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Paraneoplastic pemphigus associated with non-Hodgkin lymphoma

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Paraneoplastic pemphigus associated with non-Hodgkin lymphoma
Mariana Dias Batista1, Daniela Takano2, Renato Delascio Lopes3, Milvia M S S Enokihara2, Nilceo Schwery Michalany2, Fernando Augusto de Almeida1
Dermatology Online Journal 14 (6): 11

1. Department of Dermatology, Federal University of Sao Paulo - UNIFESP.
2. Department of Pathology, Federal University of Sao Paulo - UNIFESP
3. Department of Medicine, Federal University of Sao Paulo - UNIFESP


We report a case of a 55-year-old man who, after a 6-month history of enlargement of cervical lymph nodes, presented with multiple painful ulcerations of the oral mucosa and lips and multiple skin erosions on the trunk, back, extremities, and genitals. A lymph node biopsy was performed and revealed diffuse peripheral B-cell non-Hodgkin lymphoma. Skin biopsy revealed an acantholytic blister in the epidermis. Direct immunofluorescence showed IgG deposition in the intercellular spaces of the epidermis and linear C3 deposition in the basement-membrane zone. The indirect immunofluorescence test on rat urinary bladder epithelium was positive with a 1:320 titre. Paraneoplastic pemphigus was diagnosed based on these findings; treatment was started with cyclophosphamide, doxorubicin, vincristin and prednisone. The patient's response to treatment was poor and he developed several complications and died 2 months after diagnosis.


Paraneoplastic pemphigus (PNP) is an auto-immune disease associated with the presence of an underlying neoplasm. It was first described in 1990 as a distinct form of pemphigus because of specific clinical, pathologic and immunologic characteristics [1]. Anhalt et al. initially proposed 5 diagnostic criteria: 1. intractable stomatitis and a polymorphous skin eruption; 2. epidermal acantholysis, keratinocyte necrosis, vacuolar interface dermatitis; 3. IgG and complement deposition in the epidermal intercellular spaces and granular/linear complement deposition in the basement-membrane zone; 4. circulating antibodies against skin and transitional epithelia, such as urinary bladder; 5. immunoprecipitation of proteins of 250, 230, 210, 190 KDa, identified as plakin proteins [1]. Paraneoplastic pemphigus is most frequently associated with lymphoproliferative neoplasms, namely non-Hodgkin lymphoma, but also chronic lymphocytic leukemia, Castleman disease, thymoma, retroperitoneal sarcomas, and Waldenstrom macroglobulinemia [2]. The course of the disease involves multiple respiratory complications and death, which occurs in approximately 90 percent of the cases [2].

Case report

Figure 1Figure 2
Figure 1. Multiple blisters and erosions on the back
Figure 2. Extensive ulceration of the oral mucosa

A 55-year-old man presented with multiple painful ulcerations of the oral mucosa and lips with multiple skin erosions on the trunk, back, extremities, and genitals, which had been present for 2 weeks. Nikolsky sign was positive. An ophthalmologic examination revealed erosions of the conjunctiva, consistent with pseudomembranous conjunctivitis. His past medical history included a 1-year history of dry cough and a 6-month history of enlargement of cervical lymph nodes, associated with loss of 15 kg in this period. A lymph node biopsy was performed, and the diagnosis of diffuse peripheral B-cell non-Hodgkin lymphoma was given. Computerized axial tomography scanning revealed enlargement of cervical, supraclavicular, and mediastinal lymph nodes. An abdominal ultrasound showed extensive enlargement of retroperitoneal lymph nodes. On endoscopy, multiple ulcers were seen in the esophagus.

Figure 3Figure 4
Figure 3. Tzanck test revealing the presence of acantholytic cells
Figure 4. Skin biopsy revealing acantholytic blister in the epidermis

Figure 5Figure 6
Figure 5. Direct immunofluorescence showing IgG deposition in the intercellular spaces of the epidermis
Figure 6. Positive indirect immunofluorescence test on rat urinary bladder epithelium

In order to investigate his cutaneous manifestations, a Tzanck smear was performed and revealed the presence of acantholytic cells. Skin biopsy revealed an acantholytic blister in the epidermis. The direct immunofluorescence test showed IgG deposition in the intercellular spaces of the epidermis and linear C3 deposition in the basement-membrane zone. The indirect immunofluorescence test on rat urinary bladder epithelium was positive, with a 1:320 titre. Paraneoplastic pemphigus (PNP) was diagnosed based on these findings.

