Metastatic renal cell carcinoma to the oral cavity and clear cellmucoepidermoid carcinoma: comparative clinicopathologicand immunohistochemical studyFábio Ramôa Pires, DDS, PhD,a Rebeca Souza Azevedo, DDS, MSc,b Giuseppe Ficarra, MD,c

Abel Silveira Cardoso, DDS, MSD,d Roman Carlos, DDS,e Luiz Paulo Kowalski, MD, PhD,f

and Oslei Paes de Almeida, DDS, PhD,g Rio de Janeiro, Piracicaba, and São Paulo, Brazil;Florence, Italy; and Guatemala City, GuatemalaSTATE UNIVERSITY OF RIO DE JANEIRO, STATE UNIVERSITY OF CAMPINAS, UNIVERSITY OFFLORENCE, FEDERAL UNIVERSITY OF RIO DE JANEIRO, CENTRO CLINICO DE CABEZA Y CUELLO, ANDA. C. CAMARGO CANCER HOSPITAL

Background. Metastatic clear cell renal cell carcinoma (CCRCC) should be considered in differential diagnosis ofintraoral clear cell tumors, including mucoepidermoid carcinoma (MEC).Objective and study design. We compared the clinical, histologic, histochemical, and immunohistochemicalcharacteristics of 9 oral metastatic CCRCCs and 8 intraoral clear cell MECs.Results. Oral metastatic CCRCC affected salivary-gland containing tissues in 7 cases (78%). Microscopically, oralmetastasis revealed a proliferation of neoplastic clear cells arranged in an alveolar pattern with central blood vessels,features that were not seen in any intraoral clear cell MEC. Mucicarmine staining was positive only in clear cell MEC.Immunohistochemistry showed similarities in cytokeratin expression; vimentin and CD10 were expressed in all oralmetastatic CCRCCs but in only 1 clear cell MEC each.Conclusions. Besides clinical history, the alveolar pattern, vessel distribution, absence of mucicarmine staining, andvimentin and CD10 immunoexpression are useful in histologic differential diagnosis of CCRCC and clear cell MEC. (Oral

Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:e22-e27)

Salivary gland tumors composed of a representativecomponent of clear cells, such as mucoepidermoid car-cinomas (MECs), may present diagnostic difficulties tooral pathologists, especially when dealing with inci-sional biopsies.1-3 Characteristic areas of the tumor areusually necessary for diagnosis, but they are not alwayspresent on microscopic evaluation. Most clear cell sal-

Supported by CNPQ, FAPERJ, and FAPESP (Brazil).aProfessor, Oral Pathology, School of Dentistry, State University ofRio de Janeiro.bPhD student, Oral Pathology, Piracicaba Dental School, State Uni-versity of Campinas.cDirector, Reference Center for the Study of Oral Diseases, Univer-sity of Florence.dProfessor, Stomatology, School of Dentistry, Federal University ofRio de Janeiro.eDirector, Division of Pathology, Centro Clinico de Cabeza y Cuello,Guatemala City, Guatemala.fHead, Department of Head and Neck Surgery and Otorhinolaryngol-ogy, A. C. Camargo Cancer Hospital, São Paulo, Brazil.gProfessor, Oral Pathology, Piracicaba Dental School, State Univer-sity of Campinas.Received for publication Aug 30, 2009; returned for revision Nov 1,2009; accepted for publication Dec 8, 2009.1079-2104/$ - see front matter© 2010 Mosby, Inc. All rights reserved.

doi:10.1016/j.tripleo.2009.12.006

e22

ivary gland tumors are malignant, reinforcing the im-portance of proper diagnosis for suitable treatment.

