Nasal-type Extranodal Natural Killer (NK)/T-Cell Lymphoma Presenting with Primary Mucocutaneous Lesions Mimicking Behcet Disease

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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 27(3), , 2011 Case Report journal homepage: Nasal-type Extranodal Natural Killer (NK)/T-Cell Lymphoma Presenting with Primary Mucocutaneous Lesions Mimicking Behcet Disease Jui-Hung Tsai, Ya-Ping Chen * Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan Abstract. Mucocutaneous ulcers mimicking Behcet disease as the initial presentations of nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) are rare. We report a case of 53-year-old male with initial presentations of multiple mucocutaneous ulcers in the oral and genital areas. Serology tests for autoimmune disease (e.g. anti-nuclear antibody) were all negative except for expression of HLA-B51. Biopsy of buccal mucosa showed leukocytoclastic vasculitis. The follow-up chest plain films showed multiple lung nodules, biopsy of which revealed nasal-type ENKTCL. The patient received systemic chemotherapy as soon as the diagnosis was confirmed but died of lymphoma progression and pneumonia within one month of diagnosis. Early diagnosis and treatment are important due to ENKTCL s highly aggressive clinical course. 病例報告 Keywords : Nasal-type extranodal NK/T-cell lymphoma, Behcet disease 鼻型淋巴結外的自然殺手 /T 細胞淋巴癌以原發性黏膜皮膚病灶類似貝西氏病來表現 蔡瑞鴻陳雅萍 * 成大醫院內科部血液腫瘤科 中文摘要鼻型淋巴結外的自然殺手 /T 細胞淋巴癌以類似貝西氏病來表現乃是相當罕見的 本病例報告為一位 53 歲男性, 初期是以多處的口腔及會陰處皮膚黏膜等處之潰瘍來表現 此病患之自體免疫疾病相關之抗核抗體血清學檢查呈現陰性, 但是卻帶有 HLA-B51 口腔黏膜切片顯示白細胞破碎性血管炎 而系列追蹤胸部 X 光片顯示病人肺部有多處腫塊 進一步透過肺部組織切片檢查, 證實為鼻型淋巴結外的自然殺手 /T 細胞淋巴癌 確定診斷之後病患立即接受全身化學治療, 但最後仍死於腫瘤惡化及肺炎 對於這種快速惡化的癌症, 及早診斷與治療是相當重要的 關鍵字 : 鼻型淋巴結外的自然殺手 /T 細胞淋巴癌 貝西氏病

