QUINTESSENCE INTERNATIONAL

Paraneoplastic characterized by polymorphic oral mucosal manifestations— Report of two cases

Zhimin Yan, DDS, PhD1/Hong Hua, DDS, PhD2/Yan Gao, DDS, PhD3

Paraneoplastic pemphigus is a rare characterized by polymorphous mucocutaneous lesions in association with underlying neoplasia. We report two Chinese patients, one with chronic lymphocytic leukemia and the other with . Both of them initially presented with severe oral erosion with lichenoid features that resisted all the regular therapy. The routine histology was not typical in both patients, with features of liq- uefaction degeneration of the basal cell layer and subbasilar lymphocytic infiltration. Important differential diagnoses for the two cases include lichenoid eruption secondary to chemotherapy, pemphigus, and . Immunohistologic testing played an essen- tial role in the diagnoses. Direct shows both intercellular and base- ment membrane deposition of immunoreactants. Indirect immunofluorescence using rat bladder as the substrate has been shown to be an inexpensive and reliable diagnostic tool. Our patients’ clinical and immunopathologic features were consistent with a diagno- sis of paraneoplastic pemphigus, a special subset of pemphigus. Patients’ conditions were improved after high-dose systemic therapy after underlying malignan- cies were treated. (Quintessence Int 2010;41:689–694)

Key words: diagnosis, direct immunofluorescence, indirect immunofluorescence, oral presentation, paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP), an autoim- This report presents two Chinese mune blistering and erosive mucocutaneous patients with underlying leukemia and thy- disease, is an extremely rare but severe sub- moma, respectively, who manifested with set of pemphigus. It was first defined as a extensive polymorphic oral mucosa lesions. separate entity in 1990 by Anhalt et al for its Differential diagnosis included bullous pem- definite association with malignancy.1 Since phigoid, lichen planus, , then, approximately 200 cases have been erythema multiforme, Stevens-Johnson syn- reported worldwide. PNP is particularly drome, or a variable combination of these important in oral medicine because all cases entities. Both patients were eventually diag- have oral mucosa involvement, and 45% have nosed with PNP based on the clinical and oral erosions as the first sign. laboratory examination.

1Department of Oral Medicine, Peking University School of CASE 1 Stomatology, Beijing, China; Division of Orofacial Pain, Department of Diagnostic Sciences, University of Medicine and A 65-year-old man had been diagnosed with Dentistry of New Jersey, New Jersey Dental School, Newark, New Jersey. chronic lymphocytic leukemia and received

2Professor, Department of Oral Medicine, Peking University chemotherapy in July 2003. Two months School of Stomatology, Beijing, China. later, he complained of difficulty with intake of

3Professor and Chair, Department of Oral Pathology, Peking food due to painful oral ulcer. The oral lesions University School of Stomatology, Beijing, China. progressed despite topical treatment, and the Correspondence: Dr Hong Hua, Department of Oral Medicine, patient was referred to the dental center for Peking University School of Stomatology, 22 South further evaluation and management. Oral Zhongguancun Street, Haidian District, Beijing 100081, China. Fax: 86-10-6217-3402. Email: [email protected] examinations revealed bilateral exudative

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ab

Fig 1 Oral manifestations of the first patient. (a) Exudative erosion on the buccal mucosa with peripheral white striations. (b) Lichenoid reticular pattern on ventral tongue.

Fig 2 Histologic examination of buccal mucosa showed liquefac- tion degeneration of the basal cell layer and subbasilar lymphocytic infiltration (hematoxylin-eosin; original magnification ϫ40).

