Paraneoplastic pemphigus (PNP) is an autoimmune-mediated, blistering, erosive, and painful mucocutaneous disease that is diagnosed almost exclusively in patients with lymphocytic neoplasms. The most commonly associated neoplasms are, in decreasing order of frequency, non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, thymoma, retroperitoneal sarcoma, and Waldenstrm macroglobulinemia. When PNP is associated with an underlying malignancy, it is extremely resistant to treatment and carries a 90% mortality rate within a few months following diagnosis, independent of the course of malignancy. PNP is characterized by the presence of IgG autoantibodies that react to desmosomal and hemidesmosomal plakin proteins as well as to desmosomal transmembrane proteins called desmogleins, and these reactions result in the loss of cell adhesion of epithelial cells.
The original diagnostic criteria for PNP were devised in 1990 based on initial case reports; these criteria included:
1. Mucosal ulcerations and blisters, and polymorphous skin lesions in the context of an underlying neoplasm.
2. Histological findings of vacuolar interface change, keratinocyte necrosis, and intraepidermal acantholysis.
3. Epidermal intercellular deposition of IgG and C3, with or without linear deposition at the basement membrane zone, as demonstrated by direct immunofluorescence (DIF).
4. Serum autoantibodies that bind to the cell surface of skin mucosa in a pattern typical for pemphigus—but that also bind to simple, columnar, and transitional epithelia, as demonstrated by indirect immunofluorescence (IIF) in murine esophageal and bladder tissue.
5. Serum autoantibodies that immunoprecipitate a complex of high–molecular weight proteins from keratinocytes, with relative molecular weights of 250 kDa (desmoplakin 1), 230 kDa (bullous pemphigoid antigen [BP Ag 1]), 210 kDa (desmoplakin 2 and envoplakin), 190 kDa (periplakin), and 170 kDa (possible novel epidermal adhesion molecule antibody).
With additional experience, it became obvious that not all persons with PNP would meet all these criteria. Subsequently, minimal criteria for the diagnosis of PNP were proposed (Table 1).
PNP is generally resistant to therapy, especially with regard to stomatitis and lung involvement. Although there are no available treatment guidelines, and although PNP response may not follow the course of tumor resolution, initial treatment is aimed at the underlying malignancy in an attempt to slow the autoantibody production. Numerous immunosuppressive agents have been tried, with varying results. Systemic corticosteroids are used the most frequently, often in combination with other immunomodulatory modalities, such as rituximab, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, cyclophosphamide, and IVIg.
A 39-year-old active-duty male with grade 3 follicular lymphoma was transferred from Germany for therapy. He was treated with and responded to 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), with a 30% decline in the size of his largest mass (Figure 1). Between cycles 1 and 2, the patient developed what appeared to be grade 2 mucositis, dry eyes, and a viral rash (Figure 2). After multiple admissions, evaluations, and biopsies by ophthalmology, dermatology, and oral maxillary facial surgery for continued ocular discomfort, new-onset photophobia, and grossly worsening mucosal ulcerations, the patient was diagnosed with mucosal PNP and lichen planus of the skin. The diagnosis of PNP was not obvious given the nonspecific purple, polygonal, pruritic skin papules (Figure 3), which can also be seen in lichen planus, and a shave biopsy that revealed lichenoid interface dermatitis (Figure 4). Also, the first oral biopsies only demonstrated inflammation.
It was not until progression of his mucosal manifestations that a larger left buccal surgical biopsy was performed and the specimen sent for direct immunofluorescence (DIF), which strongly favored PNP (Figure 5). On receipt of the DIF results, the patient was started on 1mg/kg of oral prednisone, and a specimen was sent for indirect immunofluorescence (IIF). The staining pattern was diagnostic for PNP: prominent IIF staining was observed when the patient’s serum was cultured on mouse bladder and mouse tongue. IIF staining on monkey esophagus was also observed at a dilution of 1:80.
Within three days of initiation of systemic corticosteroids, the patient experienced a notable improvement in his oral and dermal lesions. However, one week later, he was admitted with shortness of breath and a new oxygen requirement. Bronchoscopy demonstrated bronchiolitis obliterans with no underlying infections. Oral cyclosporine was started.
Worsening of the oral lesions was noted seven weeks after prednisone was started, so a difficult multidisciplinary decision was made to start the patient on IVIg in the setting of ongoing CHOP therapy, oral cyclosporine, and a corticosteroid taper. Rituximab was not reinitiated because of the agent’s black-box warning regarding severe mucocutaneous reactions, limited data on its use in the setting of pulmonary involvement, and the fact that the patient began experiencing PNP-related symptoms while undergoing lymphoma treatment with rituximab. The addition of IVIg led to a complete resolution of the patient’s cutaneous lesions and a substantial improvement in his mucosal and ocular lesions, which allowed him to eat solid foods and to visualize objects clearly and without photophobia. One month later, the patient was admitted for fever and worsening shortness of breath; the repeat bronchoscopy demonstrated aspergillosis, and voriconazole (Vfend) was started. During the same hospital stay, a CT scan demonstrated stable lymphomatous masses after cycles 5 and 6 of chemotherapy, with an overall response of 39%. A repeat pulmonary evaluation one month later showed no signs of infection. However, the patient’s respiratory status declined over the next few months, and he experienced multiple admissions, increasing oxygen requirements, and the need for mechanical ventilation. He passed away 11 months after being diagnosed with follicular lymphoma and 9 months after recognition of the associated PNP.
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