Human Pathology: Case Reports 5 (2016) 23–28

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Human Pathology: Case Reports

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Myoepithelial carcinoma of the posterior mediastinum: An uncommon

site for a rare tumor

Eman Abdulfatah, M.D. ⁎, Rahman Chaudhry, M.D., M.P.H., Oudai Hassan, M.D., Faisal Qureshi, M.D.,Rafic Beydoun, M.D., Sudeshna Bandyopadhyay, M.D.Department of Pathology, Wayne State University, 540 East Canfield Avenue, Detroit, Michigan 48201

a b s t r a c ta r t i c l e i n f o

⁎ Corresponding author at: Department of Pathology, WCanfield Avenue, Detroit, Michigan 48201. Tel.: +1 203 4

E-mail address: eabdulfa@med.wayne.edu (E. Abdulfa

http://dx.doi.org/10.1016/j.ehpc.2015.10.0032214-3300/Published by Elsevier Inc. This is an open acce

Article history:Received 18 September 2015Received in revised form 27 October 2015Accepted 29 October 2015

Myoepithelial carcinoma (MC) is a rare tumor that arises from myoepithelial cells; most commonly in thesalivary glands, but other infrequent body sites such as the breast, lung, lower limb, upper limb, head andneck, vulva, and vagina can be involved. We report the first case of myoepithelial carcinoma arising in theposterior mediastinum of a 51 year-old male who presented with a mediastinal mass and subsequentlyunderwent tumor debulking surgery. Grossly, the specimen consisted of multiple tan–gray firm fragmentsof tissue with an overall measurement of 7.0 cm in greatest dimension. Histologic examination revealedan ill-defined, infiltrative lesion with a biphasic cell population. The tumor cells were diffusely positivefor epithelial and myoepithelial markers, confirming the above diagnosis. Recognition of this entity at anuncommon site may present a diagnostic challenge due to its morphologic heterogeneity and the differen-tial diagnosis includes benign and malignant tumors, which could lead to over or under-treatment,respectively.

ayne State University,35 1973.tah).

ss article under the CC

Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

2.1. Case report

1. Introduction

Myoepithelial carcinoma (MC), the malignant counter part ofmyoepithelioma, was first described by Stromeyer et al. in 1975 [1]and was included in the World Health Organization (WHO) classifi-cation of salivary gland neoplasms as a distinct clinicopathologicalentity, in 1991 [2]. MC arises from myoepithelial cells and showsboth epithelial and smoothmuscle cell characteristics but lack ductaldifferentiation [3]. They comprise less than 2% of all salivary glandcarcinomas, with the parotid gland being the most common site af-fected [4]. However, uncommon localizations have been previouslyreported such as the breast, palate, maxilla, nasophayrnx, liver,vulva, and vagina [1,3,5–8]. Morphologic heterogeneity is a typicalhistologic feature, with tumors displaying a mixture of differentcell types and growth patterns. The clinical behavior of MC tends tobe relatively aggressive, with a high rate of distant metastasis [9,10].

540 East

BY-NC-ND lice

To the best of our knowledge, this is the first case of primaryMC involving the posterior mediastinum. We describe the mor-phologic and immunohistochemical findings and discuss the dif-ferential diagnosis of this rare entity.

2. Material and methods

A 51 year-old male presented to the Urology clinic complaining of“bloody urine” for five months. As part of the workup, a computedtopographic scan (CT scan) of the abdomen and pelvis showed a sim-ple renal cyst and an incidental left atrial mass measuring 5.0 cm ingreatest dimension (on higher CT cuts). Subsequently, CT scan ofthe chest was performed which suggested a left atrial myxoma(Fig. 1). At that time, the patient had no symptoms and was lost tofollow up. Five years later, he presented with shortness of breathand palpitations. Electrocardiogram (EKG) revealed atrial flutter.Cardiac catheterization showed triple vessel coronary artery diseaseand transesophageal echo (TEE) showed a significant increase in the

nse (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Fig. 1. Computed Tomography of the chest showing heterogeneous non-enhancing mass extending superiorly to the inferior surface of the right main pulmonary artery.