erosion on the buccal mucosa, with peripher- lymphocytic infiltration consistent with al striations (Fig 1a). Lichenoid reticular pat- lichenoid eruption (Fig 2). Laboratory investiga- tern formed by white striations can be tions revealed negative titers for antinuclear observed bilaterally on the ventrolateral . Enzyme-linked immunosorbent tongue (Fig 1b). The initial diagnosis was assays () showed the presence of anti- lichenoid eruptions due to prior chemothera- intercellular against 1 py. The patient’s symptoms improved with and 3 (Dsg-1 and Dsg-3) and high titers of topical steroid (dexamethasone) and gentam- circulatory antibodies at 1:320. As paraneo- icin oral rinse, but his oral lesions did not heal. plastic pemphigus was suspected, an indirect In July 2004, he suffered from blistering, immunofluorescence test was performed papular eruption on his trunk. Physical exami- using multiple epithelial substrates (rat bladder, nations revealed a polymorphous eruption that , and small intestine). The patient’s included lichenoid plaques as well as bullae. serum showed circulating antibodies against Histopathologic examinations of cutaneous intercellular space with bright fluorescence (Fig demonstrated intraepithelial as well 3). Direct immunofluorescence using cytologi- as subepithelial bullae associated with inter- cal smear as substrates shows immuno - face . This made it difficult to distin- globulin G (IgG) deposition in the intercellular guish histopathologically between pemphigus spaces (Fig 4). Reexamination of the skin and and pemphigoid. A perilesional of buc- mucosa specimen histologically and the result cal mucosa revealed “liquefaction degenera- of direct immunofluorescence were, in retro- tion” of the basal cell layer with subbasilar spect, compatible with the diagnosis of PNP.

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Fig 3 Indirect immunofluorescence using rat blad- Fig 4 Direct immunofluorescence using cytologic smear as sub- der as the substrate showed both intercellular and strates showed IgG deposition in the intercellular spaces. basement membrane deposition of IgG (original magnification ϫ40).

The patient was treated with prednisolone lesions that worsened despite various topical 45 mg (patient body weight about 65 kg) per treatments. day, supplemented with traditional Chinese On clinical examination, the patient had medicines. His cutaneous lesions healed blood-crusted lips and polymorphic oral about 2 weeks later, and the buccal mucosa lesions. Oral erosions were generalized, and lips showed great improvement. Pred - superficial, and symptomatic (Fig 5). In nisolone dosage was slowly tapered down. ELISA studies, anti-intercellular antibodies to The patient was symptom-free until De - Dsg-1 and Dsg-3 could not be detected in cember 2004. The oral lesions came back serum samples of this patient. A mucosal and progressed into unusual extensive ero- biopsy from the tongue revealed “liquefac- sions affecting lips and the entire oral tion degeneration” of the basal cell layer with mucosa. After treatment with 60 few acantholytic cells, basal vacuolization, mg per day, the severe oral erosions were and no suprabasal bullae (Fig 6). Direct under control. The patient was then managed immunofluorescence of perilesional tissue with topical treatment and continued follow- disclosed deposits of IgG and C3 in the inter- up with the physician for control of leukemia. cellular spaces. Indirect immunofluores- cence, using rat urinary bladder, esophagus, and small intestine as substrates, revealed circulating antibodies against intercellular CASE 2 spaces and basement membrane (Fig 7). The diagnosis of PNP was made based In January 2005, a 54-year-old woman was upon the patient’s remarkable medical histo- referred to our department with extensive and ry and polymorphic oral manifestations, painful oral erosions. One year before presen- combined with characteristic histologic and tation, she was diagnosed with thymoma immunopathologic features. based upon computed tomography and biop- The patient was first treated with topical sy. Her tumor was under control after two and nystatin. It did help in courses of chemotherapy, using cyclophos- achieving some improvement. She was also phamide and cisplatin. However, 7 months encouraged to perform frequent oral rinse, later, she developed blistering, erosive oral as well as normal saline soaks over the lips

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ab Fig 5 Oral manifestations of the second patient. (a) Extensive erosions covered with hemorrhagic crust with peripheral striations. (b) Painful erosions on ventral tongue.

Fig 6 Mucous biopsy of the tongue revealed liquefaction degenera- Fig 7 Indirect immunofluorescence using rat urinary tion of the basal cell layer, but no suprabasal bullae were detected bladder as substrates revealed circulating antibodies (hematoxylin-eosin; original magnification ϫ40). against intercellular spaces and basement membrane.

followed by mupirocin ointment. Her condi- distribution. Definitive statistics on the inci- tion improved significantly after treatment with dence and prevalence is presently not avail- high doses of prednisone (60 mg/day). There able for its rarity. It often leads to severe oral was a complete remission of the mucosal erosions resembling the features of pemphi- erosions 1 month later. No recurrence was gus, pemphigoid, or lichenoid drug eruptions detected on follow-up after 6 months. and creating a diagnostic dilemma. The possibility of PNP should be borne in mind, especially if malignancy is a suspected cause.

