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Paraneoplastic Pemphigus Workup

  • Author: Lynne J Goldberg, MD; Chief Editor: Dirk M Elston, MD  more...
Updated: Mar 04, 2016

Laboratory Studies

The evaluation of patients suspected of having paraneoplastic pemphigus includes obtaining samples by skin biopsy for routine microscopy and direct immunofluorescence (DIF) testing (see image below), followed by more sophisticated testing when indicated.

Direct immunofluorescence microscopy performed on Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

If the histologic features and DIF results suggest the diagnosis, serum should be sent for indirect immunofluorescence (IDIF) testing. The choice of substrate for the IDIF is important because different substrates express different antigens. Monkey esophagus is considered more sensitive than human skin. Transitional epithelium, such as rat bladder, can also be used. If IDIF results are negative, additional assays should be performed.[32] A case of paraneoplastic pemphigus in which the DIF and IDIF results were negative initially and became positive after 6-14 weeks, respectively, has been reported.[33]

Immunoprecipitation, immunoblotting and enzyme-link immunosorbent assay (ELISA) are sensitive assays that are very helpful in confirming the diagnosis of paraneoplastic pemphigus. Several new assays have been described[34, 35, 36] ; however, commercial availability is variable, and they may only be obtainable at research laboratories.

Once the diagnosis of paraneoplastic pemphigus is established, further evaluation for malignancy may be necessary.


Other Tests

DIF testing

Skin biopsy samples for DIF testing should be taken from noninvolved, perilesional skin. IgG, with or without complement, binds in an intercellular pattern within the epidermis. Immunoglobulin A (IgA) and immunoglobulin M (IgM) also may be detected. Staining can be diffuse or focal. Positive findings limited to adnexal structures have been described.[37]

Some patients have granular or linear deposition of complement, IgG, and/or IgM along the dermoepidermal junction. The combination of intercellular and subepidermal deposition of immunoreactants is a clue to the diagnosis of paraneoplastic pemphigus.

IDIF testing

IDIF testing is performed by using sera obtained from patients suspected of having paraneoplastic pemphigus and is a good screening test for this disease. Patients with high-titer antibodies exhibit both intercellular intraepidermal antibody deposition and deposition along the dermoepidermal junction. Patients with low titers only exhibit deposition intercellularly in a pattern identical to that of pemphigus vulgaris.

Because circulating antibodies that bind to the cell surface of stratified squamous epithelia are common to all forms of pemphigus, other substrates, such as rodent bladder, can be useful in distinguishing paraneoplastic pemphigus from pemphigus vulgaris or pemphigus foliaceus. Binding to rat bladder transitional epithelium is specific for circulating autoantibodies from patients with paraneoplastic pemphigus, with a specificity of 83%;[32] sensitivity ranges from 75-86% depending on the study.

Immunoprecipitation and immunoblotting

A recent study found that immunoprecipitation for antibodies against envoplakin and periplakin or alpha2-macroglobulin-like–1 is the most sensitive test for paraneoplastic pemphigus, although the latter can also be seen in toxic epidermal necrosis. Because this test is not always readily available, the authors also suggest that the combination of IDIF on rat bladder and immunoblotting may be easier and have similar sensitivity and specificity.[31]

Sensitivity and specificity

A recent study on 19 paraneoplastic pemphigus patients revealed the following sensitivities[31] :

  • 100% and 95% - Radioactive and nonradioactive immunoprecipitation, respectively
  • 89% - Immunoblotting
  • 74% - IDIF on rat bladder
  • 63% - ELISA for envoplakin

Specificity ranged from 86-100%.


Histologic Findings

Vesicular lesions express the most characteristic histopathologic features. Oral and cutaneous lesions show variable epidermal necrosis, suprabasal acantholysis, dyskeratotic keratinocytes, vacuolar interface dermatitis, and lymphocytic exocytosis. Substantial inflammation can be present, even in early lesions.

While oral mucosal lesions show the greatest acantholysis, biopsy specimens of severe stomatitis may reveal only ulceration. Some skin lesions lack any acantholysis.  When present, suprabasal acantholysis can result in clefts and tombstoning, which is the appearance of the basal cell layer below the cleft, and histologic findings can be indistinguishable from pemphigus vulgaris.

A distinctive feature of paraneoplastic pemphigus is dyskeratosis. Dyskeratosis is a constant feature, but the number of dyskeratotic keratinocytes is variable. Dyskeratotic keratinocytes are found at all levels in the epidermis, especially within the zones of acantholysis, and they can be found in cutaneous adnexa. The presence of dyskeratosis in a person with a suprabasal acantholytic bullous disorder is a clue to the presence of paraneoplastic pemphigus.

