DERMATOPATHOLOGY

Histopathology of anti-laminin 5 mucousmembrane pemphigoid

Christian Rose, MD,a Enno Schmidt, MD, PhD,a Andreas Kerstan, MD,b Sybille Thoma-Uszynski, MD,c

Ulrich Wesselmann, MD,d Ulrich Kasbohrer, MD,e Detlef Zillikens, MD,a and Iakov Shimanovich, MDa

Lubeck, Wurzburg, Erlangen, Wuppertal, and Oldenburg, Germany

Background: Anti-laminin 5 mucous membrane pemphigoid (MMP) is an autoimmune blistering diseasecharacterized by autoantibodies against the major basement membrane component laminin 5 (laminin 332,epiligrin).

Objective and Methods: We reviewed 17 biopsy specimens from 9 patients with anti-laminin 5 MMP in anattempt to define typical histopathologic features of the disease.

Results: Fifteen specimens showed subepidermal blister formation, while two biopsy specimens revealedan epithelial ulcer. In 11 biopsies a sparse to moderate inflammatory infiltrate composed of lymphocytesand neutrophils with some eosinophils was observed. Four biopsies showed a dense infiltrate dominatedby neutrophils in two cases and by eosinophils in one case. The remaining biopsy revealed a denselymphoplasmacellular infiltrate without granulocytes. Scarring of the upper dermis was present only in 5specimens. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister,suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane.

Limitations: The number of patients studied was relatively small.

Conclusions: Histopathology of anti-laminin 5 MMP is characterized by subepidermal blistering and asparse to moderate superficial lymphohistiocytic infiltrate with neutrophils and/or eosinophils. Bothinfiltrate density and composition may vary, making anti-laminin 5 MMP indistinguishable from otherautoimmune subepidermal blistering diseases by histopathology alone. Scarring is present only in aminority of cases and is not a sensitive clue to the diagnosis of anti-laminin 5 MMP. ( J Am Acad Dermatol2009;61:433-40.)

INTRODUCTIONMucous membrane pemphigoid (MMP), formerly

referred to as cicatricial pemphigoid or benign mu-cous membrane pemphigoid, is a subepithelial au-toimmune blistering disease predominantly affectingmucous membranes. Both older terms have beenabandoned because clinically obvious scarring is notalways present and the disease often runs a

From the Departments of Dermatology, University of Lubeck,a

University of Wurzburg,b University of Erlangen,c Helios Hospi-

tal Wuppertal,d and Oldenburg Hospital.e

Funding sources: None.

Conflicts of interest: None declared.

This work was presented in part at the 28th Symposium of the

International Society of Dermatopathology, November 14-17,

2007, Paris, France.

Reprint requests: Iakov Shimanovich, MD, Department of

Dermatology, University of Lubeck, Ratzeburger Allee 160,

23538 Lubeck, Germany. E-mail: shim92@hotmail.com.

0190-9622/$36.00

ª 2009 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2009.02.012

treatment-resistant debilitating course.1 MMP is aclinical phenotype that may be induced by autoan-tibodies to different target autoantigens. These in-clude bullous pemphigoid (BP) antigen 180, BP230,laminins 5 and 6, a6b4 integrin, type VII collagen,uncein as well as unknown proteins with a molecularweight of 45 and 168 kd (reviewed in Chan et al1).

After BP180, laminin 5, also known as laminin 332,epiligrin, kalinin, and nicein, is the second mostcommon autoantigen in MMP and is targeted in upto 20% of patients with this disease.2 Laminin 5 is aheterotrimer that consists of 3 distinct protein chainsdesignated a3, b3, and g2. Most patients with anti-laminin 5 MMP have IgG autoantibodies directed

Abbreviations used:

BP: bullous pemphigoidEBA: epidermolysis bullosa acquisitaH&E: hematoxylin and eosin (stain)MMP: mucous membrane pemphigoid

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against the a3 subunit, but other chains may also betargeted. The pathogenic relevance of laminin 5especific antibodies for subepithelial blister formationhas been demonstrated using various animalmodels.3-5

Current criteria for the diagnosis of anti-laminin5 MMP include (1) subepithelial blistering by histo-pathology, (2) linear depositsof IgG with or without C3 atthe dermoepidermal junctionby direct immunofluores-cence microscopy, (3) circu-lating IgG autoantibodiesbinding to the dermal side ofNaCl-split skin by indirectimmunofluorescence micros-copy, and (4) circulating IgGantibodies to laminin 5, asdetected by immunoblottingor immunoprecipitation.2,6

Importantly, in contrast toother forms of MMP, aboutone third of patients withanti-laminin 5 MMP have anassociated solid tumor. Therelative risk for cancer inthese patients is comparableto that for adults with dermatomyositis.7

The aim of this investigation was to study thehistopathologic spectrum of anti-laminin 5 MMP.

