REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10001-1549
International Journal of Head and Neck Surgery
Volume 14 | Issue 2 | Year 2023

A Systemic Review on Similarities between Salivary and Mammary Gland Neoplasms and the Role of Antihormonal Therapy in Salivary Gland Tumors

Veena B Ganga1, Krishnappa Ramachandrappa2, Karthik Shamanna3

1,2Department of Head and Neck Onco-surgery, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

3Department of ENT, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India

Corresponding Author: Veena B Ganga, Department of Head and Neck Onco-surgery, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India, Phone: +91 9995678150, e-mail: veenaganga2007@gmail.com

Received on: 17 July 2022; Accepted on: 10 January 2023; Published on: 08 June 2023

ABSTRACT

Objective: The present review focuses on the morphological, pathological, and molecular level resemblance of salivary and mammary gland neoplasms with emphasis on the current status of hormonal therapy strategies in salivary gland tumors.

Methods: Literature review developed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and data collected from PubMed, Cochrane, Wiley library, and other related reference articles.

Results: The expression of hormonal receptors was found to be demonstrated frequently in salivary duct carcinoma, followed by a few other malignant tumors like carcinoma ex pleomorphic adenoma (PA), adenocarcinoma not otherwise specified (NOS) and mucoepidermoid carcinoma (MEC).

Conclusion: The similarities in the morphology, biology, and molecular changes between the salivary gland and breast tumors form the basis for the detection of hormonal receptors and the use of antihormonal therapies. The novel treatment strategies of antihuman epidermal growth factor receptor 2 (anti-HER2) and anti-androgen receptor (AR) are currently found to be effective in unresectable/rapidly progressive tumors and in multiple tumor recurrence cases for a few salivary gland tumor histologies.

How to cite this article: Ganga VB, Ramachandrappa K, Shamanna K. A Systemic Review on Similarities between Salivary and Mammary Gland Neoplasms and the Role of Antihormonal Therapy in Salivary Gland Tumors. Int J Head Neck Surg 2023;14(2):21-32.

Source of support: Nil

Conflict of interest: None

Keywords: Acinic cell carcinoma, Adenoid cystic carcinoma, Androgen receptor, Epidermal growth factor receptor, Estrogen receptor, Mucoepidermoid carcinoma, Progesterone receptor, Salivary duct carcinoma.

INTRODUCTION

Salivary glands are complex tubuloacinar exocrine or merocrine glands mainly secrete saliva. The parotid gland is ectodermal, while submandibular and sublingual glands are endodermal in origin. All the minor salivary glands have mixed origins with both ectodermal and endodermal components. The epithelial cells determine the type of secretion produced by the gland and the mesenchymal cells contribute to the morphology of the gland.1 Each developed gland consists of parenchyma, glandular secretory tissue, and stroma. The secretory units contain secretory cells which organize to form clusters called acini. These units can be either of the three types—mucinous, serous, and seromucinous. The secretions pass through the intercalated ducts, striated, excretory duct, and finally main excretory duct opening into the oral cavity.2

The mammary gland contains both ectodermal and mesodermal components. The ectoderm forms a mammary line which resolves into placodes. These placodes invaginate into the mesenchyme and form the rudimentary ductal structure. The embryonic mammary mesenchyme provides the key signals for epithelial cell differentiation. This epithelial differentiation was demonstrated in reciprocal tissue recombination experiments in which 12 and 16th-day-old embryonic mammary epithelium was combined with salivary mesenchyme and grown in culture. These tissue recombinants produced epithelium that was morphologically resembling salivary glands. The rudimentary ductal system forms the terminal end buds which later differentiate to form myoepithelial cells. This system will develop into terminal ductolobular units with acini which are mainly mediated by hormones.3

The matured salivary gland contains two types of cells, both luminal and abluminal cells. The luminal cells include acinar and ductal cells. The abluminal cells are myoepithelial and basal cells.4 Unlike salivary glands, mammary glands undergo complex epithelial remodeling throughout puberty, pregnancy, lactation, and weaning. The mammary gland is a highly branched ductal structure having luminal cells and myoepithelial cells.5 Each cell type in both mammary and salivary glands express a variety of markers that helps in the identification and characterization (Table 1) and (Table 2).6-8

Table 1: Important immunohistochemical markers for salivary gland cell types6
Antigen Luminal cell Myoepithelial cell Basal cell
AE1/AE3 + − −
CK5/6 − + +
CK14 − + +
P63 − + +
α-SMA − + +
Vimentin − + +
CK19 + + +
Calponin − + −

CK, cytokeratin; SMA, smooth muscle actin

Table 2: Important immunohistochemical markers for mammary gland cell types7,8
Antigen Luminal cells Abluminal cells
Acinar Ductal Myoepithelial Basal
CK (AE1,AE3) + + + +
EMA + + − −
CEA + + − −
CK14 − − + +
P63 − − + +
α-amylase + − − −
α-SMA − − + −
Muscle specific actin − − + −
Calponin − − + −
Podoplanin − − + −
Vimentin − − + −
S-100 Variable Variable Variable Variable
GFAP Variable

CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen; GFAP: glial fibrillary acidic protein; SMA, smooth muscle actin

Salivary gland tumors are distinct in their wide variety of subcategorization and rarity in occurrence. The two most widely accepted theories for the development of salivary gland tumors are the bicellular reserve cell theory and the multicellular histogenetic concept. Bicellular reserve cell theory states the two major reserve cells, also known as pluripotent cells like excretory duct reserve cells and intercalated duct reserve cells, will undergo altered differentiation. The tumors considered as excretory duct reserve cell origin are MEC, primary squamous cell carcinoma (SCC), and salivary duct carcinoma, whereas intercalated ductal origins are polymorphous adenocarcinoma, basal cell adenocarcinoma, adenoid cystic carcinoma (ADCC), and acinic cell carcinoma (ACC). Adenocarcinoma not specified is postulated to arise from any of these reserve cells and carcinoma ex-PA is considered to have uncertain histogenesis. The multicellular theory defines tumorogenesis as the multiplicity of any cell type giving rise to a wide variety of histologies.9

The tumors of the breast most commonly arise from the luminal epithelial components of the terminal duct lobular unit. The role of myoepithelial cells is studied in both salivary and breast tumors. These cells are considered tumor suppressors and are seen in many premalignant and in situ lesions which in turn will turn into low-grade tumors.10 In salivary gland tumors, these cells can undergo various morphological changes due to metaplasia, dedifferentiation, and transdifferentiation to form modified or neoplastic myoepithelial cells. But similar to the breast, these cells will lead to low-grade tumors with low metastatic potential.

The most common salivary gland tumors are glandular origin, while mammary gland tumors are ductal origin. Boecker et al. proposed a lineage differentiation model for the common tumors of both glands. According to their study, the ducts of both the glands normally contain keratin (K5/K14) and p63-positive progenitor cells, which get differentiated to glandular cells, which are K8/K18 positive and myoepithelial cells which are positive for smooth muscle actin (SMA). The progenitor cells are located in the interlobular ducts of mammary glands and striated ducts of salivary glands. All the morphologically similar tumors are hence derived from these progenitor cells, which undergo both myoepithelial, glandular, and mesenchymal differentiation.11

Most of the studies on salivary gland-like tumors of the breast are done by Foschini et al. and they divided these tumors into three categories:12

Most of the salivary gland-like tumors of the breast are triple-negative tumors with the absence of expression of progesterone receptor (PR), estrogen receptor (ER), and HER2 receptors. Hence these tumors are clinically aggressive.

Most malignant salivary gland tumors have a high rate of locoregional recurrences resulting in a grave outcome, while most breast tumors are resectable, completely resulting in a better outcome. The complexity of head and neck spaces with variable neural anatomy associated with these tumor sites results in an incomplete clearance of tumor cells in contrast to breast tumors, where the resection is simple and straightforward with the sparing of adjacent structures. The first line of treatment for salivary gland tumors is surgical excision with or without adjuvant treatment. In unresectable or rapidly progressive metastatic tumors and in cases with multiple recurrences, systemic adjuvant therapies are necessary. Adjuvant therapy is currently limited to radiotherapy. There are studies showing the role of antihormonal therapy in adjuvant settings causing cessation of tumor progression or resolution of tumor size with improved quality of life for the patients.

