ARTICLE
Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive
mucocutaneous disease first described by Anhalt et al. in 1990
[1]. It is a distinctive form of pemphigus characterized by the presence
of IgG autoantibodies directed against proteins of the plakin gene family;
plectin (> 400 kDa), desmoplakin I (250 kDa), bullous pemphigoid antigen
I (230 kDa), envoplakin, desmoplakin II (a 210-kDa double band) and periplakin
(190 kDa), desmogleins, and a yet uncharacterized 170-kDa antigen. Although
clinical manifestations of PNP are heterogeneous, most of the patients
have painful mucosal erosions and ulcerations, with or without polymorphous
skin lesions similar to those seen in erythema multiforme, lichen planus,
or pemphigoid. Almost all reported cases have been associated with an
occult or confirmed neoplasm, usually of lymphoreticular origin. The majority
of patients with PNP run a rapidly progressive and fatal course, and only
a few patients survive after complete excision of a benign neoplasm such
as Castleman's disease and thymoma. Progressive respiratory failure with
clinical features of bronchiolitis obliterans has been recognized to be
a cause of death in about 30% of patients with PNP [2]. We describe a
patient with PNP associated with a hyaline-vascular type of Castleman's
disease in the intrapelvic region showing erosions limited to the lip,
oral and genital area. This case demonstrated that bronchilitis obliterans
(BO) in paraneoplastic pemphigus could be asymptomatic, and high resolution
computed tomography would be useful for early diagnosis of BO.
Case report
A 19-year-old man with no significant medical history including allergic
diseases such as bronchial asthma was admitted to Takamatsu Red Cross
Hospital because of recalcitrant erosive lesions on his oral mucosa and
lip that had begun 18 months earlier. The patient was transferred to our
department under a tentative diagnosis of pemphigus in March 10, 2000.
On admission, there were extensive erosions in the oral mucosa and tongue
with thick hemorrhagic crusts on the lip (Fig.
1a) and erosive lesions on the glans penis. Cutaneous and conjunctival
lesions were not evident. Histological examination of a biopsy taken from
a violaceous, indurated lesion of the lower lip showed a bandlike infiltrate
of lymphocytes and histiocytes throughout the papillary dermis, hydropic
degeneration of basal keratinocytes, and necrotic keratinocytes within
the hypertrophic epidermis (Fig.
1b). Computed tomography (CT) and magnetic resonance imaging of the
abdominal cavity revealed a solid tumor of a size of 8 x 9 x 9.5 cm. Angiography
documented hypertrophic arterial supply and abundant intralesional vascularity.
Physical examination revealed slightly decreased breath sounds in both
lungs with no crackles. Mild hyperinflation without infiltrates was visible
on chest radiographs, but conventional CT of the chest showed no remarkable
abnormalities. Sputum cultures were negative for Mycobacterium tuberculosis,
fungi, and other bacteria. Infectious diseases and collagen vascular diseases
were not found in further examinations. Arterial blood gas analysis (room
air) showed mild hypoxemia, and spirometry revealed a severe obstructive
lung disease (Table I).
Immunologic studies
Direct immunofluorescence (IF) microscopy of the lip showed in vivo
bound IgG and IgA intercellular (IC) antibodies in the entire epidermis
and C3 in the cell periphery of lower epidermis, as well as numerous cytoid
bodies positive for IgG, IgM, IgA, and C3. Indirect IF microscopy using
human epidermis as substrate revealed IgG IC antibodies at a titre of
10,240 (Fig. 2a). On the
rat and mouse bladder IgG IC antibodies were found positive at a titre
of 640 (Fig. 2b). Immunoblotting
analysis using the desmosomal extract of normal human epidermis prepared
as described previously [3] disclosed the presence of antibodies to the
210, 190 and 170 kDa proteins as well as antibodies to several other unknown
polypeptides of molecular weight from 180 through 105 kDa (Fig.
3). Immunoprecipitation studies confirmed the presence of antibodies
to the 250, 210, 190, and 170 kDa proteins (not shown). Enzyme-linked
immunosorbent assay (ELISA) with Dsg3 and Dsg1 recombinant proteins was
performed according to the established method and the ELISA score was
shown as index values [4]. Cut-off values (Dsg3 ELISA = 11.0, Dsg1 ELISA
= 10.0) were determined as described previously [4]. Reactivity of patient's
sera was positive against Dsg3 (index value = 28.3) and in a gray zone
against Dsg 1 (index value = 10.5).
