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REFERATE GENERALE

GENERAL REPORTS

ASPECTE HISTOPATOLOGICE
ÎN AFECÞIUNILE GRANULOMATOASE

HISTOPATHOLOGICAL FEATURES
OF GRANULOMATOUS DISEASES
OLGUÞA ANCA ORZAN*, IRINA TUDOSE**

Bucureºti

Rezumat Summary
Afecþiunile granulomatoase reprezintã un grup de boli Granulomatous diseases are a group of various
cu etiologie ºi cu manifestãri clinice variate care au în disorders, having different etiology and clinical findings,
comun formarea de granuloame (la nivel cutanat sau al but with the same histopathological features (cutaneous or
altor organe), evidenþiabile la examenul histopatologic. other organ granulomas).
Denumirea de granulom provine din limba
The term „granuloma” comes form the latine
latinã–granulum (granula) +oma (rezultatul unei acþiuni),
–granulum (grain) +oma (the result of an action), and it is
iar din punct de vedere histopatologic se defineºte ca o
defined as a collection of histiocytes.
colecþie organizatã de histiocite.
În funcþie de aspectul histopatologic, þinându-se cont Based on histological features, taking into account the
de tipul celular predominant, aranjamentul histiocitelor, main cellular type, the histiocyte arrangement, the absence/
absenþa/prezenþa ºi tipul necrozei, precum ºi cantitatea, presence and type of necrosis, as well as the amount, the
distribuþia ºi compoziþia infiltratului inflamator, afecþiunile distribution and composition of the inflammatory infiltrate,
granulomatoase pot fi împãrþite în cinci categorii: the granulomatous disorders can be divided into five
granuloame epitelioide, cunoscute ºi sub denumirea de categories: epithelioid granuloma („naked granuloma”),
„naked granuloma”, granuloame tuberculoide, granuloame tuberculoid granuloma, palisade granuloma, suppurative
în palisadã, granuloame supurative ºi granuloame de corp granuloma and foreign body granuloma.
strãin. Key word: epithelioid granuloma, „naked
Cuvinte cheie: granulom epitelioid, „naked
granuloma”, tuberculoid granuloma, palisade granuloma,
granuloma”, granulom tuberculoid, granulom în palisadã,
suppurative granuloma, foreign body granuloma,
granulom supurativ, granulom de corp strãin, reacþie
granulomatous reaction.
granulomatoasã.

DermatoVenerol. (Buc.), 56: 79-87

* Spitalul Clinic Universitar de Urgenþã „Elias“, Bucureºti


** Spitalul Clinic de Dermato-venerologie “Scarlat Longhin”, Bucureºti

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Descrierea elementelor celulare conþinute Main cells of the granulomatous


