Paraneoplastic Pemphigus Clinical Presentation

  • Author: Lynne J Goldberg, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 13, 2012
 

History

Paraneoplastic pemphigus is usually associated with malignancy, although it can occur in association with benign neoplasms. The most common malignancy associated with paraneoplastic pemphigus is non-Hodgkin lymphoma.[9, 10, 11] Other associated malignancies and conditions include chronic lymphocytic leukemia, Castleman disease,[12, 13, 14, 15] Waldenström macroglobulinemia,[16] thymoma,[13, 17] sarcoma,[17] and lung carcinoma.

An association reported in 2009 is with systemic mastocytosis,[18] and an atypical case associated with endometrial carcinoma lacking mucosal involvement has been reported.[19] Paraneoplastic pemphigus can coexist with bullous pemphigoid[20] and has been reported to "shift" to pemphigus vulgaris.[21]

Also see Non-Hodgkin Lymphoma (pediatric focus), Chronic Lymphocytic Leukemia, Waldenstrom Hypergammaglobulinemia, and Thymoma

Patients present with painful oral erosions, often accompanied by a generalized cutaneous eruption. Oral erosions occur early and typically are severe, often involving the lateral tongue and vermilion. The eruption can assume a wide variety of morphologies. A classification system has been suggested, dividing lesions into pemphiguslike, pemphigoidlike, erythema multiforme–like, graft versus host disease–like, and lichen planus–like. Additionally, some patients report pruritus or pain. Cases without mucosal involvement have been reported, especially with the lichen planus –like variant, although these patients lacked autoantibodies.[22]

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Physical

Mucosal findings

The earliest and most constant clinical finding in paraneoplastic pemphigus is painful oral erosions. Of those patients who present with a skin eruption, all go on to develop mucositis at some point during the course of the disease. Some patients only experience oral lesions.

The erosions of paraneoplastic pemphigus can occur anywhere in the mouth, including the buccal, labial, gingival, and lingual mucosae. All surfaces of the oropharynx can be affected. Erosions and subsequent crusting on the vermilion of the lips are typical and similar to that seen in persons with Stevens-Johnson syndrome. Genital mucosal surfaces can also be affected. Finally, nasal ulcers may cause epistaxis.

Cutaneous findings

The eruption of paraneoplastic pemphigus is highly variable. Patients may present with diffuse erythema, vesiculobullous lesions, papules, scaly plaques, exfoliative erythroderma, erosions, or ulcerations. The erythema can be macular, urticarial, or targetoid, and it may be polymorphous. Patients may initially present with erythema, and they may subsequently develop bullae and erosions.

Large areas of denudation with a positive Nikolsky sign can occur. Pustules have been reported. The papular lesions may resemble lichen planus, and the oral lesions may also be mistaken for lichen planus.[23] A single patient has been reported with a solitary, pemphigus vegetans–like lesion that arose in a previous bulla. The palms and the soles may be involved.

Extracutaneous findings

Biopsy-confirmed paraneoplastic pemphigus has been reported in the gastrointestinal tract and the respiratory tract mucosa. The latter has been increasingly recognized and is a significant cause of mortality. Pulmonary involvement manifests as obstructive lung disease and progresses to bronchiolitis obliterans and death. Despite its ominous significance, signs of pulmonary involvement are subtle. Patients develop dyspnea, yet chest radiograph findings are normal. Ocular involvement ranges from mild conjunctivitis to symblepharon with corneal scarring.[24]

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Causes

The association of paraneoplastic pemphigus with malignancy is strong. Only a handful of patients have had no associated diagnosis. Some patients have had benign neoplasms, including thymoma and Castleman disease. Only a single patient without a tumor has met the diagnostic criteria, yet this patient had a rapid demise and may have died with an undiagnosed malignancy. Patients have developed paraneoplastic pemphigus while in remission of their malignancy, leading some authors to prefer the term neoplasia-induced pemphigus.[25]

Treatment of the underlying malignancy does not necessarily halt progression of the paraneoplastic pemphigus, although some have observed that clinical manifestations improve as autoantibody titers decrease following resection of the tumor.

Circulating and tissue-bound antibodies in patients with this disease are directed against a group of molecules with sequence homology and belonging to the plakin family. These molecules are found in the intracellular attachment plaques of desmosomes and hemidesmosomes, and they play a key role in intermediate filament attachment. However, the number of reported target antigens has increased over time and varies between patients. This variability likely accounts for the clinical heterogeneity of this disease. By immunoprecipitation, target antigens (in decreasing order of incidence) include desmoglein 3, desmoglein 1, envoplakin (210 kd), periplakin (190 kd), desmoplakin I (250 kd), desmoplakin II (210 kd), and bullous pemphigoid antigen I (230 kd). Plectin (>400 kd) and an unidentified 170-kd protein have also been found.[26]

How tumors induce autoantibodies to plakin proteins is not known. Tumor cells have been demonstrated to produce autoantibodies that react to epidermal proteins. Other postulates include (1) cross-reactivity of tumor antigens and epidermal antigens and (2) tumor production of plakin proteins that initiate an autoimmune response. Dysregulated cytokine production by tumor cells, specifically interleukin 6, contributing to the autoimmune process is another hypothesis. The concept of epitope spreading, with which patients develop antibodies to multiple structurally related and unrelated proteins, may explain the multitude of antibodies produced in association with this disease.