Course of the disease
The patient had been treated with prednisone (30 mg/day) with some improvement.
The pelvic tumour was completely resected on the thirteenth hospital day,
when the dose of steroid was tapered to 15 mg/day. Histopathological diagnosis
of the tumour was Castleman's tumour of a hyaline-vascular type. No lymph
node involvement was confirmed histopathologically. During one postoperative
week, the titres of IC antibodies decreased to 1,280 only temporarily
and increased again up to 5,120. Although the desmoglein ELISA showed
temporary decrease of index values of Dsg3 and Dsg1 after eight courses
of IgG immunoadsorption using tryptophan column, the titres of IC antibodies
determined by indirect immunofluorescence microscopic study was decreased
only slightly (Fig. 4a).
The patient refused videoassisted thoracoscopic surgery (VATS) to evaluate
obstructive lung disease and further treatment of immunoapheresis, and
was discharged on April 28. Regular check-up of the patient once a month
showed gradual epithelialization of the oral mucosa and complete disappearance
of the erosion on the lip five months after the resection of Castleman's
tumour. Interestingly, the titres of IC antibodies, which once decreased
down to 640 during three months after the resection of the Castleman's
tumour, increased again up to 10,240 together with a rise of Dsg ELISA
indices two month later, and then gradually decreased down to 320 (Fig.
4b). However, no clinical aggravation which correlated with the rise
of IC antibodies was noticed. The expiratory images were assessed for
the presence of air trapping. High resolution CT (HRCT) of the lung examined
in April, 2001, showed not only mosaic pattern of lung attenuation on
inspiratory images, but also typical air trapping on expiratory images,
indicating bronchiolitis obliterans (Fig.
5). Although the patient did not complain of dyspnea on exertion,
his pulmonary function became progressively worse after the resection
of Castleman's tumour (Table
I).
Discussion
Since its first description by Anhalt et al. [1], the spectrum
of paraneoplastic pemphigus (PNP) has been expanded. In addition to patients
with polymorphous, erythema multiforme-like eruptions, cases that present
clinically and histologically as lichen planus pemphigoides-like [5-7],
bullous pemphigoid-like [8, 9] and graft-versus-host disease-like eruptions
[10, 11] have been reported. The patient described here had an 18-month
history of refractory erosions limited to the tongue, palate, buccal mucosa
and lip without skin involvement even with very high titre of IC antibodies.
Although it is widely recognized that refractory erosive stomatitis is
a hallmark of PNP [6, 7, 12, 19] and it has been reported that 45% of
22 patients with PNP presented initially with isolated oral erosions [19],
patients without involvement of the skin and conjunctiva have occasionally
been reported [13-17]. Thus, if it is feasible to classify clinical phenotypes
of PNP in analogy with classic pemphigus, our case belongs to a variant
of mucosal dominant PNP [31].
Recognition of the envoplakin and periplakin bands in the immunoblotting
(IB) and indirect immunofluorescence (IIF) labeling of rodent bladder
as observed in this case are the main immunological features specific
for PNP [18, 19]. It has been shown that pathogenic anti-Dsg3 autoantibodies
can be consistently detected in PNP sera by ELISA and anti-Dsg1 autoantibodies
are concomitantly positive in 64% of patients with PNP [20]. However,
unlike pemphigus vulgaris, there is no clear association between the clinical
phenotype, i.e. mucosal and mucocutaneous phenotype, and anti-Dsg
antibody profile in PNP [31]. An interesting finding in our case is that
titres of IC antibodies and index values of Dsg1 and Dsg3 ELISA temporarily
increased 2 months after the resection of Castleman's tumour without apparent
aggravation in the clinical phenotype. The increase of anti-IC and anti-Dsg
antibodies suggests that besides the presence of autoantibodies against
plakin proteins and desmogleins, other pathogenic mechanisms such as lichenoid
tissue reaction and individual cell necrosis might be needed to form the
unique clinical features of PNP in this particular case of PNP, as reported
previously [23, 31]. The reason for this serological rebound is unknown,
but our observation revealed that production of autoantibodies in PNP
could fluctuate rather than keep on decreasing even after the resection
of Castleman's tumour.