In this review, we categorized the tumors occurring in both salivary and mammary glands into benign and malignant groups.

Salivary gland-like tumors of the breast can be classified as

METHODOLOGY

Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines of reporting were followed:

Eligibility: Inclusion criteria-studies allowed in our review were observational, in vitro and in vivo prospective and retrospective studies. The comparison of mammary and salivary glands was analyzed in a systemic way using data search keywords salivary gland-like tumors of breast or morphological similarities between salivary and mammary glands. The studies examining salivary gland tissue for hormone receptor expressions by all the methods (in situ hybridization/immunohistochemistry), which includes HER2, androgen, estrogen, and PRs were analyzed. PubMed, Cochrane, Wiley library were searched from the year 2020 using the search string salivary gland-like tumors of breast or HER2/erythroblastic oncogene B, androgen, estrogen and PR expression in salivary gland tumors or role of tamoxifen/trastuzumab/combined androgen blockade (CAB) in salivary gland cancers. In addition to this, the reference list of obtained articles was also analyzed.

Exclusion criteria: Studies reported in languages other than English, unpublished studies, studies not publishing the tumor histology subtypes, and hormone receptor expression studies published before the year 2000 were excluded. The above criteria fulfilling studies were screened and assessed. The information gathered was sorted out for individual histological subtypes and represented in tables. The comparative studies on both mammary and salivary gland tumors were analyzed and reviewed in a systemic manner.

Pleomorphic Adenoma: Pleomorphic adenoma (PA) is also known as a benign mixed tumor, the most common salivary gland neoplasm. The cell of origin is the uncommitted reserve cell of the intercalated duct that has the potential to differentiate into both epithelial and myoepithelial cells. It constitutes 75% of benign salivary gland tumors and most commonly occurs in parotid (80%). It mainly affects the 4th and 5th decade population and has no sex predilection.13

Pathologically they are solitary firm round masses. The major histological feature has both epithelial and myoepithelial components. The presence of hyalinized stroma is the most important histological predictor of malignant change. Almost all PAs have a thin capsule with pseudopodia or satellite nodules in nearly 25% of cases. In around 70% of cases, either of the cytogenetic changes, like 8q12 rearrangements/12q13–15 rearrangements, were noted.14

Regarding the hormonal receptor status in PA, few studies were found in the literature. In a study by Larbcharoensub et al., metastasizing PA showed expression of PRs and they provided evidence for the role of the hormonal receptors in the pathogenesis and treatment of metastasizing PA.14 Glas et al. demonstrated intense immunostaining with PR in recurrent PA while some authors considered ER status mainly ER β-expression has a role in PA.15 All three receptor expression was studied by Souza and colleagues and stated that ER, PR and HER2 expression is not linked with the progression, recurrence, and malignant transformation of PA.16

Contrary to these findings in carcinoma ex-PA, 31–38% shows amplification of HER2.17 Di et al. reported overexpression of HER2 in carcinoma ex-PA, which is considered as the initial event in malignant change.18 Di and colleagues presented a case of carcinoma ex-PA successfully treated with trastuzumab and radiotherapy. Several authors also demonstrated the HER2 expression in malignant luminal cells and its involvement in the progression from the intraductal to the extracapsular stage. A similar event was also reported in the breast, where high-grade ductal carcinoma in situ with HER2 overexpression often progresses to invasive ductal carcinoma. The hormone receptor expression in PA is shown in the following table (Table 3).

Table 3: Summarizes the hormone receptor expression in PA
Study No of cases PR ER AR
Moriki et al. (2001)21 3 − − +
Glas et al. (2002)17 69 + − NA
Nasser et al. (2003)22 4 NA NA −
Larbcharoensub et al. (2009)16 + − NA
Wong et al. (2009)23 NA + NA
Ito et al. (2009)24 41 − − +
Nakajima et al. (2009)25 23 NA NA +
Can et al. (2017)26 91 + + +
Aquino et al. (2018)27 18 − + +

AR, androgen receptor; ER: estrogen receptor, NA, not assessed; PR, progesterone receptor

Carcinoma Expleomorphic Adenoma

Carcinoma ex-PA is a mixed tumor with both epithelial and myoepithelial components arising from longstanding or recurrent PA. The malignancy rate in recurrent PA is 7–16%. The transformation occurs through different phases of progression, such as carcinoma in situ (retained myoepithelial layer), intracapsular tumor (abnormal proliferation within and between existing ducts), minimally invasive (breach of capsule), and widely invasive (extending to the gland and soft tissue).19

Pleomorphic adenoma (PA) of the breast is a salivary-type tumor with both epithelial and myoepithelial proliferations. A total of <100 cases have been reported in English literature so far. The first case was reported in 1906. The myoepithelial cells are located abundantly around the subareolar region and their proliferation is considered to be a key factor in histogenesis.20,21 Histologically, it is composed of epithelial and myoepithelial components in the myxoid/chondroid and osteoid matrix. Immunohistochemistry (IHC) findings are similar to salivary glands, except in a few studies, the ER was positive. Malignant change in PA is very rarely reported in the literature. Hayes et al. reported a case series of three cases of carcinoma ex-PA of the breast and all three tumors met the diagnostic criteria defined for their salivary gland counterpart, including strong positivity to p53, but none of the three cases showed HER2 positivity.32

The breast PA has a thin incomplete pseudocapsule with pseudopodia with a high rate of recurrence similar to salivary tumors mandating a minimum of 3 mm adequate margin for excision.

Myoepithelioma

They are rare, benign salivary gland tumors most commonly occurring on the palate and parotid. Pathologically they have plasmacytoid or spindled myoepithelial components, and ductal structures are extremely rare. Most of the time, they are benign tumors, but malignant transformation can occur in recurrent cases.13

Myoepithelioma breast is also a rare tumor with pure myoepithelial cell differentiation. IHC is similar to salivary glands demonstrating features of myoepithelial cells. Aquino et al. demonstrated demonstrate AR positivity 28% of myoepithelioma patients showed AR positivity.27

Sclerosing Polycystic Adenosis (SPA)

Sclerosing polycystic adenosis (SPA) was originally described as a nonneoplastic condition analog to fibrocystic changes of the breast. It is a rare benign salivary gland lesion that commonly arises in the parotid gland. It is a well-encapsulated circumscribed lesion with low chances of recurrence, around 11%.23 Most of the cases contain the proliferated apocrine ductal cells and nuclear atypia that is similar to apocrine intraductal neoplasia of the breast. SPA is characterized by genetic alterations in the phosphoinositide 3-kinase pathway and phosphatase and tensin homolog deleted on chromosome 10 expression. This molecular profile is similar to salivary duct carcinoma and the apocrine variant of intraductal carcinoma. One case of salivary duct carcinoma arising in recurrent adenosis has been reported so far.24 Rico et al. reported a case of salivary gland-type mammary carcinoma arising in microglandular adenosis. Microglandular adenosis of the breast is an uncommon benign proliferative lesion. Even though it is a benign lesion, it can progress into atypical microglandular adenosis with increased cellularity and atypia, or in around 27% of cases, it gets converted into invasive carcinoma. The epithelial cells of this benign lesion are negative for both ER, PR, and HER2 receptors. Salivary gland-type carcinomas represent the second most common morphology after invasive ductal carcinoma in microglandular adenosis. The most commonly reported is ADCC.25

Both sclerosing polycystic adenosis and microglanduar adenosis can be considered preneoplastic conditions.