Treatment was started with a cycle of cyclophosphamide, doxorubicin, vincristin and prednisone (CHOP), but the response was poor. Cutaneous and oral lesions were refractory to treatment. The patient's course was complicated by chemotherapy-induced agranulocytosis, and he experienced multiple respiratory complications, including infection and acute respiratory distress. He died 2 months after the diagnosis.


Paraneoplastic pemphigus is a heterogeneous autoimmune syndrome involving several internal organs. The pathophysiological mechanisms mediating cutaneous, mucosal, and internal involvement are not limited to autoantibodies targeting adhesion molecules. The paraneoplastic disease of epithelial adhesion known as PNP in fact represents only one manifestation of a heterogeneous autoimmune syndrome. The term "paraneoplastic autoimmune multiorgan syndrome," or PAMS, was suggested in recent studies. It may display a spectrum of at least 5 different clinical and immunopathological mucocutaneous variants (i.e., pemphigus-like, pemphigoid-like, erythema multiforme-like, graft-vs-host disease-like, and lichen planus-like) and there are evidences of small airway occlusion and deposition of autoantibodies in different organs. The pathophysiological mechanisms of PAMS involve both humoral and cellular autoimmune responses. Epithelial cell membrane antigens other than DSG1 or DSG3 are targeted by effectors of PAMS autoimmunity. Apoptosis of damaged basal cells mediates epithelial clefting and respiratory failure results possibly from obstruction of small airways with sloughed epithelial cells [3-7].

The diagnosis of PNP in the case reported here was made based on clinical, histopathological and immunofluorescence findings. Its course and prognosis were also typical for PNP.

Paraneoplastic pemphigus is characterized by polymorphous cutaneous lesions [1]. Mucosal manifestations are pronounced. In one study, 45 percent of PNP patients initially showed isolated oral lesions that could not be distinguished from oral pemphigus vulgaris [8]. Erosions of the oral cavity, when associated with EM-like, BP-like, or LP-like cutaneous lesions, were considered the most specific clinical feature to differentiate PNP from pemphigus vulgaris (PV) and pemphigus foliaceous (PF) [8]. In our case, intractable oral lesions were present.

The respiratory outcome in our case was also consistent with that reported for PNP. Nousari et al. identified bronchiolitis obliterans as a likely manifestation of respiratory failure in these patients because of infection, toxic effects of chemotherapy, neoplasia, and antibody-mediated pulmonary injury. The expression of plakin proteins by the pulmonary epithelium has been demonstrated [2, 9], and antibodies against these proteins cause the acantholytic changes in pulmonary epithelium [2]. Numerous cases of bronchiolitis obliterans occurring in PNP patients have been reported [10, 11, 12].

In terms of histological findings, our case showed suprabasal acantholysis, which is similar to a pemphigus vulgaris (PV) manifestation. This similarity between PNP and PV could denote the presence of anti-desmoglein 3 antibodies, typical of PV, in the patient's serum. Antibodies against desmoglein-3 have been detected in PNP patients and were shown to be pathogenic when transferred to mice [13]. It has been suggested that antibodies against desmogleins 1 and 3 could play an initial pathogenic role in PNP, exposing the cytoplasmatic proteins of the plakin family, particularly envoplakin and periplakin (210 kD and 190 kD) [9, 14].

Direct and indirect immunofluorescence results in this case were typical of PNP. A positive indirect immunofluorescence test on urinary bladder epithelium can differentiate PNP from PV or PF [3], although 25 percent of PNP sera can show negative results [9].

Treatment options for PNP include high doses of prednisone, prednisone and cyclosporine, pulse cyclophosphamide [15], and several other treatment modalities. However, treatment is extremely difficult, with high mortality in most cases [2].


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