Paraneoplastic pemphigus associated with Castleman's disease and asymptomatic bronchiolitis obliterans

ARTICLE

Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive mucocutaneous disease first described by Anhalt et al. in 1990 [1]. It is a distinctive form of pemphigus characterized by the presence of IgG autoantibodies directed against proteins of the plakin gene family; plectin (> 400 kDa), desmoplakin I (250 kDa), bullous pemphigoid antigen I (230 kDa), envoplakin, desmoplakin II (a 210-kDa double band) and periplakin (190 kDa), desmogleins, and a yet uncharacterized 170-kDa antigen. Although clinical manifestations of PNP are heterogeneous, most of the patients have painful mucosal erosions and ulcerations, with or without polymorphous skin lesions similar to those seen in erythema multiforme, lichen planus, or pemphigoid. Almost all reported cases have been associated with an occult or confirmed neoplasm, usually of lymphoreticular origin. The majority of patients with PNP run a rapidly progressive and fatal course, and only a few patients survive after complete excision of a benign neoplasm such as Castleman's disease and thymoma. Progressive respiratory failure with clinical features of bronchiolitis obliterans has been recognized to be a cause of death in about 30% of patients with PNP [2]. We describe a patient with PNP associated with a hyaline-vascular type of Castleman's disease in the intrapelvic region showing erosions limited to the lip, oral and genital area. This case demonstrated that bronchilitis obliterans (BO) in paraneoplastic pemphigus could be asymptomatic, and high resolution computed tomography would be useful for early diagnosis of BO.

Case report

A 19-year-old man with no significant medical history including allergic diseases such as bronchial asthma was admitted to Takamatsu Red Cross Hospital because of recalcitrant erosive lesions on his oral mucosa and lip that had begun 18 months earlier. The patient was transferred to our department under a tentative diagnosis of pemphigus in March 10, 2000. On admission, there were extensive erosions in the oral mucosa and tongue with thick hemorrhagic crusts on the lip (Fig. 1a) and erosive lesions on the glans penis. Cutaneous and conjunctival lesions were not evident. Histological examination of a biopsy taken from a violaceous, indurated lesion of the lower lip showed a bandlike infiltrate of lymphocytes and histiocytes throughout the papillary dermis, hydropic degeneration of basal keratinocytes, and necrotic keratinocytes within the hypertrophic epidermis (Fig. 1b). Computed tomography (CT) and magnetic resonance imaging of the abdominal cavity revealed a solid tumor of a size of 8 x 9 x 9.5 cm. Angiography documented hypertrophic arterial supply and abundant intralesional vascularity. Physical examination revealed slightly decreased breath sounds in both lungs with no crackles. Mild hyperinflation without infiltrates was visible on chest radiographs, but conventional CT of the chest showed no remarkable abnormalities. Sputum cultures were negative for Mycobacterium tuberculosis, fungi, and other bacteria. Infectious diseases and collagen vascular diseases were not found in further examinations. Arterial blood gas analysis (room air) showed mild hypoxemia, and spirometry revealed a severe obstructive lung disease (Table I).

Immunologic studies

Direct immunofluorescence (IF) microscopy of the lip showed in vivo bound IgG and IgA intercellular (IC) antibodies in the entire epidermis and C3 in the cell periphery of lower epidermis, as well as numerous cytoid bodies positive for IgG, IgM, IgA, and C3. Indirect IF microscopy using human epidermis as substrate revealed IgG IC antibodies at a titre of 10,240 (Fig. 2a). On the rat and mouse bladder IgG IC antibodies were found positive at a titre of 640 (Fig. 2b). Immunoblotting analysis using the desmosomal extract of normal human epidermis prepared as described previously [3] disclosed the presence of antibodies to the 210, 190 and 170 kDa proteins as well as antibodies to several other unknown polypeptides of molecular weight from 180 through 105 kDa (Fig. 3). Immunoprecipitation studies confirmed the presence of antibodies to the 250, 210, 190, and 170 kDa proteins (not shown). Enzyme-linked immunosorbent assay (ELISA) with Dsg3 and Dsg1 recombinant proteins was performed according to the established method and the ELISA score was shown as index values [4]. Cut-off values (Dsg3 ELISA = 11.0, Dsg1 ELISA = 10.0) were determined as described previously [4]. Reactivity of patient's sera was positive against Dsg3 (index value = 28.3) and in a gray zone against Dsg 1 (index value = 10.5).

