A Case of Paraneoplastic Pemphigus as a Preceding Manifestation of Underlying Follicular Lymphoma Treated with R-CHOP

Abstract

Paraneoplastic pemphigus is a rare, life-threatening disorder associated with an underlying neoplasm, which presents with painful stomatitis and polymorphous skin lesions. Successful diagnosis of paraneoplastic pemphigus can lead to the diagnosis and treatment of the underlying malignancy. However, involvement of the respiratory system is typically unresponsive to treatment. Herein, we report the case of a 44-year-old female diagnosed with paraneoplastic pemphigus with underlying follicular lymphoma treated with a chemotherapy regimen including rituximab. Her skin lesions and underlying lymphoma responded to treatment, but bronchiolitis obliterans continued to progress and resulted in fatal respiratory failure.

INTRODUCTION

Paraneoplastic pemphigus (PNP) is an autoimmune bullous disorder associated with an underlying neoplasm. The pathogenesis of PNP involves the production of autoantibodies against desmoglein and plakin proteins¹. PNP is commonly misdiagnosed because it presents with various clinical manifestations and often resembles other cutaneous diseases. The histopathologic findings of PNP are also nonspecific and include interface dermatitis and lichenoid dermatitis. The detection of autoantibodies against plakin proteins using indirect immunofluorescence (IIF) or immunoblot shows high sensitivity and specificity for the diagnosis of PNP².

There is no standardized treatment guideline for PNP. Systemic steroids are typically used as the first-line treatment, and rituximab could be considered as a secondary treatment option. Although treatment of the underlying neoplasm does not always lead to the treatment of PNP, the prognosis of PNP is determined by the nature of the underlying neoplasm¹. PNP has a high mortality rate, and bronchiolitis obliterans (BO), which results from the involvement of the respiratory system, is a common cause of death.

CASE REPORT

A 44-year-old female visited the emergency room due to a painful oral ulcer, which had developed 6 weeks prior. She had previously been diagnosed with aphthous stomatitis in the otolaryngology department and received systemic steroid treatment, but the oral lesion gradually progressed. She also complained of an erythematous maculopapular rash covering her whole body and conjunctival injection accompanied by fever, diarrhea, and weight loss (Fig. 1). The maculopapular eruption rapidly progressed to ulcerative patches, especially on her palms. She denied any medication history. Leukocytosis and eosinophilia were noted, but all other laboratory tests were within the normal ranges. Stevens-Johnson syndrome (SJS) with mucosal involvement was suspected, so she admitted to the internal medicine department for systemic steroid treatment.

Fig. 1. Clinical images taken on the initial visit. Painful stomatitis (A) and a maculopapular eruption covering the whole body (B).

The skin lesion slightly improved after 1.5 mg/kg of methylprednisolone therapy, but the stomatitis was unresponsive. The skin rashes recurred when the dose of methylprednisolone was reduced to below 1 mg/kg, and did not respond to cyclosporine or azathioprine. A skin biopsy was performed for further evaluation, and it showed interface dermatitis and subepidermal blister formation with basal vacuolization. Dyskeratotic cells were detected in the basal layer (Fig. 2). Direct immunofluorescence (DIF) was performed twice, and showed a negative result and linear deposits of C3 at the dermoepidermal junction, respectively. Antibodies against desmoglein 1 and 3 were not detected by enzyme-linked immunosorbent assay. IIF was conducted, and immunoglobulin G deposition was detected on the normal human skin, mouse bladder epithelium and mouse lung epithelium (Fig. 3). A diagnosis of PNP was made based on the IIF results.

Fig. 2. Histopathological examination showed subepidermal blister formation with interface dermatitis. Dyskeratotic cells were present in the basal layer and vacuolization was observed (H&E, ×100).

Fig. 3. Indirect immunofluorescence showed positive results on (A) normal human skin (1:10), (B) mouse bladder epithelium (1:40), and (C) mouse lung epithelium (1:10).

Chest and abdomen computed tomography were performed to detect the underlying neoplasm, and enlargement of the axillary, supraclavicular, and retroperitoneal lymph nodes was observed. Surgical excisional biopsy of the right inguinal lymph node was consistent with follicular lymphoma. Due to bone marrow involvement, the patient was diagnosed with stage IV follicular lymphoma.