Mucoepidermoid Carcinoma

Mucoepidermoid carcinoma is the most common salivary gland malignancy. Pathologically have both solid and cystic components. The hallmark in histology is the presence of three cell types—mucous, squamoid, and intermediate. Clinical staging, histological grade, and location of the tumor are the most important parameters determining the prognosis. There are various grading schemes described for MEC and the most accepted is Auclair grading, which was later modified by Brandwein et al. The most consistent finding is translocation t(11;19) (q21;p13) seen in >50% of MECs, which forms a fusion gene mastermind-like protein 2:MEC translocated gene 1.13

Mucoepidermoid carcinoma (MEC) of the breast is a rare malignancy occurring with an incidence of 0.2%. The morphology and histology are similar to salivary MEC ranging from high to low grade. The clinical behavior is based on histological grading. The genetic alteration in breast MEC is similar to the salivary gland with t(11;19) and disrupts the neurogenic locus notch homolog protein 1 (Notch 1) signaling pathway.12 These translocations are mainly observed in low and intermediate-grade tumors and are associated with favorable outcomes, whereas p53 is the most frequently mutated gene in high-grade MECs.26

So far, only 28 cases of MEC breast have been reported and the results show that the histomorphological features, biology, and clinical behavior is similar to salivary glands (Table 4).

Table 4: Summarizes the hormone receptor expression in MEC
Study Cases PR ER HER2 AR
Gibbons et al. (2001)37 22 NA NA + NA
Weed et al. (2002)38 28 NA NA + NA
Nasser et al. (2003)22 10 + + NA +
Glisson et al. (2004)39 14 NA NA + NA
Shang et al. (2008)40 46 NA NA + NA
Ito et al. (2009)24 30 − − NA +
Clauditz et al. (2011)41 319 NA NA + NA
Ettl et al. (2012)42 28 NA NA + NA
Nakano et al. (2013)43 31 NA NA + NA
Lemound et al. (2016)44 10 + − − +
Hashimoto et al. (2017)45 34 NA NA + NA
Can et al. (2017)26 16 + + + −
Aquino et al. (2018)27 13 − + NA +
Szewczyk et al. (2019)46 16 + + − +
Hsieh et al. (2020)47 24 NA NA + NA

AR, androgen receptor; ER, estrogen receptor; NA: not assessed; PR, progesterone receptor

In most of the studies of MEC assessing the hormone status, the expression of both PR and ER is either negative or weakly positive. In general, around 30% of cases of MECs show HER2 overexpression. All cases of MEC were negative for ER in a study by Pires et al. around 136 cases of MECs were assessed in that study.48 In another analysis of 16 cases by Can and colleagues, HER2 overexpression with negative AR was found in two high-grade tumors.26 Glisson and colleagues evaluated HER2 status in high-grade salivary gland carcinomas, which showed a positivity of 21% for MEC and on trastuzumab therapy, one out of three cases showed partial response.39 Gibbson and colleagues concluded a significant therapeutic role of HER2 receptors in MEC.37

Adenoid Cystic Carcinoma (ADCC)

Adenoid cystic carcinoma (ADCC) is a slowly progressing infiltrative type of tumor with a protracted course of duration. Adenoid cystic carcinomas are more reported in minor salivary gland tumors and three growth patterns are identified: tubular, cribriform, and solid. Grading based on this tumor growth pattern carries the prognostic information. Grade III, with >30% solid pattern, carries a bad prognosis. Lung metastasis which is indolent for many years and perineural invasion are the classic features. The most consistent molecular translocation found is t (6;9), which involves myeloblastosis and nuclear factor I B genes. Immunohistochemical study shows positivity to the cluster of differentiation 34 and also receptor tyrosine kinase (c-KIT) is detected in around 80–94% of cases. Surgical resection is the treatment of choice in ADCC, followed by adjuvant treatment. 10 and 20-year overall survival is 39–55% and 21–25%, respectively.15

Adenoid cystic carcinoma (ADCC) of the breast accounts for <0.1% of breast carcinomas and microscopically, the features mimic ADCC salivary glands with three growth patterns. c-KIT overexpression is found in almost all ADCC breast cases and it shares the common translocation of t (6;9) at the molecular level. This marker can be used in targeted therapy for both tumors. In contrary to salivary ADCC, breast ADCC carries a favorable prognosis with fewer chances of lymph node and distant metastasis. The incidence of perineural invasion is very rare in the breast. Based on the grade of tumor, mastectomy with or without axillary dissection is recommended. 10-year overall survival for breast ADCC is >90% (Table 5).49

Table 5: Summarizes the hormone receptor expression in ADCC
Study Cases PR ER HER2 AR
Dori et al. (2000)50 27 + − NA NA
Gibbons et al. (2001)37 6 NA NA + NA
Glisson et al. (2004)39 70 NA NA + NA
Dori S et al. (2002)51 32 NA NA + NA
Nasser et al. (2003)22 10 − − NA +
Barrera et al. (2008)52 47 + + NA NA
Ito et al. (2009)24 30 − − NA +
Riad et al. (2009)53 11 + − NA +
Luo et al. (2009)54 17 NA + NA NA
Can et al. (2017)26 26 + + NA +
Szewczyk et al. (2019)46 33 − − − +

AR: androgen receptor; ER: estrogen receptor; NA, not assessed; PR, progesterone receptor

In a study comprised of exclusively ADCC for HER2 expression, only 16% (5/32) showed positivity limiting the clinical utility of this target. Overexpression of HER2 was variable in older studies ranging from 0 to 58–100%.55 It has been shown in one study that HER2 expression was associated with significantly lower disease-free intervals.56 The incidence of estrogen and progesterone receptors also shows variable results, with 0–75% in ER and 0–50% in PR positivity. However, a case report has mentioned a partial response of parotid ADCC with tamoxifen (ER antagonist).57 AR status analysis shows only a small subset of tumor (5–15%) with weak AR expression.58

Acinic Cell Carcinoma (ACC)

Acinic cell carcinoma (ACC) is an uncommon tumor constituting around 10% of malignant tumors. Microscopically four different patterns are seen—solid/lobular, microcystic, papillary-cystic, and follicular. The presence of acinic cells and dense lymphoid infiltration with germinal centers are classical features. ACC, in general, has the best survival except for the bad histological variant papillary cystic.15

Acinic cell carcinoma (ACC) of the breast shows serous differentiation similar to salivary glands. It is similar to salivary glands regarding the morphological, immunohistochemical, and ultrastructural aspects. The prognosis of breast ACC is reported as good with a low rate of recurrences and distant metastasis.49 Very few studies evaluated the hormone receptor status of ACC and none had shown positivity to PR, but few cases were weakly positive to other receptors.26

Salivary Duct Carcinoma (SDC)

It is one of the most aggressive salivary gland tumor subtypes accounting for <10% of salivary gland tumors. Around 90% of the cases arise in the parotid gland. Microscopically most of the SDCs have large prominent ductal carcinoma in situ components with a cribriform pattern. Immunohistochemical analysis shows positivity to cytokeratins. AR, carcinoembryonic antigen, and HER2 receptors.15

Histologically SDC is similar to invasive ductal carcinoma of the breast. The morphology of SDC salivary glands is characterized by distinct ducts and acini with comedo-type necrosis. These features are analogous to the comedocarcinoma subtype of invasive mammary ductal carcinoma. At the molecular level also, similar alterations were found in the chromosomal arms 6,16q,17p, and 17q. Both tumors have similar aggressive biological behavior with a high rate of metastsis (Table 6).49

Table 6: Summarizes the hormone receptor expression in SDC
Study Cases PR ER HER2 AR
Fan et al. (2000)60 13 − − NA +
Fan et al. (2001)61 12 − − NA +
Skalova et al. (2001)62 15 NA NA + NA
Nasser et al. (2003)22 10 − − NA +
Skalova et al. (2003)63 11 NA NA + NA
Glisson et al. (2004)39 12 NA NA + NA
Jaehne et al. (2005)64 50 NA NA + NA
Williams et al. (2007)65 84 NA NA NA +
Cornolti et al. (2007)66 13 NA NA + NA
Nabili et al. (2007)67 7 NA NA + NA
Sygut et al. (2008)68 4 NA NA NA +
Ettl et al. (2008)72 12 NA NA + NA
Locati et al. (2009)70 25 − − + +
Williams et al. (2010)68 66 NA NA + NA
Clauditz et al. (2011)41 14 NA NA + NA
Dipalma et al. (2012)71 42 − − + +
Suzuki et al. (2012)72 12 NA NA + NA
Cros et al. (2013)73 3 − − + +
Nardi et al. (2013)74 27 NA NA + NA
Kondo et al. (2014)75 13 NA NA + NA
Masubuchi et al. (2014)76 32 NA NA + +
Han et al. (2015)77 25 NA NA + NA
Luk et al. (2016)78 119 NA NA + +
Kusafuka et al. (2016)79 101 NA NA + +
Lemound et al. (2016)44 38 + + + +
Can et al. (2017)27 25 + + + +
Takase et al. (2017)80 151 NA NA + +
Hashimoto et al. (2017)45 32 NA NA + NA
Khoo et al. (2017)81 15 NA NA + +
Boon et al. (2018)82 177 NA NA + +
Beck et al. (2018)83 15 NA NA + NA
Ryu et al. (2018)84 28 NA NA + −
Kanazawa et al. (2018)85 34 NA + + +
Liang et al. (2019)86 75 NA + + +
Santana et al. (2019)87 25 NA NA + +
Szewczyk et al. (2019)46 16 − − + +
Villepelet et al. (2019)88 61 NA NA + +
Gargano et al. (2019)89 28 NA NA + +
Chatzopoulos et al. (2020)90 16 NA NA + +

