Paraneoplastic pemphigus associated with non-Hodgkin lymphoma
Published Web Locationhttps://doi.org/10.5070/D36sr0r7h1
Paraneoplastic pemphigus associated with non-Hodgkin lymphoma1. Department of Dermatology, Federal University of Sao Paulo - UNIFESP. firstname.lastname@example.org
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
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 . 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 . 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 . The course of the disease involves multiple respiratory complications and death, which occurs in approximately 90 percent of the cases .
|Figure 1||Figure 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 3||Figure 4|
|Figure 3. Tzanck test revealing the presence of acantholytic cells|
Figure 4. Skin biopsy revealing acantholytic blister in the epidermis
|Figure 5||Figure 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 . 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 . 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) . 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 . 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 . 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 , although 25 percent of PNP sera can show negative results .
Treatment options for PNP include high doses of prednisone, prednisone and cyclosporine, pulse cyclophosphamide , and several other treatment modalities. However, treatment is extremely difficult, with high mortality in most cases .
References1. Anhalt JG, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, et al. Paraneoplastic Pemphigus- an autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990 Dec 20; 323(25):1729-35. PubMed.
2. Nousari HC, Deterding R, Wojtczack H, Aho S, Uitto J, Hashimoto T, et al. The mechanism of respiratory failure in paraneoplatic pemphigus. N Engl J Med. 1999 May 6;340(18):1406-10. PubMed
3. Nguyen VT, Ndoye A, Bassler KD, Shultz LD, Shields MC, Ruben BS, Webber RJ, Pittelkow MR, Lynch PJ, Grando SA. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol. 2001 Feb;137(2):193-206. PubMed
4. Heymann WR. Paraneoplastic autoimmune multiorgan syndrome. J Am Acad Dermatol. 2004 Oct; 51(4):631-2. PubMed
5. Iranzo P, Xaubet A, Carrera C, Mascaro JM, Campo E, Herrero C. Bronchiolitis obliterans associated with paraneoplastic pemphigus: a paraneoplastic autoimmune multiorgan syndrome. Arch Bronconeumol. 2004 May; 40(5):240-3. PubMed
6. Lane JE, Woody C, Davis LS, Guill MF, Jerath RS. Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus) in a child: case report and review of the literature. Pediatrics. 2004 Oct; 114(4):e513-6. PubMed
7. Wade MS, Black MM. Paraneoplastic pemphigus: a brief update. Australas J Dermatol. 2005 Feb; 46(1):1-8; quiz 9-10. PubMed
8. Joly P, Richard C, Gilbert D, Courville P, Chosidow O, Roujeau JC et al. Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol. 2000 Oct; 43(4):619-26. PubMed
9. Hashimoto T. Immunopathology of paraneoplastic pemphigus. Clin Dermatol. 2001 Nov-Dec; 19(6):675-82. PubMed
10. Takahashi M, Shimatsu Y, Kazama T, Kimura K, Otsuka T, Hashimoto T. Paraneoplatic pemphigus associated with bronchiolitis obliterans. Chest. 2000 Feb; 117(2):603-7. PubMed
11. Hasegawa Y, Shimokata K, Ichiyama S, Saito H. Constrictive bronchiolitis obliterans and paraneoplastic pemphigus. Eur Respir J. 1999 Apr; 13(4):934-7. PubMed
12. Cordel N, Ringeisen F, Antoine M, Cadranel J, Aractingi S. Paraneoplastic pemphigus with constrictive bronchiolitis obliterans. Dermatology. 2001; 202(2):145. PubMed
13. Amagai M, Nishikawa T, Noussari HC, Anhalt GJ, Hashimoto T. Antibodies against desmoglein3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest. 1998 Aug 15; 102(4):775-82. PubMed
14. Zhang B, Zheng R, Wang J, Bu D, Zhu X. Epitopes in the linker subdomain region of envoplakin recognized by autoantibodies in paraneoplastic pempigus patients. J Invest Dermatol. 2006 Apr;126(4):832-40. PubMed
15. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol. 1997; 12:77-96; discussion 97. PubMed.
© 2008 Dermatology Online Journal