lichen scrofulosorum – o formÃrarÃ de ......tuberculoza pulmonarã, þinând cont de extinderea...

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LICHEN SCROFULOSORUM – O FORMÃ RARÃDE TUBERCULOZÃ CUTANATÃ – PREZENTARE DE CAZ

LICHEN SCROFULOSORUM – A RARE FORM OF CUTANEOUS TUBERCULOSIS – CASE REPORT

TEODORA PREDESCU*, IRINA MÃRGÃRITESCU**, MARA MÃDÃLINA MIHAI*,***, ANA-MARIA FORSEA*,***, CÃLIN GIURCÃNEANU*,***

Rezumat

Lichenul scrofulosorum este o formã rarã,paucibacilarã, de tuberculozã cutanatã. Diagnosticul estedificil, aspectul clinic ºi histopatologic necesitânddiferenþierea de alte afecþiuni mai frecvente cum ar filichenul plan, lichenul nitidus, sarcoidoza, sifilidelelichenoide ºi alte dermatoze granulomatoase de origineinfecþioasã. Fiind o formã paucibacilarã, bacilii tuberculoºinu sunt de regulã identificaþi pe mediile de culturã sau lacoloraþiile speciale, iar tehnicile de identificare rapidã aADN-ului micobacterian în þesuturi (PCR) au utilitatelimitatã. Stabilirea diagnosticului de certitudine se bazeazãpe examenul histopatologic asociat cu confirmarea uneiinfecþii tuberculoase active interne. Ca în toate formele detuberculozã cutanatã, tratamentul lichenului scrofulo-sorum urmeazã aceleaºi principii de tratament ca ºituberculoza pulmonarã, þinând cont de extinderea infecþieiºi de statusul imun al pacientului.

Prezentãm cazul unei paciente de 41 de anidiagnosticatã cu lichen scrofulosorum dupã un istoric de 7ani de erupþie persistentã, asimptomaticã la nivelultrunchiului ºi feþei, cu multiple interpretãri diagnostice ºiintervenþii terapeutice. Cazul prezintã particularitãþiclinico-evolutive ºi este ilustrativ pentru dificultãþile dediagnostic ale acestei forme rare de tuberculozã cutanatã,precum ºi pentru necesitatea de a avea în vedereposibilitatea acestui diagnostic în condiþiile în care þara

Summary

Lichen scrofulosorum is a rare, paucibacillary form ofcutaneous tuberculosis. Diagnosis is difficult, requiring adifferentiation on both, clinical and histopathologicalappearance, from other common diseases such as lichenplanus, lichen nitidus, sarcoidosis, syphilides, lichenoiddermatitis and other granulomatous forms of dermatitiswith infectious origin. Being a paucibacillary form, theacid-fast bacilli are not usually identified on bacterialcultures or on special stains, therefore rapid mycobacterialDNA identification (PCR) technique from tissues havelimited utility. The diagnosis is based on histopathologicalexamination, associated with the confirmation of activeinternal TB infection. As in all cutaneous forms oftuberculosis, lichen scrofulosorum treatment followssimilar principles as pulmonary tuberculosis infection,while taking into account the infection expansion and theimmune status of the patient.

The case presented is of a 41 year old female patientdiagnosed with lichen scrofulosorum after a 7-yearhistory of persistent, asymptomatic eruption on trunkand face. During that time the patient received multiplediagnostic interpretations and therapeutic interventions.The case shows clinical course particularities and isillustrative for the diagnostic difficulties of this rare formof cutaneous tuberculosis, as well as for the need to takeinto account this disease as a possibility, given the fact

* Clinica de Dermatologie Oncologicã ºi Alergologie, Spitalul Universitar de Urgenþã ELIAS, Bucureºti, România.Oncology Clinic of Dermatology and Allergology, University Hospital Emergency ELIAS, Bucharest, Romania.

** Laboratorul de Anatomie Patologicã, OncoTeam Diagnostic, Spitalul Monza.The Morphopathology Laboratory, Diagnosis OncoTeam Hospital, Monza.

*** Universitatea de Medicinã ºi Farmacie ”Carol Davila”, Bucureºti, România.University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.

CAZURI CLINICECLINICAL CASES

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DermatoVenerol. (Buc.), 60: 19-30

Introducere

Tuberculoza este o boalã infecto-contagioasã,provocatã de diferite tipuri de micobacterii, celmai frecvent fiind incriminat Mycobacteriumtuberculosis(1). În 2014 s-au înregistrat 8 milioanede noi cazuri de tuberculozã, în timp ce infecþialatentã era prezentã la mai mult de o treime dinpopulaþia lumii(2). Incidenþa ridicatã, contagio-zitatea importantã, precum ºi mortalitatea ºimorbiditatea semnificativã, au transformattuberculoza într-o realã problemã de sãnãtatepublicã(3).

Tuberculoza cutanatã este o formã rarã detuberculozã extrapulmonarã, reprezentând doar1-2% din totalul cazurilor(4)(5). Principalii agenþietiologici ai tuberculozei cutanate suntMycobacterium Tuberculosis, Mycobacteriumbovis ºi uneori bacilul Calmette-Guerin(1). S-aobservat o frecvenþã mai mare a afectãrii cutanatela pacienþii ce asociazã o infecþie cu virusulimunodeficienþei umane ºi la cei cu tuberculozãrezistentã la tratament(6).

În România, deºi numãrul de cazuri detuberculozã este în scãdere, þara noastrã continuãsã ocupe primul loc în Europa la cele mai multecazuri de infecþii micobacteriene cu 83,72 cazurila 100 000 de locuitori(7).