DISCUSSION Etiology The etiology of PNP is still unknown. PNP was first described by Anhalt in 1990,1 Antibodies against Dsg-1 and Dsg-3, anti- and the association between PNP and malig- gens for the classic types of pemphigus, nancy has been well known for decades. This have been reported to play an important role clinically and immunologically distinct disease in the initial stage of PNP.2 The immuno- is seen principally in aged adults between precipitation studies have disclosed pres- 45 and 70 years with a near equal gender ence of against four epithelial

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Table 1 Diagnostic criteria of PNP8

Major criteria Minor criteria

• Polymorphous mucocutaneous eruption • Positive cytoplasmic staining of rat bladder epithelium by indirect immunofluorescence • Concurrent internal neoplasia • Intercellular and basement membrane zone immunoreactants on direct immunofluorescence of perilesional tissue • Characteristic serum • in biopsy specimen from at least one anatomical findings site of involvement

polypeptides in patients with PNP. They have Castleman disease, and Waldenström an estimated molecular weight of 250, 230, macro globulinemia.7 In the present patients, 210, and 190 kilodaltons (kDa), representing PNP de veloped secondary to lymphocytic 1, , leu kemia and thymoma. desmoplakin 2/en voplakin doublet, and periplakin, respectively.3,4 In 2004, Wang et Diagnosis al detected autoantibodies secreted by cul- The diagnosis of PNP is established by poly- tured tumor cells reacting against epidermal morphous mucocutaneous eruption, routine proteins. These autoantibodies could be an histology, direct and indirect immunofluores- essential factor in PNP .5 cence, and immunoprecipitation studies on extracts. Histologic examination Clinical features is often routinely performed and is of the Clinically, PNP is characterized by polymor- same importance. Suprabasal cleft or bullae phic mucocutaneous lesions resembling formation with acantholysis and keratinocyte lesions of bullous pemphigoid, lichen , inflammation at the dermal-epider- planus, pemphigus vulgaris, erythema multi- mal junction, or lichenoid infiltrate are primari- forme, Stevens-Johnson syndrome, or a vari- ly found in mucosal and/or cutaneous biopsy able combination of these entities. Nearly all specimens. To help in diagnosing PNP, patients with PNP typically have predominant Camisa and Helm proposed a set of diagnos- mucosal involvement, and 45% of them ini- tic criteria for PNP (Table 1). Diagnosis of PNP tially present with isolated oral erosions that requires three major, or two major and at least might be a sign of the underlying . two minor, criteria to be fulfilled.8 Our patients It is especially important since some patients presented two major and three minor criteria, with PNP have not been diagnosed with and a final diagnosis of PNP was thus made. malignancy at the time of presentation. Immunoprecipitation test is one of three major Awareness of this condition will prompt clini- criteria. Although sensitive, it is tedious, cians to search for underlying malignancies. expensive, and not readily available. In con- Any patient with onset of polymorphic oral trast, the indirect immunofluorescence test erosions with clinical and histopathologic against rat bladder is simpler and yet relative- findings not pathognomonic for a specific ly sensitive (76%) and specific (83%).9,10 In the diagnosis should have a detailed history present cases, indirect immunofluorescence inquiry and complete physical examination on rat bladder, esophagus, and small intestine (especially viscera roentgenogram).6 revealed circulating autoantibodies to epithe- The two reported patients with PNP initial- lial cell surface and basement membrane ly presented with severe polymorphic erosive zone, and it has been shown to be an inex- oral lesions. Both patients, respectively, had pensive and reliable diagnostic tool. developed oral lesions 2 and 7 months after In our cases, direct immunofluorescence being diagnosed with underlying malignancy. using the patient’s perilesional tissue or pem- Most frequent underlying neoplasm asso- phigus cytological smear as substrates shows ciated with PNP is non-Hodgkin , IgG and complement deposition in the inter- chronic lymphocytic leukemia, thymoma, cellular spaces between the and

