T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?

    Primary Cutaneous NK/T-cell Lymphoma of Nasal Type: An Age-related Lymphoproliferative Disease? Chun-Chieh Wu MD, Emiko Takahashi MD, Naoko Asano MD, Tomoko Miyata-Takata MD, Katsuyoshi Takata MD, Katsuya Furukawa MD, Ahmed Ali Elsayed MD, Lei-Ming Hu MD, Akira Satou MD, Kei Kohno MD, Hiroshi Kosugi MD, Kenichi Ohashi MD, Tomohiro Kinoshita MD, Shigeo Nakamura MD, Seiichi Kato MD PII: DOI: Reference:

S0046-8177(17)30309-X doi: 10.1016/j.humpath.2017.08.025 YHUPA 4323

To appear in:

Human Pathology

Received date: Revised date: Accepted date:

24 May 2017 10 August 2017 23 August 2017

Please cite this article as: Wu Chun-Chieh, Takahashi Emiko, Asano Naoko, MiyataTakata Tomoko, Takata Katsuyoshi, Furukawa Katsuya, Elsayed Ahmed Ali, Hu LeiMing, Satou Akira, Kohno Kei, Kosugi Hiroshi, Ohashi Kenichi, Kinoshita Tomohiro, Nakamura Shigeo, Kato Seiichi, Primary Cutaneous NK/T-cell Lymphoma of Nasal Type: An Age-related Lymphoproliferative Disease?, Human Pathology (2017), doi: 10.1016/j.humpath.2017.08.025

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Primary Cutaneous NK/T-cell Lymphoma of Nasal Type: An Age-related

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Lymphoproliferative Disease?

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Chun-Chieh Wu MD a,b, Emiko Takahashi MD c, Naoko Asano MD d, Tomoko

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Miyata-Takata MD e, Katsuyoshi Takata MD e,f, Katsuya Furukawa MD g, Ahmed Ali Elsayed MD b,h, Lei-Ming Hu MD b,i, Akira Satou MD b,c, Kei Kohno MD b, Hiroshi Kosugi MD g, Kenichi Ohashi MD j, Tomohiro Kinoshita MD k, Shigeo Nakamura MD

Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical

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a

, and Seiichi Kato MD b, l*

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b

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University, Kaohsiung, Taiwan, bDepartment of Pathology and Laboratory Medicine,

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Nagoya University Hospital, Nagoya, Japan, cDepartment of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan, dDepartment of Molecular Diagnostics, Nagano Prefectural Suzaka Hospital, Suzaka, Japan, eDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, fCentre for Lymphoid Cancer, BC Cancer Agency, Department of Pathology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, gDepartment of Hematology, Ogaki Municipal Hospital, Ogaki, Japan, 1

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Department of Gastroenterology, Nagoya University Graduate School of Medicine,

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Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt,

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Nagoya, Japan, jDepartment of Pathology, Yokohama City University Graduate School

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of Medicine, Yokohama, Japan, kDepartment of Hematology and Cell Therapy, Aichi

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Cancer Center, Nagoya, Japan, lDepartment of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.

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*Correspondence: Seiichi Kato, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan FAX: +81-52-757-4810

E-mail: [email protected]

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Phone: +81-52-762-6111

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Keywords: Epstein-Barr virus; primary cutaneous NK/T-cell lymphoma, nasal type; T-cell receptor phenotype; cytotoxic molecules; age-related EBV-associated lymphoproliferative disorders Running head: Primary Cutaneous EBV+ NKT-cell lymphoma The authors declare no competing financial interests.

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Summary: Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the

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extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical

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stage than the nasal variant of NKTL. However, detailed clinicopathological features of

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the localized extranasal disease have not been well documented in English literature.

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Here, we described the clinicopathological profiles of 14 patients with stage Ⅰ ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous

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(PCNKTL) cases were characterized by an older onset age (median, 76 vs. 53 years, P=0.012) and a more favorable clinical course (P=0.041), compared to 17 patients with

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stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the

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PCNKTL group were distributed in the face or neck (n=4) and limbs (n=3), but not the

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trunk, which was most frequently affected (60%, P=0.017) in the latter group. Furthermore, the stage Ⅰ cutaneous disease showed a female predominance (M:F, 2:5 vs. 7:0, P=0.021) and a significantly more favorable survival compared to the non-cutaneous stage Ⅰ ENKTL (P=0.037). These results suggested that PCNKTL constituted a distinct subgroup in the nasal type lymphoma spectrum.