PNP is a life-threatening disease with a mortality rate of more than
90 %. Malignancies underlying the disease and/or complications associated
with immunosuppressive therapy have been the major causes of the notorious
prognosis. Bronchiolitis obliterans (BO) has been reported in patients
with bone marrow or heart/lung transplantation [21] and in patients with
collagen vascular diseases. Recently, Nousari et al. demonstrated
that BO is another growing concern in patients with PNP, because it could
lead to respiratory failure and subsequent death in 30% of patients with
PNP [2]. BO occurred in patients with malignant neoplasia such as non-Hodgkin's
lymphoma [2, 9, 22-25], as well as benign tumors such as Castleman's tumor
[2, 16, 26-28]. Therefore, the prognosis of our patient with PNP depends
on not only radical tumour resection but also the development of BO. BO
may appear one month to one year after the onset of the disease [2, 9,
16, 22-24, 26, 28] or about a month after surgery [2, 27], although it
rarely precedes the development of mucocutaneous manifestation [17]. The
reason why not all but certain patients with PNP develop BO is still unclear.
The presence of inflammatory cell infiltration and the deposition of autoantibodies
in the respiratory epithelium suggest that exposure of intracellular plakin
proteins by cell-mediated cytotoxic mechanisms may be followed by the
reaction of autoantibodies to the respiratory epithelium and acantholysis
[2, 25]. Our patient did not accept VATS to prove the pathological diagnosis
of BO. However, detection of BO by transbronchial lung biopsy may not
always be useful, because of the patchy distribution of BO [28] and the
difficulty in obtaining adequate specimens of bronchioles [21]. Since
Leung et al. demonstrated that air trapping, as detected on expiratory
HRCT, was the most sensitive and accurate radiologic indicator of BO in
the lung transplant recipients [32], we assessed both the inspiratory
and the expiratory images by HRCT of our patient. This study clearly revealed
not only a mosaic pattern of lung attenuation on inspiratory images, but
also remarkable air trapping on expiratory images. Therefore, persistence
of the reduced FEV1% together with air trapping as revealed
by expiratory images of HRCT indicate the presence of BO in our patient.
Treatments of PNP include high doses of oral corticosteroids, pulsed
corticosteroids, plasmapheresis, immunosuppressive drugs such as azathioprine,
cyclosporin, methotrexate, mycophenolate mofetil and photopheresis, and
high doses of cyclophosphamide. However, there has been no promising treatment
for PNP. Moreover, it has been reported recently that medication used
for treatment of underlying malignancy such as alpha interferon and fludarabine
might be involved in the development of PNP [29, 30]. Treatment prior
to the development of BO is variable, including chemotherapy [23, 24],
chemotherapy with bone marrow transplantation [9], cytokines [22], chemotherapy
with cytokines [2], corticosteroids with azathioprine [28], high-dose
corticosteroids and immunosuppresive therapy [26], surgery with cyclosporine
and corticosteroids [2]. As for the present case, no such intensive treatment
was done before the development of BO as was observed in other cases of
PNP [16]. This suggests that no medication was related to the development
of BO. With regard to the orolabial lesion, our case also suggests that
intensive immunosuppressive therapy might not be needed if the underlying
disorder is a nonmalignant tumour which is expected to be successfully
treated by resection, and even when the titre of IC antibodies were significantly
high or increased again in the course of the disease. However, adequate
treatment to repress the development and progress of BO has not been established
yet [21]. Since it has been reported that BO could be pronounced before
rather than after completion of plasmapheresis [27], it appears that titres
of IC antibodies and indices of Dsg3 and Dsg1 cannot be a useful indicator
to assess severity of BO, as observed in this case. Recently, it has been
reported that use of anti-CD20 monoclonal antibody (Rituximab) resulted
in a rapid improvement of severe stomatitis in a patient with PNP associated
with CD20+ follicular lymphoma [12]. It is of interest to see
whether the anti-CD20 treatment is also applicable for PNP patients with
other lymphoproliferative disorders such as Castleman's tumour, and if
it effectively represses the development of BO.
