Introduction
Paraneoplastic pemphigus (PNP) is an autoimmune blistering syndrome with 5 well-described
clinicopathologic phenotypes. Nguyen et al categorized these subtypes as pemphigus-like,
pemphigoid-like, erythema multiforme-like, graft-vs-host-disease–like, and lichen
planus–like.
1
However, there is increasing recognition of PNP simulating Stevens-Johnson syndrome
(SJS) and toxic epidermal necrolysis (TEN). Herein, we propose SJS/TEN-like PNP as
a distinct subtype of PNP. We present 2 new cases of SJS/TEN-like PNP and review the
previously reported cases of this subtype. Clinicopathologic factors that merit consideration
for PNP in this context include a history of associated underlying neoplasia, the
absence of a new drug, and histopathology indicative of chronicity or acantholysis.
In patients with these features and clinical morphology typical of SJS/TEN, serologic
evaluation for IgG autoantibodies against envoplakin (EP), desmoglein (DSG) 1, and
DSG3 should be considered in order to exclude SJS/TEN-like PNP.
Patient 1
A 66-year-old man with chronic lymphocytic leukemia (CLL) had an eruption on his trunk.
Aside from ibrutinib, no other medications were associated with the onset of this
eruption. An initial biopsy demonstrated lichenoid interface dermatitis with keratinocyte
apoptosis. Topical corticosteroids and discontinuation of ibrutinib were unsuccessful
at treating the patient's condition. The eruption progressed and eventuated in the
sloughing of sheets of skin covering >90% of the body surface area (Fig 1, A). A painful
stomatitis and hemorrhagic erosions involving the lips were also present (Fig 1, B).
After a presumptive diagnosis of TEN, the patient was admitted for in-patient management.
Fig 1
A, Erythroderma with widespread and confluent epidermal detachment resembles toxic
epidermal necrolysis. B, Severe mucositis including erosive cheilitis with hemorrhagic
crust was also present.
A repeat biopsy demonstrated an intraepidermal vesicle secondary to suprabasilar acantholysis
associated with vacuolar interface dermatitis with keratinocyte necrosis. Parakeratosis
and dysmaturation, indicative of chronicity, were also evident (Fig 2, A-C). Direct
immunofluorescence highlighted cell surface and junctional reactivity with IgG (Fig
2, D). Serum studies were subsequently performed: IIF (indirect immunofluorescence)
on rat bladder was nonreactive, but immunoblotting and enzyme-linked immunosorbent
assay (ELISA) demonstrated positive index values for IgG against EP and periplakin
(PP) and for IgG against DSG1, DSG3, and EP, respectively. These immunopathologic
and serologic findings confirmed the diagnosis of PNP. Treatment was initiated with
intravenous immunoglobulin 2 g/kg divided over 4 days and high-dose systemic corticosteroids;
ibrutinib was restarted for the CLL underlying PNP. Despite improvement in cutaneous
manifestations, the patient's hemodynamic status worsened, and he died ∼2 months after
the onset of PNP.
Fig 2
A, Suprabasilar acantholysis with tombstoning of the basilar keratinocytes (single
arrow) and keratinocyte necrosis (double arrow) are present together. B, Vacuolar
interface dermatitis (single arrow) underlies keratinocyte apoptosis. C, Overlying
the intraepidermal blister, there is parakeratosis and dymaturation, with dyskeratotic
cells in the stratum corneum (single arrow), indicative of chronicity. D, Weak focal
cell surface (single arrow) and junctional (double arrow) reactivity. (A-C, Hematoxylin-eosin
stain; original magnification: A, ×100; B and C, ×200.) (D, Anti-IgG direct immunofluorescence;
original magnification: ×100.)
Patient 2
A 62-year-old woman with a history of untreated CLL presented for a progressive and
painful eruption of 3 months' duration, which began on a lower extremity and then
spread to the trunk and upper extremities. No triggering medication could be elicited.
Management with topical and systemic corticosteroids (prednisone 50 mg/day) was unsuccessful
at treating the condition.
Subsequent progression resulted in erythroderma, along with vaginal, ocular, and oral
mucosal erosions. Punch biopsy revealed acantholysis and suprabasilar clefting. IIF
on rat bladder demonstrated cell surface reactivity, and an immunoblot for IgG against
PP and EP and ELISA for IgG against EP demonstrated positive indices, confirming the
diagnosis of PNP. Treatment was initiated with a cycle of intravenous immunoglobulin
in tandem with a chemotherapy regimen for CLL: rituximab, cyclophosphamide, and prednisone.
Three months after her hospital discharge, the patient continues to do well, with
resolution of her skin rash and control of her CLL.
