ARTICLE
The association of pemphigus vulgaris (PV) with an underlying neoplasm
has long been recognized [1, 2]. In 1990, Anhalt et al. [3] described
paraneoplastic pemphigus (PNP) as an acantholytic mucocutaneous disease
associated with various malignancies, and characterized by autoantibodies
that react with a unique complex of 250 and 210 kDa, desmoplakin I and
II respectively, the 230 kDa bullous pemphigoid antigen and an as yet
unidentified 190 kDa epitope.
We report on a case of typical PNP occurring in a young woman, in association
with myasthenia gravis (MG) and a Castleman's tumour (CT).
Case report
In May 1995, a 47-year-old female, with an unremarkable past medical
history, developed a severe muscular weakness associated with ptosis and
diplopia. The diagnosis of MG was made based upon a positive anticholinesterase
test, acetylcholine-receptor antibodies and characteristic electrophysical
features. Chest and abdominal tomodensitometry revealed a bulky mediastinal
and retroperitoneal tumour which was then removed. Histological examination
of this tumor showed an angiolymphoid hyperplasia characteristic of CT.
Abnormal laboratory findings included a polyclonal hypergammaglobulinemia,
an elevated erythrocyte sedimentation rate, low titres of autoantibodies
against intrinsic factor, striated muscle and microsomes. Results of the
following tests were normal or negative: blood cells count, routine serum
chemistry, complement, antinuclear antibodies, human immunodeficiency
virus test, bone marrow aspirates. At the same time, she developed extensive,
painful, oral erosions that worsened despite various topical treatments.
A mucosal biopsy specimen revealed suprabasal blisters with few acantholytic
cells, basal vacuolization and a mild infiltrate of mononuclear cells
in the papillary dermis. Direct immunofluorescence of perilesional tissue
disclosed deposits of IgG and C3 in the intercellular spaces consistent
with the diagnosis of PV. Indirect immunofluorescence showed circulating
antibodies against intercellular spaces of normal human epidermis (1/160),
rat urinary bladder epithelium (subclass of IgG1 and IgG4) (Fig.
1) and non-epithelial tissues such as myocardium and liver. The
patient's serum identified two epidermal polypeptides of 210 and 190 kDa
of molecular weight, of the IgG4 subclass (Fig.
2). The patient was first treated with plasmapheresis and intravenous
immune globulins without success. She improved after treatment with high
doses of prednisone (100 mg/day) and azathioprine (150 mg/day). Eight
months after the onset of the blistering disease, there was a complete
remission of the mucosal erosions with no recurrence.
Discussion
Many cases of PV associated with malignancies, predominantly lymphoreticular,
have been already reported [1, 2]. The associations pemphigus-thymoma
with or without MG and pemphigus-CT are well documented [1, 2, 4-6]. The
association of CT and MG is quite uncommon [7].
In 1990 Anhalt et al. [3] reported five patients with a distinct
blistering mucocutaneous disease that was associated with an underlying
malignancy. They named this entity PNP and defined it by the following
criteria: (1) a polymorphous vesiculobullous skin eruption and painful
mucosal erosions occurring in patients with an underlying neoplasm, this
condition may look like PV, erythema multiforme or bullous pemphigoid;
(2) histologically, a suprabasilar acantholysis with some dyskeratotic
keratinocytes and a vacuolar interface dermatitis; (3) deposits of IgG
and C3 in the epidermal intercellular spaces and along the basement membrane
zone; (4) polyclonal autoantibodies directed against multiple epithelial
tissues (simple, columnar, transitional) and non-epithelial tissues such
as myocardium, liver and kidney; (5) immunoprecipitation of a characteristic
complex of epidermal proteins, including desmoplakin I and II at 250 and
210 kDa respectively, the 230 kDa bullous pemphigoid antigen and a polypeptide
of 190 kDa that has not yet been identified. This 190 kDa protein might
be a minor antigen component that is mainly recognized by PNP serum but
also by PV serum [8].
In fact, PNP serum immunoprecipitates the components
of the PNP antigen complex with various combinations [4]. The 210 and
190 kDa proteins are the most consistently and heavily labeled [9-11]
and Hashimoto et al. [10] recently demonstrated that PNP serum
also recognizes a 170 kDa antigen corresponding to a transmembrane glycoprotein,
which has not yet been clearly identified. Anhalt et al. [3] hypothesized
that reactivity to the 250 and 230 kDa is more variable than reactivity
to the 210 and 190 kDa. PV or pemphigus foliaceus antigens are not usually
recognized by PNP serum although a recent investigation showed that PV
antigen may be involved in PNP [10]. Our patient's serum recognized only
the 210 kDa (desmoplakin II) and 190 kDa epidermal antigens and failed
to precipitate the desmoplakin I and the 230 kDa bullous pemphigoid antigen.
The pathogenicity of autoantibodies in PNP is still unclear. Passive
transfer of serum in newborn mice may induce cutaneous blisters with acantholysis
[3]. Oursler et al. [4] demonstrated by immunoblotting, that desmoplakins
are not simply coprecipitated but are targets of the autoantibodies, indicating
that autoantibodies may cross-react with antigenic determinants in the
skin.
To date, approximately 30 patients with well-documented
PNP have been reported. Underlying neoplasms are usually of hematopoietic
origin: malignant lymphoma [3, 9, 11-15], chronic lymphocytic leukemia
[3, 16-19] benign thymoma [3], Waldenström macroglobulinemia [20].
Poorly differentiated sarcoma [3] and bronchogenic squamous carcinoma
[21] have also been reported. In another case, the underlying neoplasm
was not found [22].
Benign tumours in association with PNP have been reported in only two
cases in the literature, a Castleman's tumour and a thymoma [3, 23, 24].
Desmoplakins, which are major cytoskeletal structural antigens of the
desmosomal plaque, are expressed in CT as well as in thymoma. Therefore,
it is likely that patients' autoantibodies react with these tumours [4].
The temporal relationships between neoplasm and mucocutaneous lesions
of PNP are variable. In most cases, the malignant condition is identified
before the onset of mucocutaneous lesions or shortly following the development
of PNP [25, 26]. The spontaneous course of PNP is usually rapidly fatal,
with a mortality rate of 75-80% [15]. However, PNP associated with a benign
tumour, as in our case, may regress after tumour resection [3, 23, 24]
and there may be a subgroup of PNP patients with an associated malignant
neoplasm who have a more benign course [9, 18]. Some authors proposed
the term of neoplasia-induced pemphigus because the mucocutaneous changes
of PNP may not parallel that of the underlying malignancy [13, 16]. However,
because there is no direct evidence that neoplasm can induce pemphigus
we feel that the term, paraneoplastic pemphigus is currently more appropriate.
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