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1. Introduction

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Epstein-Barr virus (EBV) is a member of the Herpesviridae, and it is related to various

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lymphoid tumors.[1, 2] NK/T-cell lymphoma of nasal type (NKTL) is characterized by

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a cytotoxic phenotype and the presence of EBV-infected neoplastic cells; moreover, its

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prevalence is relatively high in Asia and Latin America.[3, 4] Most NKTLs (60% to 90%) arise in the upper aerodigestive tract. This tumor can also occur primarily in extranasal regions, including the skin, the gastrointestinal (GI) tract, and the testes.[3, 5,

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6] Nasal and extranasal NKTLs share the same histopathological features, including vascular destruction, tissue necrosis, and frequently, a CD56+ phenotype.[3, 5, 7]

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However, extranasal cases were reported to have a worse prognosis with advanced

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clinical stage compared to nasal cases.[5, 8-10] Of course, localized stage Ⅰ/Ⅱ

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disease is a favorable prognostic indicator in both of the extranasal EBV+ lymphoma and the nasal tumor.[6, 11, 12] However, the detailed clinicopathological features of stage Ⅰ extranasal NKTL (ENKTL) has not been well documented in English literature. Herein, we describe the clinicopathological characteristics of 14 patients with stage Ⅰ ENKTL compared to those of patients with stages Ⅱ-Ⅳ disease (n=45). We further shed light on the distinctiveness of the stage Ⅰ EBV+ lymphoma localized to the skin, which is regarded a primary cutaneous ENKTL (PCNKTL). 4

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2. Material and methods Patients

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2.1.

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The institutional review board of Nagoya University approved the study protocol. We

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retrospectively identified 59 Japanese patients with ENKTL from 39 collaborating

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institutions. The present study included 45 patients with ENKTL, which were examined in our previous reports.[6, 7, 13, 14] All patients were diagnosed between September 1992 and March 2014 with NK/T-cell lymphoma of nasal type according to the 2016

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World Health Organization (WHO) classification. All cases were staged by computed tomography (CT) and/or positron emission tomography (PET)/CT with bone marrow

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examination, and clinically evaluated as extranodal diseases. Patients with upper

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aerodigestive tract involvement, EBV+ T-cell lymphoproliferative disorders of

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childhood, chronic active EBV infection (CAEBV), and nodal EBV+ cytotoxic T-cell lymphoma were excluded from our series. None of the 59 enrolled patients was reported to have an episode of hypersensitivity to mosquito bites. Some cases were accompanied by peripheral blood (PB) and/or bone marrow (BM) disease. Among those cases, when PB/BM involvement included more than 30% of the nucleated cells, patients were diagnosed with aggressive NK-cell leukemia (ANKL) and were excluded from the present study. The inclusion criteria were a positive indication of EBV and detection of 5

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at least one cytotoxic molecule (i.e., TIA-1, ganzyme B, or perforin), with

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immunohistochemistry. All cases were negative for B-cell markers. The presence of

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EBV was determined by in situ hybridization, with an EBV-encoded small RNA

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(EBER-ISH) probe. The EBER-ISH test was considered positive when 50% or more of

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the neoplastic cells were stained. A patient with disseminated cutaneous lesions, without any other extranodal or nodal site at the time of diagnosis was categorized as clinical stage Ⅳ in our series. Only cases of Ann Arbor stage Ⅰ ENKTL that solely affected

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the skin were diagnosed as PCNKTL.

Histopathology and immunohistochemical analysis

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Tissue samples were fixed in 10% formalin, embedded in paraffin, cut into 4-μm-thick

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sections, and stained with hematoxylin and eosin. Three independent pathologists (CC.

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W, S.K. and S.N.) reviewed the histological slides. Cases were divided into four groups on the basis of nuclear shape: centroblastoid, pleomorphic, mixed morphology, and unspecified, as previously described.[7] Formalin-fixed paraffin sections were subjected to immunoperoxidase staining with the avidin-biotin peroxidase complex method. We used specific monoclonal antibodies raised against the following cellular molecules: CD3, CD8, L26/CD20, Ber-H2/CD30, and ALK1 (DAKO, Santa Fe, CA); CD4, CD5, and CD56 (Novocastra Laboratories, 6

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Newcastle, UK); βF1 (T-cell receptor [TCR]-β; T Cell Science, Cambridge, MA);

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granzyme B (Monosan, Uden, the Netherlands); TCR 1153 (TCRγ; clone γ3.20;

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Thermo Fisher Scientific, Waltham, MA); TCRδ constant region (clone 5A6.E9,

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Thermo Fisher Scientific); and TIA-1 (Coulter Immunology, Hialeah, FL).

