A 53-year-old man presents with a 3-month history of painful oral erosions, crusted lips, and a skin eruption involving the trunk and extremities, characterized by erythematous papules, targetoid plaques, and flaccid bullae. He has been treated with high-dose systemic corticosteroids, azathioprine, and mycophenolate mofetil without significant improvement.

A skin biopsy reveals acantholysis with interface dermatitis and necrotic keratinocytes, and direct immunofluorescence shows intercellular IgG and C3 deposition, as well as linear deposition along the basement membrane zone. Indirect immunofluorescence on rat bladder epithelium is positive.

Which of the following is the most commonly associated underlying malignancy in this condition?

A. Hodgkin lymphoma

B. Chronic lymphocytic leukemia

C. Castleman disease

D. Squamous cell carcinoma of the lung

E. Multiple myeloma

Rationale:

Severe mucositis and polymorphous skin lesions unresponsive to standard immunosuppressive therapies should raise suspicion for paraneoplastic pemphigus. The histological findings and direct immunofluorescence results showing both intercellular and basement membrane linear deposition are consistent with PNP. The indirect immunofluorescence findings showing positive rat bladder further confirm the diagnosis. Recognizing the clinical features and appropriate biopsy/testing can help diagnose the patient expeditiously. Given the association with underlying malignancies, particularly hematologic malignancies, prompt diagnosis is critical to screening and management of associated cancers.

Correct answer: B. Chronic lymphocytic leukemia (CLL)

CLL is one of the most frequently associated malignancies with PNP, especially in adults.​ A study evaluating the frequency of malignancies associated with PNP found that 39% had non-Hodgkin lymphoma, 18% had CLL, 18% had Castleman disease, 9% had carcinoma, 6% had thymomas, 6% had sarcomas, 1% had Waldenstrom macroglobulinemia, and less than 1 percent had Hodgkin lymphoma, monoclonal gammopathy, or melanoma. 

Incorrect answer choices:

A. Hodgkin lymphoma is rarely associated with PNP and is more commonly linked to other paraneoplastic syndromes.​

C. Castleman disease does have a significant association with PNP, particularly in younger patients such as pediatric and adolescent patients.​ In a case series of 14 children with PNP, 86% were found to have Castleman syndrome. However, in adults, CLL and non-Hodgkin lymphoma are more common associations.​

D. Squamous cell carcinoma of the lung can be associated with certain paraneoplastic syndromes however, PNP is not typically associated with squamous cell carcinoma of the lung.​

E. Multiple myeloma is rarely associated with PNP and is more commonly linked to other paraneoplastic conditions.​

Additional reading at Fitzpatrick's Dermatology Chapter 53: Paraneoplastic Pemphigus

References:

1. Kaplan, I., Hodak, E., Ackerman, L., Mimouni, D., Anhalt, G. J., & Calderon, S. (2004). Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations. Oral oncology, 40(6), 553-562.

2. D. Mimouni, G.J. Anhalt, Z. Lazarova, S. Aho, S. Kazerounian, D.J. Kouba, J.M. Mascaro, H.C. Nousari. (2002). Paraneoplastic pemphigus in children and adolescents, British Journal of Dermatology, 147(4), 725–732.