Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations

doi:10.1016/j.oraloncology.2003.09.020

Oral Oncology

Volume 40, Issue 6, July 2004, Pages 553-562

https://doi.org/10.1016/j.oraloncology.2003.09.020 Get rights and content

Abstract

The review included 163 cases of paraneoplastic pemphigus (PNP) reported between 1990 and 2003, including a new unique case of PNP associated with occult breast cancer and an ovarian cyst of borderline malignancy.

Hematologic-related neoplasms or disorders were associated with 84% of the cases, with non-Hodgkin lymphoma (38.6%) as the most frequent, followed by chronic lymphocytic leukemia (18.4%) and Castleman's disease (18.4%). The non-hematologic neoplasms comprised 16% of all cases: epithelial origin-carcinoma (8.6%), mesenchymal origin-sarcoma (6.2%), and malignant melanoma (0.6%). Carcinoma cases comprised 58% of the non-hematologic neoplasms. Carcinoma cases (n=14) consisted of adenocarcinoma (n=7), squamous cell carcinoma (n=2), multiple skin tumors probably basal cell carcinoma (n=1), and bronchogenic carcinoma (n=1). Of the 10 (6.2%) sarcoma cases, there was one case each of leiomyosarcoma, liposarcoma, malignant nerve sheath tumor, poorly differentiated sarcoma, reticulum cell sarcoma, dendritic cell sarcoma and inflammatory myofibroblastic tumor.

The oral mucosa was involved in all of cases. Isolated oral ulcerations were the first sign in 45% of the cases. Diffuse and persistent oral ulcerations with a progressive course could be a sign of malignancy, either recognized or occult. In the absence of a clear diagnosis, malignancy should be suspected and extensive work-up performed. The full spectrum of signs of PNP may not be present initially. Repeated biopsies, direct and indirect immunofluorescence as well as screening indirect immunofluorescence on murine bladder are required for diagnosis. Clinicians should be highly suspicious when signs and symptoms suggestive of PNP are present in cancer patients, of hematologic and non-hematologic origin.

Introduction

Paraneoplastic pemphigus (PNP), an autoimmune blistering and erosive mucocutaneous disease associated with neoplasia. It was first defined as a separate entity in 1990 by Anhalt et al.¹ Since then, at least 150 additional cases have been reported in the literature. Since oral involvement is reported in 100% of cases, PNP is particularly important in oral pathology and medicine.² Characteristically, it manifests with diffuse erosions and shallow ulcerations of the oral mucosa extending to the vermillion surface of the lips. Isolated oral lesions, as the first sign, are present in 45% of cases.³ The oropharynx and nasopharynx, tonsils, anogenital mucosa, and esophagus may also be affected.² Conjunctival lesions, which may be severe and resemble those seen in cicatricial pemphigoid, are present in about two-thirds of the patients.² Cutaneous manifestations have been reported in all but one case, in which there was only oral involvement.⁴ Cutaneous lesions with polymorphic manifestation have recently been divided into five variants: pemphigus-like, pemphigoid-like, erythema multiforme-like, graft versus host disease-like and lichen planus-like.⁵ Different morphologic patterns of skin lesions may be present concomitantly in a patient or vary during the disease course. The trunk and proximal extremities are usually affected. Palmoplantar and paronychial involvement are also frequent.²

Most PNP cases are associated with a hematologic malignancy. However, there are cases of solid non-hematologic neoplasms of different origins. Because of the relatively infrequent association of PNP with non-hematologic malignancy, awareness towards the clinical signs may be low, leading to a delay in correct diagnosis and treatment.

The purpose of the present report is to review the spectrum of different neoplasms associated with PNP, with emphasis on the group of non-hematologic malignancy, and the manifestations of PNP in the oral mucosa. A unique case of PNP associated with occult breast cancer and an ovarian cyst of borderline malignancy is presented, and the potential diagnostic pitfalls in PNP discussed.

Section snippets

Initial presentation

A 62-year-old woman presented with the chief complaint of pain and burning in the oral cavity which started the previous week. Her medical history was positive for mild hypertension and lower back pain, for which she had been prescribed Rofecoxib, a non-steroidal anti-inflammatory drug (NSAID). Oral symptoms became apparent within a week of treatment and increased in severity during the following week.