CONCLUSION
Acknowledgements
We would like to thank Pr. Grant J. Anhalt (Department of Dermatoimmunology,
Johns Hopkins University) for kindly performing immunoprecipitation study.
We also thank Mr. Akira Matsumoto for his help in photographic work.
Article accepted on 28/3/02
REFERENCES
1. Anhalt GJ, Kim S, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi
H, Ratrie III H, Mutasim D, Ariss-Abdo L, Labib RS. Paraneoplastic pemphigus,
an autoimmune mucocutaneous disease associated with neoplasia. N Engl
J Med 1990; 323: 1729-35.
2. Nousari HC, Deterding R, Wojtczack H, Aho S, Uitto J, Hashimoto
T, Anhalt J. The mechanism of respiratory failure in paraneoplastic pemphigus.
N Engl J Med 1999; 340: 1406-10.
3. O'Keefe EJ, Erickson HP, Bennet V. Desmoplakin I and desmoplakin
II. J Biol Chem 1989; 264: 8310-18.
4. Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashimoto K,
Yamada T, Kitajima Y, Ohya K, Iwanami H, Nishikawa T. Usefulness of enzyme-linked
immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis
of pemphigus. Br J Dermatol 1999; 140: 351-7.
5. Stevens SR, Griffiths CEM, Anhalt GJ, Cooper KD. Paraneoplastic
pemphigus presenting as a lichen planus pemphigoides-like eruption. Arch
Dermatol 1993; 129: 866-9.
6. Jansen T, Plewig G, Anhalt GJ. Paraneoplastic pemphigus with
clinical features of erosive lichen planus associated with Castleman's
tumor. Dermatology 1995; 190: 245-50.
7. Hsiao CJ, Hsu MML, Lee JYY, Chen WC, Hsieh WC. Paraneoplastic
pemphigus in association with a retroperitoneal Castleman's disease presenting
with a lichen planus pemphigoides-like eruption. A case report and a review
of literature. Br J Dermatol 2001; 144: 372-6.
8. Fried R, Lynfield Y, Vitale P, Anhalt G. Paraneoplastic pemphigus
appearing as bullous pemphigoid-like eruption after palliative radiation
therapy. J Am Acad Dermatol1993; 29: 815-7.
9. Fullerton DH, Woodley DT, Smoller BR, Anhalt GJ. Paraneoplastic
pemphigus with autoantibody deposition in bronchial epithelium after autologous
bone marrow transplantation. JAMA 1992; 267: 1500-2.
10. Mahler V, Antoni C, Anhalt GJ, Koch HJ, Peters KP, Manger
B, Kalden JR, Hornstein OP. 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
1998; 197: 78-83.
11. Reich K, Brinck U, Letschert M, Blaschke V, Dames K, Braess
J, Wormann B, Runger TM, Neumann C. Graft-versus-host disease-like immunophenotype
and apoptotic keratinocyte death in paraneoplastic pemphigus. Br J
Dermatol 1999; 141: 739-46.
12. Borradori L, Lombardi T, Samson J, Girardet C, Saurat JH,
Hugli A. Anti-CD20 monoclonal antibody (Rituximab) for refractory erosive
stomatitis secondary to CD20+ follicular lymphoma-associated
paraneoplastic pemphigus. Arch Dermatol 2001; 137: 269-72.
13. Bialy-Golan A, Brenner S, Anhalt GJ. Paraneoplastic pemphigus:oral
involvement as the sole manifestation. Acta Derm Venereol (Stockh)
1996; 76: 253-4.
14. Raison-Peyron N, Meunier L, Joly P, Pages M, Barneon G, Meynadier
J. Paraneoplastic pemphigus associated with myasthenia gravis and Castleman's
tumor. Eur J Dermatol 1997; 7: 371-3.
15. Schoen H, Foedinger D, Derfler K, Amann G, Rappersberger
K, Stingl G. Immunoapheresis in paraneoplastic pemphigus. Arch Dermatol
1998; 134: 706-10.
16. Kim SC, Chang SN, Lee IJ, Park SD, Jeong ET, Lee CW, Ahn
CM, Anhalt GJ. Localized mucosal involvement and severe pulmonary involvement
in a young patient with paraneoplastic pemphigus associated with Castleman's
tumor. Br J Dermatol 1998; 138: 667-71.