In addition to salivary gland tumors, differential di-agnosis of clear cell tumors must include clear cellmetastatic carcinomas, which can involve the majorsalivary glands and the mouth. Clear cell renal cellcarcinoma (CCRCC) is the most common metastaticclear cell tumor of the oral cavity, commonly involvingminor salivary gland–containing tissues, such as thetongue, palate, buccal mucosa, and floor of mouth.4-6

CCRCC can also metastasize to the major salivaryglands, particularly the parotids, and to the jaw bones,particularly the mandible.7,8

There are case reports on metastatic clear cell tumorsto the oral cavity, but very few papers have emphasizedthe differential diagnosis with clear cell salivary glandtumors,9,10 probably owing to the rarity of both lesions.The aim of the present study was to compare theclinical, microscopic, and immunohistochemical fea-tures of metastatic CCRCC to the oral cavity and in-traoral minor salivary gland MEC, the most commonclear cell–containing salivary gland tumor.

MATERIAL AND METHODSNine cases of metastatic CCRCC to the oral cavity

and maxillary bones and 8 cases of intraoral MEC with

OOOOEVolume 109, Number 4 Ramôa Pires et al. e23

an abundant clear cell component were retrieved fromthe files of 5 Institutions: Oral Pathology, State Uni-versity of Rio de Janeiro; Stomatology, Federal Uni-versity of Rio de Janeiro; Reference Center for OralDiseases, University of Florence; Center of Oral Med-icine (Guatemala City); and A. C. Camargo CancerHospital (São Paulo). Sociodemographic, clinical, di-agnostic, medical, laboratory, and outcome findingswere obtained from the laboratory registries and med-ical charts.

Immunohistochemical reactions against cytokeratins(CK), vimentin, and CD10 were performed using stan-dard protocols (Table I). In brief, deparaffinization ofthe histologic slides was followed by hydration andbathing in 10% hydrogen peroxide for 30 minutes forinhibition of endogenous peroxidase. Antigen retrievalwas performed according to the instructions for eachantibody and included citrate buffer microwave andenzyme digestions. The slides were incubated withprimary and secondary antibodies, and diaminobenzi-dine was used as chromogen, followed by hematoxylinstaining. Expression of each marker was evaluated onclear cells of CCRCC and MEC, considering each caseas negative (absence of or �10% positive cells) orpositive (�10% positive cells).

RESULTSThe 9 patients (5 male and 4 female) with CCRCC

had a mean age of 61 years, ranging from 43 to 80years. All patients complained of a swelling on theaffected area. In 4 cases, the mucosal surface showednormal color, and in the other 5 it was erythematous orviolaceous, with 3 of these cases also presenting ulcer-ation. Associated symptoms included pain (5 cases),bleeding (4 cases), teeth mobility (1 case), and pares-thesia (1 case), and 2 cases were asymptomatic. All but1 patient reported a previous history of renal cell car-

Table I. Primary antibodies, clone, source, and dilu-tion usedPrimary antibody Clone Source Dilution

Pancytokeratin AE1/AE3 Dako, Denmark 1:500Cytokeratin 7 OV-TL 12/30 Dako, Denmark 1:400Cytokeratin 8 35H11 Dako, Denmark 1:200Cytokeratin 13 KS-1A3 Novocastra

Laboratories, U.K.1:400

Cytokeratin 14 LL002 NovocastraLaboratories, U.K.

1:200

Cytokeratin 18 DC10 Dako, Denmark 1:400Cytokeratin 19 RCK108 Dako, Denmark 1:200Vimentin Vim3B4 Dako, Denmark 1:400CD10 56C6 DBS, U.S. 1:20

cinoma, diagnosed at a mean time of 55 months (rang-

ing from 3 to 156 months) before the oral metastasis.Seven patients also presented metastasis in the lung andbones (4 each) when diagnosis of the oral lesion wasestablished. In 2 patients, the oral lesion was the firstsign of distant dissemination of the disease. Site of theoral lesions included 2 each in the palate, floor ofmouth, and tongue, and 1 case each in the buccalmucosa, upper anterior gingiva, and posterior mandible(Fig. 1). Incisional and excisional biopsies were per-formed as diagnostic methods in 5 and 4 cases, respec-tively.

