Paraneoplastic Pemphigus A Retrospective Case

Published Date: 02 Nov 2017

Dermatologica Sinica

Manuscript Draft

Manuscript Number: DSI-D-13-00010

referral center in northern Taiwan

Article Type: Original Article

*Manuscript without author details

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Original Articles

Paraneoplastic pemphigus: A retrospective case series in a referral center in

northern Taiwan

Abstract

Background/Objectives�GParaneoplastic pemphigus (PNP) is a rare mucocutaneous

disease with a high mortality rate. It is defined by polymorphic mucocutaneous

manifestations, particular histological features, characteristic results of direct and

indirect immunofluorescence examinations, presences of specific auto-antibodies, and

associations with underlying neoplasms. However, currently, there is no existing study

regarding to the characteristics of PNP patients in Taiwan. In this study, we report a

case series and try to figure out the specific presentations of PNP patients in Taiwan.

Methods�GWe retrospectively recruited PNP patients treated in a referral center in

northern Taiwan from 1998 to 2012. We collected the clinical manifestations,

histopathological features, findings of direct and indirect immunofluorescence, results

of immunoblotting, and all relevant clinical information.

Results�GEleven patients were identified with an average age of 62 years old.

Polymorphic mucocutaneous manifestations were observed in almost all the patients.

The most common presentation is pemphigus-like lesions, followed by lichen

planus-like lesions. All patients had recalcitrant oral mucosal lesions. Five and four

patients had genital and eye involvements, respectively. The mostly associated

neoplasm is Castleman��s disease, followed by malignant thymoma. Acantholysis is

the mostly observed histological features, followed by lichenoid dermatitis and

interface dermatitis. Depositions of immunoglobulins or complements on the surface

of keratinocytes or along basement membrane zone were found in eight and seven

patients, respectively. Respiratory symptoms presented in eight patients. Despite

intensive treatments, seven patients expired.

Conclusion�GPatients with PNP in Taiwan is unique with a high association with

Castleman��s disease or malignant thymoma. Complete laboratory examinations and

thorough investigations for occult neoplasms are mandatory to establish a diagnosis of

PNP in patients with high clinical suspicions.

Key words: Castleman��s disease, Lymphoma, Paraneoplastic pemphigus, Thymoma

Introduction

Paraneoplastic pemphigus (PNP), first reported by Anhalt et al1 in 1990, is a rare

mucocutaneous disease with a very high mortality rate. Clinically, it is characterized

by severe mucositis with polymorphic skin eruptions, occurring in patients with

concomitant neoplasms. In the literature, most common associated neoplasms were

lymphoid neoplasms, including non-Hodgkin��s lymphoma, chronic lymphocytic

leukemia, and Castleman��s disease.2,3

In addition, several features, including histopathologic examination showing

acantholysis and interface dermatitis, positive direct immunofluorescence (DIF)

findings at the keratinocyte cell surfaces and/or along the basement membrane zone

(BMZ), positive indirect immunofluorescence (IIF) results using different epithelia;

and serum immunoblotting (IB) revealing a complex of five proteins of 250, 230, 210,

190 and 170 kd are demonstrated to be characteristic for PNP.4 Among them, the

association with a lymphoid neoplasm, positive IIF results on rat bladder, and

recognition of envoplakin (210-kd) and/or periplakin (190-kd) upon IB are the most

sensitive and specific features in the diagnosis of PNP.5

However, depositions of PNP autoantibodies were found in many tissues other

than skin and epithelium, including kidney, uninary bladder, and muscles.6 Besides, at

least five different clinical and immunopathological variants were identified,

including pemphigus-like, pemphigoid-like, erythema multiforme-like,

graft-versus-host disease-like, and lichen planus-like. Therefore, Nguyan et al.6

proposed a more encompassing term ��paraneoplastic autoimmune multiorgan

syndrome (PAMS)��. In addition, several unusual cases were reported, including

patients without a underlying neoplasm,7 patients with lichenoid eruptions without

detectable autoantibodies,8 and patients without mucosal involvement.9 All of these

point out the complexity of the disease, the variety of mucocutaneous presentations

and organ involvements, and the need for further investigations.

To date, only several case series have been reported in the literature due to rarity

of the disease. In this study, we retrospectively collected PNP patients in a referral

center in northern Taiwan and analyze the characteristics of this rare disease in the

domestic region.