PATIENTS AND METHODSPatients

We examined the histopathologic slides from 9patients with anti-laminin 5 MMP. All patients fulfilledthe following diagnostic criteria: (1) subepithelialblistering by histopathology, (2) linear deposits ofIgG with or without C3 at the dermoepidermaljunction by direct immunofluorescence microscopy,(3) circulating IgG autoantibodies binding to thedermal side of NaCl-split skin by indirect immuno-fluorescence microscopy, and (4) circulating IgGantibodies to laminin 5 as detected by immunoblot-ting or immunoprecipitation. Patients 1 through 3 and7 through 9 showed immunoblot reactivity with bothprocessed (165 kd) and unprocessed (200 kd) formsof the a3 chain of laminin 5, whereas patient 6 reactedwith the b3 chain (140 kd) of this protein. Serum frompatient 5 recognized both the a3 (165 and 200 kd)and the b3 (140 kd) chains. Serum from patient 4immunoprecipitated the entire laminin 5 trimer, butremained unreactive with the denatured form of thisprotein by immunoblotting. None of the patients’ serareacted with the epidermal side of NaCl-split skin byindirect immunofluorescence or demonstrated

circulating antibodies against BP180 (type XVII col-lagen) by enzyme-linked immunosorbent assay withrecombinant BP180 NC16A or immunoblotting withthe concentrated conditioned medium of HaCaTcells. Examples of immunoblot and indirect immu-nofluorescence reactivity of the patients’ sera areshown in Figs 1 and 2, B, respectively. Further patient

details are summarized inTable I. Five patients havebeen described in detail else-where.8,9 In addition to mu-cous membranes, skin wasaffected in all patients (Figs2, A and 3, A). In 3 patients asolid neoplasm was identi-fied. The study was approvedby the local ethics committee,and informed consent wasobtained from all patients.

Histopathology,immunohistochemistry,and immunofluorescencemicroscopy

Biopsy specimens werefixed in neutrally bufferedformalin, processed for light

microscopy and stained with hematoxylin and eosin.Slides were subjectively assessed for infiltrate density(sparse, moderate, dense) and composition. Thenumber of various cell types within the infiltratewas semiquantitatively graded as few (1), some(11), and many (111). The reduction of elasticfibers in scar tissue was visualized by means ofaldehyde fuchsin staining. Immunohistochemicalstudies were performed using peroxidase-conju-gated mouse monoclonal antibody against humantype IV collagen (clone CIV 22; Dako, Glostrup,Denmark) following the manufacturer’s instructions.Direct immunofluorescence microscopy of perile-sional skin biopsies and indirect immunofluores-cence microscopy using NaCl-split normal humanskin were performed as described.10

Immunoblot and immunoprecipitaton studiesPatient and control sera were studied for the

presence of autoantibodies against laminin 5 byimmunoblotting of extracellular matrix of culturedhuman keratinocytes or immunoprecipitation of ra-diolabeled human keratinocytes as described previ-ously.6 The reactivity of patient sera against BP180(type XVII collagen) was assessed by ELISA withrecombinant BP180 NC16A (Medical and BiologicalLaboratories, Nagoya, Japan) following the manu-facturer’s instructions and by immunoblotting with

CAPSULE SUMMARY

d Anti-laminin 5 MMP is characterized bysubepidermal blistering and a sparse tomoderate superficial lymphohistiocyticinfiltrate with neutrophils and/oreosinophils.

d It cannot be distinguished from otherautoimmune subepidermal blisteringdiseases by histopathology alone.

d Scarring is not a sensitive clue to thehistopathologic diagnosis of anti-laminin5 MMP.

d Definitive diagnosis requires directimmunofluorescence and immunosero-logic studies.

