Paraneoplastic Pemphigus Associated with Follicular Lymphoma, Sjögren’s Syndrome, and Bronchiolitis Obliterans: A Case of Prolonged Survival

Abstract

Introduction

Paraneoplastic pemphigus (PNP), also known as paraneoplastic autoimmune multiorgan syndrome, is a rare and often fatal autoimmune blistering disease associated with hematological malignancies. It is frequently complicated by severe extracutaneous manifestations such as bronchiolitis obliterans.

Case Presentation

A 67-year-old woman presented with refractory, painful oral erosions and lichenoid skin lesions. Histopathological examination, direct immunofluorescence, and immunoblotting revealed findings consistent with PNP, including antibodies against envoplakin and periplakin. Further evaluation revealed concurrent follicular lymphoma, Sjögren’s syndrome, and bronchiolitis obliterans. Combination therapy with systemic corticosteroids and rituximab-based chemotherapy achieved remission of the lymphoma and sustained control of mucocutaneous lesions. The patient survived for 34 months after initial presentation despite progressive respiratory impairment.

Conclusion

This case highlights the diagnostic complexity of PNP with overlapping autoimmune features and underscores the importance of early recognition and multidisciplinary management. Despite its typically poor prognosis, rituximab-based therapy may improve survival outcomes by targeting both the underlying malignancy and autoimmune activity.

Introduction

Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disease characterized by severe stomatitis, polymorphous skin eruptions, and the presence of autoantibodies targeting plakin family proteins [1]. It is most commonly associated with hematological malignancies, particularly non-Hodgkin lymphoma, and is frequently complicated by life-threatening bronchiolitis obliterans (BO) [2, 3]. PNP can be challenging to differentiate from other autoimmune blistering or lichenoid disorders because of its heterogeneous clinical and histopathological features [4, 5]. We describe a patient with PNP associated with follicular lymphoma and Sjögren’s syndrome (SjS), who achieved relatively prolonged survival despite the presence of BO.

Case Presentation

A 67-year-old woman presented with a 4-month history of painful erosions involving the lips and oral mucosa. She had been treated unsuccessfully for presumed oral candidiasis. Her medical history was notable for hyperthyroidism treated with thiamazole. Physical examination revealed extensive erosions of the oral mucosa and lips, along with scattered erythematous, slightly scaly plaques on the extremities without overt blister formation (shown in Fig. 1). Oxygen saturation was 92% on room air during exertion.

Fig. 1.

Clinical findings at presentation. a, b Painful erosions involving the lips and oral mucosa. c Multiple erythematous, slightly scaly plaques on the upper extremities.

Laboratory investigations showed elevated anti-desmoglein 3 antibodies, positive anti-SSA antibodies, and mildly elevated inflammatory markers. Skin biopsy from an erythematous plaque demonstrated interface dermatitis with lymphocytic infiltration and scattered keratinocyte necrosis. Lip mucosal biopsy revealed saw-tooth epithelial hyperplasia with lymphocytic infiltration and periductal lymphoid aggregates around minor salivary glands (shown in Fig. 2). Direct immunofluorescence of skin specimens demonstrated intercellular deposition of IgG and C3 (shown in Fig. 2).

Fig. 2.

Histopathological findings of the lip mucosa and skin. a, b Mucosal epithelium showing saw-tooth hyperplasia with lymphocytic infiltration and spongiosis. c Dense lymphocytic infiltration around minor salivary glands. d, e Skin lesion showing interface dermatitis with lymphocytic infiltration and dyskeratotic cells. Hematoxylin and eosin staining. f Direct immunofluorescence showing intercellular deposition of IgG and C3 in the epidermis.

Systemic prednisolone therapy was initiated, resulting in rapid improvement of cutaneous lesions and gradual reepithelialization of oral erosions. Dyspnea had already been present before admission and persisted despite bronchodilator therapy. During steroid tapering, atypical lymphocytes were detected in peripheral blood, and computed tomography revealed newly developed generalized lymphadenopathy. Lymph node biopsy subsequently confirmed grade 1 follicular lymphoma.

