J Cutan Pathol 2011: 38: 241–245doi: 10.1111/j.1600-0560.2009.01446.xJohn Wiley & Sons. Printed in Singapore

Copyright © 2009 John Wiley & Sons A/S

Journal ofCutaneous Pathology

Melkersson Rosenthal syndrome:a histopathologic mysteryand dermatologic challenge

Melkersson Rosenthal syndrome (MRS) is rare disease of unknownetiology characterized by orofacial edema, facial nerve palsy andfissured tongue. Microscopically, it shows epithelioid non-caseousgranulomas; however, edema and perivascular lymphocytic infiltrateshave been described. Two different clinical forms of MRS arepresented in this report. In the complete form (Case 1), the mainhistopathologic finding was a non-necrotizing granulomatousinflammation with 56% of the total number of cells composed of B cells(CD20+) principally located in the granuloma’s center and 33% beingT cells predominating in the surrounding area, of which 48% wereCD4+ and 16% were CD8+ lymphocytes. In the monosymptomaticform (Case 2), the inflammatory cells were dispersed into the connectivetissue without granulomatous formation. B cells were scanty, and 78%of the cells were CD45+ T cells, with 46% and 34%, CD8+ and CD4+phenotype, respectively. These cases showed different clinical,histopathological and immunohistochemical forms of MRS, suggestingdifferent host immune responses.

Kaminagakura E, Jorge J Jr. Melkersson Rosenthal syndrome: ahistopathologic mystery and dermatologic challenge.J Cutan Pathol 2011; 38: 241–245. © 2009 John Wiley & Sons A/S.

Estela Kaminagakura andJacks Jorge Jr.

Department of Oral Pathology, Faculty ofDentistry of Piracicaba, University ofCampinas, Piracicaba, Brazil

Jacks Jorge Jr., Department of Oral Pathology,Faculty of Dentistry of Piracicaba, UNICAMP, AvLimeira, 901, CEP: 13414-903, Piracicaba, SaoPaulo, BrazilTel: 0055 19 34125317Fax: 0055 19 34125218e-mail: jacks@fop.unicamp.br

Accepted for publication August 28, 2009

Melkersson Rosenthal syndrome (MRS) is a raredisease of unknown cause being characterized bynon-caseating epithelioid granulomas with mult-inucleated giant cells, perivascular mononuclearinflammatory infiltrate and diffuse edema.1 How-ever, only perivascular lymphocytic infiltrates andsubepidermal edema have been described.2 Thelater was reported in early stages of disease andnon-necrotizing granulomas were reported in somecases of longer duration.3 Because of the rarity andthe complexity of its manifestations, erroneous diag-nosis of MRS is usual.4 Case reports are important toemphasize the histopathological manifestations andtheir variations, as well as to contribute to the under-standing of the pathogenesis. Therefore, the aimof this study was to characterize and describe theinflammatory cells in two different clinical forms of

MRS, using antibodies against CD45+ (T lympho-cyte), CD8+ (suppressor lymphocyte), CD4+ (helperlymphocyte) and CD20+ (B cell) proteins.

Case reportCase 1A 24-year-old white woman was referred to theOral Diagnosis Department of the Piracicaba DentalSchool, complaining of swelling in her upper lipfor 1 year, after trauma to the area with a‘toothpick’. Except for the swelling lip, the patientwas in good health. She reported a previousurinary infection about 2 years ago; she had nohistory of allergies, neurological or gastrointestinaldisorders. There was no family history of permanentor recurrent labial swelling. Clinically, erythema,desquamation and symmetric edema of the upper

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A

B

Fig. 1. A) Case 1–Initial clinical presentation with edema of theupper lip. B) Case 1–Fissured tongue.

lip (Fig. 1A) were present. Intraorally, she had afissured tongue (Fig. 1B). A differential diagnosisof cheilitis granulomatosa or MRS was madeand an incisional biopsy in the upper lip wasperformed. Microscopically, the specimen showeda keratinized squamous stratified epithelium, thesubjacent connective tissue exhibited well-organizedgranulomas with mononuclear inflammatory cellsand edema (Fig. 2). The diagnosis of MRS was madeon the basis of history, clinical and histopathologicalexaminations. Symptomatic treatment was givenin two stages with intralesional injections of 1ml disodium phosphate and dexametazone acetate(Duo-Decadron®) in five different areas, at intervalsof 15 days. There was an improvement that becamestable after 15 follow-up months.