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concentrated conditioned medium of HaCaT cells,containing the soluble ectodomain of this protein(LAD-1 antigen), as described previously.11

RESULTSWe examined 17 biopsy specimens from 9 pa-

tients with anti-laminin 5 MMP by light microscopy ofsections stained with hematoxylin-eosin or aldehydefuchsin and by immunohistochemistry using a mon-oclonal antibody against human type IV collagen.The results of this analysis are summarized inTable II. Fifteen biopsy specimens were obtainedfrom the skin and two biopsy specimens were fromthe oral mucosa. Fifteen specimens, obtained fromfresh tense blisters, revealed subepithelial splitting,

Fig 1. Immunoblot of extracellular matrix of culturedhuman keratinocytes. Reference serum from patient withanti-laminin 5 mucous membrane pemphigoid (lane 1) aswell as sera from patients 7, 8, and 9 in this study (lanes 3-5) recognized both unprocessed (200 kd, upper arrow)and processed (165 kd, lower arrow) forms of the a3 chainof laminin 5. Serum from a healthy volunteer (lane 2)shows no reactivity.

whereas two showed epithelial ulcers. The latterwere not evaluated for infiltrate density and compo-sition, as these were considered to be secondarilymodified by ulceration. In the 15 non-ulceratedbiopsy specimens, a mixed superficial inflammatoryinfiltrate of various intensity was seen. In 11 speci-mens the inflammatory infiltrate was sparse to mod-erate and was composed of lymphocytes andneutrophils with some eosinophils (Fig 3, B andC ). Four specimens showed a dense infiltrate dom-inated by neutrophils in two specimens and byeosinophils in one. The remaining biopsy demon-strated dense lymphoplasmacellular infiltrate with-out granulocytes. In 5 specimens scarring of theupper dermis was noted and its presence confirmedby reduction of elastic fibers detected by aldehydefuchsin stain. In all biopsy specimens with scarring,significant numbers of plasma cells within the infil-trate were found (Fig 4, A and B). In 5 patientsmultiple biopsy specimens were obtained simulta-neously from various anatomic sites (see Table II). In4 of these patients the infiltrate density was uni-formly sparse or moderate in all biopsy specimens,whereas in one patient the histologic features werediscordant in various specimens. In this latter patient,the first biopsy showed a scant infiltrate withoutgranulocytes, whereas the second specimen demon-strated a dense infiltrate dominated by eosinophils.Two patients showed a dense infiltrate composedalmost exclusively of neutrophils. In the case of a 7-year-old child neutrophilic microabscesses at the tipsof dermal papillae were observed (Fig 2, C and D).

Immunoperoxidase staining with a type IV colla-gen-specific antibody was performed on 12 of 15biopsy specimens obtained from non-ulcerated le-sions. In 11 specimens type IV collagen was detectedin the floor of the blister cavity (Fig 3, D). In one case,characterized by a particularly dense inflammatoryinfiltrate, no immunoreactivity for type IV collagen atthe dermoepidermal junction was observed.

DISCUSSIONHistopathologic examination of a skin biopsy

specimen is often the first step in the diagnosis ofan inflammatory skin disease that is difficult toclassify. Although histopathology alone is insuffi-cient to establish a definitive diagnosis of an auto-immune blistering skin disease, it may providevaluable clues pointing to such a disease andprompting the physician to initiate the appropriateimmunopathologic and immunoserologic studiesnecessary for confirmation.12,13

For practical reasons clinicians prefer to obtainbiopsy specimens from skin rather than from mu-cous membranes. Therefore, in patients with anti-

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Fig 2. Patient 7. Clinical, histopathologic, and immunofluorescence findings. A, Small tenseblister in left periorbital area of 7-year-old girl. B, Indirect immunofluorescence microscopicimage on NaCl-split skin shows circulating IgG4 autoantibodies binding to dermal side of split.C, At low power, a subepidermal blister with superficial inflammatory infiltrate is seen. D,Infiltrate is mainly composed of neutrophils that form papillary microabscesses. (C and D,Hematoxylin-eosin stain; original magnifications: B, 3200; C, 312.5; D, 3400.)

Table I. Clinical features of patients with anti-laminin 5 mucous membrane pemphigoid

Patient No. Age/Sex Involved sites

Autoantibody

specificity Associated neoplasm Reference No.