Methods

We retrospectively recruited patients of PNP treated in the National Taiwan University

Hospital from 1998 to 2012. The diagnosis of PNP was according to the criteria

proposed by Camisa and Helm,10 including major criteria and minor criteria. Major

criteria include polymorphous mucocutaneous eruption, concurrent internal neoplasia,

and characteristic serum immunoprecipitation findings. Minor criteria include positive

cytoplasmic staining of rat bladder epithelium by IIF, intercellular and BMZ

immunoreactants on DIF of perilesional tissue, and acantholysis in biopsy specimen

from at least one anatomic site of involvement. Patients must fulfill with three major

or two major and two minor criteria to be diagnosed with PNP.

For patients presented with lichenoid variant of PNP not meeting the Camisa and

Helm��s criteria, we used the criteria proposed by Cummins et al.,8 which include the

following: (1) known or occult neoplasm; (2) extensive, refractory mucous membrane

ulcerations; (3) histologic examination for mucosa or skin revealing lichenoid

interface dermatitis; and (4) lichenoid or polymorphous blistering skin lesions and/or

pulmonary involvement consistent with bronchiolitis obliterans (BO).

We collected demographic data, associated malignancies, presentations of

cutaneous lesions, presences of mucosal involvements, histopathological features,

results of DIF and IIF, findings of IB, systemic symptoms, treatments, complications,

and outcomes of all the patients.

Results

Patient characteristics

Eleven patients were recruited into this study. All patients were fulfilled with the

Camisa and Helm��s criteria except two cases (Case 9 and 11). Both Case 9 and Case

11, presenting with severe mucositis with predominant lichenoid skin eruptions, met

the Cummin��s criteria and were diagnosed as lichenoid variant of PNP. The average

age was 62 years old (range 30-86). Seven patients were male and the other four

patients were female. The development of mucocutaneous lesions before or

concomitant with the diagnosis of underlying neoplasms was noted in six patients.

Others presented with mucocutaneous manifestations months or years after the

diagnosis of underlying neoplasms being made.

Associated neoplasms

All patients had at least one neoplasm. Two of them had two concomitant neoplasms.

The most common associated neoplasm was Castleman��s disease (four cases, 36%),

followed by malignant thymoma (three cases, 27%), follicular dendritic cell sarcoma

(two cases, 18%) and non-Hodgkin��s lymphoma (two cases, 18%). Most associated

neoplasms were lymphoid neoplasms. Solid organ neoplasms were only encountered

in two patients. One was squamous cell carcinoma of the lung, and the other was

thyroid papillary microcarcinoma. For those presenting with concomitant neoplasms,

one had follicular dendritic cell sarcoma arising from Castleman��s disease, and the

other had both malignant thymoma and thyroid papillary microcarcinoma.

Mucocutaneous manifestations

Mucocutaneous manifestations of the patients were polymorphic (Figure 1 and Table

1). All patients except one had more than one kind of mucocutaneous lesions. The

most common presentation was pemphigus-like, widespread, crusted erosions and

ulcerations (Figure 1A), which were observed in nine patients (82%).

Pemphigoid-like lesions such as hemorrhagic blisters on the palms were only

occasionally found (Figure 1B). Infiltrative, purpuric, polygonal, flat-topped papules

and plaques (Figure 1C) or erosive lichenoid papules and plaques (Figure 1D) were

the second most common feature and were found in eight patients (73%). Few

patients also presented with erythema multiforme (EM)-like targetoid lesions.

Pemphigus-like lesions were the predominant manifestations in six patients, while

LP-like lesions were the predominant presentations in other five patients.

All patients had extensive, refractory oral mucositis, involving lips, buccal

mucosae, and tongues (Figure 1E). Genital erosions were found in five patients (45%)

(Figure 1F), and eye involvements were observed in four patients (36%) (Figure 1G).

In addition, other less common manifestations were also encountered, including

paronychia (Figure 1H) and anonychia (Figure 1I).

Histopathology and immunopathology

The patterns of histopathology varied and depended on the type of cutaneous lesions

being sampled. Seven of the patients received more than two skin biopsies. Of all the

skin biopsies, acantholysis (Figure 2A), including suprabasal acantholysis or

intra-epithelial acantholysis, was mostly observed and presented in nine patients

(82%). Lichenoid dermatitis (Figure 2B), that was lichenoid infiltration with apoptotic

keratinocytes, was noted in skin specimen from six patients (55%). Interface

dermatitis, that was basal vacuolar change with apoptotic keratinocytes (Figure 2C),

was found in skin specimen from three patients (27%). Not surprisingly, to perform a

clinico-pathological correlation, acantholysis was mostly found in pemphigus-like

lesions and lichenoid dermatitis or interface dermatitis was mostly observed in

clinically LP-like or EM-like lesions, respectively.