17. Cordel N, Ringeisen F, Antoine M, Cadranel J, Aractingi S.
Paraneoplastic pemphigus with constrictive bronchiolitis obliterans. Dermatology
2001; 202: 145.
18. Helou J, Allbritton J, Anhalt GJ. Accuracy of indirect immunofluorescence
testing in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol
1995; 32: 441-7.
19. Joly P, Richard C, Gilbert D, Courville P, Chosidow O, Roujeau
JC, Beylot-Barry M, D'Incan M, Martel P, Lauret P, Tron F, and the members
of the French Study Group on bullous diseases. Sensitivity and specificity
of clinical, histologic, and immunologic features in the diagnosis of
paraneoplastic pemphigus. J Am Acad Dermatol 2000; 43: 619-26.
20. Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T.
Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present
in sera from patients with paraneoplastic pemphigus and cause acantholysis
in vivo in neonatal mice. J Clin Invest1998; 102: 775-82.
21. Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans
after lung transplantation, a review. Chest 1998; 114: 1411-26.
22. Komai A, Nishioka S, Nakama T, Mori O, Anhalt GJ, Hayashida
S, Matsumoto K, Ohzono H, Hashimoto T. A case of paraneoplastic pemphigus
(PNP) with respiratory failure in association with alpha-interferon (IFN-alpha)
and alpha-tumor necrosis factor (TNF-alpha) therapy. Jpn J Dermatol
1999; 109: 635-40.
23. Hasegawa Y, Shimokata K, Ichiyama S, Saito H. Constrictive
bronchiolitis obliterans and paraneoplastic pemphigus. Eur Respir J
1999; 13: 934-7.
24. Takahashi M, Shimatsu Y, Kazama T, Kimura K, Otsuka T, Hashimoto
T. Paraneoplastic pemphigus associated with bronchiolitis obliterans.
Chest 2000; 117: 603-7.
25. Nguyen VT, Ndoye A, Bassler KD, Shultz LD, Shields MC, Ruben
BS, Webber RJ, Pittelkow MR, Lynch PJ, Grando SA. Classification, clinical
manifestations, and immunopathological mechanisisms of the epithelial
variant of paraneoplastic autoimmune multiorgan syndrome. Arch Dermatol
2001; 137: 193-206.
26. Wolff H, Kunte C, Messer G, Rappersberger K, Held, Löhrs
U, Plewig G, Meurer M. Paraneoplastic pemphigus with fatal pulmonary involvement
in a woman with a mesenteric Castleman tumor. Br J Dermatol 1999;
140: 313-6.
27. Chorzelski T, Hashimoto T, Maciejewska B, Amagai M, Anhalt
GJ, Jablonska S. Paraneoplastic pemphigus associated with Casleman tumor,
myathenia gravis, and bronchiolitis obliterans. J Am Acad Dermatol
1999; 41: 393-400.
28. Saito K, Morita M, Enomoto K. Bronchiolitis obliterans with
pemphigus vulgaris and Castleman's disease of hyaline-vascular type: an
autopsy case analysed by computer-aided 3-D reconstruction of the airway
lesions. Hum Pathol 1997; 28: 1310-2.
29. Kirsner RS, Anhalt GJ, Kerdel FA. Treatment with alpha interferon
associated with the development of paraneoplastic pemphigus. Br J Dermatol
1995; 132: 474-8.
30. Gooptu C, Littlewood TJ, Frith P, Lyon CC, Carmichael AJ,
Oliwiecki S, MacWhannell A, Amagai M, Hashimoto M, Dean D, Allen J, Wojnarowska
F. Paraneoplastic pemphigus: an association with fludarabine? Br J
Dermatol 2001; 144: 1255-61.
31. Ohyama M, Amagai M, Hashimoto T, Nousari HC, Anhalt GJ, Nishikawa
T. Clinical phenotype and anti-desmoglein autoantibody profile in paraneoplastic
pemphigus. J Am Acad Dermatol 2001; 44: 593-8.
32. Leung AN, Fisher K, Valentine V, Girgis RE, Berry GJ, Robbins
RC, Theodore J. Bronchiolitis obliterans after lung transplantation. Detection
using expiratory HRCT. Chest 1998; 113: 365-70.
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