Tuberculoza cutanatã are un tablou clinicpolimorf, dependent de locul de inoculare, decalea de infectare, de statusul imun al pacientuluiºi nu în ultimul rând de virulenþamicobacterianã(1). Tuberculoza cutanatã poate fideterminatã atât prin inocularea directã aagentului infecþios, aºa cum se întâmplã înºancrul tuberculos ºi tuberculoza verucoasã, câtºi prin rãspândirea endogenã, pe calehematologicã, pe cale limfaticã, prin continuitatesau prin autoinoculare. Rãspândirea pe calehematogenã sau limfaticã este întâlnitã în lupusvulgar, tuberculoza miliarã acutã, gomatuberculoasã. Scrofuloderma ºi tuberculozaorificialã sunt determinate prin infecþia din

Introduction

Tuberculosis is a contagious infection, causedby different species of mycobacteria, of which themost frequent is Mycobacterium tuberculosis (1). In2014, 8 million new cases of tuberculosis werereported worldwide, while latent infection wasestimated to be present in more than one third inthe general population (2). The high incidence,the significant risk of transmission, as well as theimportant morbidity and mortality associatedwith this disease, all turn tuberculosis into aprimal healthcare issue.

Cutaneous tuberculosis is a rare form ofextrapulmonary tuberculosis, representing aproportion of only 1-2% from the total number ofreported cases (4) (5). The most importantethiological factors of cutaneous tuberculosis areMycobacterium tuberculosis, Mycobacterium bovisand, less often, Calmette- Guérin bacillus (1). Ahigher frequency of cutaneous manifestationswas observed in patients with an associatedhuman immunodeficiency virus (HIV) infectionand in those suffering from tuberculosisunresponsive to standard treatment (6).

In Romania, although the incidence isdecreasing, it continues to occupy the first placein Europe, with the highest number of reportedcases in 2013: 83.72 mycobacterial infections per100000 population (7).

Cutaneous tuberculosis has multiple clinicalpatterns, depending on the inoculation place, themode of transmission, the patient`s immunestatus, and, last but not least, the virulence of themycobacterial strains (1). Cutaneous tuberculosismay be caused both by the direct inoculation ofthe infectious bacilli, as in the case of tuberculouschancre and verrucous tuberculosis, as well as byendogenous dissemination, both lymphatic orhematogenous, by continuity, contiguity, orautoinoculation. The hematogenous or lymphaticspread is found in lupus vulgaris, acute miliary

noastrã rãmâne pe primele locuri în Europa ca incidenþã atuberculozei.

Cuvinte cheie: tuberculozã cutanatã, lichenscrofulosorum, dermatozã granulomatoasã, IDR.

Intrat în redacþie: 15.12.2014

Acceptat: 10.01.2015

Received: 15.12.2014Accepted: 10.01.2015

that Romania occupies one of the leading positions inEurope`s tuberculosis incidence.

Keywords: cutaneous tuberculosis, lichen scrofu-losorum, granulomatous dermatitis, IDR.

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aproape în aproape de la un focar de vecinãtatede la nivelul ganglionilor limfatici sau oaselor ºirespectiv al orificiilor nazal, bucal sau anal (1)(8).

Tuberculidele reprezintã o categorie specialãºi heterogenã de tuberculoze cutanate, pauci-bacilare, întâlnite la indivizii cu grad înalt dehipersensibilitate la Mycobacterium tuberculosis, ºiasociate cu infecþii tuberculoase active. Tabloullor clinic este polimorf, incluzând formele: lichenscrofulosorum, tuberculide papulo-necrotice,eritemul indurat Bazin. Absenþa bacililor se poateexplica fie prin distrugerea rapidã amicobacteriilor, fie prin faptul cã la nivelul pieliiajung numai produºii de metabolism ai acestora,ce acþioneazã pe un tegument hiperreactiv(9).Pânã în momentul de faþã nu a fost elucidatmecanismul de producere al acestor leziunicutanate.

Lichenul scrofulosorum este considerat ceamai rarã formã de tuberculide. A fost descrispentru prima datã în 1860 de Hebra(10). Dinpunct de vedere clinic se caracterizeazã prinpapule perifoliculare, de culoarea tegumentuluisau roºiatice, cu diametrul între 0,5-3 mm, cusuprafaþã netedã sau discret scuamoasã, uneoricu tendinþã la confluare, localizate cu predilecþiela nivelul trunchiului, axilelor ºi membrelor. Estefrecvent asociat cu alte focare de tuberculozãactivã. Din punct de vedere histopatologic seobservã granuloame tuberculoide superficiale.Culturile celulare pe medii specifice suntnegative. Diagnosticul diferenþial poate fi dificil,datoritã asemãnãrii acestuia cu lichenul plan,lichenul nitidus, sifilidele lichenoide ºi uneori cuformele micropapulare de sarcoidozã(11). La felca în celelalte forme tratamentul este reprezentatde terapia combinatã tuberculostaticã.

Acest articol prezintã un caz de tuberculozãcutanatã forma lichen strofulosorum, particularprin evoluþie ºi dificultãþile de diagnosticdiferenþial.

Prezentare de caz

O pacientã în vârstã de 41 de ani, fãrãantecedente patologice semnificative, s-aprezentat în clinica noastrã în iulie 2014 pentru oerupþie papuloasã, diseminatã, asimptomaticã,persistentã la nivelul extremitãþii cefalice ºimembrelor inferioare.

tuberculosis, and tuberculous gumma.Scrofuloderma and orificial tuberculosis arecaused by the infectious spread throughcontinuity and contiguity from a close site ofinfection, such as the lymph nodes or the bones,to the adjacent tissues, and finally to the nasal,oral or anal orifices (1) (8).