Hematoxylin and eosin–stained slides from the 9cases revealed very similar microscopic features, in-cluding, under low magnification, a monotonous pro-liferation of neoplastic clear cells arranged in an alve-olar pattern (Fig. 2, A-C). The alveolar units wereseparated by a thin layer of fibrous connective tissuecontaining variable amounts of chronic inflammatorycells, blood vessels, and hemorrhage. The neoplasticcells were concentrically arranged and the center of thenests frequently contained one or more microvessels(Fig. 2, D). The periphery of the alveolar units showedsmall- to medium-sized capillaries, venules, and arterialbranches, some of them congested and hyperemic. Tu-bular and cystic structures were seen in some areas(Fig. 2, B). Individual cells were characterized by alarge clear cytoplasm and centrally located nuclei. Cel-lular and nuclear pleomorphism, atypia, and conspicu-ous nucleoli were uncommonly observed. Small areasof necrosis were seen in a few cases, and typical andatypical mitosis were rarely found. Periodic acid–Schiff(PAS) staining, with and without diastase digestion,was positive in all cases, but mucicarmine staining wasnegative in all cases. Immunohistochemistry showedthat CK AE1/AE3, 8, and 18 were the most prominent,and vimentin and CD10 were positive in all cases(Table II; Fig. 3).

Intraoral clear cell MEC affected 5 men and 3women, with a mean age of 58 years, ranging from 33to 78 years. All patients complained of an asymptom-atic swelling on the affected area covered by normaloral mucosa. The tumors were located in the palate (5cases) and 1 case each in the buccal mucosa, floor ofmouth, and tongue. Hematoxylin and eosin–stainedslides of these 8 cases revealed the presence of largeamounts of clear cells, characterized by evident clearcytoplasm and central and eccentric pyknotic hyper-chromatic nuclei. Mitoses and atypia were not seen. Allcases showed small portions of the tumor to be com-posed of squamous, intermediate, and mucous cells,rendering the diagnosis of MEC in all cases. PASstaining, with and without diastase digestion, and mu-cicarmine staining were positive in all cases. Immuno-

histochemistry showed that CK AE1/AE3, 7, and 8

cell c

OOOOEe24 Ramôa Pires et al. April 2010

were the most prominent, and vimentin and CD10 werepositive in only 1 case each (Table II).

DISCUSSIONOral metastases represent �1% of all oral malignan-

cies and preferentially affect the maxillary bones, beingspecially derived from lung, breast, kidney, bone, andcolon/rectum.11 The parotid glands are also an impor-tant site for metastatic tumors, particularly from cuta-neous squamous cell carcinomas and melanomas, butalso from distant malignancies, such as from thyroid,lung, kidney, and breast. Oral soft tissue metastases areeven less common, showing a predilection for the gin-

Fig. 1. A, Metastatic renal cell carcinoma presenting as aComputerized tomography image showing a metastatic renal

Fig. 2. Microscopic features of oral metastatic renal cellproliferation of neoplastic clear cells disposed in an alveolar(�100); C, Detail of the neoplastic clear cells arranged in ancells and concentric blood vessels (�200).

giva and being usually associated to primary lung,

kidney, and skin tumors.11 Independently of the oralsite of the metastasis, most patients report a history ofthe primary tumor when the secondary foci are discov-ered, reinforcing the importance of careful medicalhistory during the diagnostic process.