Course of the disease

The patient had been treated with prednisone (30 mg/day) with some improvement. The pelvic tumour was completely resected on the thirteenth hospital day, when the dose of steroid was tapered to 15 mg/day. Histopathological diagnosis of the tumour was Castleman's tumour of a hyaline-vascular type. No lymph node involvement was confirmed histopathologically. During one postoperative week, the titres of IC antibodies decreased to 1,280 only temporarily and increased again up to 5,120. Although the desmoglein ELISA showed temporary decrease of index values of Dsg3 and Dsg1 after eight courses of IgG immunoadsorption using tryptophan column, the titres of IC antibodies determined by indirect immunofluorescence microscopic study was decreased only slightly (Fig. 4a). The patient refused videoassisted thoracoscopic surgery (VATS) to evaluate obstructive lung disease and further treatment of immunoapheresis, and was discharged on April 28. Regular check-up of the patient once a month showed gradual epithelialization of the oral mucosa and complete disappearance of the erosion on the lip five months after the resection of Castleman's tumour. Interestingly, the titres of IC antibodies, which once decreased down to 640 during three months after the resection of the Castleman's tumour, increased again up to 10,240 together with a rise of Dsg ELISA indices two month later, and then gradually decreased down to 320 (Fig. 4b). However, no clinical aggravation which correlated with the rise of IC antibodies was noticed. The expiratory images were assessed for the presence of air trapping. High resolution CT (HRCT) of the lung examined in April, 2001, showed not only mosaic pattern of lung attenuation on inspiratory images, but also typical air trapping on expiratory images, indicating bronchiolitis obliterans (Fig. 5). Although the patient did not complain of dyspnea on exertion, his pulmonary function became progressively worse after the resection of Castleman's tumour (Table I).

Discussion

Since its first description by Anhalt et al. [1], the spectrum of paraneoplastic pemphigus (PNP) has been expanded. In addition to patients with polymorphous, erythema multiforme-like eruptions, cases that present clinically and histologically as lichen planus pemphigoides-like [5-7], bullous pemphigoid-like [8, 9] and graft-versus-host disease-like eruptions [10, 11] have been reported. The patient described here had an 18-month history of refractory erosions limited to the tongue, palate, buccal mucosa and lip without skin involvement even with very high titre of IC antibodies. Although it is widely recognized that refractory erosive stomatitis is a hallmark of PNP [6, 7, 12, 19] and it has been reported that 45% of 22 patients with PNP presented initially with isolated oral erosions [19], patients without involvement of the skin and conjunctiva have occasionally been reported [13-17]. Thus, if it is feasible to classify clinical phenotypes of PNP in analogy with classic pemphigus, our case belongs to a variant of mucosal dominant PNP [31].

Recognition of the envoplakin and periplakin bands in the immunoblotting (IB) and indirect immunofluorescence (IIF) labeling of rodent bladder as observed in this case are the main immunological features specific for PNP [18, 19]. It has been shown that pathogenic anti-Dsg3 autoantibodies can be consistently detected in PNP sera by ELISA and anti-Dsg1 autoantibodies are concomitantly positive in 64% of patients with PNP [20]. However, unlike pemphigus vulgaris, there is no clear association between the clinical phenotype, i.e. mucosal and mucocutaneous phenotype, and anti-Dsg antibody profile in PNP [31]. An interesting finding in our case is that titres of IC antibodies and index values of Dsg1 and Dsg3 ELISA temporarily increased 2 months after the resection of Castleman's tumour without apparent aggravation in the clinical phenotype. The increase of anti-IC and anti-Dsg antibodies suggests that besides the presence of autoantibodies against plakin proteins and desmogleins, other pathogenic mechanisms such as lichenoid tissue reaction and individual cell necrosis might be needed to form the unique clinical features of PNP in this particular case of PNP, as reported previously [23, 31]. The reason for this serological rebound is unknown, but our observation revealed that production of autoantibodies in PNP could fluctuate rather than keep on decreasing even after the resection of Castleman's tumour.