Discussion
PNP is typified by painful mucositis, a polymorphic skin eruption, interface dermatitis
with or without acantholysis, immunopathology involving plakin family proteins, and
an underlying neoplasm, which is most frequently malignant. The mucositis usually
affects the oral cavity but might affect the genital or ocular mucosae.
2
Plakins, which serve as antigenic targets in PNP, include EP, PP, desmoplakin 1 and
2, and bullous pemphigoid antigen. Nonplakin antigens include DSG1 and DSG3. Bladder,
a transitional epithelium, expresses plakin family proteins but not DSG1 or DSG3,
which are specific to stratified squamous epithelium. Therefore, cell surface reactivity
detected by IIF on rat bladder can confirm the presence of pathogenic circulating
autoantibodies directed against plakins. More recently, α-2-macroglobulin-like protein
1 has been identified as an antigenic target in PNP.
3
The most commonly associated underlying neoplasms are non-Hodgkin lymphoma, CLL, Castleman
disease, thymoma, sarcomas, and Waldenstrom macroglobulinemia. Although bronchiolitis
obliterans is a frequent cause of death in PNP,
4
neither of our patients developed this pulmonary disease.
Immunoblotting, IIF, immunoprecipitation, and ELISA are serologic studies that can
be used to identify the defining autoantibodies in PNP.
5
Immunoblotting for EP or PP is almost 100% sensitive and is considered the current
standard for diagnosis, but false positive results lower the specificity to 82%-91%.6,
7, 8 IIF on rat bladder is commonly used to confirm PNP, given a recorded specificity
near 100%; however, sera from patients with SJS/TEN has been shown to react with rat
bladder, making this study less useful in distinguishing these 2 conditions.8, 9 The
histology of PNP is nonspecific and is lichenoid as often as it is acantholytic; both
reaction patterns are present in 60% of cases, as they were in patient 1. Keratinocyte
necrosis is associated with a poorer prognosis. Direct immunofluorescence has a 97%
specificity for PNP when both cell surface and junctional IgG (or C3) are identified.
However, the sensitivity of this finding is <50%.7, 8, 10 ELISA for EP, helpful in
both patients described, demonstrates variable sensitivity (30%-100%), but high specificity
(90%-100%).6, 8, 11
Five previously described cases of SJS/TEN-like PNP are described alongside the 2
patients in this series in Table I.12, 13, 14, 15, 16 In all 7 cases, an underlying
neoplasm was identified, but only 3 were identified before the diagnosis of PNP. In
cases with reported histopathology (6 of 7), both acantholysis and keratinocyte necrosis
were identified. When performed, serology demonstrated IgG autoantibodies against
EP and PP in 5 out of 7 cases.
Table I
Clinicopathologic features of reported patients with SJS/TEN-like PNP12, 13, 14, 15,
16
Source
Age, y
Sex
Tumor
Clinical presentation
Histopathology
Serology∗
Treatment
Outcome
Yamada et al
12
57
M
B-cell lymphoma†
Fever; oral, genital, ocular erosions; desquamative erythroderma
Subepidermal blister; keratinocyte necrosis
DSG3+, DSG1−, rat bladder IIF+, EP+, PP+
Corticosteroids, plasmapheresis, rituximab, IVIg
Died of MSOF
Hayanga et al
13
45
F
Follicular lymphoma†
Oral, genital, ocular erosions; desquamative erythroderma
Suprabasilar blister with acantholysis; keratinocyte necrosis
DSG3+, DSG1+
Corticosteroids, rituximab
Discharged after 8 days, further follow-up unavailable
Mar et al
14
11
F
Inflammatory fibrosarcoma†
Dyspnea; oral, genital, and ocular erosions
Suprabasilar blister with acantholysis
DSG1+, PP+, EP+
Corticosteroids, methotrexate, oral gold, tumor resection
Died of respiratory failure
Lyon et al
15
56
M
CLL‡
Fever; oral erosions, erosions of 60% BSA
NR
Rat bladder IIF+
Corticosteroids, cyclosporine
Alive and well at 2- year follow-up
Chorzelski et al
16
31
M
Castleman tumor†
Oral, genital, ocular erosions; periungual erosions and bullae
Acantholysis keratinocyte necrosis
DSG3+, DSG1+, PP+, EP+, rat bladder IIF+
Corticosteroids, tumor resection, plasmapheresis, cyclosporine
Died of respiratory failure
McLarney et al, 2017
66
M
CLL‡
Oral and genital erosions; involvement of >90% BSA
Subrabasilar blister with acantholysis; keratinocyte necrosis
DSG3+, DSG1+, PP+, EP+, rat bladder IIF−
IVIg, corticosteroids, ibrutinib
Died of MSOF
McLarney et al, 2017
62
F
CLL‡
Oral, genital, ocular erosions; erythroderma
Suprabasilar blister with acantholysis
PP+, EP +, rat bladder IIF+
§
Corticosteroids, IVIg, rituximab, cyclophosphamide
Alive and well at 3-month follow-up
BSA, Body surface area; CLL, chronic lymphocytic leukemia; DSG1, desmoglein 1; DSG3,
desmoglein-3; ELISA, enzyme-linked immunosorbent assay; EP, envoplakin; IIF, indirect
immunofluorescence; IVIg, intravenous immunoglobulin; MSOF, multisystem organ failure;
NR, not reported; PNP, paraneoplastic pemphigus; PP, periplakin; SJS, Stevens-Johnson
syndrome; TEN, toxic epidermal necrolysis.
