK) signaling pathway plays a major role[75]. The MAPK/ERK signaling pathway is activated in response to antiestrogens (e.g. tamoxifen), indicating a subset of ER-66 (-)/ER-36 (+) breast carcinomas might still respond to antiestrogen based therapy[74,75]. Finally, ER-36 protein closely interacts with EGFR protein, which is commonly expressed in ACC and triple-negative breast cancers[75]. Some investigators have reported that ACCs of the breast frequently overexpress EGFR protein in the absence of underlying EGFR gene alterations[19,29].

Cancer stem cells have been reported to be associated with tumor initiation, progression, survival, and resistance to therapy[77]. However, the cancer stem cell filed is still fairly controversial and stem cell markers have not been fully elucidated. In the majority of studies, breast cancer cells with a CD44 (+)/CD24 (-) phenotype have been proposed to have tumor-initiating properties with stem cell-like features[78], and Defaud-Hénon et al[18] recently reported that a characteristic CD44 (+)/CD24 (-) phenotype is commonly observed in the ACC of the breast. On the other hand, a frequent overexpression of c-Kit and EGFR proteins was observed in undifferentiated carcinomas with stem cell-like features[79]. Although several studies illustrated that a consistent c-Kit protein expression was detected in most ACCs[29,40-43], underlying KIT gene alterations, such as gene mutations, had not been previously detected[80]. Finally, SOX10 transcription factor appears to support stem-like properties in normal tissues and cancer cells[81]. Recently, Ivanov et al[82] described SOX10 as a novel diagnostic marker for ACCs of the salivary gland and breast basal-like carcinomas, indicating that SOX10 expression might be worth examining in ACCs of the breast.

Although the triple-negative NST breast cancers usually shows high proliferative activity, ACC of the breast exhibits a low proliferation rate using standard Ki-67 labeling index[29,83]. Interestingly, their typical proliferation rate is even lower than that of low-grade conventional breast carcinomas[84]. Mastropasqua et al[40] suggested that proliferative indices showed grater values in high-grade ACCs when compared to low-grade lesions. However, another study reported that the proliferative activity is not associated with the outcome of ACC patients with ACC[38]. In addition to low Ki-67 labeling index, ACCs of the breast, including high-grade solid-basaloid lesions, also show low p53 protein expression[29,39,83]. Trendell-Smith et al[53] described a slightly higher p53 protein expression in ACC than that in invasive cribriform carcinoma.

Finally there are several recent studies that identified potential breast ACC biomarkers. First, insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofetal protein and a component of the insulin-like growth factor-II pathway. Studies indicate that it could serve as a new biomarker for basal-like breast carcinomas[84-87], and a recent report showed that the IMP3 is commonly overexpressed in ACCs of the breast[88]. In another report, the molecular genetic analysis of a primary ACC of the breast and its kidney metastasis revealed PTEN and PIK3CA gene mutations[89].

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