Castleman\'s disease associated pemphigus. A form of paraneoplastic pemphigus

JEADV Journal of the European Academy of Dermatology and Venereology

ELSEVIER

4 (1995) 273-279

Case report

Castleman's disease associated pemphigus. A form of paraneoplastic pemphigus Daniel A. Vardy ^•*, Laurent Klapholz % Chaim Brautbar ^, Anat R. Tambur ^, Sara Pisanty S Eliezer Rosenmann '^, Neomi Ron "*, Michael A. Goldenhersh ^ ' Dermatology Department, Hadassa Uniiersity Hospital and the Hebrew University School of Medicine, P.O. Box 12000. il-91-120 Jerusalem, Israel The Tissue Typing Unit and the Lautenberg Center for General and Tumor Immunology, Hadassa University Hospital and the Hebrew Uniuersity School of Medicine, Jerusalem. Israel '^ The Department of Oral Medicine, Hadassa University Hospital and the Hebrew University School of Medicine, Jerusalem, Israel '^ The Pathology Department, Hadassah University Hospital and the Hebrew University School of Medicine, Jerusalem, Israel

Abstract We report a patient with Castleman's disease (angio-follicular lymph node hyperplasia) associated with a pemphigus vulgaris-like disorder. The patient had the hyaline-vascular mediastinai type of Castleman's disease and developed painful oral erosions and penile lesions. Histologic examination revealed an interface dermatitis including vacuolar changes, necrotic keratinocytes and a lichenoid infiltrate. In addition there was suprabasal vesiculation with acantholysis, reminiscent of pemphigus vulgaris. Direct immunoperoxidase staining for intercellular IgG was positive. HLA typing revealed that the patient did not have an HLA hapiotype known to be associated with susceptibility to pemphigus. Until now, Castleman's disease Associated Pemphigus (CDAP) has been regarded as a unique entity presenting as atypical pemphigus vulgaris. However, a review of the literature reveals that the clinical and histologic signs of CDAP are virtually identical to those of paraneoplastic pemphigus and that both entities are associated with a lymphoproliferative disorder. We suggest that CDAP is a form of paraneoplastic pemphigus. Keywords: Atypical pemphigus; Paraneoplastic pemphigus; Castieman's disease; HLA

I. Introduction

• Corresponding author. Tel: 972-2-705-778 (w), 972-7-460848 (h); Fax: 972-2-434-434, 972-2-705-726.

Castleman's disease (CD) is a benign hyperproliferative disorder characterized by massive mediastinai lymph node enlargement with dense small lymphocytes and dendritic cells [1]. 90% of

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the cases are of the hyaline-vascular variant and have no systemic symptoms. 10% are of the plasma cell variant and are associated with significant systemic symptoms [2,3]- Several reports of unusual erosive stomatitis associated with CD have recently been published, and described as atypical pemphigus vulgaris [4-10]. In this article we report a patient with CD who developed atypical pemphigus vulgaris. We present a review of the literature, discuss the differences between Castleman's disease Associated pemphigus {CDAP) and classical pemphigus vulgaris and the relationship of CDAP to the recently described paraneoplastic pemphigus.

2. Case report A 23 year old Jewish man was admitted to the Department of Dermatology Hadassah University Hospital, with a three week history of painful oral lesions. Two years previously, during workup of a febrile illness, the patient was found to have a mediastinai mass. Attempted surgical removal of the mediastinai tumor failed due to excessive hemorrhaging. A biopsy of the tumor revealed Castleman's disease of the hyaline vascular type. Physical examination of the patient on admission, revealed erosions of the buccal mucosa and of the lateral and anterior aspects of the tongue. There was a thin lichenoid papule on the glans penis. A biopsy taken from an oral lesion showed a dense lichenoid lymphocytic inflammatory cell infiltrate with a sub-epidermal cleft and many necrotic keratinocytes in the lower third of the epidermis (Fig. 1). A suprabasal cleft containing acantholytic cells was seen at the edge of the section (Fig. 2). A biopsy taken from the penile lesion demonstrated an interface dermatitis with necrotic keratinocytes and vacuolar changes. A biopsy taken from peri-lesional penile skin and stained by the immunoperoxidase technique, revealed deposits of IgG in the intercellular spaces compatible with pemphigus vulgaris. Indirect immunofluorescence testing was negative for circulating antibodies to the basement membrane or the intercellular spaces. Circulating anti-nuclear antibodies were not found and routine blood

Fig. 1. Oral lesion showing dense lichenoid infiltrates and subepidermal clefts. Necrotic kcratinocytes are seen in the epidermal fragment located in the upper right hand side of the photograph.

counts and blood biochemistry were found to be within normal limits. HLA typing was performed at the serological and DNA levels. The complement-dependent microlymphocytotoxicity technique was applied for the serological typing of HLA class I and II antigens [11]. The patients phenotype was determined as: HLA-A1^2,Cw4,Cw5,B35,B44,Bw4,Bw6,DR8, DRll,DRw52,DQl,DQ7 In order to further analyze the HLA class II allelic variants, genomic DNA was extracted and amplified by the polymerase chain reaction (PCR)