Tuberculids represent a special andheterogeneous category of cutaneous tuber-culosis, a paucibacillary subtype, encountered inindividuals with a higher sensitivity toMycobacterium tuberculosis, associated with othersites of active tuberculosis. The clinical picture ispolymophous and includes the followingcutaneous manifestations: lichen scrofulosorum,papulonecrotic tuberculids, and erythemainduratum of Bazin. The abscence of bacilli maybe explained either by the rapid immune removalof mycobacteria or by the unique involvement inthe disease pathogenesis of bacterial metabolicproducts, and not the bacteria per se, in the skin ofhyperreactive individuals (10). Until now, thepathogenic mechanism of these skin lesions hasnot been elucidated.

Lichen scrofulosorum represents the rarestform of cutaneous tuberculosis. It was describedfor the first time in 1860 by Hebra (11). Clinicallyit is characterized by skin-coloured or reddishperifollicular papules, with a diameter of 0.5-3mm, with a smooth surface or slightly scaly,sometimes with the tendency to confluence inlarger plaques, localised on the trunk, axillae andlimbs. It is frequently associated with other sitesof active tuberculosis. Histopathologically,tuberculous granulomas in the upper dermis arecharacteristic. Bacterial cultures on specific mediaare negative. Differential diagnosis may bedifficult, due to the clinical similarities withlichen planus, lichen nitidus, lichenoid secondarysyphilis, and with the rare form of micropapularcutaneous sarcoidosis (12). As well as in the othertypes of tuberculosis the treatment is representedby the standard tuberculostatic regimen.

In this article we aim to present a rare caseof cutaneous tuberculosis, the subtype of lichenscrofulosorum, with interesting particularitiesboth in the progression of the disease as well asin the difficulties encoutered in the differentialdiagnosis.

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Anamnestic, afecþiunea cutanatã a debutat înurmã cu 7 ani sub forma unor papule roºiatice,asimptomatice, localizate la nivelul coapselor,feselor ºi pleoapei ochiului stâng, cu extinderelentã. Pacienta s-a prezentat în repetate rânduri laconsultaþii dermatologice, în urma cãrora s-aemis un diagnostic clinic iniþial de granulominelar, pentru care s-a recomandat terapie topicãcorticosteroidianã; aceasta nu a avut însãrezultate semnificative. Pacienta a mai urmattratament local cu tacrolimus 0,1%, întrerupt înurma dezvoltãrii intoleranþei la acest produs ºi ocurã sistemicã cu enoxaparinã (Clexane®). S-aupracticat douã biopsii cutanate în anii 2009,respectiv 2010, cu un prim diagnostic desarcoidozã cutanatã, infirmat însã de cel de aldoilea examen histopatologic, care a ridicatsuspiciunea de lichen nitidus. În anul 2009 s-apracticat testare cutanatã la tuberculinã, cu unIDR slab pozitiv, în timp ce radiografiapulmonarã nu a prezentat modificãri. În anul2014 o nouã biopsie de la nivelul leziunilorprogresive de la nivel fesier aduce în discuþiediagnosticul de xantogranulom.

Istoricul personal ºi familial a fost negativpentru boli dermatologice sau pentrutuberculozã pulmonarã sau extrapulmonarã.

La momentul internãrii pacienta s-a prezentatîn stare generalã bunã, afebrilã, fãrã simptome ºisemne patologice la examenul clinic general.Examenul dermatologic a relevat mici papuleeritemato-violacee, lucioase, gãlbui la vitro-presiune, bine delimitate, unele confluate înplãci, asimptomatice, diseminate la nivelulantebraþelor, feselor ºi coapselor (fig. 1)(fig. 2),precum ºi discrete la nivelul pleoapelor,piramidei nazale ºi pavilionului urechii.

Testele de laborator efectuate pe parcursulinternãrii au inclus: hemograma fãrã modificãrisemnificative, cu excepþia unei discretemacrocitoze, însã fãrã alþi markeri de anemie;probe hepatice ºi renale în limite normale;sindrom biologic inflamator absent; coagulo-gramã în limite normale; proteina C reactivã,factor reumatoid, ASLO – negative; serologiesifilis ºi Borrelia burgdorferi negativã. Deasemenea, s-a dozat angiotensin convertaza alecãrei valori au fost în limite normale.

În vederea unei investigãri complete, s-auefectuat examenele microbiologice pentru

Case report

Medical history revealed the onset of the skindisease 7 years ago when redish, asymphtomaticpapules appeared on the patient’s thighs, glutealregions and on the left eyelid, slowly progressingover time. The patient repeatedly seeked medicalattention, being initially diagnosed withgranuloma annulare and treated with topicalcorticosteroids, but without any significantimprovement. Moreover, the patient followedtopical treatment with tacrolimus 0.1%, but anallergic skin reaction led to therapy cessation. Asystemic therapeutic cure with enoxaparin(Clexane®) led to significant improvement,although this approach was never repeated.

Two skin samples were taken by punchbiopsy in 2009 and 2010. While the firsthistopathologic report suggested a diagnosis ofcutaneous sarcoidosis, the second result wasdifferent, with a suspicion of lichen nitidus. In2009, a tuberculin skin test was also performed,with a weak positive result of the intradermalreaction, while a chest radiography did not showany evidence of pulmonary pathological changes.In 2014 the biopsy was repeated, with ahistopathologic diagnosis of xanthogranuloma.

The personal and the family history did notreveal the presence of skin diseases or tuber-culosis neither pulmonary or extrapulmonary.