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Contributor Information and Disclosures
Author

Lynne J Goldberg, MD  Professor, Departments of Dermatology and Pathology, Boston University School of Medicine

Lynne J Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, International Society of Dermatopathology, International Society of Dermatopathology, Massachusetts Academy of Dermatology, New England Dermatological Society, North American Hair Research Society, Phi Beta Kappa, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Coauthor(s)

Nauman Nisar  MD, Dermatopathologist, Mercy Medical Center, Sioux City, IA

Nauman Nisar is a member of the following medical societies: College of American Pathologists

Disclosure: Nothing to disclose.

Specialty Editor Board

Ponciano D Cruz Jr, MD  Vice-Chair, JB Shelmire Professor, Department of Dermatology, University of Texas Southwestern Medical Center

Ponciano D Cruz Jr, MD is a member of the following medical societies: Texas Medical Association

Disclosure: RCTS Consulting fee Independent contractor; Mary Kay Cosmetics Honoraria Consulting; Galderma Grant/research funds Principal Investigator

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD  Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Celgene Honoraria Safety Monitoring Committee

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. Dec 20 1990;323(25):1729-35. [Medline].

  2. Anhalt GJ. Paraneoplastic pemphigus. J Investig Dermatol Symp Proc. Jan 2004;9(1):29-33. [Medline].

  3. Frew JW, Murrell DF. Paraneoplastic pemphigus (paraneoplastic autoimmune multiorgan syndrome): clinical presentations and pathogenesis. Dermatol Clin. Jul 2011;29(3):419-25, viii. [Medline].

  4. Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest. Aug 15 1998;102(4):775-82. [Medline].

  5. Mahoney MG, Aho S, Uitto J, Stanley JR. The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin. J Invest Dermatol. Aug 1998;111(2):308-13. [Medline].

  6. Ruhrberg C, Watt FM. The plakin family: versatile organizers of cytoskeletal architecture. Curr Opin Genet Dev. Jun 1997;7(3):392-7. [Medline].

  7. Leung CL, Liem RK, Parry DA, Green KJ. The plakin family. J Cell Sci. Oct 2001;114:3409-10. [Medline].

  8. Li J, Bu DF, Huang YC, Zhu XJ. Role of autoantibodies against the linker subdomains of envoplakin and periplakin in the pathogenesis of paraneoplastic pemphigus. Chin Med J (Engl). Mar 5 2009;122(5):486-95. [Medline].

  9. Hertzberg MS, Schifter M, Sullivan J, Stapleton K. Paraneoplastic pemphigus in two patients with B-cell non-Hodgkin's lymphoma: significant responses to cyclophosphamide and prednisolone. Am J Hematol. Feb 2000;63(2):105-6. [Medline].

  10. Martinez De Pablo MI, Iranzo P, Mascaro JM, Llambrich A, Baradad M, Herrero C. Paraneoplastic pemphigus associated with non-Hodgkin B-cell lymphoma and good response to prednisone. Acta Derm Venereol. 2005;85(3):233-5. [Medline].

  11. Tilakaratne W, Dissanayake M. Paraneoplastic pemphigus: a case report and review of literature. Oral Dis. Sep 2005;11(5):326-9. [Medline].

  12. Hung IJ, Lin JJ, Yang CP, Hsueh C. Paraneoplastic syndrome and intrathoracic Castleman disease. Pediatr Blood Cancer. Oct 15 2006;47(5):616-20. [Medline].

  13. Marzano AV, Vezzoli P, Mariotti F, Boneschi V, Caputo R, Berti E. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma and Castleman disease. Br J Dermatol. Jul 2005;153(1):214-5. [Medline].

  14. Wang J, Zhu X, Li R, et al. Paraneoplastic pemphigus associated with Castleman tumor: a commonly reported subtype of paraneoplastic pemphigus in China. Arch Dermatol. Oct 2005;141(10):1285-93. [Medline].

  15. Koch LH, Layton CJ, Pilichowska M, Stadecker MJ, Barak O. Paraneoplastic Pemphigus and Castleman's Disease in the Setting of Herpes Simplex Virus Infection. Pediatr Dermatol. Oct 20 2011;[Medline].

  16. Perera GK, Devereux S, Mufti G, Salisbury J, Creamer D. PNP with Waldenström's macroglobulinaemia. Clin Exp Dermatol. Jan 2005;30(1):27-9. [Medline].

  17. Wang J, Bu DF, Li T, et al. Autoantibody production from a thymoma and a follicular dendritic cell sarcoma associated with paraneoplastic pemphigus. Br J Dermatol. Sep 2005;153(3):558-64. [Medline].

  18. Eccersley LR, Hoffbrand AV, Rustin MH, McNamara CJ. Paraneoplastic pemphigus associated with systemic mastocytosis. Am J Hematol. May 27 2009;[Medline].