în infiltratul granulomatos reaction
Histiocitele, denumite ºi macrofage, îºi au Histiocytes, also called macrophages have
originea în mãduva osoasã de unde sunt eliberate their origin in the bone marrow. They are
în circulaþia sangvinã îndreptându-se cãtre released into the blood flow and travel to the
þesuturi sub formã de monocite. În condiþiile unei tissues as monocytes. On proper stimulation
stimulãri corespunzatoare, monocitele se trans- monocytes develop into macrophages which are
formã în macrofage care se pot prezenta sub epithelioid and foreign body giant cells (1).
forma celulelor epitelioide ºi a celulelor gigante The macrophages have an important role
multinucleate. (1) both in the phagocytosis process, being able to
Macrofagele îndeplinesc un rol extrem de ingest large particles (microorganisms, cellular
important în procesul de fagocitozã, fiind capa- detritus, etc), and in the cellular and humoral
bile sã ingere particule mari (microorganisme, immunological reactions, processing and
detritusuri celulare, etc.), cât ºi în reacþiile presenting the antigen and releasing bioactive
imunologice mediate celular ºi umoral, prin molecules (cytokines, growth, chemotactic and
procesarea ºi prezentarea antigenului ºi secreþia coagulation factors, enzymes, fractions of the
unor molecule bioactive (citokine, factori de complement, etc).
creºtere, factori chemotactici, de coagulare, Accordingly to the histological features, the
enzime, fracþiuni ale complementului, etc). monocytes are, in general, difficult to distinguish
Din punct de vedere histopatologic, mono- by the lymphocytes as both cells have similar
citele sunt, în general, greu de diferenþiat de features: a rounded, dark nucleus and scanty
limfocite deoarece ambele tipuri celulare au cytoplasm. (1)
caracteristici similare: nucleu hipercrom, rotund Macrophages or histiocytes are larger cells
ºi citoplasmã redusã cantitativ. (1) than the monocytes, with a lightly stained
Macrofagele sau histiocitele, au dimensiuni cytoplasm, a rounded nucleus with a well visible
mai mari decât monocitele, au citoplasma mai nuclear membrane. There are cases when the
palid coloratã, nucleul rotund-ovalar ºi macrophages cannot be morphological
membrana nuclearã bine vizibilã. Existã situaþii differentiated by fibroblasts or endothelial cells.
în care macrofagele nu pot fi diferenþiate In these situations the immunohistochemical
morfologic de fibroblaste sau de celulele exams could be helpful since the macrophages
endoteliale, situaþii în care este utilã efectuarea de are positive for KiM1p and KP (CD68). (2)
teste imunohistochimice. Markerii imuno- The epithelioid cells or histiocytes develop
histochimici pozitivi pentru macrofage sunt from macrophages, especially secondary to
KiM1p ºi KP (CD68). (2) delayed hypersensitivity reactions. They are
Celulele epitelioide sau histiocitele epi- termed “epithelioid” because of their
telioide se dezvoltã din macrofage, în special, în resemblance to epithelial cells: rounded, central
urma reacþiilor de hipersensibilitate întârziatã. placed nucleus and an eosinophilic cytoplasm.
Sunt denumite astfel datoritã asemãnãrii cu These histiocytes can be found either in groups,
celulele epiteliale: au nucleul rotund-ovalar, forming the epithelioid granulomas, or among
central situat ºi citoplasma abundentã, eozinofilã. lymphocytes, macrophages and foreign body
Se gãsesc fie grupate sub forma granuloamelor giant cells. (1)
epitelioide, fie amestecate printre limfocite, Giant cells (histiocytes) are large, multi-
macrofage ºi celule gigante de corp strãin. (1) nucleate cells. There are several types of giant
Celulele (histiocite) gigante sunt celule mari, cells, but none is specific for a certain disease:
multinucleate. Existã mai multe tipuri de celule 1. Foreign body giant cells contain
gigante, dar niciunul nu este specific unei numerous nuclei, uneven distributed in
anumite afecþiuni. Se descriu astfel: the cytoplasm. They are found in all
1. Celule gigante de corp strãin care conþin foreign body reactions and several
numeroºi nuclei neregulat distribuiþi la tumors;