At admission the patient was in a generalgood health status, afebrile, conscious, withoutany pathological signs or symptoms presentduring physical examination. The skinexamination revealed the presence of multiplered-purple, shiny papules, which turned yellowat diascopy, with clearly defined borders, some ofthem confluent in plaques, asymptomatic,disseminated on the forearms, thighs and glutealregions (fig. 1)(fig. 2), as well as discrete lesionson the eyelids, nose and earlobes.

The following laboratory test results wereanalyzed: the complete blood count did not showany significant changes, with the exception of adiscrete macrocitosis, in the absence of othermarkers of anemia; liver and kidney functiontests were in normal ranges; biologicalinflamatory sindrom absent; normal ranges ofcoagulogram; C-reactive protein, rheumatoidfactor and ASLO were also negative; serologicaltests for Treponema pallidum and Borrelia

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evidenþierea unor potenþiale focare infecþioase(uroculturã, exudat faringian, exudat nazal), darcare au fost negative. Testarea cutanatã latuberculinã a prezentat o valoare a IDR de 9mm(fig. 3). Testarea prin QuantiFERON a fostnegativã. Radiografia toracicã a decelat oimportantã scoliozã toracalã, fãrã leziuni pleuro-pulmonare acute.

Pe parcursul internãrii s-au prelevat 3 piesebioptice noi de la nivelul leziunilor cutanate depe coapse care au fost înaintate spre examenulhistopatologic ºi respectiv bacteriologic.

Examenul histopatologic a relevat odermatitã perivascularã superficialã ºi profundã,perianexialã, lichenoidã, cu limfocite ºi histiocite,cu urmãtoarele caracteristici: infiltrat inflamatorlimfohistiocitar bogat, dispus lichenoid la niveluldermului papilar ºi reticular superficial, careumple ºi destinde papilele dermice pe toatãlungimea biopsiei (5 mm microscopic); infiltratalcãtuit din limfocite imixtionate cu histiocite,histiocite epitelioide cu tendinþã pe alocuri degrupare în mici colecþii ºi câteva celule gigantemultinucleate tip Langhans; infiltrat cu limfocite,histiocite ºi numeroase plasmocite dispusperivascular ºi perianexial (perifolicular, periecrin,perineural); uºoarã acantozã; discretã exocitozãcu limfocite; strat cornos de aspect normal (fig. 4)(fig. 5) (fig. 6). Pe baza acestor modificãri s-a emisdiagnosticul histopatologic de lichen scro-fulosorum.

Culturile efectuate din materialul bioptic aufost negative.

burgdorferi did not suggest the presence ofinfection. Also, normal values of angiotensincovertase were detected.

In order to perform a thorough investigationof the patient and to exclude any potentialinfectious ethiologies, various sites were sampledfor microbiological testing (nasal and pharyngealexudate, urine), all yielding negative results.Tuberculin skin test revealed an intradermalreaction with a value of approximately 9 mm (fig. 3). QuantiFERON testing was negative.Chest radiography did not reveal acute pleural orpulmonary fingings.

During the patient’s hospitalization, 3 punchbiopsies were sampled from thigh lesions andsent for histopathological and microbiologicalexamination.

The histopathological examination revealedsuperficial and deep perivascular and peri-adnexal lichenoid dermatitits, with lymplocytesand histiocytes, with the following charac-teristics: a rich inflammatory limpho-histiocitaryinfiltrate, with a lichenoid disposition, in thepapilary and the superficial reticulary dermis,which fills and expands dermal papillae, on thefull lenghth of the biopsy (5 mm); the infiltrate iscomposed of lymphocytes mixed withhistiocytes, with the tendency of some epitelioidhistiocytes to form small aggregates and withsome Langhans multinucleated giant cells;perivascular and periadnexal infiltrate (peri-follicular, perieccrine, perineural) with lympho-cytes, histiocytes, and numerous plasmocytes;

Fig. 1. Multiple papule roºiatice cu tendinþã la confluareîn plãci

Fig. 1. Multiple confluent red papules and plaques

Fig. 2. Multiple plãci localizate la nivel fesierFig. 2. Multiple plaques localised on the gluteal region

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Pe baza datelor clinice coroborate cu celehistopatologice s-a emis diagnosticul de tuber-culozã cutanatã, forma lichen scrofulosorum. Înseptembrie 2014 a fost iniþiatã terapia combinatãcu Izoniazidã 300mg/zi, Rifampicinã 600mg/zi,Pirazinamidã 2000mg/zi ºi Etambutol 1600mg/zitimp de douã luni, cu reducerea ulterioarã aschemei terapeutice (Izoniazidã 900mg/zi ºiRifampicinã 600mg/zi), cu evoluþie lent

mild acanthosis; discrete exocitosis withlymphocytes; normal statum corneum (fig. 4) (fig. 5) (fig. 6). Based on these findings, thehistopathological diagnosis of lichen scrofu-losorum was issued. Culture growth performedfrom bioptic samples were negative.

Based on the clinical data, together with thehistopathological results we established the

Fig. 3. Testare cutanatã la tuberculinã cu IDR pozitivFig. 3. Tuberculin test with positive intradermal reaction

Fig. 4. La magnificaþie joasã se observã o dermatitãperivascularã ºi perianexialã lichenoidã (HE, 25x)

Fig. 4. At low magnification we noticed a perivascular andperiadnexal lichenoid dermatitis (HE, 25x)

Fig. 5. Infiltratul inflamator umple ºi destinde papileledermice ºi înconjoarã o unitate pilosebacee (HE, 50x)Fig. 5. The inflammatory infiltrate fill and distend the

papillary dermis and surrounds the pilosebaceous unit (HE, 50x)

Fig. 6. Infiltratul este alcãtuit din histiocite epitelioide cutendinþã de grupare, câteva celule gigante multinucleate ºi

limfocite (HE, 200x).Fig. 6. The inflammatory infiltrate consists of

multinucleated giant cells, lymphocytes and epithelioidhistiocytes which have the tendency to grouptogether

(HE, 200x).