For patterns of DIF findings, depositions of immunoglobulins or complements

on the surface of keratinocytes (Figure 2D) were found in eight patients (73%). Linear

depositions of immunoglobulins or complements along BMZ (Figure 2E) were

noticed in seven patients (64%). Immunoglobulin M (IgM) cytoid bodies (Figure 2F)

were observed in three patients (27%) having LP-like lesions. For results of IIF

findings, eight patients (73%) had positive serum anti-intercellular substance (ICS)

antibodies using monkey esophagus as the substrates. Two of them also received IIF

examinations using rat bladder as the substrates and had positive staining on the

epithelium of the bladder. No patients had detectable anti-BMZ antibodies in their

sera.

Immunoblotting

Immunoblotting of serum samples were performed in five patients (Table 1). Two

patients had all characteristic bands corresponding to 250, 230, 210, 190, and 170-kd

proteins. One had antibodies reacted with 250 and 230-kd proteins, one had bands at

molecular weights of 190 and 210-kd, and another had only one band reacted with

40-kd protein.

Respiratory involvement and complications

In addition to mucocutaneous manifestations, systemic symptoms and complications

occurred frequently in PNP patients (Table 2). Respiratory symptoms, including dry

cough and dyspnea, were reported in eight patients (73%). Nevertheless, a diagnosis

of BO was confirmed in only four patients (36%). Systemic infections were the

mostly encountered complications during the period of treatment, including

disseminated tuberculosis, cryptococcemia, disseminated cytomegalovirus (CMV)

infection, and herpetic keratitis. Two of the four above-mentioned patients with eye

involvement had severe corneal perforations (Figure 1G) and needed to receive

amniotic membrane transplantations to restore their visual acuity.

Treatment and prognosis

All patients received high dose of systemic corticosteroids (Table 2). The maximal

dosage was daily 2-4 mg per kilogram body weight. Intravenous immunoglobulin

(IVIG) was used in three patients with a dosage of 2 gram per kilogram body weight.

Rituximab infusions with a dosage of 375 mg per square-meter body surface area

(mg/m2 BSA) were performed in two patients. Both patients had underlying

lymphomas. Cyclophosphamide and azathioprine were both used in two of the

patients. For treatments of underlying neoplasms, surgical interventions were

performed in eight patients (73%). Chemotherapies were used in five patients (55%).

Two of them had lymphomas. Two patients had follicular dendritic cell sarcomas, and

another one had squamous cell carcinoma of the lung. Radiotherapy was applied on

one patient (9%) with invasive lymphoma. Only one patient did not receive any

treatment for the underlying neoplasm because of the huge size of the tumor and poor

general condition.

The prognosis of the patients was dismal. Seven patients expired within 1-2

years after establishing the diagnosis of PNP. The mortality rate was 64%. All patients

with a confirmed diagnosis of BO passed away rapidly after development of

respiratory symptoms. For those patients being alive, two of them had symptoms of

respiratory distress, but none of them had a confirmed diagnosis of BO.

Discussion

In this study, we demonstrated characteristics of PNP patients in Taiwan. The main

findings of this study are (1) polymorphic presentations of clinical and

histopathological features are observed in our patients, (2) the most common

associated neoplasm is Castleman��s disease, followed by malignant thymoma, and (3)

a poor prognosis and a high mortality rate are noted.

We compared the characteristics of our PNP patients with several previously

reported case series (Table 3). Like the design of our study, Ohyma et al.11 and Leger

et al.12 reported PNP cases based on a hospital-based or nationwide database without

selection for a specific associated neoplasm or age groups. The average ages of the

patients in these two studies are similar with our study. The most common associated

neoplasm of these two studies, which is different with us, is non-Hodgkin��s

lymphoma and chronic lymphocytic leukemia, respectively. Like our findings,

polymorphic mucocutaneous manifestations are also reported in these two studies

with pemphigus-like presentation as the most common mucocutaneous manifestation.

The mortality rate and the extents of mucosal lesions are also similar except the ocular

involvement, which is less frequently observed in our study.

To clarify the reason of a higher association of Castleman��s disease in our study,

we compared our study with other previously reported case series with PNP patients

of Castleman��s disease (Table 3). Minouni et al.13 reported fourteen cases in children

and adolescents, in which twelve were associated with Castleman��s disease. They

conclude that PNP in children and adolescents is most often a presenting sign of

occult Castleman��s disease. This is consistent with one of our patients (Case 1), who

presented with longstanding mucocutaneous lesions since his adolescence and a

mediastinal Castleman��s disease complicated with focal follicular dendritic cell

sarcoma was eventually identified more than 10 years later. Similar findings are

reported in another two studies reporting PNP cases exclusively associated with

14, 15

Castleman��s disease. The average age in both studies is young. However, only

one of the four patients with Castleman��s disease in our study is young. Therefore, age

of the patients in our study could not account for the higher association. The possible

reason is that there is genetic predisposition because around 77% of PNP patients are

associated with Castleman��s disease in China.15 Although the ethnic groups in

Mainland China are more diverse than those in Taiwan, the majority of people are

belong to Han Chinese in both regions.