AR, androgen receptor; ER, estrogen receptor; NA, not assessed; PR, progesterone receptor

Recently a lot of studies evaluated the presence of hormone receptor status of SDC. The most widely studied and expressed is HER2 receptors showing variable results ranging from 25–100% in salivary glands and 20–25% in mammary glands. HER2 expression is associated with histological grade in both organs. In a recent meta-analysis by Egebjerg et al., the prevalence of HER2 positivity was found to be 43% in SDC.59 Expression of AR is reported in around 29–46% of cases over various studies. Fan et al. suggested a potential role of AR in the pathogenesis of SDC through the epidermal growth factor receptor and transforming growth α-factor.61 There is a wide disparity in the expression of ER and PR is least significant in most of the studies. Both HER2 and AR have a potential role in the pathogenesis of SDC and hence can be used as a target for therapeutic intervention.

Secretory Carcinoma

Secretory carcinoma of salivary glands was first described in 2010 by Skalava et al. they described a series of 16 cases resembling both salivary ACC and low-grade cystadenocarcinoma. The most distinct feature was strong similarities with secretory carcinoma of the breast in both morphology and IHC panel. The presence of translocation t (12;15) (p13:q25) with the ETS variant transcription factor 6 and neurotrophic receptor tyrosine kinase 3 fusion gene is specific for secretory carcinoma breast. IHC markers that are positive include S100, vimentin and mammaglobin, and negative for discovered on gastrointestinal stromal tumor 1 (DOG1). They are low-grade tumors with an indolent course.91

Similar to breast secretory carcinoma, mammary analog secretory carcinoma of salivary glands are classified as a triple negative disease with the absence of expression of ER, PR, and HER2 receptors.

Low-grade Adenosquamous Carcinoma

This was originally described in 1987 as a variant of metaplastic carcinoma breast. It is a tumor of uncertain histogenesis but morphologically similar to syringomatous carcinoma of salivary glands. Syringomatous adenocarcinoma, similar to adnexal carcinoma of the skin is now considered a newer emerging entity termed sclerosing microcystic adenocarcinoma of salivary glands. Sclerosing microcystic adenocarcinoma has exclusively been reported in minor salivary glands, including the tongue, lip, the floor of the mouth, buccal mucosa, and nasopharynx. SMA has relatively good outcome without locoregional recurrences or distant metastasis.89

The mammary counterpart of SMA is clinically present as a palpable mass in the upper lateral quadrant. Microscopically these are similar to SMA, with glandular structures filled with amorphous material and embedded in the abundant stroma. They are also composed of both glandular cells and myoepithelial cells. Low-grade adenosquamous carcinoma breast is negative for hormonal receptors and usually has an indolent behavior with relatively good outcome.90

Basal Cell Adenocarcinoma

Basal cell adenocarcinoma is rare and constitutes only 1–2% of salivary gland malignancy and almost always occurs in the parotid gland. Basal cell adenocarcinoma shows indolent behavior but is locally aggressive, with chances of recurrence in about 30% of cases. Regional and distant metastasis rates are 8–12% and 2–4%, respectively.15,94

Basal cell adenocarcinoma is a rarely reported entity in literature. In 2012, Flynn et al. published a case series of three cases of basal cell adenocarcinoma arising in salivary gland metaplasia of the breast. Microscopically made of solid nests of basaloid neoplastic cells with salivary gland-like acini.91 Walls et al. reported a literature review with 11 patients of basaloid salivary gland analog tumors of the breast.92 All tumors displayed malignant basal cells forming glands and solid nests. There are a few other case series by shin et al. and Lamovec et al. reporting basaloid tumors of the breast. But due to the paucity of literature, it is difficult to conclude the prognosis and outcome of these tumors.93,94

Very few studies evaluated the hormone receptor status of basal cell adenocarcinoma. Nasser et al. showed few cases having positivity to AR.23 The recent meta-analysis by Egebjerg et al. reported five studies of basal cell adenocarcinoma, but all had HER2 negative status.59

Benign and Malignant Myoepithelioma

Myoepitheliomas are rare benign salivary gland tumors composed of plasmacytoid or spindled myoepithelial cells, most commonly affecting the palate and parotid. Myoepithelial carcinoma is a malignant counterpart that is also very uncommon and frequently occurs in parotid glands. They have irregular borders with infiltrative growth patterns and follow the rule of 30. A total of 30% of patients will have multiple local recurrences, 30% will die of metastatic disease, and 30% will be disease-free after resection.15

Benign and malignant myoepithelioma of the breast is extremely rare. Similar to a salivary gland tumor, it is entirely made of myoepithelial cells. Prognosis is poor, with a high rate of distant and local failure.96

The hormone receptor expression was rarely studied in myoepithelial tumors due to the rarity of the lesion. Aquino and colleagues reported 28% of cases of benign myoepithelioma with AR expression.27 ER and PR expression were not found to be significant in the available studies. A total of 4.3% is the prevalence of HER2 positivity in the recent meta-analysis by Egebjerg et al.59

Adenomyoepithelioma

It is a biphasic tumor morphologically similar to epithelial, myoepithelial carcinoma of salivary glands with a fairly good outcome.96

In the breast, it occurs as adenomyoepithelioma, histologically made of dual cell proliferation lining the glandular lumen. The prognosis of adenomyoepithelioma breast is good, with chances of recurrence on incomplete primary excision.95

The prevalence of HER2 positivity in epithelial, myoepithelial carcinoma corresponds to 1.8%, according to a recent meta-analysis.56 The status of hormonal receptors is the least studied in this entity.

Oncocytic Carcinoma

Oncocytic lesions are usually benign in salivary glands. They are extremely rare and are characterized by malignant oncocytes with adenocarcinomatous differentiation with features of locoregional and distant invasion. Most of the reported cases are high-grade with increased rates of locoregional and distant failure.95

Oncocytic tumor of the breast occurs in elderly females and are composed of >70% oncocytes. These are extremely rare variants of breast carcinoma with variable expression of hormone receptors.96 HER2 receptor expression was not identified in studies, including oncocytic carcinoma while AR was found positive in a few studies.27

Polymorphous Adenocarcinoma

It is the second most common intraoral malignant salivary gland tumor, with approximately 60% occurring in the palate. These tumors are histologically characterized by cytological uniformity, morphological diversity, and infiltrative growth pattern. A salient feature is the wide variation of morphological configuration and perineural involvement is common. The prognosis is relatively good.15

Polymorphous carcinoma of the breast morphologically resembles low-grade adenocarcinoma salivary glands composed of the proliferation of monotonous neoplastic cells arranged in an Indian file pattern. IHC shows strong positivity to B-cell leukemia/lymphoma 2 protein.98 Only a few cases have been reported so far. HER2 expression is not found in adenocarcinomas and few studies show expression of ERs.26

CURRENT ROLE OF HORMONE RECEPTOR STATUS IN TREATMENT OF SALIVARY GLAND TUMORS

Tumors originating from the excretory ducts (MEC, SCC, and SDC) may show higher rates of HER2 overexpression than tumors originating from intercalated ducts (ADCC, ACC, adenocarcinoma NOS, myoepithelial carcinoma).