PNP is a life-threatening disease with a mortality rate of more than 90 %. Malignancies underlying the disease and/or complications associated with immunosuppressive therapy have been the major causes of the notorious prognosis. Bronchiolitis obliterans (BO) has been reported in patients with bone marrow or heart/lung transplantation [21] and in patients with collagen vascular diseases. Recently, Nousari et al. demonstrated that BO is another growing concern in patients with PNP, because it could lead to respiratory failure and subsequent death in 30% of patients with PNP [2]. BO occurred in patients with malignant neoplasia such as non-Hodgkin's lymphoma [2, 9, 22-25], as well as benign tumors such as Castleman's tumor [2, 16, 26-28]. Therefore, the prognosis of our patient with PNP depends on not only radical tumour resection but also the development of BO. BO may appear one month to one year after the onset of the disease [2, 9, 16, 22-24, 26, 28] or about a month after surgery [2, 27], although it rarely precedes the development of mucocutaneous manifestation [17]. The reason why not all but certain patients with PNP develop BO is still unclear. The presence of inflammatory cell infiltration and the deposition of autoantibodies in the respiratory epithelium suggest that exposure of intracellular plakin proteins by cell-mediated cytotoxic mechanisms may be followed by the reaction of autoantibodies to the respiratory epithelium and acantholysis [2, 25]. Our patient did not accept VATS to prove the pathological diagnosis of BO. However, detection of BO by transbronchial lung biopsy may not always be useful, because of the patchy distribution of BO [28] and the difficulty in obtaining adequate specimens of bronchioles [21]. Since Leung et al. demonstrated that air trapping, as detected on expiratory HRCT, was the most sensitive and accurate radiologic indicator of BO in the lung transplant recipients [32], we assessed both the inspiratory and the expiratory images by HRCT of our patient. This study clearly revealed not only a mosaic pattern of lung attenuation on inspiratory images, but also remarkable air trapping on expiratory images. Therefore, persistence of the reduced FEV₁% together with air trapping as revealed by expiratory images of HRCT indicate the presence of BO in our patient.

Treatments of PNP include high doses of oral corticosteroids, pulsed corticosteroids, plasmapheresis, immunosuppressive drugs such as azathioprine, cyclosporin, methotrexate, mycophenolate mofetil and photopheresis, and high doses of cyclophosphamide. However, there has been no promising treatment for PNP. Moreover, it has been reported recently that medication used for treatment of underlying malignancy such as alpha interferon and fludarabine might be involved in the development of PNP [29, 30]. Treatment prior to the development of BO is variable, including chemotherapy [23, 24], chemotherapy with bone marrow transplantation [9], cytokines [22], chemotherapy with cytokines [2], corticosteroids with azathioprine [28], high-dose corticosteroids and immunosuppresive therapy [26], surgery with cyclosporine and corticosteroids [2]. As for the present case, no such intensive treatment was done before the development of BO as was observed in other cases of PNP [16]. This suggests that no medication was related to the development of BO. With regard to the orolabial lesion, our case also suggests that intensive immunosuppressive therapy might not be needed if the underlying disorder is a nonmalignant tumour which is expected to be successfully treated by resection, and even when the titre of IC antibodies were significantly high or increased again in the course of the disease. However, adequate treatment to repress the development and progress of BO has not been established yet [21]. Since it has been reported that BO could be pronounced before rather than after completion of plasmapheresis [27], it appears that titres of IC antibodies and indices of Dsg3 and Dsg1 cannot be a useful indicator to assess severity of BO, as observed in this case. Recently, it has been reported that use of anti-CD20 monoclonal antibody (Rituximab) resulted in a rapid improvement of severe stomatitis in a patient with PNP associated with CD20⁺ follicular lymphoma [12]. It is of interest to see whether the anti-CD20 treatment is also applicable for PNP patients with other lymphoproliferative disorders such as Castleman's tumour, and if it effectively represses the development of BO.

CONCLUSION

Acknowledgements

We would like to thank Pr. Grant J. Anhalt (Department of Dermatoimmunology, Johns Hopkins University) for kindly performing immunoprecipitation study. We also thank Mr. Akira Matsumoto for his help in photographic work.

Article accepted on 28/3/02

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