Case 2A 48-year-old white woman presented with a 2-year history of symmetric swelling of her lowerlip (Fig. 3). The areas affected by edema weresensitive to acidic and spicy foods and she hada left side hearing problem. She reported facialpalsy about 20 years ago that was treated bythiamine monohydrate, pyridoxine hydrochlorideand cyanocobalamin (Citoneurin®) two pills per day

for 20 days, associated with physiotherapy, withoutpositive results. The palsy persisted for 2 years anddisappeared gradually. The patient had a 10-yearhistory of hypertension and depression treated withpropanolol chlorhydrate and hydrochlorthiazide(Tenadren® 40 mg-antihypertensive), estazolan(Noetal® 2 mg hypnotic) and lorazepan (Lorax® 1mg antidepressive). There were no gastrointestinalor allergic complaints. The patient used a totalupper and lower prosthesis. Differential diagnosesof lymphangioma, Quinck’s edema and MRS wereentertained and a lower lip biopsy was performed.Microscopically, the affected area was covered by anacantotic hyperorthokeratinized squamous stratifiedepithelium with spongious areas. The subjacentconnective tissue showed diffuse edema, lymphocytesperivascular aggregates, plasmocytes and a few

Fig. 2. Case 1–Photomicrography of labial mucosa showing thenon-necrotizing granulomas surrounded by fibrous connective tissue(H&E ×100).

Fig. 3. Case 2–Initial clinical presentation with edema of the lowerlip.

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eosinophils. The diagnosis of MRS was confirmed,based on all clinical and histopathological finds.

Immunohistochemical findingsImmunohistochemical studies were performed in thetwo cases reported. Briefly, 3-μm slides were deparaf-finized, hydrated in alcohol and washed in 10%hydrogen peroxide for 30 min to inhibit endoge-nous peroxidase. Microwave antigen retrieval usingcitrate buffer and overnight incubation with theprimary antibodies against CD45+, CD8+, CD4+and CD20+ (Table 1) were performed to iden-tify T, suppressor and helper lymphocytes and Bcells, respectively. Secondary antibodies conjugatedto streptavidin-biotin-peroxidase (StrepABC Com-plex/HRP Duet kit, Dako A/S, Glostrup, Denmark)were used, followed by diaminobenzidine (DAB,Sigma Chemical Co., St. Louis, MO, USA) as thechromogen. Slides were counterstained with Carazzihematoxylin and mounted. Negative (absence of pri-mary antibody) and positive controls were includedin all reactions. The percentage of positive nuclei wascalculated with the aid of an image computer ana-lyzer (Dako’s Automated Cellular Imaging System;Dako, Carpinteria, CA, USA) in a blinded analysisperformed independently by the authors.

Case 1–About 56% of the cells were B cells(CD20+), especially in the granuloma’s center; theremaining 33% of the cells were T-lymphocytes(CD45+), with the CD4+ phenotype prevailing in48% (Fig. 4A–C). Some CD4+ lymphocytes werealso found in the granuloma’s center and scatteredwithin the connective tissue, mainly near bloodvessels and the epithelium of the lip and 16% of theT cells were of the CD8+ phenotype and surroundedthe granuloma’s center (Fig. 4D).

Case 2–The inflammatory cells were dispersedinto the connective tissue: B cells were scanty, 78%of cells were CD45+ T cells, of which 46% wereCD8+ and 34%, CD4+ phenotype (Fig. 5A–D).

Table 1. List of primary antibodies used

Antigen Dilution ClonePositivecontrol Supplier

CD45 1 : 200 UCHL-1 Tonsil Dako Corp. Carpenteria,CA, USA

CD8 1 : 100 C8/144B Tonsil Dako Corp. Carpenteria,CA, USA

CD4 1 : 200 OPD4 Tonsil Dako Corp. Carpenteria,CA, USA

CD20 1 : 10000 L26 Tonsil Dako Corp. Carpenteria,CA, USA

All clinical, histopathological and immunohisto-chemical findings are summarized in Table 2.

