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Annals of Diagnostic Pathology 16 (2012) 292–297

Epithelial-myoepithelial carcinoma of the lacrimal gland: a rare case☆

Geetika Singh, MDa, Mehar Chand Sharma, MDa,⁎, Shipra Agarwal, MDa,G. Lakshmi Prasad, MBBSb, Shashwat Mishra, Mchb, Man Mohan Singh, Mchb,

Ajay Garg, MDc, Vaishali Suri, MDa, Chitra Sarkar, MDa

aDepartment of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, IndiabDepartment of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India

cDepartment of Neuroradiology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India

Abstract Epithelial-myoepithelial carcinoma is a rare tumor of the salivary gland constituting only 1% of all

☆ This research rthe public, commercia

⁎ Corresponding aE-mail address: sh

1092-9134/$ – see frodoi:10.1016/j.anndiag

tumors. It is a low-grade malignancy characterized by a classical biphasic morphology and immuno-phenotype. In the lacrimal gland, it is extremely rare with only 3 cases reported in the English medicalliterature. We describe the fourth case of epithelial-myoepithelial carcinoma, the first case in a femalepatient, and review the available literature.

© 2012 Elsevier Inc. All rights reserved.

Keywords: Epithelial myoepithelial carcinoma; Histopathology; Immunohistochemistry; Lacrimal gland; Salivary gland

1. Introduction

Epithelial-myoepithelial carcinoma (EMC) is an uncom-mon tumor purportedly of intercalated duct origin [1] andclassically described in the salivary glands and most com-monly in the parotid gland. Recently, although extremelyrare, it has also been reported in the lacrimal gland [2-4].Epithelial tumors constitute only 20% of lacrimal glandlesions, and their morphology is in close parallel to that ofthe salivary gland [5]. Based on similar morphology andtumor behavior, recent literature proposes the adoption of theupdated classification of salivary gland tumors for thepurpose of the lacrimal gland as well [6]. In the salivarygland, EMC is known to behave as a low-grade malignancywith 5-year survival rates of approximately 94% andrecurrences are reported even decades after initial surgery[7]. The behavior of lacrimal gland tumors is yet to bedetermined. Herein, we report an EMC of the lacrimal glandin a 62-year-old woman and review the available literatureon this very rare tumor.

eceived no specific grant from any funding agency inl, or not-for-profit sectors.uthor. Tel.: +91 11 26593371; fax: +91 11 26588663.armamehar@yahoo.co.in (M.C. Sharma).

nt matter © 2012 Elsevier Inc. All rights reserved.path.2011.02.004

2. Case report

This 62-year-old woman presented with history of aslowly enlarging soft tissue swelling in the right orbit of4 years' duration with rapid progression for the last 6months. There was no associated pain. Examination showednonaxial proptosis with displacement of the globe inferiorly.The extraocular movements were preserved, and the visionin the involved eye was unaffected (6/6 with pinhole correc-tion). On palpation, a firm, rubbery, nontender mass waspalpable through the upper eyelid. No significant comorbid-ity was present. Computed tomography scan showed aheterogenously enhancing lobulated mass in the region of theright lacrimal gland measuring 2.7 × 2.4 × 2 cm displacingthe eyeball inferomedially. Expansion and thinning of theoverlying bone of the lacrimal fossa were noted (Fig. 1).Magnetic resonance imaging showed that the tumor washypointense on T1-weighted images and heterogeneouslyhyperintense on T2-weighted images (Fig. 2).

Based on clinical and radiologic findings, diagnosis of alacrimal gland tumor was entertained and complete excisionof the tumor was done through right fronto-orbital cranio-tomy. After elevation of the bone flap, the tumor was feltthrough the periorbita with an area of bony erosion andintracranial extension without dural invasion. The periorbitawas incised, and the tumor was seen as an extraconal grayish,globular firm mass with a well-defined tumor capsule. The

Fig. 1. Contrast-enhanced computed tomography scan shows a well-defined soft tissue density mass lesion (arrow) in the right lacrimal gland region causingerosion of overlying bone (A and B).