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along the basement membrane.11 However, ACKNOWLEDGMENTS direct immunofluorescence result could be 12,13 equivocal or negative in some patients. We thank Dr Junad Khan and Dr Andrew Young for their Therefore, the fact to be stressed is that if PNP help with the revision of this manuscript. is strongly suspected clinically, negative direct immunofluorescence does not completely rule out the possibility of the disease. REFERENCES Treatment and prognosis Due to presence of underlying malignancy, 1. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic patients with PNP often are unresponsive to pemphigus. An autoimmune mucocutaneous dis- ease associated with neoplasia. N Engl J Med 1990; routine therapy. Therapy entails management 323:1729–1735. of underlying malignancy as well as high- 2. Seishima M, Oda M, Oyama Z, et al. Antibody titers to dose systemic steroids. Other strategies 1 and 3 in a patient with paraneoplas- include immunosuppressive therapy with tic pemphigus associated with follicular dendritic , methotrexate, azathio- cell sarcoma. Arch Dermatol 2004;140:1500–1503. prine, colchicine, and . 3. Schoen H, Foedinger D, Derfler K, et al. Immunoaphe - Prognosis of PNP is poor in general. Most resis in paraneoplastic pemphigus. Arch Dermatol 1998;134:706–710. patients die either from the effects of the 4. Bowen GM, Peters NT, Fivenson DP, et al. Lichenoid underlying tumor, from respiratory failure due dermatitis in paraneoplastic pemphigus: A patho- to acantholysis of the respiratory epithelium, or genic trigger of epitope spreading? Arch Dermatol from the severe lesions that do not respond to 2000;136:652–656. therapy.14 Unless the neoplasia is definitely 5. Wang L, Bu D, Yang Y, Chen X, Zhu X. Castleman’s cured, which happens in rare cases, patients tumours and production of in para- with PNP should be under long-term follow-up. neoplastic pemphigus. Lancet 2004;363:525–531. In both patients, after the control of under- 6. Allen CM, Camisa C. Paraneoplastic pemphigus: A review of the literature. Oral Dis 2000;6:208–214. lying malignancy, oral lesions improved or 7. Younus J, Ahmed AR. The relationship of pemphigus cleared with corticosteroid therapy. However, to neoplasia. J Am Acad Dermatol 1990;23:498–502. they are still under close follow-up, and long- 8. Camisa C, Helm TN. Paraneoplastic pemphigus is a term efficacy is not predictable. distinct neoplasia-induced autoimmune disease. Arch Dermatol 1993;129:883–886. 9. Helou J, Allbritton J, Anhalt GJ. Accuracy of indirect immunofluorescence testing in the diagnosis of SUMMARY paraneoplastic pemphigus. J Am Acad Dermatol 1995;32:441–447. 10. Joly P, Richard C, Gilbert D, et al. Sensitivity and speci- Paraneoplastic pemphigus is a rare subset of ficity of clinical, histologic, and immunologic fea- pemphigus that has an absolute association tures in the diagnosis of paraneoplastic pemphigus. with underlying malignancies. Polymorphic J Am Acad Dermatol 2000;43:619–626. oral ulcerations can be the sole and character- 11. Nguyen VT, Ndoye A, Bassler KD, et al. Classification, istic manifestation of the severe disease. Early clinical manifestations, and immunopathological recognition may prevent delayed diagnosis mechanisms of the epithelial variant of paraneo- plastic autoimmune multiorgan syndrome: A reap- and inappropriate treatment. Diagnosis of PNP praisal of paraneoplastic pemphigus. Arch Dermatol in the present patients was supported by the 2001;137:193–206. indirect immunofluorescence test with rat blad- 12. Barnadas MA, Curell R, Alomar A, Gelpí C. Para - der. Based on better control of the neoplasia, neoplastic pemphigus with negative direct immuno - patients may benefit from high-dose systemic fluorescence in or mucosa but positive corticosteroids and/or immunosuppressives. findings in adnexal structures. J Cutan Pathol 2008; 36:34–38. 13. Tilakaratne W, Dissanayake M. Paraneoplastic pem- phigus: A case report and review of literature. Oral Dis 2005;11:326–329. 14. Rosenkrantz WS. Pemphigus: Current therapy. Vet Dermatol 2004;15:90–98.

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