Lichen planus-like lesions are the main presentations in PNP patients associated

13-15

with Castleman��s disease.Being consisted with this finding, three of four patients

associated with Castleman��s disease in our study have LP-like lesions as their main

clinical manifestation. In addition, LP-like lesions present in all three patients

associated with malignant thymoma in this study and are the predominant clinical

presentations in two of them. Although the association of pemphigus and thymoma is

well established,16 pemphigus-like presentations are not the main finding in PNP

patients associated with malignant thymoma in this study. There are some reasons

which could explain our observations. In addition to pemphigus, several reports have

17,18

indicated that thymoma may be associated with lichen planusand

graft-versus-host-like diseases.19 Moreover, thymoma has been linked to numerous

autoimmune diseases, including myasthenia gravis, hypogammaglobulinemia,

alopecia areata, pure red cell aplasia, and so on.20 The fact that thymus is an important

immune organ to maintain central tolerance is logical to explain the occurrence of

immune dysregulation in the setting of thymic tumors.21 A previous study has

provided evidences to support this notion. They demonstrated circulating

CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared

with normal controls as well as intratumoral T cell development that is abnormally

skewed toward the CD8+ phenotype.22 Therefore, we propose that these abnormal

CD8+ T cells in patients with thymoma may account for the development of clinical

LP-like presentations and histopathological lichenoid infiltrations in our patients.

However, further investigations are needed to confirm our hypothesis.

The mortality rate of this study is 64%, which is comparable to the previous

reports. Leger et al.12 found 1-year overall survival rate was 49% which was

consistent with our observation that most of the expired cases passed away within 1-2

years after diagnosis. The development of respiratory symptoms might be the most

important risk factor for mortality in our study. Six of seven expired patients had

respiratory symptoms, including dry cough and dyspnea. Four of them had a

confirmed diagnosis of BO. In line with our finding, pulmonary injury with

respiratory failure has been demonstrated to be the cause of death in most PNP

patients associated with Castleman��s disease.14 In addition, infections account for the

cause of death in the majority of cases in another study,12 which might be resulted

from the use of high dose immunosuppressants. Indeed, high dose corticosteroids

and/or combined with other immunosuppressants or immunomodulators were used in

all of our patients. Several episodes of infections were encountered in our patients as

above mentioned. We think that infections work synergistically with respiratory

involvements in these patients leading to a fatal outcome. In addition to these causes

of death, PNP patients with EM-like skin lesions have been demonstrated to have a

more severe and rapid fatal outcome.12 Four patients with EM-like presentations in

our study did have more refractory courses and all of them expired.

In this study, treatments for PNP and treatments for underlying neoplasms seem

12,14

not to affect the prognosis, which is consistent with previous studies.However, a

promising outcome has been reported in a study composed of 22 PNP patients

associated with Castleman��s disease, thymoma, and follicular dendritic cell sarcoma,

who received surgical resections of their neoplasms.23 Only 27% of the patients

expired in that study. Of note, respiratory symptoms persisted in 13 patients. The

similar scenario occurred in Case 1 of this study, whose mucocutaneous lesions

became stationary after the operation despite the respiratory symptoms persisted.

Nevertheless, another patient, Case 11 of our patients, experienced exacerbation of

respiratory symptoms and development of myasthenia gravis after surgical removal of

malignant thymoma.

Four of our patients had eye involvement. Two of them had severe corneal

perforations and required an amniotic membrane transplantation. Corneal perforations

24, 25

or melting in PNP patients have been reported.The exact mechanism is still

26 27

undetermined. Both humoraland cellularmechanisms might be involved in the

pathogenesis of the disease. Although the best treatment for this condition is not fully

investigated, amniotic membrane transplantations are the current standard of

treatment and work well in our patients to prevent symblephara and further

deterioration of visual acuity. Patients with PNP should monitor for the possibility of

eye involvements and evaluate whether corneal erosions or melting present. Early

identification with prompt management can reduce the risk of irreversible damage of

visual acuity.

In conclusion, our study is the first case series of PNP in Taiwan and outlines the

characteristics of these patients. Polymorphic mucocutaneous presentations, frequent

associations with Castleman��s disease and malignant lymphoma, and a poor prognosis

with a high mortality rate indicate that a high clinical suspicion, a thorough

investigation for underlying neoplasm, and intensive treatments are mandatory to

manage patients with PNP.