293G. Singh et al. / Annals of Diagnostic Pathology 16 (2012) 292–297

tumor was enucleated, and the tumor capsule was sharplydissected away from the orbital contents. Gross total excisionof the tumor was achieved, and the postoperative coursewas uneventful.

2.1. Pathologic examination

Grossly, the tumor measured 4 × 2 × 2 cm and wasmultinodular and circumscribed with adherent surroundingadipose tissue at one end. Its cut surface was glistening whiteto tan and firm to feel (Fig. 3). No areas of hemorrhage ornecrosis were seen. The tumor tissue was fixed in 10%neutral buffered formalin, routinely processed, and paraffinembedded. Five-micrometer-thick sections were cut forhematoxylin and eosin staining and immunohistochemistry.

2.2. Microscopic examination

The whole tumor was processed in its entirety, andmultiple sections were examined. They showed a tumor witha multinodular growth pattern invading the surrounding softtissue in broad fronts (Fig. 4A). The tumor nodules wereseparated by dense sclerotic stroma (Fig. 4B). The classical“biphasic” architecture was identifiable in the form of tubularstructures lined by ductal epithelial cells and surrounded byone or many layers of clear cells, which were further enve-loped by a well-defined basement membrane (Fig. 4C). Theductal epithelial cells were cuboidal with round nuclei andmoderate amounts of eosinophilic cytoplasm resembling

Fig. 2. The tumor is hypointense on T1-weighted (A) and heterogeneously hypgadolinium administration, the lesion shows intense enhancement (C).

intercalated duct cells. The clear cells were large andpolygonal with abundant clear cytoplasm. In the predomi-nant part (approximately 85% of tumor area), these tubulesgave way to cords and sheets of oval to stellate cells lying ina loose myxoid to hyalinized background (Fig. 4D-E). Smallfoci of stromal calcification were also noted. These cellswere moderately pleomorphic and had vesicular nuclei,conspicuous nucleoli, and moderate amounts of cytoplasm(Fig. 4F). Some of the cells had a “plasmacytoid appearance”with eccentrically placed nuclei and abundant denseeosinophilic cytoplasm (Fig. 4G). Mitotic figures were fre-quently seen in these more solid areas with a mitotic rateranging from 2 to 8 per 10 high-power fields. Highermitotic rates were noted at the infiltrating edge of the tumor(Fig. 4H). In contrast, only an occasional mitotic figure wasidentified in the ductal epithelial tubules. Prominent peri-neural invasion was identified in the tumor; however, notumor necrosis or angiolymphatic invasion was seen(Fig. 4I). The tumor was reaching up to the margins of thespecimen, and on extensive sampling, no component ofresidual pleomorphic adenoma was seen. No preservedlacrimal gland parenchyma was noted.

The ductal epithelial cells were found to be stronglyreactive for pan-cytokeratin AE1/AE3 (dilution, 1:200;DAKO, Glostrup, Denmark) and c-kit/CD117 (dilution,1:500; DAKO) but negative for S100 (dilution, 1:1000;DAKO) and smooth muscle actin (dilution, 1:50; DAKO),whereas the clear, spindle, and plasmacytoid myoepithelial

ointense on T2-weighted (B) coronal magnetic resonance imaging. After

Fig. 3. Gross photograph showing a multinodular and circumscribed tumorwith adherent fat. Cut surface is grayish white to tan.

294 G. Singh et al. / Annals of Diagnostic Pathology 16 (2012) 292–297

cell component showed strong nuclear and cytoplasmicreactivity for S100, patchy cytoplasmic reactivity for smoothmuscle actin and BCL2 (dilution, 1:50; Neomarker,Fremont, CA), and weak cytoplasmic reactivity for pan-cytokeratin. Both epithelial and myoepithelial cells showedcytoplasmic reactivity for MIC2 (dilution, 1:200; DAKO)(with some membrane accentuation) and were negative forglial fibrillary acidic protein (GFAP; dilution, 1:1000;DAKO) and p53 (dilution, 1:1000; Santa Cruz Biotechnol-ogy Inc., Paso Robles, CA). The MIB-1 labeling index(dilution, 1:200; DAKO) was approximately 11% in themyoepithelial areas, whereas only occasional MIB-labelednuclei (b1%) were identified in the ductal epithelial cells.

