Laboratory Data

A sample from the buccal mucosa reveals irregular epidermal hyperplasia, dyskeratosis, and blister formation. There is a dense lichenoid infiltrate comprised primarily of lymphocytes as well as a deep mixed inflammatory infiltrate. DIF was negative though the biopsy was secured after the patient had initiated therapy and his B cell count was nearly zero.

Paraneoplastic pemphigus

The patient was admitted from the emergency room and treated with methylprednisolone and Rituximab and his oral lesions improved markedly. Shortly after discharge, he was started on CVP-R (Cytoxan, Vincristine, Prednisone and Rituximab) to aggressively treat his NHL. Following his first course of CVP-R, he was also started on mycophenolate mofetil and his prednisone was gradually tapered down to 10mg PO daily with control of his oral lesions.

After seven courses of CVP-R, he declined further treatment due to fear of recurrent bouts of neutropenia. He has since been treated with Rituximab for maintenance therapy. Since stopping CVP-R, his oral lesions have worsened and he has developed “grittiness” in his eyes. He responds to increases in prednisone but his lesions recur once his steroids are tapered. He is also on dexamethasone washes and tacrolimus 0.1% topically BID, although these are only for symptomatic control at sites of recurrent ulceration.

Although he has never developed shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, or platypnea, the disease became rapidly progressive and blistering attacks prevented the patient from being able to eat. He became depressed due to an inability to sleep through the night and massive lower extremity edema (as a complication of high dose oral prednisone pulses), which have severely impacted his ambulation.

After several discussions, daclizumab was offered as therapy, but due to a theoretical reactivation of his lymphoma, the patient declined. Rather, alemtuzumab was used three times weekly for a twelve week course. Intravenous immunoglobulin was also infused monthly. After three infusions with alemtuzumab, the patient has been in near complete remission. He is able to enjoy foods, has no dysphagia or hoarseness and we have been able to rapidly wean off his prednisone dosing back to 20 mg per day.

If this regimen fails, a trial of photopheresis, and possibly plasmapheresis may be future considerations.

Paraneoplastic pemphigus (PNP) is most commonly associated with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymomas, spindle cell neoplasms and Waldenstrom's macroglobulinemia.

These patients present with mucosal lesions that appear lichenoid or Stevens-Johnson-like with crusting of the lips. Recalcitrant stomatitis, consisting of erosions and ulcerations is often the most persisting feature of PNP. Involvement of other mucocutaneous surfaces, including the eyes, can occur in the form of pseudomembranous conjunctivitis, which may progress to scarring and obliteration of the conjunctival fornices. Furthermore, cutaneous lesions are polymorphic and can resemble pemphigus vulgaris, bullous pemphigoid, EM, and lichenoid eruptions. Upper GI, respiratory, and genital mucosal lesions also occur, as well as involvement of the kidneys, muscle and heart.

Indeed, because of the multiorgan involvement and variable cutaneous manifestations that can occur, it has also been proposed that the term PNP only describes the classic epithelial manifestations of this syndrome, and that a more appropriate name for this constellation of findings is paraneoplastic autoimmune multiorgan syndrome (PAMS).

Classic histological findings in PNP/PAMS include epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes and vacuolar change of the basalar epidermis.

Autoantibodies can be directed against desmogleins 1 and 3, the major plaque protein of BP Ag1 (230 KD), and all the plakin family members. DIF shows IgG and C3 deposition in the intercellular spaces of the epithelium or at the basement membrane zone. However, antigens other than the ones listed above have also been identified, and recently several seemingly “IF negative” cases of PNP/PAMS, such as our patient, have been reported.

Furthermore, in addition to the humoral response, the pathophysiology of PNP/PAMS also incorporates a cellular autoimmunity response, mediated by CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages. There is also an association of PNP/PAMS with HLA-DRB1*03.

PNP/PAMS is traditionally difficult to treat. Prednisone +/- additional immunosuppressive agents, including immunoablative cyclophosphamide without stem cell rescue, cyclosporin A, plasmapheresis, immunoapheresis and rituximab are often recommended.

