A skin rash and what lies beneath: Paraneoplastic pemphigus, an atypical presentation of follicular cell lymphoma
Authors: Muhamad Alhaj Moustafa, Justin L. Seningen, Hayan Jouni, Preet P. Singh, Rokea A. el‐Azhary, Thomas E. Witzig
Journal: American Journal of Hematology (2013)

A 68-year-old male with a history of hypertension, dyslipidemia, and type 2 diabetes mellitus was admitted to our hospital for a gradually worsening “skin rash.” He was previously healthy until approximately one year prior to admission. He initially developed dysuria thought to be secondary to urethral scarring. Several months later, he developed painful oral ulcerations and blistering of the finger tips with subsequent erosion and nail loss of the involved digits. Evaluation at the outside institution suggested the patient had lichen planus and he was treated with oral prednisone starting at 40 mg daily and tapered gradually over 3 months. This resulted in some improvement but not resolution of the lesions. As the prednisone was tapered the skin lesions worsened and they progressed to involve his entire body. He was then referred to our institution for further evaluation. At admission, he had widespread erythematous papules, targetoid in appearance, many with a central scale or erosion. These skin lesions involved his oral mucous membranes with a painful erosive and exfoliative eruption involving the lips and entire buccal mucosa. Similar ulcerative lesions were almost confluent on the entire scalp. He had both dorsal and palmar involvement of his hands with erosion and loss of several fingernails (Image 1A,B). Biopsy of the skin lesions showed lichenoid and vacuolar interface inflammation with scattered apoptotic keratinocytes. Direct immunofluorescence demonstrated strong deposition of IgG and C3 on epithelial cell surfaces in a pattern typical for pemphigus. Desmoglein (DSG) antibodies were significantly elevated [DSG-1 antibodies: 62.4 U (reference range <14); DSG-3 antibodies: 36 U (reference range <9)]. The suspicion of paraneoplastic pemphigus (PNP) was raised given the lack of concordance of an interface vacuolar reaction on biopsy (a lichenoid pattern) with the immunofluorescence findings (pemphigus pattern). BP180/230 antibodies (pemphigoid) were negative, however, indirect immunofluorescence with human salt-split skin showed basement membrane antibody florescence predominantly on the epidermal side suggestive of pemphigoid, again raising the suspicion of PNP. The diagnosis of PNP was confirmed by positive rat bladder immunofluorescence indicating that there are multiple circulating autoantibodies directed toward epithelial tissue. Laboratory findings showed mild normocytic anemia, an elevated C-reactive protein, and a very mildly elevated lactate dehydrogenase at 262 U/L (reference range 122–222 U/L). A full body computed tomography scan revealed a bulky mesenteric mass measuring 18 cm in greatest diameter in addition to scattered mesenteric, retroperitoneal, and retrocrural lymphadenopathy (Image 1C). A CT-guided biopsy of a retroperitoneal lymph node was obtained and showed grade 1 follicular lymphoma (FL; Image 1D–G). Further staging was performed with a positron emission tomography scan (Image 1H) that demonstrated the FL to be FDG avid with a low standardized uptake value (SUV) (4.7). Staging bone marrow biopsy was positive for FL (Image 1I–J). The patient was treated with standard bendamustine-rituximab (BR) to treat his underlying FL. Interestingly, his PNP responded well with gradual improvement of his skin lesions shortly after the first cycle of BR. Unfortunately, his course was complicated with recurrent infections and the regimen was simplified to rituximab/prednisone. After 6 months of therapy, FL and PNP improved significantly (Image 2) and DSG-1/DSG-3 antibodies normalized. The patient subsequently developed multiple infectious complications including toxic megacolon from clostridium difficile requiring total colectomy. At the time of surgery, no abdominal FL was detected. He passed away of infectious complications without active FL or PNP 10 months after diagnosis. Occult malignancies occasionally present with dermatologic manifestations. Hodgkin lymphoma can present with refractory pruritus whereas in non-Hodgkin lymphomas (NHL) the skin lesions are usually the result of direct invasion of malignant cells. In the case of our patient, the skin lesions were due to a paraneoplastic phenomenon 2, 3. PNP in the context of NHL is very rare. The name PNP was first given by Anhalt et al. 4 who described five cases of PNP, two of which were NHL. PNP usually manifests as polymorphous and painful mucocutaneous ulcerations which clinically can present as Steven Johnsons syndrome (as in this case), pemphigus vulgaris, and erosive lichen planus. Diagnosis of PNP relies on characteristic discordant immunofluorescence findings including the presence of multiple epithelial autoantibodies which leads to the search for an underlying malignancy 5. Therefore, in the setting of a blistering skin disorder compatible with Stevens Johnsons syndrome, pemphigus or erosive lichen planus, clinicians should always search for a potential occult malignancy when immunofluorescence studies suggest the presence of multiple epithelial autoantibodies. PNP treatment is usually directed against the underlying occult malignancy. In our case, treatment of the underlying FL did produce clearing of the PNP. In addition to the images presented herein, a collage of high-quality images can be found in the Supporting Information. 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