Based on the biphasic epithelial-myoepithelial morphol-ogy and immunohistochemical profile of the tumor, a finaldiagnosis of epithelial-myoepithelial carcinoma was made(Fig. 5).

3. Discussion

In a survey of 1264 cases of orbital space–occupyinglesions at a referral ocular oncology service over a period of30 years, Shields et al [5] observed that lacrimal glandtumors represent almost 9% of the space occupying orbitallesions, with epithelial lesions accounting for 20% of thetotal and inflammatory and lymphatic lesions for theremaining 80%. Among the epithelial lesions, 55% werebenign and 45% were malignant with increasing incidenceof malignancy in the elderly population. Among malignantlacrimal gland tumors, adenoid cystic carcinoma (ACC)was the most common (66%), followed by carcinoma ex

pleomorphic adenoma (18%), primary adenocarcinoma(9%), and mucoepidermoid carcinoma (3%).

The observation of similar morphology and clinicalcharacteristics of salivary gland and lacrimal gland tumorshas led to the adoption of salivary gland neoplasiaclassification in lacrimal gland tumors. The first of suchclassifications appeared in the 2006 Armed Forces Instituteof Pathology monograph on lacrimal tumors and was basedon the 1992 World Health Organization classification ofsalivary gland tumors [6]. Weis et al [7], in their retros-pective multicenter study of 118 cases of lacrimal epithelialneoplasia, concluded that the use of the more histologicallydiverse classification of salivary gland tumors can be suc-cessfully applied to the epithelial lacrimal gland neoplasms.This expanded classification system led to reclassification of14% of their cases. They noted that even the rare salivarygland neoplasms have been reported to occur in the lacrimalgland as well, including ductal carcinoma, acinic cell carci-noma, primary squamous cell carcinoma, mucoepidermoidcarcinoma, oncocytic carcinoma, polymorphous low-gradeadenocarcinoma, myoepithelial carcinoma, lymphoepithelialcarcinoma, etc.

Epithelial-myoepithelial carcinoma is a rare yet well-described entity in salivary gland tumor pathology consti-tuting 1% of all tumors [8]. It is a low-grade malignancycharacterized by a classical biphasic morphology andimmunophenotype. It is postulated to arise from the inter-calated ducts of the salivary glands evidenced by the tubulargrowth pattern of this tumor and background intercalatedduct hyperplasia reported in some cases of EMC [1].Because the lacrimal gland also has similar histologyincluding intercalated ducts, it is not surprising that thetumor is capable of arising in the lacrimal gland as well.However, to date, there are only 3 such reports of this tumorinvolving the lacrimal gland (Table 1).

The first report was in 1994 of a 63-year-old man whopresented with slowly progressive, painless proptosis for8 years with sudden increase in size over 2 months, possiblyheralding malignant change. Histopathology of the tumorshowed features classical for EMC with areas of benignmixed tumor at the periphery. The authors proposed that themalignant tumor had arisen from the preexisting pleomor-phic adenoma [2].

The other 2 reports were of primary tumors without anyevidence of preexisting neoplasm (de novo) in the lacrimalgland. The case reported by Chan et al [3] was about an 80-year-old man with a subcutaneous mass in the left eyelid of 9months' duration. Similarly, the case published by Wiwat-wongwana et al [4] was about an 86-year-old man whoresented with diplopia for 6 months. The case under dis-cussion is the first case reported in a female patient. Theswelling was present for 4 years and rapidly increased in sizeover 6 months, possibly because of malignant change in aprevious benign tumor; however, we did not find any histo-pathologic evidence of the same on extensive sampling ofthe tumor.