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Immunostaining was performed according to published methods.[7] The reactions, including TIA-1, granzyme B, and TCRβ, γ, and δ, were considered positive when more than 30% of the tumor cells stained positive. In situ hybridization

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2.3.

The presence of EBV small ribonucleic acids was determined by in situ hybridization

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using EBER oligonucleotides on formalin fixed, paraffin-embedded sections, as

TCRγ PCR analysis

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2.4.

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previously reported.[6]

DNA was extracted from formalin-fixed tissues. PCR analysis of the TCRγ gene was conducted with the BIOMED2 protocol, as described elsewhere.[15] 2.5.

Statistical analysis

Correlations between the two groups were determined with the Fisher exact test and Mann-Whitney U test. Patient survival data were analyzed with the Kaplan-Meier method and compared with the log-rank test. A univariate analysis was performed with 7

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the Cox proportional hazard regression model. All statistical analyses were performed

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with the STATA software package v.11 (Stata Corporation, College Station, Texas).

Characteristics of patients with stage Ⅰ and stages Ⅱ-Ⅳ ENKTL

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3.1.

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3. Results

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Table 1 summarizes the clinical features of patients with Ann Arbor stage Ⅰ and stages Ⅱ-Ⅳ ENKTL at presentation. In the present study, 14 patients had stage Ⅰ ENKTL, including 7 in skin, 5 in the GI tract, and 2 in the central nervous system

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(CNS). Compared to 45 patients with stages Ⅱ-Ⅳ disease, patients in stage I exhibited less frequent adverse clinical parameters: two showed B symptoms (15%, P<0.001),

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one showed thrombocytopenia (7%, P=0.001), and three had a performance status

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(PS) >1 (27%, P=0.050). Four patients with stages Ⅱ-Ⅳ EBV+ lymphoma had

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peripheral blood (PB) involvement, but in those cases, leukemic cells comprised less than 12% of the nucleated cells. In addition, one patient, a 54-year-old female, with disseminated cutaneous lesions in the neck, chest, abdomen, back, and limbs, was categorized as clinical stage Ⅳ disease, according to the Ann Arbor staging system. She was lost to follow-up at 6.1 months after the diagnosis. Of note, the patients with stage Ⅰ ENKTL showed an older age distribution than those with stages Ⅱ-Ⅳ disease (median age: 73 vs. 53 years; P=0.011; Fig. 1). Among all 8

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ENKTL cases, the percentage of stage Ⅰ disease tended to increase in parallel with

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age; the highest peak was observed among patients over 80 years old. Table 2 shows the

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differences in age distributions between stages Ⅰ and stages Ⅱ-Ⅳ for patients with

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cutaneous and GI tract ENKTL tumors. Among 24 patients with ENKTL with

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cutaneous involvement (CNKTL), those with stage Ⅰ disease (n=7) were significantly older at onset than those with stages Ⅱ-Ⅳ disease (76 vs. 53 years, P=0.012). However, the age difference between patients in stage Ⅰ (n=5) and stages Ⅱ-Ⅳ

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(n=6) was not confirmed among 11 patients with ENKTL with GI tract involvement (median age, 75 vs. 68 years; P=0.27).

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We found no significant difference in histopathological features, including morphology

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and immunophenotype, between individuals with stage Ⅰ and stages Ⅱ-Ⅳ ENKTL.

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However, the former group showed higher positivity for cytoplasmic CD3 than the latter group, although the difference was not statistically significant (100% vs. 76%, P=0.052, Table S1). Pleomorphic medium and large-cell appearances were observed in 8 patients (57%) with stage Ⅰ disease (Fig. 2A-C). This frequency was comparable to that of patients with stages Ⅱ-Ⅳ disease (70%, P=0.51).

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3.2.