Pulmonary function tests performed during this period demonstrated severe mixed ventilatory impairment (FEV1 0.69 L, %FEV1 37.7%, FEV1/FVC 43.67%, %VC 63.9%). Chest computed tomography showed no apparent pneumonia or typical findings such as mosaic attenuation or air trapping; however, based on the progressive clinical course, poor response to bronchodilator therapy, and pulmonary function impairment, a diagnosis of BO was made.

Rituximab plus bendamustine chemotherapy was initiated for lymphoma, leading to complete remission. Subsequent immunoblot analysis demonstrated IgG antibodies against envoplakin (210 kDa) and periplakin (190 kDa), confirming the diagnosis of PNP (shown in Fig. 3). The mucocutaneous symptoms remained well controlled; however, the respiratory symptoms progressively worsened, eventually requiring hospitalization for severe dyspnea despite inhaled and systemic corticosteroid therapy. The patient ultimately died of respiratory failure 34 months after initial presentation.

Fig. 3.

Immunoblot analysis using epidermal extracts. Serum shows distinct bands corresponding to envoplakin (210 kDa) and periplakin (190 kDa), consistent with PNP.

Discussion

PNP, first described by Anhalt et al. [1] in 1990, is a rare autoimmune blistering disorder associated with underlying neoplasia, most commonly lymphoproliferative malignancies. The disease is characterized by severe, treatment-refractory mucosal erosions and polymorphous cutaneous manifestations, reflecting the complex interplay of humoral and cellular immune responses directed against epithelial adhesion molecules [2–4]. The present case illustrates several clinically important aspects of PNP: diagnostic challenges at presentation, association with follicular lymphoma and SjS, development of BO, and relatively prolonged survival despite respiratory involvement.

PNP exhibits marked clinical and histopathological heterogeneity, often mimicking other autoimmune or inflammatory dermatoses such as pemphigus vulgaris, lichen planus, erythema multiforme, or graft-versus-host disease [2–5]. In our patient, the initial presentation with painful oral erosions and lichenoid skin lesions, together with positive anti-desmoglein 3 antibodies, led to a provisional diagnosis of pemphigus vulgaris and lichen planus in the setting of SjS. Histopathological findings demonstrated interface dermatitis with lymphocytic infiltration and keratinocyte necrosis rather than prominent acantholysis, consistent with previously reported lichenoid-dominant variants of PNP [6, 7]. These features emphasize that PNP should be considered in patients with refractory mucosal disease and mixed pemphigus- and lichenoid-like features, even in the absence of classic suprabasal acantholysis.

Immunopathologically, PNP is characterized by autoantibodies targeting plakin family proteins, including envoplakin and periplakin, which are essential components of desmosomes and hemidesmosomes [1, 4]. In addition to humoral immunity, cell-mediated immune mechanisms also play a critical role, with CD8-positive cytotoxic T lymphocytes and proinflammatory cytokines implicated in keratinocyte apoptosis and lichenoid tissue injury [7, 8]. In the present case, dense infiltration of CD4- and CD8-positive lymphocytes was observed in both mucosal and cutaneous lesions, supporting the involvement of combined humoral and cellular immune responses in disease pathogenesis.

The coexistence of SjS in this patient is noteworthy. SjS is a systemic autoimmune disease characterized by chronic lymphocytic infiltration of exocrine glands and is associated with an increased risk of B-cell lymphomas, particularly non-Hodgkin lymphomas [9]. Although the coexistence of SjS and PNP has rarely been reported, shared mechanisms of immune dysregulation and chronic B-cell activation may predispose patients to both lymphomagenesis and autoantibody production. In this context, SjS may have served as an immunological background facilitating the development of follicular lymphoma and subsequent PNP in our patient.