The patient received chemotherapy including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. Complete remission of the lymphoma was achieved after six cycles of chemotherapy, confirmed by positron emission tomography. The stomatitis and skin rash were also dramatically improved and well-maintained with low-dose steroid therapy (5 mg/day) for 8 months (Fig. 4). However, the patient developed BO and invasive pulmonary aspergillosis, and died from respiratory failure 20 months after the initial manifestation of PNP.

Fig. 4. The stomatitis (A) and skin eruption (B) entered clinical remission after rituximab treatment.

DISCUSSION

Anhalt et al.³ first described PNP as a rare autoimmune blistering disease characterized by painful stomatitis and a polymorphous cutaneous eruption accompanied by the production of autoantibodies. The associated neoplasms are mainly lymphoproliferative disorders. In contrast to other autoimmune blistering diseases, PNP-associated autoantibodies invade not only stratified squamous epithelium but also other types of epithelium including the transitional epithelium of the bladder. When IIF is performed, these autoantibodies react with rat bladder epithelium, so this diagnostic test can be used to distinguish PNP from other blistering diseases.

The diagnosis of PNP is challenging due to its rare prevalence and various cutaneous manifestations. Given its mucosal involvement, PNP is frequently misdiagnosed as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Although the prevalence of SJS/TEN-like PNP is lower than that of SJS/TEN, its mortality is much higher⁴. In some cases, PNP is diagnosed before the detection of an underlying malignancy, so early diagnostic work-up of the underlying neoplasm is necessary for treatment. Therefore, the differential diagnosis of SJS and SJS/TEN-like PNP is important, and PNP should be considered in patients with an atypical clinical course of SJS/TEN.

Anhalt et al.³ proposed five diagnostic criteria for PNP, including immunoglobulin G or complement deposition in the intercellular spaces of the epidermis or basement membrane zone, which can be detected using DIF. Our patient showed a negative DIF result, which prevented an earlier diagnosis. DIF shows a sensitivity lower than 50% in the diagnosis of PNP, and PNP is known to have a higher false negative rate than other types of pemphigus¹,⁴. In contrast, IIF on rat bladder has high sensitivity and specificity in the diagnosis of PNP². Therefore, if PNP is suspected, the presence of autoantibodies in the patient's serum should be evaluated.

The prognosis of PNP is highly associated with the nature of the underlying neoplasm. If the underlying tumor is benign or localized, PNP shows good prognosis and early resection of the tumor can lead to a good outcome⁵. However, treatment of the underlying neoplasm does not always lead to the improvement of PNP¹. Systemic steroids are typically used as the first-line treatment for PNP. Recently, several cases of PNP successfully treated with rituximab have been reported⁶,⁷,⁸. Rituximab is thought to act by depleting CD20-expressing B cells that produce autoantibodies⁹.

Our patient exhibited clinical remission of the underlying follicular lymphoma and cutaneous, mucosal involvement of PNP after rituximab treatment. However even after remission, BO progressed and the patient died from respiratory failure. The exact mechanism underlying respiratory tract involvement remains unclear. Autoantibodies may react with plakin proteins on the respiratory epithelium, and destruction of the bronchial epithelium may lead to irreversible airway obstruction¹. BO is resistant to conventional treatment for PNP, and lung transplantation is considered the only effective treatment. A previous case report demonstrated that rituximab unsuccessfully treated BO, though evidence for the effectiveness of rituximab against PNP-related BO is still lacking⁷. In this case, although rituximab successfully treated PNP and the underlying neoplasm, it was ineffective against BO. To the best of our knowledge, this is the first report to discuss the effectiveness of rituximab against PNP and PNP-related BO in a Korean patient. Our case emphasizes the necessity of close monitoring and respiratory support even after PNP enters clinical remission.

In conclusion, PNP should be suspected in patients presenting with refractory stomatitis with a polymorphous cutaneous eruption, and corresponding diagnostic tests should be performed. Rituximab could be an effective treatment option for PNP, but physicians should be aware of the development of BO.

DATA SHARING STATEMENT

Research data are not shared.