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nivelul citoplasmei. Se întâlnesc în toate 2. Langhans giant cells have the nuclei
reacþiile de corp strãin ºi în unele tumori; arranged as a horseshoe at the periphery
2. Celule gigante Langhans în care nucleii of the cell. They are found in infectious
sunt aranjaþi sub formã de potcoavã la conditions, including tuberculosis;
periferie. Apar în procese infecþioase, 3. Touton giant cells have numerous nuclei
inclusiv TBC; placed around a central and condensate
3. Celule gigante de tip Touton în care existã cytoplasm, and between the nuclei and
numeroºi nuclei situaþi în jurul unei the membrane cell there are inclusions
citoplasme centrale, condensate, iar între with lipids. The lipids are dissolved by
nuclei ºi membrana celularã se gãsesc usual fixation and tissue preparation
incluzii lipidice. Aceste incluzii nu pot fi (paraffin sections). They can be identified
evidenþiate pe secþiunile la parafinã, on frozen sections using Sudan III and
pentru vizualizarea acestora fiind Scharlac stains. Touton giant cells are
necesarã efectuarea de secþiuni la gheaþã found in xanthomas, juvenil xantho-
si coloratii special Sudan III si Scharlac. granuloma, xantomatous dermato-
Celulele gigante de tip Touton sunt fibroma and foreign body reactions. (3)
întâlnite în xantoame, xantogranulom
juvenil, dermatofibrom xantomatos ºi
Histopathological classification
reacþii de corp strãin. (3)
of granulomatous diseases
Clasificarea histopatologicã a afecþiunilor Based on histological features, taking into
granulomatoase account the main cellular type, the histiocyte
arrangement, the absence/ presence and type of
În funcþie de aspectul histopatologic, necrosis, as well as the amount, the distribution
þinându-se cont de tipul celular predominant, and composition of the inflammatory infiltrate,
aranjamentul histiocitelor, absenþa/prezenþa ºi the granulomatous disorders can be divided into
tipul necrozei, precum ºi cantitatea, distribuþia ºi five categories:
compoziþia infiltratului inflamator, afecþiunile 1. epithelioid granuloma („naked granu-
granulomatoase pot fi împãrþite în cinci categorii: loma”)
1. granuloame epitelioide, cunoscute ºi sub 2. tuberculoid granuloma
denumirea de „naked granuloma” 3. palisading granuloma
2. granuloame tuberculoide 4. suppurative granuloma
3. granuloame în palisadã 5. foreign body granuloma.
4. granuloame supurative
5. granuloame de corp strãin 1. Epithelioid granuloma (fig. 1, 2, 3) is a
collection of epithelioid cells throughout
1. Granulomul epitelioid (fig.1, 2, 3) este the dermis, without or with minimal
alcãtuit din celule epitelioide grupate în associated lymphocyte infiltrate (“naked
derm, cu un infiltrat inflamator minim granuloma”). Because the “specific”
sau absent („naked granuloma”). Întrucât histopathological changes in sarcoidosis
modificarea histopatologicã „specificã” were considered to be the epithelioid
din sarcoidozã este consideratã ca fiind granulomas, they were also called
granuloamul epitelioid, acesta a mai fost sarcoidal granulomas. However, these are
denumit ºi granulom sarcoidal. Cu toate not specific for sarcoidosis, as they can be
acestea, el nu este specific sarcoidozei, also found in several granulomatous
mai putând fi întâlnit ºi în alte dermatite dermatitis as a response to a foreign
granulomatoase, de exemplu ca rãspuns material (beryllium, zirconium, silica,
la un corp strãin (beriliu, zirconiu, siliciu, tattoo pigments) (4), to infectious agents
pigment din tatuaje) (4), la un agent (5), in immunodeficiency disorders (6),

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Fig. 1. Multiple granuloame de tip epitelioid (HEx40). Fig. 2. Granuloame epitelioide care nu conflueazã (HEx100).
Multiple epithelioid granulomas (HEx40). Non-coalescing epithelioid granulomas (HEx100).
Fig. 1. Multiple epithelioid granulomas type (HEx40). Fig. 2. Epithelioid granulomas not confluence (HEx100).
Multiple epithelioid granulomas (HEx40). Non-coalescing epithelioid granulomas (HEx100).

Fig. 3. Granulom epitelioid înconjurat de infiltrat inflamator


limfocitar ºi fãrã necrozã fibrinoidã sau de cazeificare (HEx200).
Epithelioid granuloma surrounded by a lymphocytic infiltrate
with neither fibrinoid nor caseation necrosis (HEx200).
Fig. 3. Epithelioid granuloma surrounded by lymphocytic
inflammatory infiltrate without fibrinoid necrosis or cazeificare
(HEx200). Epithelioid granuloma Surrounded by a lymphocytic
infiltration with fibrinoid cloud neither caseation necrosis
(HEx200).

infecþios (5), în sindroame de imuno- lymphoproliferative disorders (7) and


deficienþã (6), boli limfoproliferative (7) ºi drug eruptions (8).
erupþii postmedicamentoase (8). 2. Tuberculoid granuloma is a collection of
2. Granulomul tuberculoid se formeazã histiocytes (multinucleate –Langhans
prin gruparea histiocitelor (multinucleate type and epithelioid histiocytes)
– de tip Langhans ºi epitelioide), surrounded by a dense lymphocytic
înconjurate de o coroanã limfocitarã, iar infiltrate and sometimes with a central
în centru, uneori, de o zonã de necrozã de caseation necrosis. Ziehl-Neelson stain
cazeificare. Cu ajutorul coloraþiei Ziehl- identifies acid fast bacilli, especially in the
Neelson pot fi identificaþi bacilii (de zone of necrosis (the bacilli are colored in
culoare roz pe fond albastru deschis, pink on a light blue background and they
bacili cu lungimea de 4 nm), mai ales în are 4 nm in diameter). The tuberculoid
zona centralã de necrozã de cazeificare. granulomas are seen in infections with
Granuloamele de tip tuberculoid apar în Mycobacterium tuberculosis or atypical
infecþiile cu Mycobacterium tuberculosis mycobacteria. In leprosy, the granulomas
sau alte mycobacterii atipice. Granu- are perivascular and along the