Interface dermatitis is a frequent finding in persons with paraneoplastic pemphigus, and it can be found both with and without acantholysis. Exocytosis of inflammatory cells into the epidermis is common, and the amount and degree are directly proportional to the degree of dyskeratosis. Satellite cell necrosis (a lymphocyte adjacent to a necrotic keratinocyte) can occur. Lesions showing marked vacuolar alteration are accompanied by melanophages in the papillary dermis.

Dermal changes include a superficial perivascular infiltrate of variable intensity, which is mostly composed of lymphocytes. As in the oral mucosa, the pattern of cutaneous inflammation can be lichenoid, leading to a misdiagnosis of lichen planus.[38] Papillary dermal edema is present in early lesions, whereas older lesions may exhibit mild dermal fibrosis.

Contributor Information and Disclosures

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, Massachusetts Academy of Dermatology, New England Dermatological Society, North American Hair Research Society, Phi Beta Kappa, Women's Dermatologic Society

Disclosure: Nothing to disclose.


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

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

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, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: XOMA; Biogen/IDEC; Novartis; Janssen Biotech, Abbvie, CSL pharma<br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor and intermittent author; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

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

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, 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: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

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

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

  3. Zimmermann J, Bahmer F, Rose C, Zillikens D, Schmidt E. Clinical and immunopathological spectrum of paraneoplastic pemphigus. J Dtsch Dermatol Ges. 2010 Aug. 8 (8):598-606. [Medline].

  4. Martel P, Loiseau P, Joly P, Busson M, Lepage V, Mouquet H, et al. Paraneoplastic pemphigus is associated with the DRB1*03 allele. J Autoimmun. 2003 Feb. 20 (1):91-5. [Medline].

  5. Liu Q, Bu DF, Li D, Zhu XJ. Genotyping of HLA-I and HLA-II alleles in Chinese patients with paraneoplastic pemphigus. Br J Dermatol. 2008 Mar. 158 (3):587-91. [Medline].

  6. Czernik A, Camilleri M, Pittelkow MR, Grando SA. Paraneoplastic autoimmune multiorgan syndrome: 20 years after. Int J Dermatol. 2011 Aug. 50 (8):905-14. [Medline].

  7. Qian SX, Li JY, Hong M, Xu W, Qiu HX. Nonhematological autoimmunity (glomerulosclerosis, paraneoplastic pemphigus and paraneoplastic neurological syndrome) in a patient with chronic lymphocytic leukemia: Diagnosis, prognosis and management. Leuk Res. 2009 Mar. 33 (3):500-5. [Medline].

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

  9. Yong AA, Tey HL. Paraneoplastic pemphigus. Australas J Dermatol. 2013 Nov. 54(4):241-50. [Medline].

  10. 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. 2000 Feb. 63(2):105-6. [Medline].

  11. 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].

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

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

  14. 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. 2005 Jul. 153(1):214-5. [Medline].

  15. 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. 2005 Oct. 141(10):1285-93. [Medline].

  16. 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. 2011 Oct 20. [Medline].

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

  18. 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. 2005 Sep. 153(3):558-64. [Medline].

  19. Tull T, Papineni P, Cook C, Mee J, Bower M, Morar N. Paraneoplastic pemphigus in patient infected with the human immunodeficiency virus. Clin Exp Dermatol. 2014 Jan. 39(1):83-5. [Medline].

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

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

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

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

  24. 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. 2007 Jan. 56(1):153-9. [Medline].

  25. 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. 2005 May. 44(5):366-71. [Medline].

  26. Leger S, Picard D, Ingen-Housz-Oro S, Arnault JP, Aubin F, Carsuzaa F. Prognostic factors of paraneoplastic pemphigus. Arch Dermatol. 2012 Oct. 148(10):1165-72. [Medline].

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

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

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

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

  31. Poot AM, Diercks GF, Kramer D, Schepens I, Klunder G, Hashimoto T. Laboratory diagnosis of paraneoplastic pemphigus. Br J Dermatol. 2013 Nov. 169(5):1016-24. [Medline].

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

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

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

  35. 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. 2008 Nov. 129(2):304-12. [Medline].

  36. 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. 2009 Sep 6. [Medline].

  37. 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. 2009 Jan. 36(1):34-8. [Medline].

  38. Khudhur AS, Di Zenzo G, Carrozzo M. Oral lichenoid tissue reactions: diagnosis and classification. Expert Rev Mol Diagn. 2014 Mar. 14 (2):169-84. [Medline].

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

  40. 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. 2006 Jan. 20(1):69-74. [Medline].

  41. 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. 2009 Feb. 5(1):1-7. [Medline]. [Full Text].

  42. Hohwy T, Bang K, Steiniche T, Peterslund NA, d'Amore F. Alemtuzumab-induced remission of both severe paraneoplastic pemphigus and leukaemic bone marrow infiltration in a case of treatment-resistant B-cell chronic lymphocytic leukaemia. Eur J Haematol. 2004 Sep. 73 (3):206-9. [Medline].

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.
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