Metastatic CCRCC to the head and neck is un-common and can affect parotid and submandibularglands,12-14 mandible,7,12 maxilla and paranasal si-nuses,12,15 nasopharynx/palate,12 nasal cavity,15,16 eth-moid sinus/orbital region,17 and thyroid.12,18 Intraoralsoft tissue metastases from CCRCC are very rare, af-fecting the tongue,6,15-17,19-23 palate,5,15,24 buccal mu-cosa/upper lip,25 gingiva,26,27 lower lip,15 and floor of

rated mass on the upper palatal and gingival margin. B,arcinoma in the floor of the mouth.

ma (hematoxylin and eosing staining). A, Circumscribed(�50); B, Cystic areas lined by clear cells and hemorrhage

ar pattern (�100); D, Alveolar arrangement of the neoplastic

n ulce

carcinopatternalveol

mouth.4 Clinically, oral metastatic CCRCC can show

OOOOEVolume 109, Number 4 Ramôa Pires et al. e25

typical features of aggressive malignant lesions, such asan ulcerated hemorrhagic symptomatic swelling, or itcan appear as an asymptomatic submucosal nodule.Owing to the rich vascularization that characterizes thisneoplasm, oral metastatic CCRCC can show spontane-ous or stimulated bleeding. Head and neck metastaticCCRCC is usually detected 1-7 years after diagnosis ofthe primary tumor, reinforcing the indolent behavior ofthese tumors, but some metastatic tumors have beenfound synchronically or before the primary tumor.24,28

Microscopically, CCRCC is characterized by a pro-liferation of large homogeneous clear cells, arranged insolid nests commonly in an alveolar pattern, sur-rounded by thin areas of connective tissue. Althoughmost tumor cells show a glycogen- and lipid-containingclear cytoplasm, some cells can show a moderatelyeosinophilic cytoplasm.29,30 The stroma is highly vas-cularized, showing confluent hemorrhagic areas and adelicate network of uniform small vessels separatingeach alveolar proliferation of the tumoral clear cells.30

The alveolar proliferation of the clear cells gives rise toa concentric pattern of distribution highly suggestive ofthis tumor, characterized by the presence of tumoralcells on the periphery and the presence of vascularhemorrhagic channels at the center, eventually contain-ing a proteinaceous eosinophilic material.30 Cystic ar-eas can be found, and most lesions are considered to bewell differentiated tumors showing only discreteanaplasia.29 These features were encountered in all ofthe 9 cases included in the present study, being highlysuggestive of CCRCC.

Curiously, oral metastatic CCRCCs do not predom-inantly affect the gingiva, which most oral soft tissue

Table II. Histochemistry and immunohistochemicalexpression of cytokeratins (CKs), vimentin, and CD10in 9 oral metastatic clear cell renal cell carcinoma(CCRCC) and 8 intraoral clear cell mucoepidermoidcarcinoma (MEC)

Staining/marker Metastatic CCRCC Clear cell MEC

PAS without diastase 9 (100%) 8 (100%)PAS with diastase 9 (100%) 8 (100%)Mucicarmine 0 (0%) 8 (100%)AE1/AE3 9 (100%) 8 (100%)CK 7 3 (33%) 6 (75%)CK 8 9 (100%) 7 (88%)CK 13 5 (56%) 2 (25%)CK 14 4 (44%) 1 (13%)CK 18 8 (89%) 4 (50%)CK 19 5 (56%) 4 (50%)Vimentin 9 (100%) 1 (13%)CD10 9 (100%) 1 (13%)

PAS, Periodic acid–Schiff.

metastases do. As described above, they usually occur

in minor salivary gland– containing areas. Therefore,it is important to differentiate clear cell rich salivarygland tumors, particularly MEC, from metastaticCCRCC. Previous history of CCRCC is very impor-tant, because most, though not all, metastatic foci arediscovered after diagnosis of the primary tumor. Asshown by the present results, there are some distinctmicroscopic differences between clear cell MEC andCCRCC. The histologic pattern of CCRCC, with cellsarranged in nests surrounded by blood vessels, was notobserved in any of the clear cell MECs included in thisstudy. In fact, the characteristic abundance of microves-sels in metastatic CCRCC is helpful to differentiate thistumor from clear cell MEC.31 Additionally, clear cellsin MEC usually presented peripherally displaced nu-clei, whereas neoplastic cells in metastatic CCRCCpredominantly show central nuclei.