Human epidermal growth factor receptor 2 (HER2) belongs to the class of the epidermal growth factor receptor. It possesses a tyrosine kinase activity gene and is involved in signal transduction of cell growth. HER2 overexpression can be measured semiquantitatively by immunohistochemistry and gene amplification can be measured by fluorescent in situ hybridization technique. HER2 overexpression or amplification is linked to the response to trastuzumab in breast cancers. HER2 receptor status acts as a therapeutic target and a prognostic factor in breast carcinoma. HER2 expression is associated with the worst prognosis and using monoclonal antibody trastuzumab for patients exhibiting HER2 overexpression is the standard of care in breast carcinoma now.101 The morphological similarity of salivary duct carcinoma to invasive carcinoma of the breast and molecular resemblance to apocrine breast cancer makes HER2 a novel target for therapeutic intervention in salivary glands. HER2 expression is most frequently found in this subtype in most of the studies. HER2 scoring system used for breast cancer is applied for salivary gland carcinoma. Treatment of HER2 positive cases may include monoclonal antibodies (trastuzumab and pertuzumab) or HER2 tyrosine kinase inhibitors (lapatinib). The present evidence offers HER2 targeted therapies (trastuzumab plus taxane, pertuzumab plus trastuzumab, or ado-trastuzumab emtansine) as first-line or subsequent-line therapies for HER2 positive salivary gland carcinoma.102 Recent two trials with HER2 targeted therapies showed a good response rate of 90 and 60% with ado-trastuzumab emtansine and a combination of trastuzumab and pertuzumab, respectively. In an open-label phase IIa basket trial, complete response was observed in SDC and partial response most commonly was seen in the adenocarcinoma subtype.103 In the National Cancer Institute Molecular Analysis for Therapy Choice trial with ado-trastuzumab emtansine for HER2 amplified pathologies, two out of three salivary gland carcinomas with MEC and SCC subtypes showed partial response.104

Androgen, estrogen, and PRs are members of the nuclear hormone receptor family of transcription factors. Androgens bond to AR, resulting in the promotion of certain genes and pathways involved in tumor cell growth and resistance. AR is expressed in the majority of SCCs and a minority of other subtypes, such as adenocarcinoma NOS.58

For patients with AR-positive salivary gland cancer, CAB may be offered.36 AR-positive cases treated using leuprorelin acetate and bicalutamide showed an overall response rate of 42% in a phase II study. 94% of cases were SDC and the rest were adenocarcinoma NOS.105 There are few retrospective studies demonstrating response to androgen deprivation therapy, either single-agent or CAB [lutenizing hormone releasing hormone (LHRH) LHRH analog plus bicalutamide].106-108 The first prospective trial on AR-positive salivary tumors, single agent enzalutamide showed stable disease in more than half the patients.109

Several studies observed ER and PR receptor expression in salivary gland tumors, but there is a vast disparity in the results ranging from 0–86% and 0–50% for both ER and PR, respectively. Williams et al. described the expression of ER-β in most of the tumors of the breast and salivary glands. The absence of ER-β is associated with local recurrences. ER-β inhibit cell proliferation through the cyclin D1 pathway and apoptotic pathway.36,65 Several strategies are used in breast cancer for targeting ER-positive tumors, like ovarian suppression drugs, estrogen production blockage with aromatase inhibitors, and, most commonly, selective estrogen receptor modulators like tamoxifen.110 There are a few case reports of the use of tamoxifen for ADCC showing stable disease.111 Another case report of SDC parotid treated with tamoxifen and anastrozole (aromatase inhibitor) showed an objective response with long-term disease stability.112

The role of PR was extensively studied by Yoshimura et al. in human ADCC cell lines. Progesterone was found to markedly inhibit cell proliferation. In both salivary and mammary glands, this inhibitory effect was observed. In both types of cancers, Id-1 and cellular Myc was downregulated and p21 was upregulated after progesterone treatment. Hence progesterone is homeostatic for both cancers and triggers a tumor dormancy state.113 Selective PR modulators have significant activity against breast cancer in clinical trials, but due to cross-reactivity with glucocorticoids, it is less tolerated by patients. Targeted ER/PR therapy is currently not being used in the treatment of salivary gland carcinomas, likely due to the lower frequency of positive receptor status and less likely benefit of targeting these receptors.

CONCLUSION

The resemblance of mammary and salivary gland tumors is the basis for the newer concept of antihormonal therapies in salivary gland tumors. Even though these tumors differ in incidence, most of them show similar clinical behavior and biology. Based on the expression of hormone receptors in breast cancer, similar tumors of salivary glands can be evaluated for targeting these receptors. A wide range of receptor expression is observed in a wide variety of subgroups of salivary gland tumors. It could also be due to variability in antibody clones, fixation processes, scoring systems, and observer variability. Current evidence manages relevant information regarding the status of HER2 and ER expression of tumors. These receptors are significantly expressed more in salivary duct carcinoma and in the minority of carcinoma ex PA, adenocarcinoma NOS, and MEC. The novel treatment strategies of anti-HER2 and anti-AR therapies are currently found useful mainly for SDC and a few cases of adenocarcinoma NOS and MEC. The wide range of protein expression and the vast diversity of salivary gland tumors mandates more accurate data from multi-institutional prospective trials to establish the role of hormonal therapies in salivary gland tumors.

Limitations

The statistical analysis of the prevalence of each receptor status on individual histological subtypes was not done.

REFERENCES

1. Sangeetha P, Anitha N, Rajesh E, et al. Embryology and development of salivary gland. Eur J Mol Clin Med 2020;7(10):764–770.

2. Tucker Tucker AS, Miletich I (eds): Salivary Glands. Development, Adaptations, and Disease. Front Oral Biol Basel, Karger, 2010;14:1–20.

3. Macias H, Hinck L. Mammary gland development. Wiley Interdiscip Rev Dev Biol 2012;1(4):533–557. DOI: 10.1002/wdev.35

4. Lewis AG, Tong T, Maghami E. Diagnosis and management of malignant salivary gland tumors of the parotid gland. Otolaryngol Clin North Am 2016;49(2):343–380. DOI: 10.1016/j.otc.2015.11.001

5. Kratochwil K. Organ specificity in mesenchymal induction demonstrated in the embryonic development of the mammary gland of the mouse. Dev Biol 1969;20(1):46–71. DOI: 10.1016/0012-1606(69)90004-9

6. Namboodiripad PC. A review: immunological markers for malignant salivary gland tumors. J Oral Biol Craniofac Res 2014;4(2):127–134. DOI: 10.1016/j.jobcr.2014.05.003

7. Aydogan A, Metin N. Detection of cell origin by immunohistochemistry in canine mammary tumours. Revue Med Vet 2013;164:395–399.

8. Liu H. Application of immunohistochemistry in breast pathology. Arch Pathol Lab Med 2014;138(12):1629–1642. DOI: 10.5858/arpa.2014-0094-RA

9. Dwivedi N, Agarwal A, Raj V, et al. Histogenesis of salivary gland neoplasms. Indian J Cancer 2013;50(4):361–366. DOI: 10.4103/0019-509X.123629

10. Rao RS, Patil S, Amrutha N, et al. The ambiguous salivary myoepithelial cells. J Contemp Dent Pract 2014;15(4):523–528. DOI: 10.5005/jp-journals-10024-1573

11. Triantafyllou A, Hunt JL, Devaney KO, et al. A perspective of comparative salivary and breast pathology. Part I: microstructural aspects, adaptations and cellular events. Eur Arch Otorhinolaryngol 2014;271(4):647–663. DOI: 10.1007/s00405-013-2488-y

12. Gudjonsson T, Adriance MC, Sternlicht MD, et al. Myoepithelial cells: their origin and function in breast morphogenesis and neoplasia. J Mammary Gland Biol Neoplasia 2005;10(3):261–272. DOI: 10.1007/s10911-005-9586-4

13. Boecker W, Stenman G, Loening T, et al. K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation. Mod Pathol 2013;26(8):1086–1100. DOI: 10.1038/modpathol.2013.45

14. Foschini MP, Morandi L, Asioli S, et al. The morphological spectrum of salivary gland type tumours of the breast. Pathology 2017;49(2):215–227. DOI: 10.1016/j.pathol.2016.10.011

15. Davud B Sirjani, Lewis James S, Beadle Beth M, et al. Malignant neoplasms of the salivary glands, chapter85, Cummings otolaryngology and head and neck surgery, 7th edition, volume 2, Kennedy JK, Philadelphia, 2021. pp. 1189–1212.

