Paraneoplastic Pemphigus (Paraneoplastic Autoimmune Multiorgan Syndrome): Clinical Presentations and Pathogenesis

Paraneoplastic pemphigus is a rare condition with extremely high rates of mortality. Although its pathogenesis is incompletely understood, its pathologic findings have significant overlap with other autoimmune blistering diseases, such as pemphigus vulgaris, bullous pemphigoid, erythema multiforme and erosive lichen planus. A universally accepted consensus definition is needed to firmly define the condition. This would aid in identification of paraneoplastic pemphigus and the institution of timely and appropriate treatment to avoid rapid patient deterioration as well as recruitment for trials to further examine the pathogenesis and new therapeutic modalities. This article reviews the varied clinical presentations and pathologic characteristics pertaining to paraneoplastic pemphigus.

Paraneoplastic pemphigus (PNP) is a life-threatening autoimmune blistering disease, which is commonly associated with lymphoproliferative neoplasms. It was first described in a case series in 1990 by Anhalt and colleagues and approximately 250 case reports of PNP have been documented since that time. PNP has a wide geographic distribution and equal predominance across both genders with an average age of onset of 51 years. It is characterized by painful mucosal erosions with a polymorphous skin eruption (not always defined by bullae) in association with an occult or verified neoplasm. These neoplasms are typically of a lymphoproliferative type (chronic lymphocytic leukemia, lymphoma, Castleman’s disease, thymoma, and so forth) although case reports have described rare occurrences of the condition in other neoplasms, such as metastatic melanoma. Mortality due to the disease has been reported to be as high as 90%. Response to therapy is highly variable, with an incomplete knowledge of the pathogenesis of the disease making targeted therapies a challenge. This article reviews the varied clinical presentations and pathologic characteristics pertaining to PNP. Management of PNP will be covered in the next issue of this journal.

Presentations of PNP

PNP has a variety of clinical presentations, with painful mucosal and skin lesions presenting a wide variation in morphology ( Fig. 1 ). There has also been well-documented evidence of involvement of internal organs, such as lungs, thyroid, kidney, smooth muscle, and gastrointestinal tract. Such internal organ involvement has led to the proposal that the term, paraneoplastic pemphigus , should be replaced by the term, paraneoplastic autoimmune multiorgan syndrome (PAMS ), to more accurately describe the full spectrum of presentations and pathologic findings associated with this condition, although this proposed change has been met with mixed reaction by professionals in the field.

Currently, no consensus definitions exist as to the precise characteristics that define PNP/PAMS. Three different definitions have been put forward by various investigators and are presented in Table 1 . Examples of common aspects present in all proposed definitions of PNP/PAMS include initial mucosal involvement, detection of circulating autoantibodies against envoplakin and/or periplakin, and detection of a neoplasm.

Table 1

Three different proposed definitions for paraneoplastic pemphigus

Proposed Consensus Definitions	Zhu and Zhang	Anhalt et al	Joly et al
Year	2007	1990	2000
Clinical Characteristics	Painful mucosal involvement and polymorphic cutaneous eruption	Painful mucosal erosions with a polymorphous skin eruption culminating in vesicles/bullae in the context of an occult/confirmed neoplasm	Presence of painful oral erosions
Histopathology	Intraepidermal acatholysis, keratinocyte necrosis, and vacuolar interface dermatitis	Intraepidermal acantholysis, vascular interfacial dermatoses, and keratinocyte necrosis	Suprabasal acantholysis with keratinocyte necrosis or vacuolar interface dermatitis or lichenoid infiltrate
DIF	Not specified	Deposition of complement and IgG in intracellular epidermal spaces and in the basement membrane zone in linear granular lesions	Presence of circulating or in vivo bound antiepithelial cell surface and anti–basement membrane zone antibodies
IIF	IIF of patient serum with rat bladder epithelia shows intercellular staining	Not specified	Labeling of rat bladder
Circulating Autoantibodies	Not specified	Detection in the serum similar to that of pemphigus.	Confirmation of autoantibodies to periplakin and/or envoplakin
Presence of a neoplasm	Occult or confirmed	Occult or confirmed	Association with lymphoproliferative disorders

Data from Refs.

The clinical presentation of PNP, although highly varied, typically begins with a florid, painful eruption of mucous membrane lesions, which may involve the oropharynx, nasopharynx, tongue, vermillion of the lips, conjunctiva, anogenital region, or esophagus. The onset of cutaneous lesions has a variable delay after the appearance of mucous membrane lesions, ranging from days to months. The heterogeneity in the presentation of the cutaneous manifestations of this disease has led to a stratification of PNP/PAMS based on their similarity to other dermatologic conditions into 5 different clinical variants ( Table 2 ). These cutaneous manifestations often present in waves of lesions and, in contrast to pemphigus vulgaris, blisters in PNP/PAMS do not arise from normal skin but typically develop from inflammatory papules or macules, which greatly outnumber bullous eruptions in PNP/PAMS on individual patients.

Table 2

Clinical, histologic, and immunofluorescence findings in the 5 proposed subtypes of PNP/PAMS

PNP/PAMS Subtype	Pemphigus-like	Bullous Pemphigoid–like	Erythema Multiforme–like	Graft-versus-Host Disease–like	Lichen Planus–like
Clinical Presentation	Superficial vesicles with occasional erythema	Scaling erythematous papules without bullous lesions	Scaling erythematous papules with occasional ulceration or erosions	Scaled, dusky red papules	Violaceus papules
Common Sites of Cutaneous Lesions	Head, trunk, and proximal extremIties	More commonly seen on extremities	Mucosae, trunk, and extremities	Trunk and extremities	Trunk and extremities, which may include acral regions
Histologic Findings	Intraepidermal and/or subepidermal bullae	Dyskeratosis and mild mononuclear infiltrate at the dermal-epidermal junction	Dyskeratosis with areas of epidermal separation due to disintegration of the basal layer and perivascular infiltrate	No detachment, hyperparakeratosis, orthoparakeratosis, parakeratosis, and dyskeratosis and pronounced interface dermatitis	No blisters, hyperkeratosis, dyskeratosis, or lichenoid infiltrate
DIF Findings	Epidermal intracellular as well as intercellular/linear deposits of IgG and complement C3
IIF Findings	IgG and complement C3 reaction with stratified squamous, transitional and simple columnar epithelium (typically rate bladder and myocardial tissue)