1 76/F Skin, mouth, pharynx,larynx

a3 Adenocarcinoma of colon 8

2 70/F Skin, mouth, eye, nose,pharynx, larynx, vulva

a3 Squamous cellcarcinoma of cervix

8

3 65/F Skin, mouth, nose, pharynx,larynx, vulva

a3 None 8

4 74/F Skin, eye, nose, pharynx,larynx, vulva

Laminin 5* None 8

5 70/M Skin, mouth a3 and b3 None 96 76/F Skin, mouth, eye b3 None New case7 30/M Skin, mouth a3 None New case8 7/F Skin, mouth a3 None New case9 54/M Skin, mouth a3 Small cell carcinoma of lung New case

*Immunoprecipitation demonstrated autoantibodies against the laminin 5 trimer; immunoblot studies were negative.

laminin 5 MMP, skin biopsy specimens will be oftensubmitted for histopathologic examination even ifmucous surfaces represent the most severely af-fected anatomic sites. A recently published reviewfound that skin involvement was present in 86% of 35patients with anti-laminin 5 MMP.2 Thus it is not

surprising that a vast majority of our biopsy speci-mens (88%) were obtained from the patients’ skinand not mucous membranes.

The published data on histopathology of anti-laminin 5 MMP are quite sparse. The original reporton 3 patients with anti-laminin 5 MMP by Domloge-

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Fig 3. Patient 4. Clinical and histopathologic findings. A, Tense blisters on non-inflamed skin.B, Low-power view of subepidermal blister. C, Higher magnification reveals very fewinflammatory cells. D, Immunohistochemical mapping of blister using a monoclonal antibodyagainst type IV collagen localizes this protein to the blister floor. (B and C, Hematoxylin-eosinstain; original magnifications: B, 312.5; C and D, 3400.)

Table II. Histopathologic and immunohistochemical findings in anti-laminin 5 mucous membrane pemphigoid*

Patient

No. Biopsy site

Infiltrate

density Lymphocytes Neutrophils Eosinophils

Plasma

cells Scarring

Type IV collagen

staining

1 I. Upper arm I. Sparse 1 1 e e e I. DermalII. Shoulder II. Sparse 1 1 e e e II. Dermal

2 I. Upper leg I. Moderate 1 e 1 1 1 I. DermalII. Oral mucosa II. Moderate 1 e 1 e e II. ND

3 Upper arm Sparse 1 1 e e e Dermal4 I. Chest I. Moderate 11 e e 11 1 I. Dermal

II. Chest II. Sparse 1 e 1 e e II. DermalIII. Upper arm III. Sparse 1 e 1 e e III. Dermal

5 I. Dorsum of hand I. Sparse 1 1 1 e e I. DermalII. Lower arm II. Moderate 1 11 e e e II. Dermal

6 I. Dorsum of foot I. Dense 1 1 111 11 1 I. NDII. Knee II. Sparse 1 e e 1 1 II. Dermal

7 Lower leg Dense 11 e e 11 1 ND8 Upper leg Dense e 111 e e e Dermal9 Upper leg Dense e 111 1 e e Negative

ND, Not done.

*Two biopsy specimens with ulceration were not assessed for infiltrate density and composition and are not included in this table.

Hultsch et al14 provides no histopathologic descrip-tion. In the second article by the same authors, lightmicroscopic findings of subepithelial separationwith a moderately dense lymphoplasmacytoid infil-trate in the submucosa are reported only for 1 of 3

patients.15 The subsequent 16 case reports, contain-ing any kind of histopathological data, describefindings of 12 skin and 2 oral mucosa biopsies.16-30

While subepithelial split formation was present in allsamples, no detailed information on the density and

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composition of the inflammatory infiltrate was pro-vided in a majority of cases. In 6 cases the infiltratewas described as absent or mild18,19,24,26,29,30 and inone case as moderately dense.25 The infiltrate com-position was usually reported as mixed, not other-wise specified.17,18,22,24,25,27 In 5 biopsies thepresence of eosinophils was noted,19-21,28,29 whileone additional specimen contained neutrophil gran-ulocytes.23 In two cases both eosinophils and neu-trophils were described.30 Interestingly, only onespecimen from the oral mucosa showed any evi-dence of scarring.17 In the majority of our patients wesaw a sparse superficial inflammatory infiltrate. In 4cases the infiltrate was moderate and in 3 patients avery dense infiltrate was observed. In one of thepatients, showing a dense infiltrate, the microscopicpicture was dominated by eosinophils and mimickedBP, while in two other patients the infiltrate wasmainly composed of neutrophils suggesting linearIgA disease, dermatitis herpetiformis, anti-p200 pem-phigoid or the inflammatory variant of epidermolysisbullosa acquisita (EBA). Interestingly, one of thepatients, demonstrating a dense neutrophilic infil-trate, was a 7-year-old girl who presented withmultiple small blisters and erosions in her mouthso that linear IgA disease was suspected. However,