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loamele din leprã sunt mai alungite, cu perineurovascular bundels. These granu-
dispoziþie, mai ales, perivascularã ºi lomas can also occur after BCG
perineuralã. Se mai pot dezvolta ºi dupã vaccination and after immunotherapy, in
vaccinarea BCG ºi dupã imunoterapie, în late secondary syphilis (numerous
sifilis secundar tardiv (asociazã nume- plasmocytes associated), perioral
roase plasmocite), dermatita perioralã, dermatitis, granulomatous rosacea,
rozaceea granulomatoasã, boala Crohn cutaneous Crohn disease and granulo-
cutanatã ºi cheilita granulomatoasã matous cheilitis (Melkerson-Rosenthal
(sindrom Melkerson-Rosenthal). syndrome).
3. Granulomul în palisadã (fig. 4, 5) este 3. Palisading granuloma (fig. 4, 5) is
alcãtuit dintr-o zonã centralã de degene- characterized by a central zone of altered
rescenþã a colagenului ºi/sau necrozã collagen and/or necrosis, surrounded by
înconjuratã de histiocite epitelioide ºi epithelioid and giant multinucleate
celule gigante. Pot fi clasificate în granu- histiocytes. They can be classified in
loame „albastre” datoritã depozitelor de “blue” granulomas due to mucin
mucinã (granulom inelar) (fig. 6, 7) sau (granuloma annulare) (fig. 6, 7) or due to
datoritã prafului nuclear neutrofilic neutrophilic nuclear dust (palisading
(dermatitã granulomatoasã ºi neutrofilicã granulomatous and neutrophilc der-
în palisadã sau granulomul Churg- matitis or Churg-Strauss dermatitis), and
Strauss) ºi roºii datoritã hialinizãrii “red” granuloma due to degenerated
colagenului (necrobiozã lipoidicã, xanto- collagen (necrobiosis lipoidica, necro-
granulom necrobiotic) (fig. 8), depozitelor biotic xanthogranuloma), (fig. 8) deposits
de fibrinã (noduli reumatoizi) sau of fibrin (rheumatoid nodules) or altered
eozinofilelor degradate (sindrom Wells ºi eosinophils (Wells syndrome and Churg-
sindrom Churg-Strauss). Strauss syndrome).
4. Granuloamul supurativ (fig. 9, 10) con- 4. Suppurative granuloma (fig. 9, 10)
þine pe lângã celule gigante numeroase contains in addition to histiocytes,
neutrofile ºi o zonã de necrozã tisularã. numerous neutrophils and, possible, a

Fig. 4. Granulom în palisadã -fibre de colagen îngroºate ºi Fig. 5. Granulom în palisadã (HEX100). Palisading
degenerate (HEx40). Palisading granuloma -degenerated granuloma (HEx100).
collagen fibers (HEx40). Fig. 5. Granuloma in the palisade (HEX100). Palisading
Fig. 4. Granuloma in the palisade-thick collagen fibers and granuloma (HEx100).
degenerated (HEx40). Granuloma-degenerated collagen
Palisading Fibers (HEx40).

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Fig. 6. Granulom inelar -depozite centrale de mucinã cu Fig. 7. Granulom inelar -depozite de mucinã (AAx200).
histiocite dispuse în palisadã în periferie (AAx100). Granuloma annulare -deposits of mucin (AAx200).
Granuloma annulare - central deposits of mucin (AAx100). Fig. 7. Granuloma annular-mucin deposits (AAx200).
Fig. 6. Granuloma annular-central mucin deposits with Annular granuloma-deposits of mucin (AAx200).
histiocite arranged in the peripheral palisade (AAx100).
Annular granuloma-central deposits of mucin (AAx100).