∗
DSG1 and DSG3 autoantibodies were assessed by ELISA, and EP and PP autoantibodies
were assessed by ELISA, immunosorbent assay, or both.
†
Undiagnosed before onset of PNP.
‡
Known diagnosis before onset of PNP.
§
Direct immunofluorescence was not performed with samples from this patient.
SJS/TEN-like PNP is challenging to distinguish from true SJS/TEN for several reasons.
Although severe mucositis is common to both entities, PNP is very rare relative to
SJS/TEN, which might prompt a presumptive clinical diagnosis of the more common disease.
Keratinocyte necrosis and interface dermatitis are overlapping features of PNP and
SJS/TEN on light microscopy; acantholysis indicative of pemphigus might not develop
until PNP is advanced. An underlying neoplasm might not be recognized before the onset
of mucocutaneous manifestations. Furthermore, in patients with a known history of
underlying malignancy, their medication could be a confounding factor. Finally, use
of disease-defining serologic studies might be limited by cost and access, and their
interpretation and applications requires knowledge of pertinent sensitivities and
specificities, as described above. Table II
2, 5, 9, 13, 17 compares the clinical, histologic, and serologic features of SJS/TEN
and SJS/TEN-like PNP: notably, IIF on rat bladder might be reactive and autoantibodies
against α-2-macroglobulin-like protein 1 and PP might be identified in the sera of
patients with SJS/TEN.
9
In this context, the most helpful distinguishing features are chronicity by history
and/or histopathology (ie, parakeratosis), acantholysis, and identification of IgG
autoantibodies against EP, DSGs, or both.
Table II
Comparison of SJS/TEN and SJS/TEN-like PNP2, 4, 9, 13, 17
Category
SJS/TEN
SJS/TEN-like PNP
Epidemiology
Common
Rare
History of known neoplasm
Variable
Variable
Common drug trigger∗
Present
Variable
Mucosal involvement
Always present
Always present
Histopathology
Interface dermatitis with epidermal necrosis, normal stratum corneum
Interface dermatitis with epidermal necrosis,† suprabasilar acantholysis,† parakeratosis,
and dysmaturation (well-established)
Serology‡
PP+, rat bladder IIF+, A2ML1+, EP−, DSG1−, and DSG3−
PP+, rat bladder IIF+, A2ML1+, EP+, DSG1+, and DSG3+
Involvement of other organ systems
Renal, gastrointestinal, respiratory
Pulmonary (bronchiolitis obliterans)
Effect of drug discontinuation
Beneficial
Not beneficial
Management
Discontinue offending drug, cyclosporine, corticosteroids
Treat underlying neoplasm, IVIg, rituximab
Prognosis and course
SJS: 1%-5% mortalityTEN: 25%-30% mortalityAcute and self-limited
62%-90% mortality, chronic and relentlessly progressive
A2ML1, α-2-Macroglobulin-like-protein 1; DSG1, desmoglein 1; DSG3, desmoglein-3; ELISA,
enzyme-linked immunosorbent assay; EP, envoplakin; IIF, indirect immunofluorescence;
IVIg, intravenous immunoglobulin; PNP, paraneoplastic pemphigus; PP, periplakin; SJS, Stevens-Johnson
syndrome; TEN, toxic epidermal necrolysis.
∗
Commonly implicated drugs include allopurinol, nonsteroidal anti-inflammatory drugs,
trimethoprim-sulfamethoxazole, lamotrigine, phenobarbital, phenytoin, carbamazepine,
nevirapine, minocycline, sulfasalazine, and fluoroquinolones.
†
Either pattern, or both, might be present in representative biopsies.
‡
DSG1, DSG3, and A2ML1 autoantibodies are assessed by ELISA, and EP and PP autoantibodies
are assessed by ELISA, immunosorbent assay, or both.
In conclusion, SJS/TEN-like PNP represents a diagnostically challenging subtype. Recognition
is important, given the guarded prognosis and association with internal malignant
neoplasia, frequently unidentified before the onset of mucocutaneous manifestations.