BO is one of the most severe extracutaneous complications of PNP and represents a major determinant of prognosis. BO has been reported in at least 20% of PNP cases and is frequently progressive and refractory to treatment [3, 10]. Although the pathogenesis of BO in PNP remains incompletely understood, it is thought to involve both antibody-mediated epithelial injury and T-cell-mediated cytotoxicity directed against the respiratory epithelium [8, 10]. Notably, the progression of BO does not necessarily parallel mucocutaneous disease activity [11]. Consistent with this, our patient showed progressive respiratory symptoms despite good control of skin and mucosal lesions, highlighting the need for vigilant respiratory monitoring even when dermatological manifestations appear stable.

The diagnosis of BO in PNP can be challenging, particularly in older patients with limited respiratory reserve. Histological confirmation by lung biopsy is often impractical due to respiratory compromise, and diagnosis therefore frequently relies on a combination of clinical features, pulmonary function testing, and imaging findings [10, 11]. In particular, expiratory CT has been shown to be useful for early detection of BO by demonstrating air trapping, even when inspiratory CT findings are unremarkable [11]. In the present case, progressive exertional dyspnea, severe mixed ventilatory impairment on pulmonary function testing, and a clinical course consistent with small airway disease supported the diagnosis of BO, despite the absence of histopathological confirmation. Similar diagnostic approaches have been adopted in previously reported PNP cases, reflecting real-world clinical constraints. Importantly, the dissociation between mucocutaneous disease improvement and persistent respiratory decline further supports the diagnosis of BO rather than infection or drug-induced lung injury.

A comparison with previously reported cases of PNP complicated by BO provides important prognostic context. BO-associated PNP generally carries an extremely poor prognosis, with a high mortality rate within the first year after diagnosis despite aggressive immunosuppressive therapy [12]. Survival beyond 2 years is rare, and long-term survivors are exceptional. Chen et al. [13] reported a patient with BO-associated PNP related to chronic lymphocytic leukemia who remained alive at 30 months of follow-up. The present patient survived for 34 months after initial presentation, representing a similarly prolonged clinical course among BO-associated PNP cases. This relatively prolonged course may be attributed to a combination of early recognition of respiratory involvement, sustained control of mucocutaneous disease, and effective treatment of the underlying lymphoma.

There is currently no established standard therapy for PNP, and management generally requires systemic corticosteroids, immunosuppressive agents, and treatment of the underlying neoplasm [14]. Rituximab, a monoclonal antibody targeting CD20-positive B cells, has emerged as a promising therapeutic option for PNP, particularly when associated with B-cell malignancies [12, 15]. By depleting pathogenic B cells, rituximab reduces autoantibody production and may also indirectly modulate T-cell-mediated immune responses through effects on antigen presentation and cytokine networks. In the present case, rituximab-based chemotherapy achieved complete remission of follicular lymphoma and sustained long-term control of mucocutaneous lesions. Nevertheless, respiratory function continued to decline, highlighting the relative refractoriness of BO once established. Despite this limitation, the relatively prolonged survival in this case suggests that early and effective control of the underlying malignancy and systemic autoimmune activity may contribute to improved outcomes, even when irreversible pulmonary damage has already occurred.

In conclusion, this case emphasizes the diagnostic and therapeutic challenges of PNP, particularly when complicated by overlapping autoimmune conditions and lymphoproliferative disorders. Since PNP may precede the detection of underlying malignancy, dermatologists play a pivotal role in early diagnosis. Vigilant longitudinal respiratory monitoring is essential, as BO represents a frequent and often fatal complication that can develop even when mucocutaneous disease is controlled. Multidisciplinary management with hematologists and pulmonologists is crucial, and prompt initiation of appropriate systemic therapy, including rituximab, may improve disease control and extend survival.

Statement of Ethics

This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient’s next of kin for publication of this case and accompanying images. Ethical approval was not required for this single case report according to institutional policy. The CARE Checklist has been completed by the authors for this case report and is available as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552169).

Conflict of Interest Statement

Toshiyuki Yamamoto was a member of the journal’s Editorial Board at the time of submission. The authors have no other conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

M.Y. managed the patient, collected clinical data, and drafted the manuscript. N.I. performed and interpreted serological analyses. T.Y. supervised the study and critically revised the manuscript. All authors read and approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All relevant data are included in this published article. Further inquiries can be directed to the corresponding author.