24 E. Abdulfatah et al. / Human Pathology: Case Reports 5 (2016) 23–28

size of the left intra-atrial mass which was 10.0 cm in the greatest di-mension, compressing the superior vena cava and right main pulmo-nary artery. Based on these findings, a decision was made toperform coronary artery bypass graft (CABG) and tumor debulkingsurgery.

Intraoperatively, the mass appeared to be mediastinal in origin(rather than atrial), coursing behind the left atrium, posterior partof the ascending aorta and involving the wall of the right and leftatrium.

Table 1Panel of antibodies used in this study

Antibody Source/Clone

Cytokeratin DAKO/AE1AE3CK5/6 DAKO/DC10Calponin DAKO/CALPP63 DAKO/4A4SMA DAKO/1A4GFAP DAKO/6F2S100 DAKO/polyclonalCalretinin DAKO/CalretVimentin DAKO/Vim3B4Caldesmon DAKO/h-CDCD99 DAKO/12E7Bcl-2 DAKO/124CD34 ImmunotechDesmin DAKO/D33WT-1 DAKO/6 F-H2

2.2. Histology and Immunohistochemistry

Tissue sections were fixed in 10% neutral buffered formalin, em-bedded in paraffin, sectioned at 4-μm thickness, and stained with he-matoxylin and eosin. The immunohistochemistry was performedand evaluated at Wayne State University (Detroit Medical Center,Detroit, MI), where the Ventana BenchMark Autostainer (VentanaMedical System, Tucson, Arizona) was used on 4-μm thickformalin-fixed and deparaffinized sections with the following

Dilution Result

1:500 Positive1:200 Positive1:600 Positive1:300 Positive1:400 Positive1:400 Positive1:1000 NegativeReady-to-use Negative1:400 Negative1:500 NegativeReady-to-use Positive (cytoplasmic)Ready-to-use Negative1:100 Negative1:100 Negative1:200 Negative

Fig. 2. (A)Dual color break apart DNA probe showingnegative results for SS18 gene rearrangement. (B) The tumor consists of sheets and fascicles of spindle and epithelioid looking cells invarying proportions within a hyalinized stroma (100×). (C) Clear and epithelioid looking cells with scant amount of eosinophilic cytoplasm and monotonous, hyperchromatic nuclei(400×). (D) Closely packed fascicles of spindle cells with oval hyperchromatic nuclei (200×).

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markers: AE1/AE3, CK5/6, calponin, p63, smooth muscle actin(SMA), GFAP, WT1, calretinin, vimentin, caldesmon, CD99, bcl-2,CD34, S-100 and desmin (Table 1).

2.3. Cytogenetic studies

Tumor cellsweremicro-dissected from tissue block. Fluorescent in-situhybridization (FISH) analysis of the SS18 gene rearrangement was per-formed at Detroit Medical Center University Laboratories (Detroit, MI)using the LSI SS18/18q11.2 dual color break apart DNA probe (Vysis Inc.).

3. Results

3.1. Gross and microscopy

Grossly, the specimen consisted of tan–gray, firm fragments oftissue with an overall measurement of 7.0 × 7.0 × 3.0 cm. Histo-logical examination revealed an ill-defined infiltrative tumor,with a biphasic cell population, spindle and epithelioid, in vary-ing proportions, which blended with each other in a hyalinizedand occasionally myxoid stroma (Fig. 2B). The predominant spin-dle cell areas consisted of solid sheets and fascicles of closelyspaced cells with scant amount of eosinophilic cytoplasm and

monotonous, hyperchromatic, ovoid nuclei (Fig. 2C-D). In otherareas, few pseudoglandular structures which consisted mainlyof epitheloid cells with eosinophilic cytoplasm and round nucleiwere identified. Nuclear atypia as well as mitosis was minimaland no areas of necrosis were appreciated.