DiscussionThe etiology of MRS remains unknown; however,infectious factors of bacterial,4 or allergic origin,5

as well as hereditary and family factors6 can beinvolved. Family predisposition, with autosomaldominant characteristics and incomplete penetrancehas been reported.6 A possible hereditary etiologyis suggested by the fact that in Case 2, a15-year-old daughter of the patient had hadepidodes of facial palsy, each lasting a month,always proceeded by otalgia but without labialor gingival edema, or fissured tongue. However,facial palsy can occur because of direct facial nervegranulomatous infiltration or secondary to nervecompression by edema.7 Authors have describedMRS as a polietiological disease that has genetic oracquired predisposition to a functional disturbanceof autonomous nervous system, associated withgranulomatous reaction from an allergic response toan undescribed circulating antigen.1,6 However, thishypothesis has been contradicted in other studies.8,9

It is very hard to correlate MRS to a specificetiologic agent and possibly it should be classifiedas autoinflammatory disorder. Autoinflammatorydisorders are characterized by recurrent episodesof inflammation in the absence of pathogens,autoantibodies or antigen specific T cells as inCrohn’s, or Behcet’s diseases and sarcoidosis.10

Granulomatous inflammation is the mainhistopathological finding in MRS; however, it is

Fig. 4. Case 1–A) About 56% of CD20+ cells were mainly found inthe granuloma’s center; B) 33% CD45+ were found in the granulomaperiphery and some at the center; C) CD4+ cells representing48% of T-lymphocytes; D) CD8+, 16% were observed at thegranuloma periphery (×200 immunoperoxidase with hematoxylincounterstain).

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Fig. 5. Case 2–A) Scanty CD20+ cells; B) 78% CD45+ cells; C) CD4+ cells representing 34% of T-lymphocytes; D) CD8+ representing 46%of T-lymphocytes (×200 immunoperoxidase with haematoxylin counterstain).

Table 2. Clinical, histopathological and immunohistochemical findings in the two cases reported

Case Clinical features Histopathological features CD20+ (%) CD45+ (%) CD4+ (%)* CD8+ (%)*

1 Upper lip swelling/lingua plicata Granulomatous inflammation 56 33 48 162 Lower lip swelling Lymphocytes perivascular infiltrates <1 78 34 46

∗Representing only percentage of T-lymphocytes.

not essential to establish a MRS diagnosis as thiscan be based upon the clinical and microscopiccharacteristics.11 The tuberculoid type of granulomais composed of small epithelioid cells, surroundedby lymphocytes, plasmocytes, macrophages and dif-fuse edema within the interstitial connective tissue,whereas the lymphonodular type shows a well-demarcated, central lymphocytic nodule marginatedby plasmocytes and macrophages in the edematousconnective tissue.1 In this study, we found granulo-mas of the lymphonodular plasmocyte type, withoutthe presence of multinucleated giant cells (Langhanstype) as described in some reports.8 The infectiouspossibilities were investigated using Ziehl-Neelsonand Periodic Acid Schiff stains, which were negativein both cases. Ronnblom et al.12 showed that pres-ence of T-lymphocytes with CD4+ predominance inMRS, can initiate a cellular immune response andcontribute to granulomatous formation. However, adecreased CD4/CD8 ratio was reported also in apatient with the monosymptomatic form of MRS.11

Facchetti et al.13 did not identify B lymphocytes in

granulomas of the monosymptomatic form; instead,they were composed of CD68+ epithelioid cells andT lymphocyte α/β receptors They observed also adecrease in the T CD4/CD8 relationship. In ourstudy, in the complete form of MRS, the granu-lomas were composed mainly of B lymphocytes inthe center and T-lymphocytes with CD4 pheno-type predominance were found in the periphery.In monosymptomatic form, we observed that non-granulomatous formation had a lower CD4/CD8ratio. The discrepancies in our two cases may reflectthe heterogenicity of this pathology, suggesting differ-ent host immune responses. An alternative possibilityis that the lymphocytic infiltrates without granula-tion formation may represent early stages of MRSand non-necrotizing granulomas, cases of longerduration.3 Epithelioid granulomas and giant cellsseem to be related to an immunologic phenomenon,especially to a hypersensitivity type IV reaction7

such as in Case 1, despite the lack of giant cells in thegranulomas.