Clinicopathological comparison between PCNKTL and non-cutaneous stage

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Ⅰ ENKTL

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Patients with PCNKTL were predominantly female (M:F, 2:5 vs. 7:0, P=0.021), and

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less frequently had a PS>1 (0% vs. 75%, P=0.024) compared to patients with

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non-cutaneous Ann Arbor stage Ⅰ ENKTL (Table 3). There was no significant difference in morphology or immunophenotype between these two groups (data not shown). Figure 3 shows the unadjusted overall survival curves for the cutaneous and

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non-cutaneous subgroups of patients with stage Ⅰ ENKTL. Their median survival was 43 and 3 months, respectively (P=0.037, log-rank). Detailed clinicopathological features of PCNKTL

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3.3.

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Table 4 demonstrates the detailed clinicopathological findings of our 7 patients with

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PCNKTL. All of these patients were over 59 years old at onset. The gross appearance of these cutaneous lesions was variable from erythematous nodules with and without erosion to indurated ulcers. There were few scattered or large B-cells in the background of PCNKTL. They had tumors on the face or neck (n=4) or limbs (n=3). No skin lesion was detected on the trunk among stage Ⅰ cases; in contrast, 60% of patients with stages Ⅱ-Ⅳ CNKTL had trunk skin lesions (P=0.017, Table S2). The PCNKTL group had a more favorable prognosis than the latter group (P=0.041, log-rank, data not 10

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shown). Three patients with PCNKTL (43%) remained alive without disease in the 24 -

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100 months follow-up period. The involved sites of these survivors were found on the

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neck or face. Of note, two (Nos. 3 and 6) of five patients treated with RT alone survived

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for more than 44 months.

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4. Discussion

The present study is the largest series to date reporting the clinicopathological features of 59 “extranasal” NKTL (ENKTL) cases. Notably, patients with Ann Arbor stage Ⅰ

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EBV+ disease had an older age distribution than patients with stages Ⅱ-Ⅳ disease (P=0.011). In stage Ⅰ ENKTL, a half of the lesions arose in the skin. Among patients

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with CNKTL, median age of PCNKTL (n=7) were older than those with stages Ⅱ-Ⅳ

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(n=17, 76 vs. 53 years; P=0.012). Our findings provided additional support to our

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preferred hypothesis that PCNKTL is an age-related disease. Our group previously showed that younger patients with ENKTL (≤50 years) had clinical stage III/IV disease more frequently than older patients with ENKTL (>50 years).[13] The clinicopathological profile of the younger group overlapped with the profile of patients with ANKL and monoclonal CAEBV-associated T/NK-cell lymphoproliferative disorders of the NK-cell type. The higher frequency of localized ENKTL presentations among aged patients suggested that the pathogenesis of EBV+ 11

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tumors is different in older and younger individuals; this difference may be associated

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with immunological deterioration due to aging, that is, senescence in immunity.[16]

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The present study is the first to highlight the clinicopathological distinctiveness of

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PCNKTL, i.e., the clinical stage Ⅰ CNKTL. According to the 2005 joint

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WHO-European Organization for Research and Treatment of Cancer classification, the term “primary cutaneous lymphoma” refers to a cutaneous lymphoma that presents in the skin with no evidence of extracutaneous disease at the time of diagnosis.[17]

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However, all previous series of patients with CNKTL included 36-60% of patients with stage Ⅲ/Ⅳ disease.[18-20] In the present study, none of the patients with PCNKTL

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had skin lesions on the trunk. This result clearly contrasted with the higher incidence of

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trunk lesions (60%, P=0.017) observed in patients with stages Ⅱ-Ⅳ cutaneous disease.

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Based on these findings, PCNKTL appeared to be clinicopathologically different from CNKTL at advanced clinical stages. Moreover, our finding that the primary cutaneous EBV+ lymphoma showed female predominance compared to non-cutaneous stage Ⅰ ENKTL (M:F, 2:5 vs. 7:0, P=0.021) has not been described in any previous studies on nasal (M:F, 1.8-2.0:1) or extranasal NKTLs (M:F, 1.3-2.3:1).[5, 9, 12, 21] Of note, patients with the primary cutaneous disease had significantly more favorable outcomes than patients with the non-cutaneous stage Ⅰ EBV+ lymphoma (P=0.037). These 12

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observations further supported our assertion that PCNKTL is biologically distinct from

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the other types of ENKTL.

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All of our PCNKTL patients were noted to show the affected sites on their face, neck or

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limbs, but not on the trunk. This specific distribution of the primary cutaneous disease

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may raise the question if sun exposure may play a role in its pathogenesis. One of them showed solar elastosis in the dermis adjacent to the tumor, but which has not been well confirmed in the remaining 6 cases because of the dense infiltrate of neoplastic cells

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obscuring the evaluable area in the dermis. Indeed, sun exposure is known to be sometimes closely associated with the onset of hydroa vacciniforme–like

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lymphoproliferative disorder affecting the childhood and young adult, which has been

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listed under the umbrella term of CAEBV of T/NK type in the 2016 WHO classification.