Fig. 4. Microphotographs showing a tumor with a multinodular growth pattern invading the surrounding soft tissue in broad fronts and the tumor nodulesseparated by dense sclerotic stroma (A and B, high power). The classical “biphasic” architecture in the form of tubular structures lined by ductal epithelial cellssurrounded by a layer of clear myoepithelial cells further enveloped by a well-defined basement membrane is noted at the periphery of nodules (C, mediumpower). In large areas, these tubules give way to cords and sheets of oval to stellate cells lying in a loose myxoid background (D and E, low power). Myoepithelialcells showing oval to stellate differentiation displaying moderate pleomorphism forming cords and small nests (F, high power), at places with a “plasmacytoid”appearance (G, high power). Frequent mitoses were identified in the myoepithelial nodules along with prominent perineural invasion (H and I, high power).

295G. Singh et al. / Annals of Diagnostic Pathology 16 (2012) 292–297

In all these cases, the morphology of the tumorrecapitulated that which is noted in the salivary glands,that is, a biphasic tumor composed of glands lined by 2 celltypes, inner epithelial and outer myoepithelial, along withsolid areas composed of nests and sheets of oval to spindledmyoepithelial cells. Seethala et al [8] in their study of61 cases of EMC of the salivary gland and upper aero-digestive tract identified four histologic predictors of recur-rence: (a) margin status, (b) angiolymphatic invasion, (c)tumor necrosis, and (d) myoepithelial anaplasia. Fonseca andSoares [9] reported that tumors with more than 20% of cellsshowing nuclear atypia are associated with a poorerprognosis. In the present case, positive margins andmoderate myoepithelial atypia in the form of moderatecellular pleomorphism and mitoses were noted. No tumornecrosis or vascular invasion was seen; however, prominentperineural invasion was identified.

Seethala et al [8] also identified different histologicvariants of EMC including dedifferentiated EMC, oncocyticEMC, EMC ex pleomorphic adenoma, double clear EMC,and EMC with myoepithelial anaplasia. None of the cases oflacrimal gland EMC reported showed any specific histologicfeature to suggest a variant of EMC. Although myoepithelialanaplasia was noted in two of the three reported cases [3,4],it was not severe and therefore did not represent the variantof “EMC with myoepithelial anaplasia.”

Of the myoepithelial markers, p63 has been found to bemost sensitive and specific followed by S100, smoothmuscle actin, and vimentin. However, S100 protein mayshow significant staining of the epithelial component as well.c-kit (CD117) was positive in the epithelial component in69.2% of cases, bcl2 in both epithelial and myoepithelialcomponents in 66.7% of cases, but GFAP was negative. Themean Ki67 index was 16.9% in the series by Seethala et al

Fig. 5. Immunohistochemical staining showing immunopositivity for pan-cytokeratin and CD117 (c-kit) in the ductal epithelial cells (A and B, medium power)and S100 immunopositivity (nuclear and cytoplasmic reactivity) in the myoepithelial cells (C, low power). Myoepithelial cells showing immunopositivity forsmooth muscle actin (D, medium power) and bcl2 (E, high power). Both epithelial and myoepithelial cells are immunopositive for MIC2 (F, high power).

296 G. Singh et al. / Annals of Diagnostic Pathology 16 (2012) 292–297

[8]. In our case, a MIB-1 labeling index of 11% was noted inthe myoepithelial areas.