In our comparison, mucicarmine staining and immu-nohistochemistry seemed to be important additionaldiagnostic tools in differentiating metastatic CCRCCfrom intraoral clear cell MEC. The coexpression of CKand vimentin, a feature that is not common for themajority of other carcinomas, and the expression ofCD10 are characteristic of CCRCC, as highlighted byour results. CCRCC expresses CK 8 and 18, as con-firmed by our results, and is considered to be negativefor CK 7 and 20 although we have found expression ofCK 7 to be relatively common.30,32 However, becauseMEC can show a very heterogeneous profile, express-ing CK 7, 8, 10, 13, 14, and 18,33 their isolated use indifferential diagnosis of these tumors seems not to beuseful, highlighting the importance of concomitant vi-mentin expression. CD10 was expressed by all of theCCRCCs included in the present study, and it wasfocally expressed by only 1 MEC. Other markers thatcan be expressed by CCRCC cells include renal cellcarcinoma marker, von Hippel–Lindau tumor suppres-sor gene product, epithelial membrane antigen (EMA),E-cadherin, and S-100 protein,30,34-38 but some can alsobe expressed in salivary gland tumors or are not com-mon in daily practice, restricting their use as diagnostictools.

Differential diagnosis of head and neck metastaticCCRCC may vary depending on the site of the meta-static focus. When affecting the jaw bones, clear cellodontogenic carcinoma and other odontogenic tumorscontaining clear cells (such as clear cell calcifyingepithelial odontogenic tumor) should be considered.Other metastatic tumors, such as metastatic melanomas,and prostate, colon, thyroid, and liver carcinomas, alsoshould be excluded, and, besides some microscopicdistinct features, immunohistochemistry is essential inmost cases.1,39 When affecting the nasal and paranasal

regions, clear cell squamous cell carcinoma, MEC, and

OOOOEe26 Ramôa Pires et al. April 2010

the so-called renal cell–like carcinoma of the nasalcavity should be considered.34 For these lesions, con-comitant cytokeratin-vimentin expression is not ex-pected to be encountered. Besides MEC, other clearcell–rich salivary gland tumors, such as epithelial-myo-epithelial carcinoma, clear cell oncocytomas, clear cellacinic cell adenocarcinoma, and sebaceous carcinomas,also should be included in differential diagnosis,1-3,31

but they usually show at least 1 typical area of thetumor, facilitating diagnosis. Clear cell carcinoma, stilla controversial entity, also is an important differentialdiagnosis, because it is microscopically characterizedby a proliferation of monomorphic polygonal roundedclear or slightly eosinophilic cells, with rounded, baso-philic, and eccentric nuclei with conspicuous nucleoli.Tumoral cells are arranged in sheets, cords, and islands,and cyst formation and ductal structures are not fre-quent. CCRCC also usually shows cells with centralnuclei, rich vascularization, hemorrhage, and an alve-olar pattern.36,40

In conclusion, oral metastatic CCRCC can affectsalivary gland–containing tissues and should be con-sidered in differential diagnosis of intraoral clear cellsalivary gland tumors, including MEC. Histologically,the alveolar pattern of large clear cells with centrallylocated nuclei and the central and peripheral microves-sel distribution are suggestive of CCRCC. In addition,negative staining to mucicarmine and concomitant im-munoexpression of CK 8 and 18, vimentin, and CD10

Fig. 3. Immunopositivity in tumor cells of metastatic renal cAE1/AE3; B, vimentin; C, D, CD10.

seem to represent a common profile for oral metastatic

CCRCC, helping in the differentiation from intraoralclear cell MEC.

The authors thank Mrs. Ana Cristina do Amaral Godoyfor her assistance with the immunohistochemical reactions.

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Reprint requests:

Professor Fábio Ramôa Pires, DDS, PhDOral Pathology, School of DentistryState University of Rio de Janeiro (UERJ)Boulevard 28 de Setembro, 157Vila IsabelCEP: 20550-030Rio de Janeiro/RJBrazil

ramoafop@yahoo.com