DA. Vardy et al./J. Eur Acad. Dermatol. Venereol. 4 (1995) 273-279 Table 1 Distribution and type of clinical lesions Published report Oral

275

Genital

Ocular

Other Sites

Tagami [4]

erosions

focal scaling of the penis

erosive keratitis

-

Ortone |9]

erosions

-

-

-

Redon [5]

blisters

vulvar blisters

-

hand blisters

Coulson 16]

ulcerations

vulvar ulcerations

cicatrieial conjunctivitis

palms and soles: lichenoid plaques

Monpoint [7]

ulcerations

erosions

conjunctivitis

-

Gili 18]

ulcerations

vaginal ulcerations

conjunctivitis punctate corneal keratitis

—

Plewig [lO]

erosions

-

-

hand, foot, baek: lichenoid papules

Our case

erosions

Lichenoid papules of the penis

-

-

technique, for the DRBl, DRB3, DQAl and DQBl genes. 80 different sequence-specific oligonucleotide probes (SSOPs) were labelled using non-radioactive methods [12], and their pattern of hybridization revealed the following genotype: RBI' nO3,DRBI' 0804,DRB3" 0202,DQA! * 050J. DQAl' 0103.DQBJ * 0301,DQBi' 0603

Table 2 Histopathological and immunological Published Lichenoid reports Tagami [4] yes Ortonne (9] not noted Redon [5] not noted Coulson [6] yes oral yes hand Monpoint [7] not noted yes Gili m Plewig [10] oral yes yes hand Our case oral yes yes penis

features of CDAP Erythema multiforme like

The patient was treated with oral prednisone 1 mg/kg/day and clinical improvement was seen within a week with gradual clearing of the lesions. The dosage of prednisone was gradually tapered by reducing 10 mg/day every week. The patient was successfully maintained disease free on a dose of 25 mg/day. Any reduction of the dose below 25 mg/day resulted in a flare of the oral lesions. By adding azathioprine (imuran) 100 mg/ day to the regimen, the patient was maintained

Pemphigus like

Deposit of IgG in skin lesions

IIF (titer)

? yes yes

no

not noted not noted 1/320

no yes no no

yes

0

yes yes

PV PV PV PV

yes yes

yes no

PV

1/128

not noted

yes yes

yes yo

PV

yes

not noted no

no

not noted PV

1/640 1/320

0

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disease free on a dosage of 20 mg prednisone every other day.

3. Discussion There have been several previous reports of unusual skin and mucous membrane lesions in patients suffering from Castleman's disease (CD) [4-10]. In the first report, the patient had severe erosive stomatitis and a focal scaly penile lesion [4]. The histological picture was of a dense dermal lymphocytic cell infiltrate and a subepidermal cleft with focal basal layer degeneration. Direct immunofluorescence testing of the oral lesions failed to demonstrate immunoglobulin deposition. Later reports of CD associated with oral lesions were published and interpreted by the authors as pemphigus vulgaris [5-10]. The salient clinical and histological findings in these reports are summarized in Tables 1 and 2, respectively. The causative association between CD and

CDAP was demonstrated by the fact that, in most reported cases, removal of the mediastinai tumor resulted in alleviation of the cutaneous disease; a reduction or cessation of oral steroid therapy was achieved. A review of the literature suggests that CDAP differs from classical pemphigus vulgaris (PV) in several aspects and may be regarded as a separate disease. The clinical differences between CDAP and PV are summarized in Table 3. CDAP appears at a much earlier age than PV, most of the patients have penile and corneoconjunctival lesions and one case was associated with a lichenoid skin eruption. The characteristic histological finding in PV is a suprabasal vesicle with acantholysis. This is usually associated with a superficial perivascular, mainly lymphocytic, inflammatory cell infiltrate with eosinophils. In CDAP there appear to be three characteristic histologic findings: (1) suprabasal acantholytic vesicle; (2) necrotic keratinocytes along the basal layer of the epidermis; and (3) a dermal lichenoid

Table 3 Comparison between pemphigus vulgaris (PV) and Castleman's disease assoeiated pemphigus (CDAP) PV CDAP Clinical findings Age of onset (years)

>40

15-21

Lesions distribution oral genital ocular

>90% rare rare

100% 6/8 cases 3/8 cases

Type of lesions Other associated lesions

blisters: erosions none

blisters; erosions lichenoid papules

Histological features Acantholysis with suprabasal blister pemphigus like)

100%

100%

Lichenoid infiltrate

no

5/8 cases

•Necrotic keratinocytes (E-M like)

no

4/8 cases

100%

6/8 cases

80-90%

4/8 eases

I. corticosteroids 2. other immunosuppressive drugs

1. tumor resection 2. corticosteroids 3. other immunosuppressive drugs

Immunological features Deposit of IgG in the intercellular substance Circulating pemphigus antibodies Treatment

DA. Vardy et al. /J. Eur. Acad. Dermatol. Venereol 4 (1995) 273-279

Fig. 2. Same lesion as Fig. 1. showing suprabasal vesiculation with acantholysis.