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favorabilã. Reevaluarea dermatologicã dupã 6luni de tratament a relevat leziuni la nivelulfeselor ºi coapselor în regresie, aplatizate, cureducerea eritemului ºi discretã hiperpigmentare.Leziunile de la nivelul feþei, periorbital, au avutiniþial o discretã progresie în momentul reduceriischemei de tratament tuberculostatic, urmatãapoi de stabilizare, sub tratament adjuvant cudermatocorticoizi.

Discuþii

Tuberculoza cutanatã rãmâne o afecþiunecutanatã rarã, dar care ridicã problemesemnificative de diagnostic ºi tratament, încadrul unui spectru larg de forme clinice.Formele multibacilare, în care numãrul de bacilipoate fi detectat uºor în þesutul cutanat, cum ar fiºancrul tuberculos, scrofuloderma, tuberculozaorificialã, tuberculoza miliarã acutã ºi gomatuberculoasã, pot fi diagnosticate cu mai multãuºurinþã prin examene microbiologice(12).Cultura micobacterianã Lowenstein-Jensenreprezintã standardul de aur pentru deter-minarea infecþiei active ºi permite diferenþiereaformelor de M. Tuberculosis de alte micobacteriiºi stabilirea sensibilitãþii la antibiotice(13).Metodele speciale de colorare (Ziehl-Neelson)pentru identificarea bacililor acid alcoolo-rezistenþi este de asemenea utilã în cazulformelor multibacilare.

În schimb, în formele paucibacilare, în carebacilii sunt rari sau chiar absenþi la examenulhistopatologic ºi care includ tuberculozaverucoasã, lupusul vulgar, eritemul induratBazin, lichenul scrofulosorum ºi tuberculidelepapulo-necrotice diagnosticul etiologic estedificil, mai ales în absenþa unor focare interneactive de tuberculozã(12).

Am prezentat cazul unei paciente cu formãde lichen scrofulosorum, una din cele mai rareforme de tuberculozã cutanatã a cãrui frecvenþãîn cadrul spectrului clinic al tuberculozeicutanate este de doar 6,8%(14). Cu toate acestea,în douã studii efectuate pe 142 respectiv 103pacienþi, lichenul scrofulosorum a fost prezentîntr-un procent de 25,5% respectiv 33%(15)(16).Numãrul mic de studii efectuate pânã în prezentface dificilã stabilirea cu exactitate a incidenþeiacestuia în cadrul tuberculozelor cutanate.

diagnosis of cutaneous tuberculosis, the subtypelichen scrofulosorum. In september 2014, the tuberculosatic regimen with Isoniazid300mg/day, Rifampicin 600mg/day Pyrazinamide2000mg/day and Ethambutol 1600mg/day wasinitiated and maintained for 2 months, followedby the reduction of the therapeutical agents toIsoniazid 900mg/day and Rifampicin 600mg/day alone, with favorable results. After 6 monthsof treatment, at the dermatologic reevaluation,the patient presented with skin lesions, localisedon the gluteal region and on the thighs, with animproved appearance, in regression, with areduction of the erythema and with discretehyperpigmentation. The palpebral facial lesionshad a mild progression at the reduction of thetuberculostatic regimen, followed by stabilizationunder dermatocorticoid topical treatment.

Discussions

Cutaneous tuberculosis a rare skin disease,which raises significant issues of diagnosis andtherapeutic approach, with a large spectrum ofclinical manifestations. The multibacillary formscan be diagnosed without difficulty bymicrobiological examination, because the bacillican be easily determined in the cutaneous tissuesamples. This is the case of tuberculous chancre,scrofuloderma, orificial tuberculosis, acutemiliary tuberculosis, and tuberculous gumma.Special stains, such as Ziehl Neelsen, allow theidentification of acid-alcohol resistant bacillusand are useful in the case of multibacillaryinfection. The bacterial culture on the selectivemedia Lowenstein-Jensen represents the gold standard in the diagnosis of an activeinfection and allows the identification of M.tuberculosis subspecies and their susceptibility toantibiotics (12).

On the other hand, paucibacillary forms, withrare or even absent bacilli at histopathologicalexamination, include verrucous tuberculosis,lupus vulgaris, erythema induratum of Bazin,lichen scrofulosorum, and papulo-necrotictuberculids (13). Their diagnosis is more difficult,particularly when internal active sites oftuberculosis are absent.

We presented the case of a patient diagnosedwith lichen scrofulosorum, a rare manifestation

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Lichenul scrofulosorum este frecvent întâlnitla copii ºi la adolescenþi. Datele din literaturã auarãtat o frecvenþã mai mare a lichenuluiscrofulosorum la tineri, formele prezente la adultfiind raportate foarte rar. Majoritatea cazurilor,circa 84%, apar la pacienþii sub 15 ani, cu o uºoarãpredominanþã a sexului masculin(17). În cazulnostru, pacienta avea 34 de ani la momentulapariþiei primelor leziuni cutanate.

