Paraneoplastic Autoimmune Multiorgan Syndrome (Paraneoplastic ) in a Child: Case Report and Review of the Literature

Joshua E. Lane, MD*; Carol Woody, MD*; Loretta S. Davis, MD*; Margaret F. Guill, MD‡; and Rita S. Jerath, MD§

ABSTRACT. Paraneoplastic autoimmune multiorgan bronchiolitis obliterans resulting in pulmonary de- syndrome, also known as paraneoplastic pemphigus, has struction and death. We report the case of a 10-year- been observed only rarely among children. We describe a old child who developed a diffuse mucocutaneous 10-year-old boy with typical clinical and histologic find- eruption that was clinically and immunopathologi- ings of paraneoplastic pemphigus associated with Castle- cally consistent with PAMS. Systemic evaluation re- man’s disease. His disease was refractory to resection of vealed a retroperitoneal Castleman’s tumor. the tumor and aggressive combination immunosuppres- sive therapies. The patient died 1 year after presentation, as a result of complications of bronchiolitis obliterans. CASE REPORT This case is unusual because of the young age of the A 10-year-old, previously healthy, white boy presented with a patient. Pediatrics 2004;114:e513–e516. URL: www. 2-month history of a papular eruption of the trunk, conjunctivitis, pediatrics.org/cgi/doi/10.1542/peds.2004-0436; paraneo- erosive stomatitis, proximal nail fold inflammation, and nail dys- plastic pemphigus, paraneoplastic autoimmune multior- trophy. Prior evaluation included a positive mycoplasma titer and a skin that was interpreted as indicating erythema multi- gan syndrome, child, Castleman’s tumor. forme/Stevens-Johnson syndrome. The mucocutaneous lesions were resistant to systemic treatment. The patient was referred to our institution because of progressive symptoms. ABBREVIATIONS. PAMS, paraneoplastic autoimmune multior- System review results included fever, cough for 6 to 8 weeks, gan syndrome; CT, computed tomography; C3, complement com- fatigue, constipation, and weight loss, with poor food intake at- ponent 3; Ig, immunoglobulin. tributable to painful oral ulcers. The physical examination re- vealed a thin boy with perioral cyanosis and resting tachypnea. A facial examination revealed bilateral exudative bulbar and palpe- araneoplastic autoimmune multiorgan syn- bral conjunctivitis, nasal septal erosions with crust, gray erythem- drome (PAMS) (paraneoplastic pemphigus) atous desquamation of the tongue and gums, and erosive ery- encompasses a multitude of mucocutaneous thema of the interdental gingiva (Figs 1 and 2). Erythematous P plaques were present on both palms, with erythema and edema of and systemic findings. Mucocutaneous involvement in paraneoplastic pemphigus is prominent, with the distal digits and dystrophic nail changes (Fig 3). In addition, an erythematous plaque with focal erosion was present on the painful erosive lesions involving the oral, nasal, up- glans penis. Pustules were present on the knees and ankles. Right per gastrointestinal, respiratory, ocular, and genital and left upper quadrant tenderness and fullness were noted in the epithelium.1 Cutaneous manifestations are variable abdominal examination. The initial differential diagnosis included and often consist of polymorphous inflammatory Reiter’s syndrome, Behcet’s disease, lupus erythematosus, der- matomyositis, and PAMS. macules, papules, and plaques. Histopathologic ex- Laboratory investigations revealed a normal complete blood aminations classically reveal , intraepi- count, normal erythrocyte sedimentation rate (8 mm/hour), and dermal blister formation, and immunoreactant dep- negative titers for antinuclear (Hep-2), anti-double- osition along the basement membrane and within stranded DNA, anti-SSA/Ro, anti-SSB/La, anti-Smith, anti-U1- epithelial intercellular spaces. Associated neoplasia ribonucleoprotein, anti-Jo-1, cytoplasmic anti-neutrophil cytoplas- mic antibody, perinuclear