At presentation, diffuse, irregular shallow ulcerations involving the tongue, floor of mouth,

Literature review

The first definition of PNP as a distinct entity was introduced by Anhalt et al.,¹ and included the following clinical, histologic, DIF, IIF and immunoprecipitation tests as diagnostic criteria:

1.
Painful mucosal erosions and polymorphous skin eruptions.
2.
Histopathologic features of intraepidermal acantholysis, dyskeratosis and vacuolar interface dermatitis.
3.
DIF findings of intercellular epidermal IgG and complement, with or without granular linear complement deposition along the basement membrane

Discussion

Ulcerative lesions of the oral mucosa could be the presenting symptom of several diseases or conditions, including viral and bacterial infections, reactions to drugs or local irritants, as well as auto-immune diseases. Association with malignant diseases is rare, and probably is the least frequent etiology for oral ulcerative lesions. Therefore, it is rare for PNP to be included in the differential diagnosis of oral ulcerative lesions unless the existence of a primary tumor is known before the

Conclusion

The presence of diffuse and persistent oral ulcerations, which fail to meet the clinical, histologic and DIF criteria for any specific disease, should be highly suspicious for PNP, even in the absence of an overt malignancy, The full spectrum of signs described as diagnostic for PNP may not be initially present in all cases. It could take several months until the disease progresses and all characteristic signs “unveil” for the correct diagnosis to be made. In the absence of a clear diagnosis

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Puntos para una lectura rápida
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  Ante la sospecha de EAA es clave la derivación de manera preferente al servicio de dermatología para la toma de biopsia, confirmación diagnóstica e inicio precoz del tratamiento.
- •
  En los pacientes con EAA diagnosticada, el papel del médico de atención primaria es clave para el control de la morbimortalidad asociada tanto a la enfermedad como a la medicación inmunosupresora que precisa.
- •
  Las EAA pueden estar desencadenadas por fármacos. Es necesario revisar los fármacos prescritos, la relación temporal con la clínica cutánea y conocer aquellos fármacos que se relacionan más frecuentemente con las EAA, como las gliptinas en el penfigoide ampolloso.
- •
  Las curas domiciliarias con antisépticos, soluciones astringentes y apósitos vaselinados, junto con la corticoterapia tópica, es crucial para la evolución favorable de estos pacientes.
- •
  El penfigoide ampolloso es la EAA más frecuente. Su sospecha es clave en pacientes que presentan prurito de larga evolución y lesiones eritemato-edematosas con signos de rascado.
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  La presencia de erosiones dolorosas en mucosa oral nos obligan a descartar pénfigo vulgar.
- •
  Los pacientes con dermatitis herpetiforme pueden no presentar clínica digestiva de enfermedad celiaca y debemos descartarla en aquellos pacientes con prurito intenso y lesiones de rascado en codo, rodillas, nalgas y posterior de cuello.
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ReviewNeoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations

Abstract

Introduction

Section snippets

Initial presentation

Literature review

Discussion

Conclusion

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

Am. J. Ophthalmol.

Oral Surg. Oral Med. Oral Pathol.

Dermatol. Clin.

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

J. Invest. Dermatol.

Chest

Oral Oncol.

Oral Oncol.

Chest

J. Am. Acad. Dermatol.

J. Invest. Dermatol.

J. Am. Acad. Dermatol.

Rev. Med. Inerne.

Ann. Oncol.

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

Ann. Oncol.

J. Am. Acad. Dermatol.

Mayo. Clin. Proc.

Ophthalmology

J. Am. Acad. Dermatol.

Int. J. Radiat. Oncol. Biol. Phys.

Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia

N. Engl. J. Med.

Paraneoplastic pemphigus

Int. J. Dermatol.

Paraneoplastic pemphigus: oral involvement as the sole manifestation

Acta. Derm. Venereol.

Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus

Arch. Dermatol.

Paraneoplastic pemphigus is a distinct neoplasia-induced autoimmune disease

Arch. Dermatol.

Paraneoplastic pemphigus with autoantibody deposition in bronchial epithelium after autologous bone marrow transplantation

JAMA

Human antibodies against desmoplakins in paraneoplastic pemphigus

J. Clin. Invest.

Histologic features of paraneoplastic pemphigus

Arch. Dermatol.

Paraneoplastic pemphigus in a child with a T-cell lymphoblastic lymphoma

Br. J. Dermatol.

Paraneoplastic pemphigus: revaluation of a case from the past

Arch. Dermatol.

A case of bullous pemphigoid with antidesmoplakin autoantibodies

Br. J. Dermatol.

Paraneoplastic pemphigus triggered by radiotherapy

Australas. J. Dermatol.

Paraneoplastic pemphigus: the first case report from Japan

Dermatology

Paraneoplastic pemphigus in a patient with non-Hodgkin's lymphoma

Am. J. Hematol.

A progressive blistering eruption in a patient with lymphoma. Paraneoplastic pemphigus

Arch. Dermatol.

Paraneoplastic pemphigus occurring in a patient with B-cell non-Hodgkin's lymphoma

Cutis

Graft-versus-host-like mucocutaneous eruptions with serological features of paraneoplastic pemphigus and systemic lupus erythematosus in a patient with non-Hodgkin's lymphoma

Dermatology

Pemphigus paraneoplastic lichenoide au cours d'un lymphoma de bas grade

Ann. Dermatol. Venereol.

Paraneoplastic pemphigus presenting as erosive lichen planus

Br. J. Dermatol.

Constrictive bronchiolitis obliterans and paraneoplastic pemphigus

Eur. Respir. J.

Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus

Br. J. Dermatol.

Review
Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations