Lyrer, P.

Meier, M.

Roten, S.

Steck, A.

Strnad, P.

Went, P.

Winkler, D.

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J Neurol (2007) 254:1601–1603DOI 10.1007/s00415-007-0588-6D. T.WinklerP. StrnadM. L.MeierS. RotenP.WentP. LyrerA. J. SteckMyasthenia gravis,paraneoplasticpemphigus and thymoma,a rare triadeReceived: 30 October 2006Received in revised form: 26 February 2007Accepted: 12 March 2007Published online: 3 August 2007Sirs: Among human neoplasms,thymomas are associated withhighest frequency with paraneo-plastic autoimmune diseases.Myasthenia gravis (MG) is presentin 30 to 60 % [1], depending on thesubtype of thymoma. Paraneoplas-tic pemphigus (PPP) on the otherhand is only rarely associated withthymomas. The coincidence of MGand PPP is very rare. Both, MG [2]and PPP [3], are associated withthe occurrence of various autoanti-bodies. Around 80 % of myastheniapatients test positively for acetyl-choline receptor antibodies [4]while in PPP desmoglein-3 anti-body titers are characteristicallyelevated [5]. We here studied thecourse of autoantibody titers be-fore and after thymectomy in a pa-tient with thymoma, MG and PPP.Antibodies against acetylcholinereceptors (AChR) and againstdesmoglein-1 and –3 showed a sig-nificant decrease after thymectomyin parallel to clinical improvement.We report the case of a 53-year-old woman who was admitted toour hospital with fluctuatingdiplopia, ptosis on her right sideand progressive fatigue for severalweeks. She reported progressivedysphagia and weight loss of 15 kgwithin a 6 month period. Further-more, aphtous oral lesionsappeared five months prior toadmission. Neurological examina-tion revealed slight weakness of thecervical musculature, inconsistentdiplopia and ptosis on the rightside. Clinical myasthenic symp-toms and elevated anti-acetyl-choline receptor antibodies (3.3pmol/ml; norm < 0.2 pmol/ml) ledto the diagnosis of myastheniagravis with predominant involve-ment of oropharyngeal and ocularmuscles. CT scans of the chest re-vealed a homogeneous 1.7 x 5.0 x8.5 cm anterior mediastinal massconsistent with a thymic tumor. CTscans of the abdomen and thepelvis were normal. Multiple geni-tal, oral and pharyngeal bullousand ulcerating eruptions were ob-served, partly covered with whitecreamy candida spots (Fig. 1A, in-let). Histological findings includedinterface dermatitis, apoptotickeratinocytes and focal areas ofsuprabasal acantholysis and wereconsistent with the diagnosis ofparaneoplastic pemphigus(Fig. 1A). In line with the clinicaland histological findings,desmoglein-1 (anti-Dsg-1) anti-bodies were initially normal (2.7U/l; norm < 14 U/l), while thedesmoglein-3 (anti-Dsg-3) titer(13.69 U/l; norm < 7 U/l) reachedtwice the norm at admission(Fig. 2).LETTER TO THE EDITORSJON 2588D. T. Winkler, MD, PhD · P. Strnad, MD · P. Lyrer, MD · A. J. Steck, MDDept. of NeurologyUniversity Hospital BaselPetersgraben 44031 Basel, SwitzerlandP. Strnad, MDPalo Alto Veterans Affairs Medical CenterPalo Alto, California 94304, USAM. L. Meier, MDConsultant DermatologistHôpital du Jura, DelémontS. Roten, MDImmunosa SA1001 Lausanne, SwitzerlandP. Went, MDInstitute of PathologyUniversity Hospital BaselBasel, SwitzerlandD. T. Winkler ()Dept. of NeurologyUniversity Hospital BaselPetersgraben 34031 Basel, SwitzerlandTel.: +41-61/265-2525Fax: +41-61/265-4100E-Mail: winklerd@uhbs.chFig. 1 A Paraneoplastic pemphigus with genital and oral blistering lesions (left inlet). Histology of genital blis-tering lesions shows suprabasal acantholysis (bold arrows) and lichenoid tissue reaction (small arrow, magnifi-cation 10x). Apoptotic keratinocytes are present (right inlet, arrowheads, 40x magnification). B Infiltration of themediastinal fat by the thymoma indicates stage III according to Masaoka (magnification 10x). Inlet demonstrat-ing large polygonal epithelial cells with few lymphocytes in an area of thymoma type B3 (magnification 40x)1601_000_Winkler_JON_2588  08.11.2007  11:18 Uhr  Seite 16011602Treatment with pyridostigminebromide, corticosteroids and aza-thioprine lead to an improvementof the myasthenic symptoms. Aftersignificant recovery from myas-thenic symptoms, the patient un-derwent an elective transsternalthymectomy seven weeks after herfirst admission. Intraoperativefindings showed an infiltration ofmediastinal fat by the thymoma(Stage Masaoka III) and simultane-ous resection of pericardium andthe vena anonyma became neces-sary. Histology showed a combinedthymoma of B2 and B3 type ac-cording to the WHO classification(Fig. 1B). The anterior medi-astinum was postoperatively irra-diated with a cumulative dose of54 Gy.Postoperatively, anti-Dsg-1 and–3 antibodies showed a transientincrease. In contrast, AChR anti-bodies dropped to almost normallevels already seven weeks post-operation and the patient showednormal muscle strength undercontinued pyridostigmine andimmunosuppressive therapy. Fourmonths after thymectomy,desmoglein antibodies