16. Larbcharoensub N, Cert PK, Tungkeeratichai J, et al. Expression of hormonal receptor in patients with metastasizing pleomorphic adenoma of the major salivary gland; a clinicopathological report of three cases. J Med Assoc Thai 2009;92(9):1250–1255.

17. Glas AS, Hollema H, Nap RE, et al. Expression of estrogen receptor, progesterone receptor, and insulin-like growth factor receptor-1 and of MIB-1 in patients with recurrent pleomorphic adenoma of the parotid gland. Cancer 2002;94(8):2211–2216. DOI: 10.1002/cncr.10445

18. De Souz AA, Altemani A, de Araujo NS, et al. Estrogen receptor, progesterone receptor, and her-2 expression in recurrent pleomorphic adenoma. Clin Pathol 2019;12:2632010X19873384. DOI: 10.1177/2632010X19873384

19. Di Palma S, Skálová A, Vanìèek T, et al. Non-invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER-2/neu and MIB1 immunohistochemistry. Histopathology 2005;46(2):144–152. DOI: 10.1111/j.1365-2559.2005.02058.x

20. Di Palma S. Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions. Head Neck Pathol 2013;7(Suppl 1):S68–S76. DOI: 10.1007/s12105-013-0454-z

21. Moriki T, Ueta S, Takahashi T, et al. Salivary duct carcinoma: cytologic characteristics and application of androgen receptor immunostaining for diagnosis. Cancer 2001;93(5):344–350. DOI: 10.1002/cncr.9050

22. Nasser MD, Faquin WC, Dayal Y, et al. Expression of androgen, estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors. Am J Clin Pathol 2003;119(6):801–806. DOI: 10.1309/RVTP-1G0Q-727W-JUQD

23. Wong MH, Dobbins TA, Tseung J, et al. Oestrogen receptor beta expression in pleomorphic adenomas of the parotid gland. J Clin Pathol 2009;62(9):789–793. DOI: 10.1136/jcp.2009.065102

24. Ito FA, Ito K, Coletta RD. Immunohistochemical study of androgen, estrogen and progesterone receptors in salivary gland tumors. Braz Oral Res 2009:23(4):393–398. DOI: 10.1590/s1806-83242009000400008

25. Nakajima Y, Kishimoto T, Nagai Y, et al. Expressions of androgen receptor and its co-regulators in carcinoma ex pleomorphic adenoma of salivary gland. Pathology 41(7):634–639. DOI: 10.3109/00313020903071595

26. Can NT, Lingen MW, Mashek H, et al. Expression of hormone receptors and HER-2 in benign and malignant salivary gland tumors. Head Neck Pathol 2017;12(1):95–104. DOI: 10.1007/s12105-017-0833-y

27. Aquino G, Collina F, Sabatino R, et al. Sex hormone receptors in benign and malignant salivary gland tumors: prognostic and predictive role. Int J Mol Sci 2018;19(2):399. DOI: 10.3390/ijms19020399

28. Weiler C, Zengel P, van der Wal JE, et al. Carcinoma ex pleomorphic adenoma with special reference to the prognostic significance of histological progression: a clinicopathological investigation of 41 cases. Histopathology 2011;59(4):741–750. DOI: 10.1111/j.1365-2559.2011.03937.x

29. Takahashi K. Diagnosis of an extremely rare pleomorphic adenoma of the breast with core needle biopsy: A case report. Ann Med Surg (Lond) 2018;36:242–245. DOI: 10.1016/j.amsu.2018.10.037

30. Leekha N, Muralee M, Mathews A, et al. Pleomorphic adenoma of breast-a case report and review of literature. Indian J Surg Oncol 2014;5(2):152–154. DOI: 10.1007/s13193-014-0310-y

31. Moore M, Mills A, Dillon P, et al. Pleomorphic adenoma of the breast: a potential morphologic and molecular pitfall in the era of genomic risk stratification. Current problems in cancer; case reports 2021;3. DOI: 10.1016/j.cpccr.2020.100047

32. Hayes MM, Lesack D, Girardet C, et al. Carcinoma ex-pleomorphic adenoma of the breast. Report of three cases suggesting a relationship to metaplastic carcinoma of matrix-producing type. Virchows Arch 2005;446(2):142–149. DOI: 10.1007/s00428-004-1137-7

33. Seethala RR, Stenman G. Update from the 4th edition of the World Health Organization classification of Head and Neck tumours: tumors of the salivary gland. Head and Neck Pathol 2017;11(1):55–67. DOI: 10.1007/s12105-017-0795-0

34. Bishop JA, Gagan J, Baumhoer D, et al. Sclerosing polycystic “adenosis” of salivary glands: a neoplasm characterized by pi3k pathway alterations more correctly named sclerosing polycystic adenoma. Head Neck Pathol 2020;14(3):630–636. DOI: 10.1007/s12105-019-01088-0

35. Rico V, Shibahara Y, Monteiro M, et al. Salivary gland-type mammary carcinoma arising in microglandular adenosis: A case report and clinicopathological review of the literature. Cancer Treat Res Commun 24:100178. DOI: 10.1016/j.ctarc.2020.100178

36. Murase R, Sumida T, Ishikawa A, et al. Novel therapeutic strategies for malignant salivary gland tumors: lessons learned from breast cancer. Int J Otolaryngol 2011;2011:187623. DOI: 10.1155/2011/187623

37. Gibbons MD, Manne U, Carroll WR, et al. Molecular differences in mucoepidermoid carcinoma and adenoid cystic carcinoma of the major salivary glands. Laryngoscope 2001;111(8):1373–1378. DOI: 10.1097/00005537-200108000-00011

38. Weed DT, Gomez-Fernandez C, Pacheco J, et al. MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma. Head Neck 2004;26(4):353–364. DOI: 10.1002/hed.10387

39. Glisson B, Colevas AD, Haddad R, et al. Her2 expression in salivary gland carcinomas: dependence on histological subtype. Clin Cancer Res 2004;10(3):944–946. DOI: 10.1158/1078-0432.CCR-03-0253

40. Shang J, Shui Y, Sheng L, et al. Epidermal growth factor receptor and human epidermal growth receptor 2 expression in parotid mucoepidermoid carcinoma: possible implications for targeted therapy. Oncol Rep 2008;19(2):435–440. DOI: 10.3892/or.19.2.435

41. Clauditz TS, Reiff M, Gravert L, et al. Human epidermal growth factor receptor 2(HER2) in salivary gland carcinomas. Pathology 2011;43(5):459–464. DOI: 10.1097/PAT.0b013e3283484a60

42. Ettl T, Stiegler C, Zeitler K, et al. EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis. Hum Pathol 2012;43(6):921–931. DOI: 10.1016/j.humpath.2011.08.006

43. Nakano T, Yamamoto H, Hashimoto K, et al. HER2 and EGFR gene copy number alterations are predominant in high-grade salivary mucoepidermoid carcinoma irrespective of MAML2 fusion status. Histopathology 2013;63(3):378–392. DOI: 10.1111/his.12183

44. Lemound J, Schenk M, Keller G, et al. Cytogenetic and immunohistochemical biomarker profiling of therapy-relevant factors in salivary gland carcinomas. J Oral Pathol Med 2016;45(9):655–663. DOI: 10.1111/jop.12429

45. Hashimoto K, Hayashi R, Mukaigawa T, et al. Concomitant expression of Ezrin and HER2 predicts distant metastasis and poor prognosis of patients with salivary gland carcinomas. Hum Pathol 2017;63:110–119. DOI: 10.1016/j.humpath.2017.02.017