anti-neutrophil cytoplasmic antibody, is a requisite finding of PAMS but may be occult at anticardiolipin , cryoglobulins, HLA-B27, and HLA-B5. the onset of cutaneous lesions. Patients with PAMS Urinalysis results were normal. Chest radiograph results were frequently have significant pulmonary involvement, initially normal. which accounts for the high mortality rate. Histopathologic examinations of cutaneous demon- strated interface vacuolar with minimal acantholysis, a The occurrence of PAMS in childhood has been slight increase in connective tissue mucin, and focal basement reported infrequently. When PAMS occurs among membrane thickening. The stratum corneum was compact and children, however, Castleman’s disease is the most parakeratotic. A specimen obtained after corticosteroid therapy common underlying , with progressive showed vacuolar interface dermatitis with ulceration, acantholy- sis, abscess formation, and underlying vasculitis. No direct immu- nofluorescence was observed for immunoglobulin (Ig) G, IgA, IgM, or complement component 3 (C3). Indirect immunofluores- From the *Section of Dermatology, Department of Medicine, ‡Section of cence assays showed intercellular and dermal/epidermal staining Pulmonology, Department of Pediatrics, and §Section of Rheumatology, for IgG and C3 on monkey bladder (Fig 4). Paraneoplastic pem- Department of Pediatrics, Medical College of Georgia, Augusta, Georgia. phigus was diagnosed on the basis of clinical and histopathologic Accepted for publication May 19, 2004. findings. A neoplasm was not evident at that time. doi:10.1542/peds.2004-0436 Persistent constipation and the presence of abdominal fullness Address correspondence to Loretta S. Davis, MD, Section of Dermatology, prompted computed tomography (CT) evaluation of the abdo- Department of Medicine, Medical College of Georgia, 1004 Chafee Ave, men, which showed a mass (5.5 cm ϫ 7cmϫ 9 cm) in the right Augusta, GA 30912. E-mail: [email protected] lower retroperitoneal space. An open biopsy, complicated by sig- PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- nificant bleeding, was interpreted as indicating a hemangioma. emy of Pediatrics. Magnetic resonance angiography was performed to delineate the

www.pediatrics.org/cgi/doi/10.1542/peds.2004-0436Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 25, 114 2021 No. 4 October 2004 e513 Fig 3. Prominent erythema and nail dystrophy of the distal dig- Fig 1. Exudative bulbar and palpebral conjunctivitis. its.

blepharon as a result of chronic conjunctivitis, and he eventually lost his fingernails. Fourteen months after presentation, the patient’s lung function had progressively deteriorated. Chest CT scans showed new de- velopment of lower-lobe bronchiectasis, with progression of pre- viously identified, thin-walled, cystic lesions in both lungs and increasing areas of ground glass opacity, especially in the left lower lobe. Bronchoalveolar lavage was performed and showed no superficial inflammation or friability of the mucosa. Cultures were negative for bacterial, fungal, or viral infection. Sections from an open lung biopsy performed on the same day showed evidence of small-airway disease, with mucostasis and an absence of respi- ratory bronchioles in the visible sections. There was also mild cellular interstitial pneumonia, with small nonnecrotizing granu- lomas and multinucleated giant cells present, which was likely an incidental finding in the context of small-airway disease. Subse- quent CT scans of the abdomen and pelvis showed a residual tumor (2 cm ϫ 3 cm) inferior to the right kidney in the pelvis. One month after the lung biopsy, despite aggressive medical therapy, end-of-life issues needed to be discussed with the patient and his parents. The patient was discharged from the hospital with hos- Fig 2. Gray erythematous desquamation of the tongue and gums, pice care and died