Localizarea predilectã a lichenului scrofulo-sorum este la nivelul trunchiului(17). Au fostdescrise însã cazuri cu localizãri la nivelulfeþei(18), membrelor, palmo-plantar(19) ºi genital(20)(21). În ceea ce priveºte localizarea erupþieicutanate, cazul prezentat este particular, deoarecepe lângã localizãrile de elecþie ale lichenuluiscrofulosorum, pacienta a prezentat multiplepapule la nivelul piramidei nazale, pleoapelor ºipavilionului urechii.

Lichenul scrofulosorum este o formãpaucibacilarã, bacilii tuberculoºi nefiind aproapeniciodatã identificaþi pe mediile de culturã sau lacoloraþiile speciale, ceea ce limiteazã utilitateaacestor investigaþii. Tehnicile moderne deamplificare a acizilor nucleici (PCR) permitidentificarea rapidã a ADN-ului micobacterian înþesuturile afectate. Testul are valoare diagnosticãîn condiþiile în care, la nivelul leziunilor cutanate,existã descãrcare de ADN micobacterian(22).Lichenul scrofulosorum, fiind o formãpaucibacilarã, utilitatea PCR-ului este multlimitatã. În literaturã sunt citate doar douã cazuride lichen scrofulosorum la care s-a pututidentifica ADN-ul micobacterian(23)(24).

Testarea cutanatã la tuberculinã este un testde depistare a persoanelor cu sensibilitate la M.Tuberculosis, ºi constã în injectarea intradermicãa 5 unitãþi de tuberculinã, cu urmãrirea reacþieilocale la inoculare(25). Rezultatele sunt citite la48-72 de ore de la inoculare, fiind consideratepozitive în cazul unei induraþii mai mari de 5mm.În literaturã LS este frecvent asociat cu un IDR latuberculinã intens pozitiv (mai mare de18mm)(17). Cu toate acestea au fost citate cazuricu rezultate negative la testarea cutuberculinã(26)(24). Testarea la QuantiFERONreprezintã o tehnicã modernã ºi rapidã ce permitestabilirea expunerii la micobacterii. Pentruefectuarea ei este necesarã o probã din sângelepacientului, iar interpretarea ei depinde de

of skin tuberculosis, with a frequency of 6,8% inthe spectrum of cutaneous tuberculosis (14).Nevertheless, in 2 clinical studies conducted on142 and, respectively, 103 patients, lichenscrofulosorum was diagnosed in 25.5%,respectively 33% of the cases (15) (16). The smallnumber of studies conducted so far makes itdifficult to accurately determine the incidence ofcutaneous tuberculosis.

Lichen scrofulosorum is frequently found inchildren and adolescents. Data from the scientificliterature showed a higher frequency of lichenscrofulosorum in young individuals, the adultdisease being rarely reported. Most cases,approximately 84%, occur in patients under 15years, with a male predominance (15). In ourcase, the patient was 34 years old at the time ofthe first appearance of skin lesions.

The election site of lichen scrofulosorum is onthe trunk (17). Several other distributions werereported, with skin lesions localised on the face(18), on the limbs, palms and soles, and on thegenital region (20) (21). The particularity of thepresented case resides in the atypical distributionof the skin lesions. In addition to the election sitesof lichen scrofulosorum, the patient presentedmultiple papules on the eyelids, nose andearlobe.

Lichen scrofulosorum is a paucibacillaryform of cutaneous tuberculosis since themycobacteria are almost never identified withspecial stains or by microbial culturing, confiningthe usefulness of these investigations. Modernmolecular diagnosis techniques, such asPolymerase Chain Reaction, allow a rapididentification of mycobacterial DNA in theaffected tissues. The test has a diagnostic value, ifthere is a release of bacterial DNA in the skinlesions. In lichen scrofulosorum, a paucibacillaryinfection, the utility of PCR may be questioned.In the scientific literature only 2 reported cases oflichen scrofulosorum had positive mycobacterialDNA in the sampled tissues (22)(23).

Tuberculin skin test screens for individualswith a higher susceptibility to M. tuberculosis, andconsists in the intradermal injection of 5 units oftuberculin and the evaluation of the reaction atthe site of inoculation (25). The results are read48-72 h after the inoculation and are consideredpositive if the induration has a diameter larger

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cantitatea de γ-interferon eliberatã de limfocitelesensibilizate(13). În literaturã, în cazurile delichen scrofulosorum sunt citate atât rezultatepozitive (27) cât ºi negative (28) la testarea laQuantiFERON.

Studiile clinice realizate pânã în prezent auevidenþiat o asociere în 72% din cazuri alichenului scrofulosorum cu alte focare tuber-culoase profunde. În o treime din cazuri pacienþiiau prezentat limfadenopatie tuberculoasã,urmatã de tuberculozã pulmonarã ºi cere-bralã(17). Pentru identificarea focarelor infec-þioase profunde sunt necesare investigaþiisuplimentare sangvine, urinare, probe micro-biologice de sputã, radiografie toracicã ºitomografie computerizatã osoasã. În cazulpacientei noastre culturile microbiologice ºiinvestigaþiile imagistice nu au evidenþiatpotenþiale focare tuberculoase active. Într-unstudiu efectuat pe un lot de 39 pacienþi cu lichenscrofulosorum, s-a observat cã în 28% nu a fostidentificat un focar infecþios profund(17).

Diagnosticul este adeseori întârziat din cauzasimilitudinilor clinice cu alte leziuni cutanateprecum lichen plan, lichen nitidus, sifilidelichenoide sau forma micropapuloasã desarcoidozã.