Fig. 8. Granulom în palisadã -fibre de colagen îngroºate ºi Fig. 9. Granulom supurativ (HEx100). Suppurative
fragmentate (PASx200). Palisading granulomma -thickened granuloma (HEx100).
and altered collagen fibers (PASx200). Fig. 9. Suppurative granuloma (HEx100). Suppurative
Fig. 8. Granuloma in the palisade-thickened and fragmented granuloma (HEx100).
collagen fibers (PASx200). Palisading granulomma-
thickened and altered collagen Fibers (PASx200).

Cele mai frecvente situaþii în care apar central necrosis. The two most common
reacþii granulomatoase supurative cuta- causes of suppurative granulomantous
nate sunt datorate agenþilor infecþioºi reaction in the skin are infectious agents
(micoze profunde, boala ghearelor de (deep fungi, cat scratch disease, etc) and
pisicã, etc) ºi corpilor strãini (cel mai foreign body (most commonly the
adesea conþinutul unui chist rupt). (9) contents of a ruptured cyst).(9)
5. Granulomul de corp strãin (fig. 11, 12, 5. Foreign body granuloma (fig. 11, 12, 13)
13) apare ca reacþie la materiale exogene is developed as a reaction to exogenous

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Fig. 10. Granulom supurativ (HEx200). Suppurative Fig. 11. Reacþie de corp strãin în jurul unor fragmente de
granuloma (HEx200). keratinã de la nivelul tijei foliculului pilos (HEx200).
Fig. 10. Granulom suppurative (HEx200). Suppurative Foreign body reaction around fragments of keratin from a
granuloma (HEx200). hair follicle (HEx200).
Fig. 11. Foreign body reaction around the fragments of
keratin from hair follicle stem (HEx200). Foreign body
reaction around fragments of keratin from the hair follicle
(HEx200).

Fig. 12. Reacþie de corp strãin -celule gigante multinucleate Fig. 13. Celule gigante de corp strãin cu resturi de keratinã
cu resturi de keratinã intracitoplasmaticã (HEx200). Foreign intracitoplasmatic (HEx400). Multinucleate giant cells with
body reaction - multinucleate giant cells with intra- intracytoplasmic fragments of keratin (HEx400).
cytoplasmic fragments of keratin (HEx200). Fig. 13. Foreign body giant cells with intracytoplasmic
Fig. 12. Foreign-body reaction with multinucleated giant keratin debris (HEx400). Multinucleated giant cells with
cells and intracytoplasmic keratin debris (HEx200). Foreign- intracytoplasmic fragments of keratin (HEx400).
body reaction with multinucleated giant cells intra-
cytoplasmic fragments of keratin (HEx200).

(aºchii, materiale de suturã, siliciu, sticlã) material (splinters, sutures, mouthparts


sau materiale endogene (uraþi, calciu, of a tick) and to endogenous material
keratinã, pãr). Din punct de vedere (hair, keratin, calcium, etc). It must be
histopatologic poate avea aspect de noted that foreign bodies can induce any
granulom epidelioid, în palisadã sau type of granuloma formation, i.e.
supurativ. sarcoidal, tuberculoid, palisading and
suppurative.

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Tabel 1. Clasificarea afecþiunilor granulomatoase

Granuloame Granuloame Granuloame Granuloame


epitelioide tuberculoide Granuloame în palisadã supurative de corp strãin

- sarcoidozã - TBC Granuloame Granuloame "roºii" - infecþii - materiale exogene


- reacþii de corp - infecþii cu "albastre" - colagen hialinizat: - chiste foliculare (aºchii, materiale
strãin (tatuaje, mycobacterii - mucinã: • necrobioza rupte de suturã, siliciu,
siliciu, etc) atipice granulom inelar lipoidicã - corpi exogeni sticlã)
- leprã - neutrofile: - depozite de fibrinã: - corpi endogeni - materiale
- sifilis tertiar granulomatoza • nodul reumatoid endogene (uraþi,
- rozacee Wegener - eozinofile de calciu, keratinã,
granulomatoasã generate: pãr).
- boala Crohn • sindrom Well's
cutanatã • sindrom Churg-
- cheilita Strauss
granulomatoasã
- leishmania

Table 1. Classification of granulomatous diseases

Epithelioid Tuberculoid Suppurative Foreign body


granuloma granuloma Palisading granuloma granuloma granuloma

- sarcoidosis - tuberculosis “Blue” granulomas: “Red” granuloamas: - infections - exogenous