shortly thereafter. with mild nasal septal erosions and crusting. DISCUSSION An association between polymorphous skin le- vascular nature of the mass; it revealed a large feeding vessel to sions, including bullae, and internal malignancies the mass, which was embolized. has long been recognized. However, a distinct entity, Early in the disease course, the patient’s respiratory symptoms worsened. CT evaluation of the chest demonstrated a diffuse ie, PAMS (paraneoplastic pemphigus), was formally 1 interstitial infiltrate. The patient was unable to undergo pulmo- characterized by Anhalt et al in 1990, as an autoim- nary function testing because of the fixation of his mouth and mune bullous disease associated with neoplasia (of- painful oral lesions. A clinical diagnosis of bronchiolitis obliterans ten occult). The disease is typified by painful muco- was made. The patient was treated with (50 mg daily, sal ulcerations and polymorphous cutaneous lesions 2 mg/kg per day) and then intravenously administered ␥-globulin (24 g of Ig) and cyclosporine (350 mg/day). The skin findings progressing to bullae among patients with underly- transiently improved, except for those for the distal phalanges. ing neoplasia. Histopathologic findings include epi- Therapy with (monoclonal antibody against B cells) and dermal , acantholysis with suprabasilar cleft- daclizumab (antibody against interleukin-2 receptor) was subse- ing, vacuolar-interface changes (sometimes lichenoid quently initiated.2,3 Four months after presentation, the patient was referred to a inflammation), and exocytosis of inflammatory cells. nearby academic center and underwent partial resection of the Direct assessment of perile- tumor. The histopathologic examination revealed a vascular vari- sional skin shows intercellular IgG and C3 staining ant of Castleman’s tumor. Immunohistochemical examination for similar to that found in pemphigus, with additional human herpesvirus 8 yielded negative results. Three months after staining along the dermal-epidermal junction. surgery, the patient received radiotherapy to his abdomen. 1 Pulmonary function testing was performed 5 months after the Anhalt et al demonstrated that 4 desmosomal and initial presentation and after partial tumor resection, when the hemidesmosomal protein , with molecular oral lesions had improved. The studies were consistent with se- masses of 250 kDa ( I), 230 kDa (bullous vere restrictive and obstructive pulmonary disease with air trap- I), 210 kDa, and 190 kDa, were ping. There was no bronchodilator responsiveness to the obstruc- tive pattern. the targets of IgG . These autoantibod- During the disease course, the patient underwent multiple ies, when injected into mice, reproduced the disease admissions because of fever and weight loss. He developed sym- clinically and histopathologically. Later it was dis-

e514 PARANEOPLASTICDownloaded PEMPHIGUS from www.aappublications.org/news IN A CHILD by guest on September 25, 2021 The of PAMS may be attributable to tumor-induced inhibition of tolerance to keratino- cyte junctional antigens. In other words, the antitu- mor immune response cross-reacts with normal epi- thelial proteins. Another concept used to explain the disease is “epitope spreading,” in which chronic in- flammation of the dermal-epidermal junction leads to exposure of new self-antigens, triggering a hu- moral response. In addition to this humoral re- sponse, there is evidence that a cytotoxic (CD8ϩ)T lymphocyte response contributes to the pathogenesis by causing death.7 Several cases have been reported to arise during or soon after chemo- therapeutic treatment of malignancies. A recent study showed that PAMS is associated with HLA- DRB1*03.8 Intercellular staining of rodent (mouse or rat) uri- nary bladder transitional epithelium in indirect immunofluorescence assays is highly specific (83– 98.9%) for paraneoplastic pemphigus.9,10 