46. Szewczyk M, Marszałek A, Sygut J, et al. Prognostic markers in salivary gland cancer and their impact on survival. Head Neck 2019;41(9):3338–3347. DOI: 10.1002/hed.25857

47. Hsieh MS, Lee YH, Jin YT, et al. Clinicopathological study of intraductal carcinoma of the salivary gland, with emphasis on the apocrine type. Virchows Arch 2020;477(4):581–592. DOI: 10.1007/s00428-020-02823-7

48. Pires FR, da Cruz Perez DE, de Almeida OP, et al. Estrogen receptor expression in salivary gland mucoepidermoid carcinoma and adenoid cystic carcinoma. Pathol Oncol Res 2004;10(3):166–168. DOI: 10.1007/BF03033746

49. Foschini MP, Krausz T. Salivary gland-type tumors of the breast: a spectrum of benign and malignant tumors including “triple negative carcinomas” of low malignant potential. Semin Diagn Pathol 2010;27(1):77–90. DOI: 10.1053/j.semdp.2009.12.007

50. Dori S, Trougouboff P, David R, et al. Immunohistochemical evaluation of estrogen and progesterone receptors in adenoid cystic carcinoma of salivary gland origin. Oral Oncol 2000;36(5):450–453. DOI: 10.1016/s1368-8375(00)00029-4

51. Dori S, Vered M, David R, et al. HER2/Neu expression in adenoid cystic carcinoma of salivary gland origin: an immunohistochemical study. J Oral Pathol Med 2002;31(8):463–467. DOI: 10.1034/j.1600-0714.2002.00017.x

52. Barrera JE, Shroyer KR, Said S, et al. Estrogen and progesterone receptor and p53 gene expression in adenoid cystic cancer. Head Neck Pathol 2008;2(1):13–18. DOI: 10.1007/s12105-007-0032-3

53. Riad S et al. Expression of sex steroid hormone in adenoid cystic carcinoma of salivary gland origin. Alex Dent J 2009;34(1–3):37–44.

54. Luo SD, Su YC, Chuang HC, et al. Estrogen receptor overexpression in malignant minor salivary gland tumors of sinonasal tract. Otolaryngol Head Neck Surg 2009;141(1):108–103. DOI: 10.1016/j.otohns.2009.03.003

55. Khan AJ, DiGiovanna MP, Ross DA, et al. Adenoid cystic carcinoma: a retrospective clinical review. Int J Cancer 2001;96(3):149–158. DOI: 10.1002/ijc.1013

56. Press MF, Pike MC, Hung G, et al. Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis. Cancer Res 199454(21):5675–5682.

57. Shadaba A, Gaze MN, Grant HR, et al. The response of adenoid cystic carcinoma to tamoxifen. J Laryngol Otol 1997;111(12):1186–1189. DOI: 10.1017/s0022215100139684

58. Yeoh CC, Dabab N, Rigby E, et al. Androgen receptor in salivary gland carcinoma: A review of an old marker as a possible new target. J Oral Pathol Med 2018;47(7):691–695. DOI: 10.1111/jop.12741

59. Egebjerg K, Harwood CD, Woller NC, et al. HER2 positivity in histological subtypes of salivary gland carcinoma: A systemic review and metaanalysis. Front Oncol 2001;11:693394. DOI: 10.3389/fonc.2021.693394

60. Fan CY, Wang J, Barnes EL, et al. Expression of androgen receptor ans prostatic specific markers in salivary duct carcinoma: an immunohistochemicalanalysis of 13 cases and review of the literature. Am J Surg Pathol 2000;24(4):579–586. DOI: 10.1097/00000478-200004000-00014

61. Fan CY, Melhem MF, Hosal HS, et al. Expression of androgen receptor epidermal growth factor receptor, and transforming growth factor receptor alpha in salivary duct carcinoma. Arch Otolaryngol Head Neck Surg 2001;127(9):1075–1079. DOI: 10.1001/archotol.127.9.1075

62. Skaálovaá A, Staárek I, Kuerovaá V, et al. Salivary duct carcinoma - a highly aggressive salivary gland tumor with her-2/neu oncoprotein overexpression. Pathol Res Pract 2001;197(9):621–626. DOI: 10.1078/03440338-00136

63. Skálová A, Stárek I, Vanecek T, et al. Expression of HER-2/neu gene and protein in salivary duct carcinomas of parotid gland as revealed by fluorescence in-situ hybridization and immunohistochemistry. Histopathology 2003;42(4):348–356. DOI: 10.1046/j.1365-2559.2003.01600.x

64. Jaehne M, Roeser K, Jaekel T, et al. Clinical and immunohistologic typing of salivary duct carcinoma: a report of 50 cases. Cancer 2005;103(12):2526–2533. DOI: 10.1002/cncr.21116

65. Williams MD, Roberts D, Blumenschein GR Jr, et al. Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: biologic significance and potential role in therapeutic stratification of patients. Am J Surg Pathol 2007;31(11):1645–1652. DOI: 10.1097/PAS.0b013e3180caa099

66. Cornolti G, Ungari M, Morassi ML, et al. Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg 2007;133(10):1031–1036. DOI: 10.1001/archotol.133.10.1031

67. Nabili V, Tan JW, Bhuta S, et al. Salivary duct carcinoma: a clinical and histologic review with implications for trastuzumab therapy. Head Neck 2007;29(10):907–912. DOI: 10.1002/hed.20614

68. Sygut D, Bień S, Ziółkowska M, et al. Immunohistochemical expression of androgen receptor in salivary gland cancers. Pol J Pathol 2008;59(4):205–210.

69. Ettl T, Schwarz S, Kleinsasser N, et al. Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas. Histopathology 2008;53(5):567–577. DOI: 10.1111/j.1365-2559.2008.03159.x

70. Locati LD, Perrone F, Losa M, et al. Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCS). Oral Oncol 2009;45(11):986–990. DOI: 10.1016/j.oraloncology.2009.05.635.

71. Di Palma S, Simpson RH, Marchiò C, et al. Salivary duct carcinomas can be classified into luminal androgen receptor-positive, HER2 and basal-like phenotypes. Histopathology 2012;61(4):629–643. DOI: 10.1111/j.1365-2559.2012.04252.x

72. Suzuki S, Dobashi Y, Minato H, et al. EGFR and HER2-Akt-mTOR signaling pathways are activated in subgroups of salivary gland carcinomas. Virchows Arch 2012;461(3):271–282. DOI: 10.1007/s00428-012-1282-3

73. Cros J, Sbidian E, Hans S, et al. Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours. Ann Oncol 2013;24(10):2624–2629. DOI: 10.1093/annonc/mdt338

74. Nardi V, Sadow PM, Juric D, et al. Detection of novel actionable genetic changes in salivary duct carcinoma helps direct patient treatment. Clin Cancer Res 2013;19(2):480–490. DOI: 10.1158/1078-0432.CCR-12-1842

75. Kondo Y, Kikuchi T, Esteban JC, et al. Intratumoral heterogeneity of HER2 protein and amplification of HER2 gene in salivary duct carcinoma. Pathol Int 2014;64(9):453–459. DOI: 10.1111/pin.12195

76. Masubuchi T, Tada Y, Maruya S, et al. Clinicopathological significance of androgen receptor, HER2, Ki-67 and EGFR expressions in salivary duct carcinoma. Int J Clin Oncol 2015;20(1):35–44. DOI: 10.1007/s10147-014-0674-6

77. Han MW, Roh JL, Choi SH, et al. Prognostic factor and outcome analysis of salivary duct carcinoma. Auris Nasus Larynx 2015;42(6):472–477. DOI: 10.1016/j.anl.2015.04.005

78. Luk PP, Weston JD, Yu B, et al. Salivary duct carcinoma: Clinicopathologic features, morphologic spectrum, and somatic mutations. Head Neck 2016;38 Suppl 1:E1838–E1847. DOI: 10.1002/hed.24332

79. Kusafuka K, Kawasaki T, Maeda M, et al. Salivary duct carcinoma with rhabdoid features: a salivary counterpart of pleomorphic lobular carcinoma of the breast. Histopathology 2017;70(2):164–173. DOI: 10.1111/his.12987