  19. Kennedy NA, Dawe S. Atypical paraneoplastic pemphigus secondary to endometrial carcinoma with no mucosal involvement. Clin Exp Dermatol. Jul 2009;34(5):e130-3. [Medline].

  20. Kakurai M, Demitsu T, Iida E, et al. Coexistence of paraneoplastic pemphigus and bullous pemphigoid. J Eur Acad Dermatol Venereol. Aug 2009;23(8):962-4. [Medline].

  21. Ishii N, Hashimoto T. A case of paraneoplastic pemphigus who shifted to pemphigus vulgaris. J Eur Acad Dermatol Venereol. Mar 2008;22(3):374-5. [Medline].

  22. Cummins DL, Mimouni D, Tzu J, Owens N, Anhalt GJ, Meyerle JH. Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies. J Am Acad Dermatol. Jan 2007;56(1):153-9. [Medline].

  23. Coelho S, Reis JP, Tellechea O, Figueiredo A, Black M. Paraneoplastic pemphigus with clinical features of lichen planus associated with low-grade B cell lymphoma. Int J Dermatol. May 2005;44(5):366-71. [Medline].

  24. Laforest C, Huilgol SC, Casson R, Selva D, Leibovitch I. Autoimmune bullous diseases: ocular manifestations and management. Drugs. 2005;65(13):1767-79. [Medline].

  25. Camisa C, Helm TN. Paraneoplastic pemphigus is a distinct neoplasia-induced autoimmune disease. Arch Dermatol. Jul 1993;129(7):883-6. [Medline].

  26. Proby C, Fujii Y, Owaribe K, Nishikawa T, Amagai M. Human autoantibodies against HD1/plectin in paraneoplastic pemphigus. J Invest Dermatol. Feb 1999;112(2):153-6. [Medline].

  27. Helou J, Allbritton J, Anhalt GJ. Accuracy of indirect immunofluorescence testing in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol. Mar 1995;32(3):441-7. [Medline].

  28. Bennett DD, Busick TL. Delayed detection of autoantibodies in paraneoplastic pemphigus. J Am Acad Dermatol. Dec 2007;57(6):1094-5. [Medline].

  29. Huang Y, Li J, Zhu X. Detection of anti-envoplakin and anti-periplakin autoantibodies by ELISA in patients with paraneoplastic pemphigus. Arch Dermatol Res. Nov 2009;301(10):703-9. [Medline].

  30. Mouquet H, Drenovska K, Lartigue A, et al. Detection and characterization of anti-envoplakin linker autoantibodies in paraneoplastic pemphigus using specific bead-based assay. Clin Immunol. Nov 2008;129(2):304-12. [Medline].

  31. Probst C, Schlumberger W, Stocker W, et al. Development of ELISA for the specific determination of autoantibodies against envoplakin and periplakin in paraneoplastic pemphigus. Clin Chim Acta. Sep 6 2009;[Medline].

  32. Barnadas MA, Curell R, Alomar A, Gelpi C. Paraneoplastic pemphigus with negative direct immunofluorescence in epidermis or mucosa but positive findings in adnexal structures. J Cutan Pathol. Jan 2009;36(1):34-8. [Medline].

  33. Frew JW, Murrell DF. Current management strategies in paraneoplastic pemphigus (paraneoplastic autoimmune multiorgan syndrome). Dermatol Clin. Oct 2011;29(4):607-12. [Medline].

  34. Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. Aug 2007;34(8):503-11. [Medline].

  35. Barnadas M, Roe E, Brunet S, et al. Therapy of paraneoplastic pemphigus with Rituximab: a case report and review of literature. J Eur Acad Dermatol Venereol. Jan 2006;20(1):69-74. [Medline].

  36. Peterson JD, Chan LS. Effectiveness and side effects of anti-CD20 therapy for autoantibody-mediated blistering skin diseases: A comprehensive survey of 71 consecutive patients from the Initial use to 2007. Ther Clin Risk Manag. Feb 2009;5(1):1-7. [Medline].

  37. Hashimoto T. Immunopathology of paraneoplastic pemphigus. Clin Dermatol. Nov-Dec 2001;19(6):675-82. [Medline].

  38. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol. Aug 1992;128(8):1091-5. [Medline].

  39. Joly P, Richard C, Gilbert D, et al. Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol. Oct 2000;43(4):619-26. [Medline].

  40. Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic pemphigus. Dermatol Clin. Jul 1993;11(3):473-81. [Medline].

  41. Stone SP, Buescher LS. Life-threatening paraneoplastic cutaneous syndromes. Clin Dermatol. May-Jun 2005;23(3):301-6. [Medline].

  42. Wade MS, Black MM. Paraneoplastic pemphigus: a brief update. Australas J Dermatol. Feb 2005;46(1):1-8; quiz 9-10. [Medline].

  43. Wakahara M, Kiyohara T, Kumakiri M, et al. Paraneoplastic pemphigus with widespread mucosal involvement. Acta Derm Venereol. 2005;85(6):530-2. [Medline].

 
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