Bladder ep- ithelium has a high concentration of desmosomes. This relatively inexpensive and simple test is the best diagnostic tool9 to distinguish paraneoplastic pem- phigus from occurring coinci- dentally with neoplasia.11 However, immunoprecipi- tation or immunoblotting of antibodies may be the standard method for diagnosis. Although PAMS is rare, it has been reported with a variety of , including non-Hodgkin’s , chronic lymphocytic leukemia and other lymphoid malignancies, Castleman’s disease without human herpesvirus-8, Waldenstrom’s mac- roglobulinemia, benign , poorly differen- tiated sarcomas, and carcinomas of the lung, colon, pancreas, and cervix.12–19 It is now well recognized that autoimmune mucocutaneous bullae should prompt physicians to search for occult malignancies Fig 4. Indirect immunofluoresence assays, revealing cell surface among patients with no history of malignancy or for staining of rodent bladder substrate with IgG (1:5 dilution; mag- recurrence among patients with a known history of nification: ϫ20) (A), staining of monkey substrate (se- malignancy. If a tumor is not readily detectable, then rum, 1:20; magnification: ϫ40) (B), and staining of split-skin sub- continued surveillance is indicated. Notably, the skin strate ( separated from after NaCl incubation) (serum, 1:10; combined [epidermal and dermal] pattern; magnifi- lesions of paraneoplastic pemphigus do not always cation: ϫ20). Epidermis and dermis correspond to top and bottom, parallel the activity of the underlying malignancy. respectively, in (C). The cutaneous eruption in paraneoplastic pemphi- gus may resemble pemphigus vulgaris, pemphigus covered that the 210-kDa protein was actually 2 sep- vegetans, , erythema multiforme arate 210-kDa proteins, ie, desmoplakin II and envo- major (Stevens-Johnson syndrome), toxic epidermal plakin.4 The 190-kDa protein was shown to be necrolysis, graft-versus-host disease, lichen planus identical to periplakin.4 I and II, en- pemphigoides, or lichen planus. Pustules have been voplakin, periplakin, and bullous pemphigoid anti- described.20 Nikolsky’s sign may be positive. Pa- gen I all belong to the plakin family of cytoplasmic tients may have hemorrhagic crusting of the lips, proteins. This combination of autoantigens is unique severe ulcerative stomatitis/gingivitis, desquama- to paraneoplastic pemphigus. Hemidesmosome1/ tive esophagitis and tracheobronchitis, scarring con- plectin (another plakin) and an unidentified 170-kDa junctivitis, and genital erosions. In fact, the variety of protein were recently shown to be additional targets clinical lesions is characteristic of the disease. A re- in paraneoplastic pemphigus. Mahoney et al5 cent study showed that autoantibodies are found in showed that a homologous region near the carboxy kidney, bladder, smooth muscle, and striated mus- terminus of the plakins serves as the antigenic site in cle, in addition to skin, upper digestive tract, and paraneoplastic pemphigus. Antibodies against the respiratory tract epithelium.21 In light of this multi- cell-surface proteins 1 and desmoglein 3 system involvement and the clinical and immuno- are also usually present in paraneoplastic pemphi- pathologic heterogeneity of this entity, Nguyen et gus.6 The autoantibodies cause loss of cell-cell and al21 suggested the broader term PAMS. cell-basement membrane adhesion, resulting in acan- Unfortunately, with few exceptions, paraneoplas- tholysis histopathologically and blistering clinically. tic pemphigus has a very poor prognosis and a high