2 134 J. H. Tsai et al./jcrp 27(2011) INTRODUCTION Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is common in Asia [1,2]. It occurs most often in adults, more commonly in men than women. ENKTCL are aggressive, locally destructive mid-facial necrotizing lesions characterized by extranodal involvement, with the nose and upper airway (nasal cavity, nasopharynx, paranasal sinuses, and palate) most frequently involved. In addition to the nasal region, these lymphomas happen less often in other areas, including skin, soft tissues, testis, and gastrointestinal tract [3]. The initial signs and symptoms are often localized to the nasal region and include nasal obstruction and chronic rhinorrhea. The clinical course of ENKTCL varies with the clinical stage. Patients with limited-stage disease (usually nasal disease) typically have an indolent course with tumor restriction to the original site. In contrast, patients with advanced disease mostly suffer rapid progression to systemic dissemination, which is often accompanied by hemophagocytosis or disseminated intravascular coagulation. Patients with disseminated disease should receive systemic chemotherapy as soon as possible. Despite aggressive treatment, however, most of those showed poor response and died within one year [4]. CASE REPORT This 53-year-old gentleman was generally well until two months prior to admission. Several ulcerations were found during these two months over his tongue, buccal mucosa and genital areas. Also, he developed several erythematous papules over his left forearm about one month prior to admission. Subse- *Corresponding author: Ya-Ping Chen M.D. * 通訊作者 : 陳雅萍醫師 Tel: ext.4559 Fax: i @info.hosp.ncku.edu.tw quently, these skin rashes became ulcerated vesicles. Due to fever and mild cough, he came to the emergency department of our hospital. Physical examination showed multiple mucocutaneous ulcerations in the peri-orbital, buccal mucosa, genital areas and four extremities but no palpable lymphadenopathy (Figure 1). The nasal cavity and nasopharyngeal area were quite normal. In view of clinical presentations, autoimmune disease was taken into consideration, especially Behcet disease. We checked the anti-nuclear antibody (ANA) and human leukocyte antigen (HLA). The ANA test was normal, but the HLA typing showed the presence of HLA-B51. The pathergy test was negative. Human immunodeficiency virus (HIV) antibody was negative, too. Tongue and buccal mucosa biopsy were performed, and histological findings showed leukocytoclastic vasculitis. The serial follow-up of chest plain films showed multiple lung nodules. The chest computed tomography scan showed bilateral lung nodules, with the largest one, measuring 2 cm in diameter, in the left lower lung (Figure 2). The lung biopsy revealed diffuse infiltrate of large, pleomorphic lymphoid cells with angulated or bizarre nuclei. Those cells were positive for CD3 and CD56 but negative for CD20 and CD68. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization was positive. These findings were compatible with nasal-type ENKTCL. The skin biopsy also revealed atypical lymphocyte infiltration with strongly positive staining of EBER, confirming lymphoma involvement (Figure 3). Pancytopenia gradually developed during follow-up, with white blood cell count 2800/ μl, hemoglobin 10.6 g/ dl, and platelet count 81,000/ μl. The serum ferritin level was elevated as high as 15,916 ng/ml. Lactate dehydrogenase level was 685 U/l. Bone marrow exam showed lymphoma involvement with hemophagocytosis. Later, the patient also presented ulcerative mass over his nasal cavity with pathological confirmation of lymphoma involvement (Figure 4, 5). The Ann Arbor staging was stage IVBE with the hemophagocytosis. The patient s

3 J. H. Tsai et al./jcrp 27(2011) and prednisolone) regimen. Initially the tumors responded to the chemotherapy, but they soon regrew. The patient died within 1 month of diagnosis because of tumor progression and overwhelming pneumonia. Figure 1. The mucocutaneous ulcerations in this patient (a) peri-orbital, tongue, (b) thigh, (c) peri-anal, and (d) wrist Figure 2. Chest computed tomography of this patient showed multiple pulmonary nodules, with the largest one measuring about 2 cm shown in this figure Eastern Cooperative Oncology Group (ECOG) performance status was 4. We started chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, DISCUSSION ENKTCL is commonly known as lethal midline granuloma. It is rare in Western countries but more prevalent in Asia, Central and South America. A retrospective study conducted by Chen et al. reported on 70 patients with upper aerodigestive tract lymphoma, 31.4% of whom had ENKTCL [5]. The upper aerodigestive tract, especially the nasal or sinonasal regions, was the most commonly involved area. Other less frequent sites include skin, soft tissues, gastrointestinal tract and testis. The major clinical features are nasal obstruction and epistaxis. The initial manifestation mimicking Behcet disease is rare, especially without nasal involvement. In this case, the initial mucocutaneous manifestations made clinicians take Behcet disease into consideration. Previous report revealed that Behcet disease may have similar cutaneous ulcerations as well as lung nodules in some rare instances [6]. Chia et al. described a case of ENKTCL with leg ulcers as presentation. That was a purely cutaneous form of ENKTCL without other organ involvement [7]. Saito et al. reported a case of ENKTCL with skin ulceration in the right arm and bilateral lung nodules [8]. So, tissue proof is important to make the final diagnosis. Nasal-type ENKTCL is an aggressive lymphoma. Patients will die quickly without treatment. The prognosis with treatment is largely related to the location of disease and its stage at diagnosis. In one case series study reported by Au et al., 136 patients of NK/T-cell lymphoma were identified through the International Peripheral T-cell Lymphoma Project. That study revealed that, when compared with patients with nasal presentations, patients with extra-nasal disease had a significantly shorter median overall survival (4 versus 36 months) [9]. Another case series, of 77 patients s