3.2. Immunohistochemistry

Based on thesemorphologic features, the differential diagnosis of bi-phasic tumors included synovial sarcoma, biphasic mesothelioma,myoepithelial carcinoma, thymoma and malignant peripheral nervesheath tumor (MPNST). To further characterize the lesion, a panel of im-munohistochemical stains was performed. The tumor cells were dif-fusely positive for epithelial markers including AE1/AE3 and CK5/6and myoepithelial markers including calponin, p63, smooth muscleactin (SMA) and GFAP (Fig. 3). In addition, WT1, calretinin, vimentin,caldesmon, CD99 (cytoplasmic), bcl-2, CD34, S-100 and desminimmunostains were performed and were negative (Table 1).

3.3. Cytogenetics studies

Due to the high clinical and morphological suspicion of synovialsarcoma, fluorescent in-situ hybridization (FISH) analysis of the

Fig. 3. Immunohistochemical staining of tumor cells showed diffuse positivity for (A) AE1/AE3, (B) CK5/6, (C) SMA, and (D) P63.

26 E. Abdulfatah et al. / Human Pathology: Case Reports 5 (2016) 23–28

SS18 gene rearrangement was performed and was found to be nega-tive, making this diagnosis less likely (Fig. 2).

Based on themorphology, imunophenotype and cytogenetic results,the diagnosis of myoepithelial carcinoma/malignant myoepitheliomawas rendered. Due to the presence of residual tumor following surgery,adjuvant radiation therapy was recommended. The patient passedaway four months later due to a subarachnoid hemorrhage, not relatedto MC.

4. Discussion

Myoepithelial tumors are rare and distinguishing benign frommalignant can be a major challenge. Although MC was described as anentity more than 40 years ago [1], it remains under recognized, and itsdiagnostic criteria as well as prognostic factors are still notwell delineated. Given its morphologic heterogeneity, MC maybe misdiagnosed, particularly when involving unusual sites.For definitive diagnosis of this tumor, histopathological charac-teristics and immunohistochemical profile must be utilized to-gether [8].

Histologically, the most characteristic feature of MC is itsmultinodular architecture and its zonal cellular arrangement.These tumors typically display solid, trabecular and/or reticular

patterns, with a variably prominent myxoid and/or hyalinizedstroma. The myxoid stroma is predominantly composed of chon-droitin sulfate proteoglycans, while the eosinophilic hyaline com-ponent represents basement membrane-related elements [11].Additionally, different cell types including spindle shaped, epi-thelioid, plasmacytoid and clear cells are often seen within thesame tumor. Focal luminal formations can be observed; however,true ducts are almost never identified, which are required to de-fine epithelial–myoepithelial carcinoma. Various forms of meta-plasia, including squamous, chondroid and sebaceousdifferentiation may be seen, with squamous metaplasia beingthe most common [12]. In our case, the tumor consisted ofsolid sheets of spindle and epithelioid cells, present within ahyalinized and occasionally myxoid stroma. Few pseudoglandularstructures were seen, but no true ducts were identified. More-over, none of the previously reported metaplasia was noted.

Determination of myoepithelial differentiation on the solebasis of morphology may be difficult. In such cases, the use ofimmunohistochemical stains might be helpful. Given that neo-plastic myoepithelial cells may vary in their immunohistochemi-cal protein expression profiles, the WHO has proposed thatreactivity for a cytokeratin and at least one of the myoepithelialmarkers, including S100, SMA, calponin, GFAP and p63, is re-quired to definitively diagnose MC [13]. Kane and Bagwan [14],reported S100 positivity in the majority (95%) of their reportedseries. Our case showed strong reactivity of the tumor cells

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with AE1/AE3, CK5/6 and myoepithelial markers includingcalponin, p63, smooth muscle actin (SMA) and GFAP, thus fulfill-ing the WHO criteria of a myoepithelial tumor. However, incontrast to the previous studies, S100 was negative.