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-0436 by guest on September 25, 2021 e515 mortality rate. It is characterized by severe respira- 7. Reich K, Brink U, Lefschert M, et al. Graft-versus-host disease-like tory compromise associated with IgG deposits in the immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus. Br J Dermatol. 1999;141:739–746 epithelium of the bronchi, as well as pulmonary ep- 8. Martel P, Loiseau P, Joly P, et al. Paraneoplastic pemphigus is associ- ithelial acantholysis and intraepithelial cleavage. No ated with the DRB1*03 allele. J Autoimmun. 2003;20:91–95 therapy has been consistently successful. Eradication 9. Liu AY, Valenzuela R, Helm TN, Camisa C, Melton AL, Bergfield WF. of the associated tumor is occasionally curative but Indirect immunofluorescence on rat bladder transitional epithelium: a test with high specificity for paraneoplastic pemphigus. J Am Acad not uniformly helpful. Treatment is palliative immu- Dermatol. 1993;28:696–699 nosuppression. Systemic corticosteroid treatment, 10. Helou J, Allbritton J, Anhalt GJ. Accuracy of indirect immunofluores- cyclosporine, , , gold, cence testing in the diagnosis of paraneoplastic pemphigus. J Am Acad dapsone, thalidomide, mycophenolate mofetil, ritux- Dermatol. 1995;32:441–447 imab administration, intravenous Ig administration, 11. Mehregan DR, Oursler JR, Leiferman KM, Muller SA, Anhalt GJ, Peters MS. Paraneoplastic pemphigus: a subset of patients with pemphigus , immunopheresis, and photophere- and neoplasia. J Cutan Pathol. 1993;20:203–210 2,3,22,23 sis have been tried. These treatments are gen- 12. Chorzelski T, Hashimoto T, Maciejewska B, Amagai M, Anhalt GJ, erally ineffective and usually, at best, only slightly Jablonska S. Paraneoplastic pemphigus associated with Castleman tu- delay the patient’s rapid demise as a result of pro- mor, myasthenia gravis, and bronchiolitis obliterans. J Am Acad Derma- tol. 1999;41:393–400 gressive obstructive lung disease and respiratory 13. van Mook WNK, Fickers MM, Theunissen PH, et al. Paraneoplastic failure or infection. pemphigus as the initial presenting sign of chronic lymphocytic leuke- Autoimmune blistering diseases are much more mia. Ann Oncol. 2001;12:115–118 common among adults and elderly subjects than 14. Hartz RS, Daroca PJ. Clinical-pathological conference: cutaneous para- among children and adolescents. Chronic bullous neoplastic pemphigus associated with benign encapsulated . J Thorac Cardiovasc Surg. 2003;125:400–406 disease of childhood (linear IgA disease) and derma- 15. Leyn J, Degreef H. Paraneoplastic pemphigus in a patient with a thy- titis herpetiformis are the autoimmune bullous dis- moma. Dermatology. 2001;202:151–154 eases seen most commonly among children.24 Para- 16. Takahashi M, Shimatsu Y, Kazama T, Kimura K, Otsuka T, Hashimoto neoplastic pemphigus has been observed rarely T. Paraneoplastic pemphigus associated with bronchiolitis obliterans. 22,25–28 27 Chest. 2000;117:603–607 among children. Mimouni et al recently an- 17. Matz H, Milner Y, Frusic-Zlotkin M, Brenner S. Paraneoplastic pemphi- alyzed 14 cases of paraneoplastic pemphigus among gus associated with pancreatic carcinoma. Acta Derm Venereol (Stockh). patients Ͻ18 years of age. Among those patients, 1997;77:289–291 Castleman’s disease, bronchiolitis obliterans, and a 18. Niimi Y, Kawana S, Hashimoto T, Kusunoki T. Paraneoplastic pemphi- fatal outcome were common. gus associated with uterine carcinoma. J Am Acad Dermatol. 2003;48: S69–S72 19. Hinterhuaer G, Drach J, Riedl E, et al. Paraneoplastic pemphigus in ACKNOWLEDGMENT association with hepatocellular carcinoma. J Am Acad Dermatol. 2003;49: We thank Grant J. Anhalt, MD, for assistance with immunoflu- 538–540 orescence studies. 20. Rivollier C, Vaillant L, Machet MC, et al. 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Downloaded from www.aappublications.org/news by guest on September 25, 2021 Paraneoplastic Autoimmune Multiorgan Syndrome (Paraneoplastic Pemphigus) in a Child: Case Report and Review of the Literature Joshua E. Lane, Carol Woody, Loretta S. Davis, Margaret F. Guill and Rita S. Jerath Pediatrics 2004;114;e513 DOI: 10.1542/peds.2004-0436

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