Standardul de aur în stabilirea diagnosticuluide certitudine este reprezentat, prin urmare, deexamenul histopatologic, în asociere cuconfirmarea unei infecþii tuberculoase activeinterne. La examenul histopatologic se evi-denþiazã, în cazul LS, granuloame epiteloidelocalizate la nivelul dermului papilar ºiperivascular. Granuloamele sunt compuse dinhistiocite epitelioide, cu nuclei mari ºi citoplasmãintens eosinofilicã, celule gigant multinucleate detip Langhans ºi limfocite mici situate în periferie.Frecvent este prezent ºi un infiltrat inflamator,dispus atât în dermul superficial cât ºi în celprofund(27). În majoritatea cazurilor nu existãmodificãri epidermice, iar granulomul cu necrozãcentralã este excepþional(29). Diagnosticuldiferenþial histopatologic este larg, incluzândlichen nitidus, sifilide, brucelozã, leishmaniozãcutanatã cronicã, infecþii micobacteriene atipice.Histopatologic diagnosticul poate fi dificil,aspectul de dermatitã granulomatoasã nece-sitând corelaþii clinico-patologice aprofundate. Încazul pacientei noastre, primele biopsii au

than 5 mm. The QuantiFERON test is a moderntechnique that allows a rapid determination ofthe exposure to mycobacteria. In order toperform the test, a blood sample should becollected from the patient. The interpretationdepends on the amount of γ-interferon releasedby the lymphocytes. QuantiFERON testing inspecialized literature however, is associated withboth positive (27) and negative results (28).Clinical trials completed to date have shown anassociation in 72% of cases of lichenscrofulosorum with other active sites of deeptuberculosis. One third of cases presentedtuberculous lymphadenopathy, followed bypulmonary and cerebral tuberculosis (17). Inorder to identify deeper sites of infection furtherinvestigations, including blood count, renalfunction, microbiological examination of thesputum, chest X-ray and Computed Tomographyscan of the bones should be performed.However, in the presented case themicrobiological studies and the imaginginvestigations did not reveal active sites ofinfection.

The golden standard for diagnosis isrepresented, therefore, by histopathologicalexamination, in association with confirmation ofother internal active tuberculosis infection sites.In case of LS, histopathological examinationreveals epithelioid granulomas localized in thepapillary dermis and perivascular. Thegranulomas are composed of epithelioidhistiocytes with intense eosinophilic cytoplasmand large nuclei, giant multinucleated Langhanscell type and small lymphocytes located in theperiphery. Frequently, an inflammatory infiltrateis present, in the upper and lower layers of thedermis (27). In most cases there are no epidermalchanges and granuloma with central necrosis isvery rare (28). Histopathological differentialdiagnosis is broad and includes lichen nitidus,syphilides, brucellosis, chronic cutaneousleishmaniasis, cutaneous infection with atypicalmycobacteria. Histopathologic diagnosis can bedifficult, with granulomatous dermatitisrequiring thorough clinicopathological cor-relations. In our patient case, the first biopsypresented histopathological changes interpretedas sarcoidosis, lichen nitidus, but also asxantogranulom. Lichenoid secondary syphilis

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prezentat modificãri histopatologice interpretateca sarcoidozã, lichen nitidus ºi respectivxantogranulom. Sifilidele lichenoide ar fi putut filuate în considerare, prin prezenþa a numeroaseplasmocite, alãturi de infiltratul granulomatos.Totuºi, absenþa neutrofilelor, a acantozeipsoriaziforme ºi a modificãrilor vasculare facluesul secundar mai puþin probabil. Afectarea decãtre infiltratul limfocitar ºi granulomatos atuturor papilelor dermice pe toatã lungimeabiopsiei ºi dispunerea ºi perianexialã a acestuianu au fost în favoarea unui lichen nitidus.

Patogenia LS nu este complet elucidatã, însãmulþi autori sunt de pãrere cã acest proces esteîntâlnit la pacienþii cu reactivitate anormalã latuberculinã, ce asociazã ºi un focar infecþiosprofund. De la nivelul focarului infecþios, are loco diseminare pe cale hematogenã, capabilã sãproducã hiperreactivitate, urmatã de formarea decomplexe antigen-anticorp, care pot induce oreacþie de hipersensibilitate de tipul IV,determinând granulomul tuberculos. Rezultatelenegative la testarea la tuberculinã raportate înunele cazuri de lichen scrofulosorum suntinterpretate de unii autori ca fiind expresiavariabilitãþii în timp a statusului imun alpacientului(19).

Tuberculoza cutanatã, urmeazã aceleaºiprincipii de tratament ca ºi tuberculozapulmonarã, þinând cont ºi de extinderea infecþieiºi de statusul imun al pacientului. Prima linie detratament este reprezentatã de terapia combinatã.Medicamentele cel mai frecvent folosite suntIzoniazida, Rifampicina, Pirazinamida ºi Etam-butol. Tratamentul chimioterapic se desfãºoarãpe o perioadã de 6-9 luni ºi este divizat în douãfaze: o fazã rapidã sau bactericidã, cu scopul de areduce rapid încãrcãtura bacterianã ºi o a douafazã menitã sã sterilizeze complet focareleinfecþioase(30). Dupã primele opt sãptãmâni detratament, pacienþii nu mai sunt consideraþicontagioºi, însã continuarea tratamentuluisistemic este obligatorie. Rãspunsul la tratamenteste evaluat pe baza examenului clinic.

În ceea ce priveºte atitudinea terapeuticã dincazul prezentat, pacienta a beneficiat de terapiecombinatã tuberculostaticã, cu controlul periodical funcþiei hepatice, renale ºi evaluareoftalmologicã. Terapia a fost iniþiatã înseptembrie 2014, cu evoluþie lent favorabilã, dar

could be taken into account, due to the presenceof numerous plasma cells, together with agranulomatous infiltrate. However, the absenceof neutrophils, of psoriasiform acanthosis andvascular changes make secondary syphilis lesspossible. Damage caused by lymphocyte andgranulomatous infiltration of all dermal papillaeon the entire biopsy lenght, but also itsperianexial arrangement were not in favor oflichen nitidus.