Newer therapies include daclizumab and alemtuzumab, though most reports detail progress when these advanced therapeutics are used to treat concurrent, active lymphoma. Prognosis depends on the nature of the underlying malignancy, and the development of severe respiratory compromise. Identifying patients with respiratory complaints early is paramount, as development of bronchiolitis obliterans-like symptomatology is usually difficult to treat and is an ominous sign. Delay in diagnosis is often the case because these respiratory complaints are out of proportion with clear radiographic studies. Chest roenterograms and computed tomography studies are often negative. On pulmonary function testing however, marked obstructive patterns with limitation in diffusion capacity are diagnostic

Unfortunately, because the inciting malignancy and the paraneoplastic syndrome need not evolve in the same direction, patients with PNP/PAMS may often progress to recalcitrant mucosal disease or pulmonary disease even in cases when the malignancy has been treated and is in remission.

Cummins DJ, Mimouni, D, Tzu, J., et al. (2007). Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies. J Am Acad Dermatol. 56:153-9.

Kaplan I, Hodak E, Ackerman L, et al. (2004). Neoplasms associated with paraneoplastic pemphigus: a review of literature with emphasis on non-haematologic malignancy and oral manifestations. Oral oncology 40:553–562.

Martel P, Loiseau P, Joly P, et al. (2003). Paraneoplastic pemphigus is associated with the DRB1*03 allele. 1: J Autoimmun. 20(1):91-5.

Nousari HC, Deterding R, Wojtczack H, et al. (1999). The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 340:1406-10.

Nguyen, VT, Ndoye, A, Bassler, KD, et al. (2001). Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol.137(2):193-206.

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David Elpern M.D., Dermatologist, Williamstown, MA, USA on May 25, 2008

This is a superb presentation. Dr. Ibrahimi and his colleagues are to be congratulated. I found a very useful review of this syndrome from the Department of Dermatology, Mayo Clinic, USA :

Billet SE, Grando SA, Pittelkow MR. Paraneoplastic autoimmune multiorgan syndrome: review of the literature and support for a cytotoxic role in pathogenesis. Autoimmunity. 2006 Nov;39(7):617-30.

Paraneoplastic autoimmune multiorgan syndrome (PAMS), first described as paraneoplastic pemphigus in 1990, is an autoimmune blistering disease associated with neoplasia. Patients with this rare disorder have severe blistering and painful erosions of the oral cavity and various other cutaneous findings ranging from classic pemphigus vulgaris-like erosions to targetoid lesions resembling erythema multiforme and papular to more confluent lichenoid eruptions. This syndrome involves multiple organ systems, and its high rate of mortality often stems from constrictive bronchiolitis obliterans. The histologic findings are as diverse as the clinical presentation, often making diagnosis difficult initially. Immunodermatologic and serologic laboratory findings typically establish the diagnosis. These results can be confirmed with immunoprecipitation profiling of specific molecular weight protein markers. The proposed pathogenesis of PAMS continues to evolve, and recent reports implicate the involvement of cell-mediated, cytotoxic immunity, in addition to humoral autoantibodies. This review characterizes and summarizes the clinical, pathologic, and immunohistologic features of PAMS and outlines the possible role of cytotoxic T lymphocytes in the pathogenesis of this syndrome.

Henry Foong FRCP, Dermatologist, Ipoh, Malaysia on May 25, 2008

This is an excellent and a very instructive case. The clinical images and the histology are of superb quality.

It is interesting to note that "IF negative” cases of PNP/PAMS have been reported and does not exclude the diagnosis of PAMS. Especially so if the patient has initiated therapy with rituximab and if the B cell count is very low. We must be aware of this disease and the difficulty in relying on IF studies to make a diagnosis.

Ref: Daniel D. "Delayed detection of autoantibodies in paraneoplastic pemphigus" J Am Acad Dermatol 2007;57:1094-1095

Shahbaz Janjua MD, Dermatologist, Ayza Skin & Research Center, Lalamusa, Pakistan on May 30, 2008

It's a wonderful case presentation. I learnt a lot about PAMS from this case. Thank you and congratulations. Would you suggest to consult a pulmonologist to evauate the respiratory invovement in such cases?