4 136 J. H. Tsai et al./jcrp 27(2011) Figure 3. EBER stain of skin biopsy showed strongly positive staining. (100X magnification) Figure 4. H & E stain of nasopharynx biopsy showed dense infiltrate of atypical lymphocytes. (200X magnification) chemotherapy alone was also associated with treatment failure in 40% of patients, who needed the use of salvage RT for further control of their diseases. In view of these previous studies, chemotherapy and RT can be given sequentially or concomitantly to improve the treatment outcome [12,13]. A phase II study of concurrent chemoradiation for the localized nasal NK/T-cell lymphoma was conducted in Taiwan (Taiwan Cooperative Oncology Group- T1405) to investigate whether it will increase the response rate and overall survival. The results are not published yet. Figure 5. EBER stain of nasopharynx mass biopsy Most patients with advanced disease tend to be showed focally positive staining. (200X treated with chemotherapy, such as CHOP, but show magnification) poor response. Based on these poor results, a novel L-asparaginase based chemotherapeutic regimen termed SMILE (steroid, methotrexate, ifosfamide, with sinonasal NK/T-cell or T-cell lymphoma per- L-asparaginase, and etoposide) was developed. The formed by Li et al., showed that the outcome was SMILE regimen consists of methotrexate 2 g/m2 on dismal for patients with systemic disease, with a com- day 1, ifosfamide 1500 mg/m2, etoposide 100 mg/m2 plete remission rate of 43% and a 5-year survival rate and dexamethasone 40 mg/body from days 2 to 4, and of 25% [10]. For localized stage I/II disease, radio- L-asparaginase 6000 U/m2 every other day from day 8 therapy (RT) has been used as the primary treatment. to day 20 (7 doses). Results of phase I and subsequent However, systemic failure occurred in more than 30% phase II study demonstrated an excellent anti-tumor of patients, suggesting subclinical dissemination in affect, with an overall response rate of 74% and com- these apparently early-stage patients [11]. The use of plete response rate of 40% for newly diagnosed stage

5 J. H. Tsai et al./jcrp 27(2011) IV or relapsed/refractory ENKTCL [14]. SMILE or other regimens including L-asparaginase are therefore promising for these previously incurable diseases, although long-term results await further studies. We have reported this extraordinary presentation of ENKTCL, which we may encounter sometimes in our daily practice in Taiwan. It is quite important to diagnose and treat the disease in view of its highly aggressive behavior. REFERENCES 1. Jaffe ES, Chan JK, Su IJ, et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 20: , Liang R. Advances in the management and monitoring of extranodal NK/T-cell lymphoma, nasal type. Br J Haematol 147: 13-21, Cheung MM, Chan JK, Lau WH, et al. Primary non-hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 16: 70-77, Suzuki R, Suzumiya J, Yamaguchi M, et al. Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type. Ann Oncol 21: , Chen SW, Chang ST, Lu CL, et al. Upper aerodigestive tract lymphoma in Taiwan. J Clin Pathol 63: , Hiller N, Lieberman S, Chajek-Shaul T, et al. Thoracic manifestations of Behcet disease at CT. Radiographics 24: , Chia HY, Tey HL, Tan KB, et al. Nasal-type extranodal natural killer/t-cell lymphoma presenting with extensive leg ulcers. Clin Exp Dermatol 34: e , Hamaguchi R, Saito H, Kegasawa K, et al. [A case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung]. Nihon Kokyuki Gakkai Zasshi 47: , Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/t-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood 113: , Li CC, Tien HF, Tang JL, et al. Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/t-cell or T-cell lymphoma. Cancer 100: , Kwong YL. Natural killer-cell malignancies: diagnosis and treatment. Leukemia 19: , Yamaguchi M, Tobinai K, Oguchi M, et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/t-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol 27: , Kim SJ, Kim K, Kim BS, et al. Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol 2735: , Yamaguchi M, Suzuki R, Kwong YL, et al. Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci 99: , 2008.