The pathogenesis of lichen scrofulosorum isnot completely elucidated, although manyauthors believe that this disease develops inpatients with tuberculin hyperreactivity, whoalso present deeper sites of infection. From theinfectious site, the hematogenous spread ofbacteria enables them to cause immunehyperreactivity, followed by the formation ofantigen-antibody complexes, which may inducea Type IV hypersensitivity reaction, causingtuberculous granulomas. Negative results oftuberculin skin test, reported in some cases, wereinterpreted by some authors as an expression of patients immunological status variability intime (19).

Cutaneous tuberculosis follows the sametherapeutical principles as in pulmonarytuberculosis, taking into account the extension ofthe infection and the patient’s immune status.The first line in treatment is the combinationtherapy. The drugs most commonly used areIsoniazid, Rifampicin, Pyrazinamide andEthambutol. Chemotherapy is conducted for aperiod of 6-9 months and is divided into twoparts: the rapid or bactericidal phase, in order torapidly reduce the bacterial load, and the secondphase aimed to completely sterilize the infectioussites (27). After eight weeks of treatment, thepatients are no longer considered contagious, butfurther systemic treatment is mandatory.Treatment response is clinically evaluated.

Regarding the therapeutic approach of thepresented case, the patient received tuber-culostatic therapy, with periodical monitoring ofthe renal and liver function, and repeatedophtalmological evaluation. The therapy wasinitiated in september 2014 with a slow clinicalimprovement, with lesions persisting especiallyon face region. Studies show that a favorablecourse of lichen scrofulosorum, with the

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cu remanenþa leziunilor în special la nivelul feþei.În literaturã, evoluþia favorabilã cu rezoluþialeziunilor de tip lichen scrofulosorum la 6-8sãptãmâni de tratament este descrisã(17). Înschimb au fost raportate cazuri de apariþie a LS lacâteva sãptãmâni dupã iniþierea tratamentuluiantituberculos pentru o infecþie sistemicã. Acestfenomen poate fi corelat cu natura imunogenicã aLS, ce reprezintã o manifestare de hiper-sensibilitate la prezenþa antigenului mico-bacterian, distrugerea masivã a bacililortuberculoºi în alt focar putând alimenta unrãspuns imun celular crescut la nivel cutanat(27).Acest lucru ar explica remiterea rapidã aleziunilor cutanate la pacienþii cu multiple focaretuberculoase.

Concluzii

Cazul prezentat este ilustrativ pentrudificultãþile de diagnostic ºi tratament, precum ºipentru variaþiile individuale de aspect, statusimun ºi evoluþie în tuberculoza cutanatã.Diagnosticul de certitudine al lichenuluiscrofulosorum este adeseori întârziat datoritãraritãþii acestei manifestãri cutanate, cât ºidatoritã diagnosticului diferenþial complex.Prezenþa unor leziuni papuloase ºi granulo-matoase persistente, rezistente la terapiile clasicear trebui sã conducã spre un astfel de diagnostic.De asemenea, acest diagnostic trebuie avut învedere în mod particular în þara noastrã, undeincidenþa ºi prevalenþa TBC se menþin la coteridicate.

Menþiune: Autoarea Mara Mãdãlina Mihaieste implicatã în proiectul POSDRU/159/1.5/S/141531, intitulat „Dezvoltarea resurselorumane- doctoranzi ºi postdoctoranzi - pentrucercetare de excelenþã în domeniile sãnãtate ºibiotehnologii“.

resolution of the disease, occurs in 6-8 weeks oftreatment (17). On the other hand, some reportspresent patients who developed lichenscrofulosorum several weeks after initiation oftuberculostatic treatment for systemic infection.This can be correlated with the immunogenicnature of lichen scrofulosorum: a massivemycobacterial destruction in another site ofinfection leads to a hypersensitivity response tothe released antigens, with an increased cellularimmune response in the skin. This would explainthe rapid remission of cutaneous lesions inpatients with multiple sites of infection.

Conclusions

The presented case reflects the difficultiesencountered in the diagnosis and treatment ofcutaneous tuberculosis, as well as the individualcharacteristics of the clinical picture, the immunestatus and disease progression. The positivediagnosis of lichen scrofulosorum is frequentlydelayed, due to its rarity, as well as its complexdifferential diagnosis. The pressence of persistentpapular and granulomatous lessions resistant toother therapies should be taken intoconsideration at diagnosis. Also, this diagnosticmust be considered particularly in our country,where TB incidence and prevalence remains high.

Acknowledgement: The author MaraMãdãlina Mihai is part of the projectPOSDRU/159/1.5/S/141531, entitled “HumanResource Development - PhD students andpostdocs - for research excellence in health andbiotechnology”.

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Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresa de corespondenþã: Ana-Maria ForseaDepartamentul de dermatologie, Spitalul Universitar de Urgenþã Elias, Bulevardul Mãrãºti nr 17.Telefon/fax: 0722765884E-mail: [email protected]

Correspondance address: Ana-Maria ForseaDepartment of Dermatology, University Emergency Hospital Elias,Boulevard Marasti No 17.Phone / fax: 0722765884E-mail: [email protected]

lichen scrofulosorum – o formÃrarÃ de ......tuberculoza pulmonarã, þinând cont de extinderea...

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