80. Takase S, Kano S, Tada Y, et al. Biomarker immunoprofile in salivary duct carcinomas: clinicopathological and prognostic implications with evaluation of the revised classification. Oncotarget 2017;8(35):59023–59035. DOI: 10.18632/oncotarget.19812

81. Khoo TK, Yu B, Smith JA, et al. Somatic mutations in salivary duct carcinoma and potential therapeutic targets. Oncotarget 2017;8(44):75893–75903. DOI: 10.18632/oncotarget.18173

82. Boon E, Bel M, van Boxtel W, et al. A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands. Int J Cancer 2018;143(4):758–766. DOI: 10.1002/ijc.31353

83. Beck ACC, Lohuis PJFM, Al-Mamgani A, et al. Salivary duct carcinoma: evaluation of treatment and outcome in a tertiary referral institute. Eur Arch Otorhinolaryngol 2018;275(7):1885–1892. DOI: 10.1007/s00405-018-5000-x

84. Ryu HJ, Koh YW, Yoon SO. The implications of TrkA and MET aberrations in novo salivary duct carcinoma. Hum Pathol 2018;81:18–25. DOI: 10.1016/j.humpath.2018.04.027

85. Kanazawa T, Misawa K, Fukushima H, et al. Epigenetic inactivation of galanin receptors in salivary duct carcinoma of the parotid gland: potential utility as biomarkers for prognosis. Oncol Lett 2018;15(6):9043–9050. DOI: 10.3892/ol.2018.8525

86. Liang L, Williams MD, Bell D. Expression of PTEN, androgen receptor, HER2/neu, cytokeratin 5/6, estrogen receptor-beta, HMGA2, and PLAG1 in salivary duct carcinoma. Head Neck Pathol 2019;13(4):529–534. DOI: 10.1007/s12105-018-0984-5

87. Santana T, Pavel A, Martinek P, et al. Biomarker immunoprofile and molecular characteristics in salivary duct carcinoma: clinicopathological and prognostic implications. Hum Pathol 2019;93:37–47. DOI: 10.1016/j.humpath.2019.08.009

88. Villepelet A, Lefèvre M, Verillaud B, et al. Salivary duct carcinoma: prospective multicenter study of 61 cases of the Réseau d’Expertise Français des Cancers ORL rares. Head Neck 2018;41(3):584–591. DOI: 10.1002/hed.25194

89. Gargano SM, Senarathne W, Feldman R, et al. Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling. Cancer Med 2019;8(17):7322–7329. DOI: 10.1002/cam4.2602

90. Chatzopoulos K, Collins AR, Sotiriou S, et al. Increased ERBB2 gene copy numbers reveal a subset of salivary duct carcinomas with high densities of tumor infiltrating lymphocytes and PD-L1 expression. Head Neck Pathol 2020;14(4):951–965. DOI: 10.1007/s12105-020-01163-x

91. Skálová A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599–608. DOI: 10.1097/PAS.0b013e3181d9efcc

92. Rooper LM. Emerging entities in salivary pathology: a practical review of sclerosing microcystic adenocarcinoma, microsecretory adenocarcinoma, and secretory myoepithelial carcinoma. Surg Pathol Clin 2021;14(1):137–150. DOI: 10.1016/j.path.2020.10.003

93. Pia-Foschini M, Reis-Filho JS, Eusebi V, et al. Salivary gland-like tumours of the breast: surgical and molecular pathology. J Clin Pathol 2003;56(7):497–506. DOI: 10.1136/jcp.56.7.497

94. Flynn C, Kadivar M, Kwon MY, et al. Basal cell adenocarcinoma arising in salivary gland metaplasia of the breast: a novel salivary gland-type tumor developing in the breast. Hum Pathol 2012;43(10):1764–1771. DOI: 10.1016/j.humpath.2012.02.013

95. Walls AL, Middleton LP, El-Naggar AK, et al. Basaloid salivary gland-analogue tumors of the mammary gland: clinicopathologic assessment of a rare subtype. Int J Pathol Clin Res 2016;2(3). DOI: 10.23937/2469-5807/1510042

96. Shin SJ, Rosen PP. Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Am J Surg Pathol 2002;26(4):413–420. DOI: 10.1097/00000478-200204000-00002

97. Lamovec J, Falconieri G, Salviato T, et al. Basaloid carcinoma of the breast: a review of 9 cases, with delineation of a possible clinicopathologic entity. Ann Diagn Pathol 2017;187(10):2139–2151. DOI: 10.1016/j.anndiagpath.2007.01.009

98. Geyer CF, Pareja F, Weigelt B, et al. The spectrum of triple-negative breast disease: High- and low-grade lesions. Am J Pathol 2017;187(10):2139–2151. DOI: 10.1016/j.ajpath.2017.03.016

99. Seethala. Salivary Gland Tumors: Current Concepts and Controversies. Surg Pathol Clin 2017;10(1):155–176. DOI: 10.1016/j.path.2016.11.004

100. Giordano G, Gabrielli M, Gnetti L, et al. Oncocytic carcinoma of parotid gland: a case report with clinical, immunohistochemical and ultrastructural features. World J Surg Oncol 2006;4:54. DOI: 10.1186/1477-7819-4-54

101. Oh DY, Bang YJ. HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol 2020;17(1):33–48. DOI: 10.1038/s41571-019-0268-3

102. Geiger JL, Ismaila N, Beadle B, et al. Management of salivary gland malignancy: ASCO guideline. J Clin Oncol 2021;39(17):1909–1941. DOI: 10.1200/JCO.21.00449

103. Kurzrock R, Bowles DW, Kang H, et al. Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study. Ann Oncol 2020;31(3):412–421. DOI: 10.1016/j.annonc.2019.11.018

104. Jhaveri KL, Wang XV, Makker V, et al. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q. Ann Oncol 2021;30(11):1821–1830. DOI: 10.1093/annonc/mdz291

105. Fushimi C, Tada Y, Takahashi H, et al. A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma. Ann Oncol 2018;29(4):979–984. DOI: 10.1093/annonc/mdx771

106. Boon E, van Boxtel W, Buter J, et al. Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: a nationwide case series of 35 patients in The Netherlands. Head Neck 2018;40(3):605–613. DOI: 10.1002/hed.25035

107. Viscuse PV, Price KA, Garcia JJ, et al. First line androgen deprivation therapy vs. chemotherapy for patients with androgen receptor positive recurrent or metastatic salivary gland carcinoma—a retrospective study. Front Oncol 2019;9:701. DOI: 10.3389/fonc.2019.00701

108. Locati LD, Perrone F, Cortelazzi B, et al. Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptor-positive salivary gland cancers. Head Neck 2016;38(5):724–731. DOI: 10.1002/hed.23940

109. Ho AL, Foster NR, Zoroufy AJ, et al. Phase II study of Enzalutamide for patients with androgen receptor-positive salivary gland cancers (Alliance A091404). J Clin Oncol 2022;40(36):4240–4249. DOI: 10.1200/JCO.22.00229

110. Omar TA, ElDidi F, Nawar WM, et al. A potential role of sex hormone receptor anagonists in the treatment of malignant salivary gland tumors, as compared to breast cancer: a review of literature. Tanta Dental Journal 2013;10(2):75–85. DOI: 10.1016/j.tdj.2013.08.006

111. Elkin AD, Jacobs CD. Tamoxifen for salivary gland adenoid cystic carcinoma: report of two cases. J Cancer Res Clin Oncol 2008;134(10):1151–1153. DOI: 10.1007/s00432-008-0377-3

112. Campos-Gómez S, Flores-Arredondo JH, Dorantes-Heredia R, et al. Case report: anti-hormonal therapy in the treatment of ductal carcinoma of the parotid gland. BMC Cancer 2014;14:701. DOI: 10.1186/1471-2407-14-701

113. Yoshimura T, Sumida T, Liu S, et al. Growth inhibition of human salivary gland tumor cells by introduction of progesterone (Pg) receptor and Pg treatment. Endocr Relat Cancer 2007;14(4):1107–1116. DOI: 10.1677/erc.1.01253

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