The histologic differential diagnosis of MC includes biphasictumors such as synovial sarcoma, biphasic mesothelioma, MPNSTand thymoma. Synovial sarcoma, particularly the biphasic form,may show a marked resemblance to MC. The tumor consists of fasci-cles of spindle cells admixed with numerous glandular structureslined by cuboidal to columnar epithelium, set in a background ofvariably collagenous stroma [15]. Immunohistochemically, in additionto the positive staining in the epithelial component, the spindle cellelement shows at least focal positivity to EMA and cytokeratin.CD99 shows membranous staining while bcl-2 shows cytoplasmicstaining in either or both components. Myoepithelial markersare negative. Furthermore, 90% of synovial sarcomas show acharacteristic t(X;18)(p11.2;q11.2) [16]. While our case did exhibitimmunoreactivity to cytokeratin, bcl-2 and CD99 (cytoplasmic,rather than membranous), the presence of strong expression ofmore than one myoepithelial marker and the lack of characteristiccytogenetic abnormality, made this diagnosis less likely.

Biphasic mesothelioma should also be considered in the dif-ferential diagnosis of MC, particularly in the mediastinum.These tumors present with a diffuse growth pattern usually in-volving the visceral and parietal pleura and are characterizedby a combination of epithelioid and sarcomatoid elements invarying proportions. Similar to MC, the tumor cells are positiveto cytokeratin (AE1/AE3) and CK5/6; however, they lack immu-noreactivity to myoepithelial markers. In addition, specificmarkers of mesothelial origin such as calretinin and WT1 areexpressed in the majority of mesotheliomas [17], which help indifferentiating them from MC.

Thymomas must be taken into account due to the mediastinalorigin of the tumor; however these tumors involve the anteriorrather than the posterior mediastinum. Microscopically these tu-mors are generally encapsulated, with thick fibrous septa divid-ing them into lobules. Type A thymoma consists of fascicles ofspindle shaped epithelial cells with focal areas of glandular dif-ferentiation, mimicking MC. In addition, scant amount of T cellsis present in the background [18]. Immunohistochemically, thespindled epithelial cells stain positive for cytokeratin and EMA,and the T-cell population exhibits a cortical thymocyte pheno-type of TdT+, CD1a, and CD99 [19]. In our case, due to the in-filtrative growth pattern, posterior mediastinal involvement,lack of co-existent lymphocytic component, and the characteristicimmunoprofile, thymoma was ruled out.

MPNST, the main differential diagnosis of synovial sarcoma,shows epithelial (glandular) differentiation on rare occasionsand may require distinction from MC. These tumors typicallyhave a spindle-celled fascicular appearance and perivascularwhorling of tumor cells. Immunohistochemically, 50% of thecases of MPNST are S-100 positive, whereas 20%–30% are GFAPpositive. Rare cases exhibit EMA positivity; however, none ofthem show myoepithelial differentiation which is essential indifferentiating it from MC [20].

The clinical behavior of MC tends to be relatively aggressive.In a recent study by Kong et al. [10], approximately one thirdof the patients diagnosed with MC of salivary glands developeddistant metastasis, with lung being the most common site. Amajor issue regarding MC has been the assessment of tumorgrading. Previous studies have shown no clear correlationbetween different histologic features of MC and its clinical behav-ior [14]. Savera et al. [12] classified MC as low grade whenthe tumors displayed relatively uniform small sized nuclei andas high grade when they showed marked cytologic atypia,nuclear pleomorphism and high proliferative activity. Moreover,

Kong et al. showed that the presence of tumor necrosiscorrelated significantly with a worse clinical behavior and there-fore suggested defining high grade MC on the basis of tumor ne-crosis. Due to the rarity of MC, particularly in unusual sites,the outcome and optimum management of these tumorsremain uncertain. Case studies have shown that chemotherapyhas a limited role and that surgical excision remains the main-stay of treatment. Pertaining to our case, the tumor was consid-ered unresectable. The patient underwent a suboptimal tumordebulking surgery. Postoperative radiotherapy was initiated withsymptomatic improvement; however, the patient passed awayfour months after surgery due to subarachnoid hemorrhage, notrelated to MC.

In summary, we report the first case of MC arising in the pos-terior mediastinum. The morphologic heterogeneity of these tu-mors requires supportive immunohistochemical stains to aiddiagnosis, especially for tumors in unusual sites. Greater aware-ness of the occurrence of MC in the posterior mediastinummay lead to increased recognition of this rare entity, with subse-quent improved understanding of the optimum clinical manage-ment and outcomes.

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