The main histologic differential diagnosis is from ACCwhich also has a dual epithelial-myoepithelial phenotype;

Table 1Epithelial-myoepithelial carcinoma of the lacrimal gland in the English medical li

Author (y) Age/sex

Clinical features Computed tomography Histopathol

Marginstatus

Aninv

Present case(2010)

62/F Right orbitalswelling × 4 y,rapid progression× 6 mo

27 × 24 × 20-mmheterogenouslyenhancing lobulatedmass with thinningof the overlying bone

+ −

Wiwatwongwanaet al [4]

86/M Diplopia × 6 mo 25 × 18-mm moderatelyhomogenoushyperattenuating masswith scalloping of thelacrimal fossa

+ −

Chan et al [3] 80/M Left orbitalpalpebralmass × 19 mo

24 × 15 × 18-mm mildlyenhancing soft tissuemass. No bony erosion

+ −

Ostrowskiet al [2]

63/M Painlessproptosis × 8 ywith suddenincrease insize × 2 mo

25 × 15-mm oblongmass with sharplymarginated irregularborders and focalcalcification. Nobony erosion

+ −

M indicates male; F, female; RT, radiotherapy.

however, EMCs have presence of a clear cell abluminalcomponent and tend to form branching glandular structuresrather than cribriform areas as in ACC. In addition, EMCslack basophilic mucosubstance in the microcystic spaces and

terature

ogy Treatment Follow-up

giolymphaticasion

Tumornecrosis

Myo-epithelialanaplasia

− + Right fronto-orbitalcraniotomy andgross total resectionfollowed by RT

No recurrenceor metastasesat 3 mo

+ + Lateral orbitotomy,tumor excisionwith bone followedby RT

Died after15 mo, norecurrence

− + Lateral orbitotomyand tumor excision(RT refused bypatient)

No recurrenceor metastasesat 2 y

− − Orbital exenteration No recurrenceor metastasesat 2 1/2 y

297G. Singh et al. / Annals of Diagnostic Pathology 16 (2012) 292–297

have a relatively lower Ki67 index. Differentiation frompleomorphic adenoma and its malignant counterpart is basedon the absence of stromal elements, classically, the chondro-myxoid stroma. In addition, GFAP reactivity is not noted inthe myoepithelial component of EMCs [10].

Epithelial-myoepithelial carcinomas of the salivary glandoccur most commonly in the parotid gland in the sixth to theseventh decade and show a female predominance. Survivalrates at 5 and 10 years were 93.5% and 81.8%, respectively,in the study by Seethala et al [8]. Recurrences were morecommon than death caused by the tumor, with recurrencerates of 36.3%, which may occur decades after initial sur-gery. Interestingly, postoperative radiotherapy did notsignificantly impact disease-free survival; however, it isroutinely recommended in case of positive margin status.The behavior of EMC of the lacrimal gland is difficult tocharacterize owing to its rarity. The longest recurrence-freefollow-up period of 2 1/2 years was reported by Ostrowskiet al [2]. The patient under discussion is recurrence free at3 months and scheduled to receive radiotherapy.

We report the fourth case of epithelial-myoepithelialcarcinoma of the lacrimal gland and the first case in a femalepatient in the English medical literature. Even in the lacrimalgland, it appears to be a low-grade malignancy that canappear de novo or from malignant transformation of a benigntumor and would require close postsurgical follow-up. It isimportant for the histopathologist to recognize such rareepithelial tumors of the lacrimal gland and not to misdiag-nose them as the more common ACC and pleomorphic

adenoma. An extensive immunohistochemical panel can behelpful in this regard.

References

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[2] Ostrowski ML, Font RL, Halpern J, et al. Clear cell epithelial-myoepithelial carcinoma arising in pleomorphic adenoma of thelacrimal gland. Ophthalmology 1994;101:925-30.

[3] Chan WM, Liu DT, Lam LY, et al. Primary epithelial-myoepithelialcarcinoma of the lacrimal gland. Arch Ophthalmol 2004;122:1714-7.

[4] Wiwatwongwana D, Berean KW, Dolman PJ, et al. Unusual carci-nomas of the lacrimal gland: epithelial-myoepithelial carcinoma andmyoepithelial carcinoma. Arch Ophthalmol 2009;127:1054-6.

[5] Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients withorbital tumors and simulating lesions: the 2002 Montgomery lecture:Part 1. Ophthalmology 2002;111:997-1008.

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[9] Fonseca I, Soares J. Epithelial-myoepithelial carcinomas. Am J ClinPathol 1994;101:242.

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