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Treatment for MRS is difficult because ofthe unknown etiology.2 Case 1 was treated withcorticosteroid intralesional injections in the lip andhad a significant improvement, although without thecomplete remission which has been reported in theliterature.6 Even though some authors have reportedskeleton muscle degeneration, necrosis and cicatricialtissue formation after corticosteroid intralesionalinjections,14 these were not observed in Case 1.The patient in Case 2 had systemic corticosteroidtreatment with good results related to her lip edema.There were no significant side effects. At present, bothpatients are stable at 15 months and 4 years of followup, respectively. In cases resistant to conventionaltherapy, the infliximab was recommended;2,15 it isa chimeric monoclonal antibody that binds solublebioactive TNF-α and neutralizes its proinflammatoryeffects.15

In summary, the complete clinical form of MRSshowed non-necrotizing granulomas with CD20+cell predominance whereas the monosymptomaticform did not show granulomatous formation andhad a lower CD4/CD8 ratio. Collaborative studieswith other centers to increase the number ofcases will be necessary to determine whether themonosymptomatic form is the initial phase of MRSor whether the different clinical manifestations trulyrepresent different host responses.

References1. Hornstein OP. Melkersson-Rosenthal syndrome. A neuro-

muco-cutaneous disease of complex origin. Curr ProblDermatol 1973; 5: 117.

2. Ratzinger G, Sepp N, Vogetseder W, Tilg H. Cheilitis gran-ulomatosa and Melkersson-Rosenthal syndrome: evaluation ofgastrointestinal involvement and therapeutic regimens in a seriesof 14 patients. J Eur Acad Dermatol Venereol 2007; 21: 1065.

3. Greene RM, Rogers RS III. Melkersson-Rosenthal synd-rome: a review of 36 patients. J Am Acad Dermatol 1989; 21:1263.

4. Ozgursoy OB, Karatayli Ozgursoy S, Tulunay O, Kemal O,Akyol A, Dursun G. Melkersson-Rosenthal syndrome revisitedas a misdiagnosed disease. Am J Otolaryngol 2009; 30: 33.

5. Chiu CS, Tsai YL. Cheilitis granulomatosa associated withallergic contact dermatitis to betel quid. Contact Dermatitis2008; 58: 246.

6. Sciubba JJ, Said-Al-Naief N. Orofacial granulomatosis: presen-tation, pathology and management of 13 cases. J Oral PatholMed 2003; 32: 576.

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8. Ridder GJ, Fradis M, Lohle E. Cheilitis granulomatosaMiescher: treatment with clofazimine and review of theliterature. Ann Otol Rhinol Laryngol 2001; 110: 964.

9. Masson F, Barete S, Fremeaux-Bacchi V, et al. Melkersson-Rosenthal syndrome and acquired C1 inhibitor deficiency.Dermatology 2008; 217: 114.

10. Galeazzi M, Gasbarrini G, Ghirardello A, et al. Autoinflamma-tory syndromes. Clin Exp Rheumatol 2006; 24: S79.

11. Henry CH. Orofacial granulomatosis: report of a case withdecreased CD4/CD8 ratio. J Oral Maxillofac Surg 1994;52: 317.

12. Ronnblom L, Forsum U, Evrin PE, Gillnas T, Nethander G.Intralesional T lymphocyte phenotypes and HLA-DRexpression in Melkersson-Rosenthal syndrome. Int J OralMaxillofac Surg 1986; 15: 614.

13. Facchetti F, Signorini S, Majorana A, Manganoni MA, SapelliP, Imberti L. Non-specific influx of T-cell receptor alpha/betaand gamma/delta lymphocytes in mucosal biopsies from apatient with orofacial granulomatosis. J Oral Pathol Med 2000;29: 519.

14. Williams PM, Greenberg MS. Management of cheilitisgranulomatosa. Oral Surg Oral Med Oral Pathol 1991; 72:436.

15. Barry O, Barry J, Langan S, Murphy M, Fitzgibbon J, LyonsJF. Treatment of granulomatous cheilitis with infliximab. ArchDermatol 2005; 141: 1080.

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