infiltrate. The latter two findings are not seen in PV. HLA typing of classical PV patients of Jewish as well as non Jewish patients of Austrian and American origin demonstrates a significant association of PV with HLA haplotypes: DRBl' 0402,DQBl' 0302 and DRBl' 14O1,DQB1' 0503 [13,14]. HLA typing of the patient with CDAP presented in this article revealed that he did not carry any of these HLA hapiotypes implicated in susceptibility to PV. These findings further suggest that CDAP is indeed clinically and etiologically different from PV. It is quite probable that CDAP is a variant of

277

the paraneoplastic pemphigus which was first described in 1990 [15]. Both diseases are characterized by painful erosions associated with a polymorphous eruption resembling erythema multiforme or lichen planus in association with a visceral neoplasm. The association between classical pemphigus vulgaris, myasthenia gravis and thymoma has been well characterized [16]. Interestingly a case of CD with myasthenia gravis has been reported [17]. Castleman's disease is usually a benign lymphoproliferative disorder. The patient we describe here and the patients described in the literature as having a pemphigus-like disorder with coexistent Castleman's disease had a form of pemphigus with a clinical and histological picture almost indistinguishable from the paraneoplastic pemphigus described by Anhalt et al. [15]. In these cases too, the association of paraneoplastic pemphigus is with a lymphoproliferative disorder: chronic lymphatic leukemia (CLL) and lymphoma in three out of five patients, a thymoma and a sarcoma. In a later report of paraneoplastic pemphigus by Camisa et al. [18] the three patients had CLL and lymphoma and a cutaneous clinical and histological picture identical to the syndrome described by Anhalt et al. [15]. Anhalt et al. [15] set forth five criteria for the diagnosis of paraneoplastic pemphigus: 1. Painful mucosal erosions and a polymorphous skin eruption, with papular lesions progressing to blisters and erosive lesions affecting the trunk, extremities and palms and soles, in the context of an occult confirmed neoplasm. 2. Histological changes that include intraepidcrmal acantholysis, keratinocyte necrosis and interface vacuolar changes. 3. Direct immunofluorescence for IgG and complement both in the intercellular spaces and in the basement membrane zone. 4. Serum antibodies reactive with the intercellular substance of simple, transitional and columnar epithelia. 5. Serum antibodies that will precipitate several epidermal peptides (250, 230, 210 and 190 kd antigens). Oursler et al. [19] have recently found that the 250 and 210 kD antigens, precipitated by the

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autoantibodies in patients with paraneoplastic pemphigus, are actually desmoplakin I and desmoplakin II, proteins which arc part of the desmosomal complex in keratinocytes. The 230 kD protein corresponds to the bullous pemphigoid antigen [20] while the 190 kD antigen is still uncharacterized. Castleman's disease associated pemphigus may well be described by criteria 1-4 suggested for paraneoplastic pemphigus. The fifth criterion, characterizing the serum autoantibodies has not yet been examined in CD but is likely to be found there too. Indeed, Horn and Anhalt [21], in a review of the histologic features of paraneoplastic pemphigus, describe the findings in six patients: 3 with lymphoma, one with CLL, one with a thymoma and one patient with Castleman's disease. They concluded that paraneoplastic pemphigus represents a unique clinical, histological and immunological disease associated with lymphoproliferative disorders, including CD. Plewig et al. [10] described a patient with pelvic CD and a mucocutaneous syndrome, with features of both lichen planus and PV, compatible with paraneoplastic pemphigus. They suggested that the high association of CD with various immune diseases indicates a causative pathophysiological role of CD in these disorders. There seems to be sufficient evidence to support the proposition that CD is associated with a cutaneous disorder similar to PV but clinically, histologically and immunologiealiy equivalent to paraneoplastic pemphigus. Castleman's tumor is a pseudolymphoma that contains numerous small lymphocytes with significant numbers of B-cells [22]. Yabuhara et al. [23] observed a case of CD to be associated with overproduction of B-cell differentiation factor. Paraneoplastic pemphigus has also been shown to be associated with B cell proliferation, suggesting that abnormal B cell activity in CLL, lymphoma or Castleman's disease is responsible for the production of serum autoantibodies directed against several components of the epidermis with the result of the paraneoplasticpemphigus syndrome. Liu et al. [24] found the autoantibodies in paraneoplastic pemphigus to be of polyclonal origin suggesting normal B-cells as the source, possi-

bly stimulated by abnormal antigens presented by neoplastic cells. Helm et al. [25] suggested that the term "neoplasia-induced pemphigus" be used rather than paraneoplastic pemphigus. In view of the association of this distinct syndrome with lymphoproliferative diseases of both benign and malignant nature, we feel the term paraneoplastic pemphigus, implying a remote effect of the neoplasm, can be applied to CDAP and the previously described disorders. The histopathological findings in CDAP which are reminiscent of PV may be the result of precipitation of the autoantibodies against desmoplakin I and II in the epidermis while the interface dermatitis picture seen is probably in response to autoantibodies to the basement membrane zone.

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