- foreign body - infections with - mucin: granuloma - degenerated - ruptured materials
reactions atypical annulare collagen infundibular cysts (splinters, sutures,
(tattoo, sillicca, mycobacteria - neutrophils: • necrobiosis – foreign bodies etc)
etc) - leprosy Wegener lipoidicã - endogenous
- tertiary sifilis granulomatosis - deposits of fibrin materials (hair
- granulomatous • rheumatoid follicles, keratin).
rozacea nodule
- cutaneous Crohn - altered eosinophils
disease • Well’s syndromE
- granulomatous • Churg-Strauss
cheilitis syndrome
- leishmania

În ultima perioada, date din literaturã fac Lately, there are more and more reports in the
referire din ce în ce mai frecvent la un tip literature about a special type of foreign body
particular de granulom de corp strãin, ºi anume granuloma, namely, the granuloma secondary to
granulomul apãrut secundar injectãrii unei injection of a dermal filler agent. Along with the
substanþe de tip „filler”. Utilizarea acestor significant increased of using of dermal fillers,
„fillere” a crescut semnificativ în ultimul deceniu, the number of complications associated to this
crescând ºi incidenþa complicaþiilor asociate technique has increased as well. A characteristic
utilizãrii acestei proceduri dermato-cosmetice. O feature of these pathological reactions is the
trãsãturã caracteristicã a acestor reacþii patologice heavy inflammation which often it is a
este inflamaþia excesivã care cel mai adesea este granulomatous one. There are cases when the
granulomatoasã, dar poate fi ºi supurativã sau type of the inflammatory infiltrate helps

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limfo-plasmocitarã. Existã situaþii în care tipul identifying the type of the used cosmetic agent.
infiltratului inflamator ajutã la identificarea Understanding of the histopathological features
compoziþiei agentului cosmetic utilizat. Înþe- of the fillers used is important for a correct
legerea caracteristicilor histopatologice ale diagnosis, as well as for a correct therapeutic
fillerelor este importantã pentru stabilirea unui strategy. (10)
diagnostic corect ºi pentru adoptarea une Received: 1.02.2011
conduite terapeutice corespunzãtoare.
Intrat în redacþie: 1.02.2011

Bibliografie/Bibliography
1. Lever W.F., Schamburg-Lever G. Histopathology of the Skin 6th Edition. J.B. Lippincott Company, p 51-53;
2. Lu K.Q. Granulomatosis in Clinical and Basic Immunodermatology by Gaspari A.A, Tyring S.K; Springer-Verlag
London 2008, p 645-659;
3. Simmons J.R. Granulomas in Dermatopathology by Sanchez R.L, Raimer SS; Landes Bioscience 2001, p 110-124;
4. Callen J.P. The presence of foreign bodies does not exclude the diagnosis of sarcoidosis. Arch Dermatol 2001; p 137-
485;
5. Ferrara G., Cannone M., Scalvenzi M., et al. Facial granulomatous diseases. A study of four cases tested for the
presence of Mycobacterium tuberculosis DNA using nested polymerase chain reaction. Am J Dermatopathol 2001;
p 23-28;
6. Levine T.S., Price A.B., Boyle S., Webster ADB. Cutaneous sarcoid-like granulomas in primary immunodeficiency
disorders. Br J Dermatol 1994; p 130-118;
7. Scarabello A., Leinweber B., Ardigo M., et al. Cutaneous lymphomas with prominent granulomatous reaction: a
potential pitfall in the histopathologic diagnosis of cutaneous T and B-cell lymphomas. Am J Surg Pathol 2002; p
1226-1259;
8. Wendling J., Descamps V., Grossin M., et al. Sarcoidosis during combined interferon alpha and ribavirin therapy
in two patients with chronic hepatitis C. Arch Dermatol 2002; p 138-546;
9. Stander S., Boer A., Ackerman B. Rudiments: Granulomatous inflammation and granuloma: definitions and a
critique of them. Dermatopat: Practical & Conceptual Oct-Dec 2003;
10. Mercer S.E., Kleinerman R., Goldenberg G., et al. Histopathologic identification of dermal filler agents. J Drugs in
Dermatol 2010; p 1072-78.

Adresã de corespondenþã: Dr. Olguþa Anca Orzan


Correspondence adress: E-mail: olguta@gmail.com

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