Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP) is a rare and often fatal autoimmune blistering disease associated with both benign and malignant neoplasms. PNP has a strong association with hematologic disorders which account for 84% of the cases, with non-Hodgkin lymphoma the most frequent disorder (38.6%) in this group, followed by chronic lymphocytic leukemia (18.4%), and Castleman disease (18.4%). Non-hematological neoplasms represent a fraction of cases (16%) of which carcinomas account for most of them (8.6%), followed by sarcomas (6.2%) and malignant melanoma (0.6%). Due to the significant morbidity and mortality associated with this autoimmune disease, timely and accurate diagnostic work-up is imperative for management.

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KSL Beutner Laboratories offers a comprehensive testing menu for patients suspected of this diagnosis. 

Pathophysiology

  • PNP was first described by Anhalt et al. in 1990 as a distinct autoimmune entity from pemphigus vulgaris (PV). This entity displayed exhibited distinctive autoantibodies against desmoplakin I and the bullous pemphigoid 230-kd antigen (BP230). Subsequently, the term paraneoplastic autoimmune multiorgan syndrome (PAMS) was proposed to encompass the numerous clinical phenotypes and multiorgan involvement observed in patients with this disease. 

  • Histopathological and clinical features found in PNP/PAMS reflect the complexity of its pathophysiology which includes both cellular and humoral immunity. Humoral immunity includes development of autoantibodies to the plakins such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, A2ML1, Dsg1 and Dsg3, also known as the paraneoplastic pemphigus complex. 16% of patients do not demonstrate (develop?) antibodies to proteins in this complex   

  • Etiopathogenesis of PNP is not fully known. Skin lesions are thought to be caused by an autoimmune response generated by antibodies to tumor antigens that cross-react with epithelial antigens. Tumor autoantibodies produce and release cytokines (such as interleukin-6) that favor the differentiation of B-cells and foster the development of the humoral branch of the immune system.

 

Clinical features 

  • Painful stomatitis and polymorphous cutaneous eruption with lesions that may be blistering, lichenoid, or like erythema multiforme or GVH.  

  • PNP may also involve the mucous membranes of the esophagus, stomach, duodenum, and intestines and the pulmonary epithelium 

  • Patients with PNP can develop life-threatening restrictive bronchiolitis consistent with bronchiolitis obliterans. 

 

Diagnosis 

  • Histology (Test#003)

    • Skin or mucosal biopsy specimen may reveal changes depending upon the clinical phenotype,  i.e blisters reveal acantholysis and erythematous maculopapular lesions show interface dermatitis may be observed. The two findings may be observed in the same lesion (in approximately 60% cases. Use blue top tube (10% buffered formalin) for specimen collection and transport of biopsy specimens for this test. 

  • Direct immunofluorescence (Test #001)

    • Direct immunofluorescence shows IgG and C3 in intercellular areas in the epidermis or epithelium and co-existent  granular/linear C3/IgG deposition in basement membrane zone (less than 50% cases). False negatives due to necrotic tissue and in lichenoid lesions. Sensitivity of DIF for PNP ranges from 27%-75%.  

    • Specimen collection: For skin lesions, take skin biopsy with ~2/3 normal skin and ~1/3 lesion edge and for mucosal lesions, take normal mucosa ~3 mm from lesion or Nikolsky sign. Specimens should be collected and transported in Michel’s medium (yellow top tube). 

  • Serology (Tests #013, 015, 016, 017, 009 or Paraneoplastic Pemphigus Profile, #026)

    • Indicated for confirmation of the diagnosis of PNP.  

    • IIF on rat bladder has a sensitivity of 66-86% and specificity of 83%-99%. Anti-Dsg1 and/or anti-Dsg3 ELISA are 80% to 86% sensitive in PNP. Detection of anti-Dsg autoantibodies does not offer acceptable specificity for the diagnosis of PNP, which is defined by autoimmunity against plakin family proteins. Beutner Laboratories offers an ELISA for autoantibodies to Envoplakin (test#009). In the experience of this laboratory, the sensitivity and specificity of this test are 75% and 97.1% respectively. The tests for other autoantibodies are available in research laboratories. 

    • Specimen requirements: Collect 5-10 ml of blood in a red top or serum separator tube. If possible, separate serum from clot and place into red capped tube provided with Beutner Laboratories collection kits. If separation facilities are not available, the blood can be sent in the tube used for collection.  

Paraneoplastic Pemphigus Tests:

Selected References

  • G.J. Anhalt, S.C. Kim, J.R. Stanley, N.J. Korman, D.A. Jabs, M. Kory, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med.1990; 323:1729-1735 

  • T. Nguyen, A. Ndoye, K.D. Bassler, L.D. Shultz, M.C. Shields, B.S. Ruben, et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol. 2001; 137: 193-206 

  • Amber KT, Valdebran M, Grando SA. Paraneoplastic autoimmune multiorgan syndrome (PAMS): Beyond the single phenotype of paraneoplastic pemphigus. Autoimmun Rev. 2018;17:1002-1010.  

  • Leger S, Picard D, Ingen-Housz-Oro S, et al. Prognostic Factors of Paraneoplastic Pemphigus. Arch Dermatol. 2012;148:1165–1172.

  • Anhalt GJ and Mimouni D (2019). In: Paraneoplastic Pemphigus. Fitzpatrick’s dermatology in general medicine. 9th edition, McGraw Hill Education     

  • Powell JG, Grover RK, Plunkett RW, Seiffert-Sinha K, Sinha AA. Evaluation of a Newly Available ELISA for Envoplakin Autoantibodies for the Diagnosis of Paraneoplastic Pemphigus. Journal of drugs in dermatology. 2015;14: 1103-1106.