Fig 4. Patient 4. Further histopathologic findings. A,Subepidermal blister with moderately dense infiltrateand scarring in upper dermis. B, Note plasma cells ininflammatory infiltrate and thickened collagen fibers evi-dent at higher magnification. (A and B, Hematoxylin-eosinstain; original magnifications: A, 3100; B, 3400.)

immunofluorescence and immunoblotting studiesestablished the diagnosis of anti-laminin 5 MMP.This observation underscores the fact that while thepattern of subepithelial blistering with a superficialinfiltrate rich in granulocytes is highly suggestive ofan autoimmune subepidermal blistering disease, itcannot reliably distinguish between its various typesas defined by the predominant autoantibody classand antigen specificity. Parenthetically, this patientrepresents the youngest case of anti-laminin 5 MMPpublished to date.

MMP, including anti-laminin 5 MMP, was formerlyknown as cicatricial pemphigoid, as its lesions oftenheal with scarring. Apart from EBA, characterized byIgG antibodies against type VII collagen, scarring andplasma cells are usually not seen in other autoim-mune subepidermal blistering diseases. We foundmicroscopic evidence of scarring in the superficialdermis of only 5 biopsy specimens from 4 patients. Asscarring is a chronic inflammatory process, it is notsurprising that we also observed plasma cells in thesespecimens. We assume that clinicians tend to biopsyfresh blisters so that scarring typical of long-standinglesions in patients with MMP is rarely evident inroutine histopathology samples. In addition, MMPlesions do not always heal with scarring, and itspresence has recently been abandoned as a neces-sary prerequisite for the diagnosis of MMP.1

The pathogenic relevance of autoantibodies tolaminin 5 has been demonstrated using variouspassive transfer animal models. Passive transfer ofrabbit anti-laminin-5 IgG or its Fab fragments intoneonatal mice elicited blisters in skin and mucousmembranes of the mice.3,4 In addition, IgG from twopatients with anti-laminin 5 MMP induced subepi-dermal blisters in human skin grafted onto SCIDmice.5 In all these models histopathological exami-nation of skin biopsy specimens showed subepider-mal blisters completely devoid of inflammatoryinfiltrate. Therefore, in contrast to antibodies againsttype VII collagen or BP180, laminin 5especificautoantibodies are thought to be directly pathogenicand do not require granulocyte activation for dis-ruption of dermoepidermal adhesion.3 The majorityof skin biopsies in the current study revealed sparseto moderate inflammatory infiltrate, a finding in linewith the data obtained in animal studies. However, in3 patients a dense inflammatory infiltrate dominatedby neutrophils or eosinophils was found. Thisobservation suggests that in certain patients withanti-laminin 5 MMP granulocytes might also contrib-ute to the subepithelial blister formation.

Direct and indirect immunoelectron microscopicstudies have demonstrated that IgG autoantibodiesin anti-laminin 5 MMP bind to the lower lamina

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lucida and lamina lucida-lamina densa interface,resulting in split formation within the lamina lucidaof the basement membrane.14 Immunohistochemicalanalysis performed in the present study localizedtype IV collagen to the blister floor of lesional skinfrom patients with anti-laminin 5 MMP, confirmingthat dermoepidermal separation occurs within thelamina lucida. This technique may sometimes behelpful for separation of anti-laminin 5 MMP fromEBA in situations where immunoblotting or immu-noprecipitation studies are impossible or unavail-able. Both EBA and anti-laminin 5 MMP arecharacterized by autoantibodies directed to the der-mal side of salt-split skin. In EBA in contrast to anti-laminin 5 MMP subepidermal splitting may occur inthe subelamina densa region and type IV collagenthen localizes to the blister roof.31 However, in somepatients with EBA, particularly in those with a denseinflammatory infiltrate, splitting may develop withinthe lamina lucida.32 In these cases anti-laminin 5MMP cannot be distinguished from EBA by usingtype IV collagen mapping.

In conclusion, the histopathologic findings in anti-laminin 5 MMP may be diverse. While subepidermalblistering accompanied by a sparse inflammatoryinfiltrate is typically observed, some patients mayshow a dense infiltrate more suggestive of BP, linearIgA disease, dermatitis herpetiformis, anti-p200 pem-phigoid or inflammatory EBA. Scarring is not asensitive clue as it is found only in a minority ofcases. In patients suspected of having MMP onroutine histopathology, immunopathologic and im-munoserologic studies are mandatory to confirm thediagnosis and to characterize the target autoantigenas laminin 5.

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