also showeda significant decrease associatedwith a slow resolution of themucous lesions.Myasthenia gravis and pemphi-gus are both part of an interestinggroup of autoimmune diseases inwhich the passive transfer of anti-bodies can reproduce the diseasemanifestation [3, 6]. While MG isfrequently associated with thy-moma, PPP has only rarely beenreported in thymoma patients[7–11]. We now report on a patientwith the rare triade of thymoma,MG and PPP and describe for thefirst time the course of desmogleinantibodies before and afterthymectomy. In parallel with theclinical recovery four months afterthymectomy, all, AChR and anti-Dsg-1 and –3 antibodies showed animpressive decline (Fig. 2). Thepresent case thus points out theparallel dynamics of two autoim-mune mechanisms with a possiblecommon denominator. In our case,the levels of pemphigus-associatedantibodies had increased sevenweeks after thymectomy whileAChR antibodies already signifi-cantly dropped. In parallel, clinicalstabilization of myasthenic symp-toms preceded the resolution of themucous lesions. Furthermore, epi-tope spreading leading to transi-tion from an initial, mucosal domi-nant type with only anti-Dsg3antibodies, to an anti-Dsg1 (27.3U/l) and anti-Dsg-3 (35.6 U/l) posi-tive form had occurred. A similarbeneficial effect of tumor ablationhas recently also been reported inthe case of Castleman’s tumor, arare lymphoproliferative diseasethat is sometimes associated withparaneoplastic pemphigus [12].Our data provide further evidencefor the important role of auto-antibodies in the pathogenesis ofmyasthenia gravis and paraneo-plastic skin diseases in thymomapatients and document the im-provement of the associated dis-eases after radical treatment of thethymoma with concomitant im-munosuppressive treatment.Further studies are necessary toanalyze the pathomechanismunderlying the different timecourse of the serological and clini-cal resolution of MG and PMP afterthymectomy as presented in ourcase.References1. Chiu HC, Vincent A, Newsom-Davis J,Hsieh KH, Hung T (1987) Myastheniagravis: population differences in dis-ease expression and acetylcholine re-ceptor antibody titers between Chineseand Caucasians. Neurology 37(12):1854–18572. Vincent A, Palace J, Hilton-Jones D(2001) Myasthenia gravis. Lancet357(9274):2122–21283. Anhalt GJ, Labib RS, Voorhees JJ, BealsTF, Diaz LA (1982) Induction ofpemphigus in neonatal mice by passivetransfer of IgG from patients with thedisease. N Engl J Med 306(20):1189–11964. Lindstrom JM, Seybold ME, LennonVA, Whittingham S, Duane DD (1976)Antibody to acetylcholine receptor inmyasthenia gravis. Prevalence, clinicalcorrelates, and diagnostic value.Neurology 26(11):1054–1059Fig. 2 Serum titers of antibodies against acetylcholine receptors, desmoglein-1 and –3, all of which declinedfour months after thymectomy. Interestingly, early postoperative levels of desmoglein-1 and –3 antibodiesdemonstrated a transient post-interventional increase (the vertical arrow indicates the date of surgery), whereasthe acetylcholine receptor antibody titer was already lower40 U/l35 U/l30 U/l25 U/l20 U/l15 U/l10 U/l5 U/l0 U/lMayAprMarFebJanDecNovDesmoglein-3 antibodies (U/l)Desmoglein-1 antibodies (U/l)AChR antibodies (pmol/l) 4.0 pmol/l2.0 pmol/l1.0 pmol/l0.0 pmol/l3.0 pmol/l1601_000_Winkler_JON_2588  08.11.2007  11:18 Uhr  Seite 160216035. Amagai M, Nishikawa T, Nousari HC,Anhalt GJ, Hashimoto T (1998) Anti-bodies against desmoglein 3 (pemphi-gus vulgaris antigen) are present insera from patients with paraneoplasticpemphigus and cause acantholysis invivo in neonatal mice. J Clin Invest102(4):775–7826. Toyka KV, Drachman DB, Griffin DE,et al. (1977) Myasthenia gravis. Studyof humoral immune mechanisms bypassive transfer to mice. N Engl J Med296(3):125–1317. Patten SF, Dijkstra JW (1994) Associa-tions of pemphigus and autoimmunedisease with malignancy or thymoma.Int J Dermatol 33(12):836–8428. Sherer Y, Shoenfeld Y (1999) A malig-nancy work-up in patients with can-cer-associated (paraneoplastic) auto-immune diseases: pemphigus andmyasthenic syndromes as cases inpoint (review). Oncol Rep 6(3):665–6689. Leyn J, Degreef H (2001) Paraneoplas-tic pemphigus in a patient with a thy-moma. Dermatology 202(2):151–15410. Izumi Y, Kinoshita I, Kita Y, et al. (2002)Myasthenia gravis with diffuse alope-cia areata and pemphigus foliaceus.J Neurol 249(10):1455–145611. Takeshita K, Amano M, Shimizu T,et al. (2000) Thymoma with pemphigusfoliaceus. Intern Med 39(9):742–74712. Wang L, Bu D, Yang Y, Chen X, Zhu X(2004) Castleman’s tumours and pro-duction of autoantibody in paraneo-plastic pemphigus. Lancet 363(9408):525–5311601_000_Winkler_JON_2588  08.11.2007  11:18 Uhr  Seite 1603

Myasthenia gravis, paraneoplastic pemphigus and thymoma, a rare triade

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Myasthenia gravis, paraneoplastic pemphigus and thymoma, a rare triade

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