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Further investigations are expected to clarify the role of sun exposure in the pathogenesis of this peculiar disease. So far examined in the English literature, we identified 12 patients with PCNKTL (a median age of 61 years, range 43-80; M:F, 10:1; Table S3).[22-31] Cases lacking information on EBV harboring were excluded from this review. They were appeared to be different from our series in their relatively younger onset and male predominance. However, median age of these 12 cases seems to be older than those of patients with 13

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ENKTL including cutaneous and non-cutaneous disease described in previous papers

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(45-53 years).[5, 6] To our interest, limbs were entirely affected in these previously

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documented cases with an additional involvement of trunk in two, the feature of which

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overlapped with the anatomical sites of ours. Their median OS was 24 months as a

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whole group, but noted to be not reached by the PCNKTL patients featured by one skin area (#1-6, Table S3), and better than those (3.5-6.6 months) previously documented among ENKTL cases.[5, 6, 9]

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In summary, the present study has shed light on the clinicopathological features of localized ENKTL, particularly those associated with the primary cutaneous disease.

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Patients with PCNKTL had an older age distribution than patients with stages II-IV

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CNKTL. Furthermore, the primary cutaneous disease was characterized by a favorable

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outcome, and an absence of skin lesions on the trunk. These results suggested that PCNKTL constitutes a distinct subgroup in the spectrum of ENKTLs.

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Acknowledgments

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This work was supported, in part, by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Science, and Technology, Japan (Grant Number

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JP15K19052), and the National Cancer Center Research and Development Fund

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(26-A-4), Japan. The authors would like to thank Y. Katayama, Y. Inagaki, and K. Kito

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for technical assistance.

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Figure legends

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Figure 1. A, The age distribution of ENKTL. B, The percentages of stage Ⅰ disease in

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all age groups with ENKTL tends to increase in parallel with age, showing the highest

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peak in patients over 80 years old.

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Figure 2. Morphological and phenotypic features of PCNKTL. (A-C, case No. 6; D-F, case No.3) Lymphoma cells had (A) a pleomorphic appearance in case No. 6, and (D) a mixed morphology in case No. 3. Both of these cases demonstrated positivity for (B, E)

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TIA-1 and (C, F) EBV, detected by in situ hybridization. Figure 3. Unadjusted overall survival curves of the cutaneous and non-cutaneous

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subgroups for patients with stage Ⅰ ENKTL. The median survival time were 43 and 3

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months, respectively (P=0.037, log-rank).

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Fig. 1

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Fig. 2

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Fig. 3

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Research highlights Primary cutaneous NK/T-cell lymphoma of nasal type (PCNKTL) was reported.

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PCNKTL showed an older onset age than the other extranasal EBV+ NK/T-cell

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lymphoma.

PCNKTL affected face, neck or limbs, but not trunk, with a better outcome.

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PCNTKL seems distinct from the other EBV+ NK/T-cell lymphoma.

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Table 1 Differences in the clinical characteristics of ENKTL between Ann Arbor stage Ⅰ and Ⅱ-Ⅳ disease Stage Ⅰ Stages Ⅱ-Ⅳ (n=14) (n [%]) (n=45) (n [%]) P Age at diagnosis (median [range]) 73 (21-89) 53 (16-89) 0.011 (y) Age at diagnosis >50 yr 12/14 (86) 24/45 (53) 0.057 Sex (male/female) 9/5 23/22 0.54 PS>1 3/11 (27) 26/42 (62) 0.050 B symptoms present 2/13 (15) 33/44 (75) <0.001 Nodal involvement 0/14 (0) 37/45 (82) <0.001 Extranodal sites Skin 7/14 (50) 17/45 (38) 0.54 GI tract 5/14 (36) 6/45 (13) 0.11 CNS 2/14 (14) 2/45 (4) 0.24 BM 0/14 (0) 19/45 (42) 0.002 Liver 0/14 (0) 21/45 (47) 0.001 Lung 0/14 (0) 9/45 (20) 0.10 PB 0/14 (0) 4/44 (9) 0.56 IPI high-intermediate/high 1/12 (8) 34/44 (77) <0.001 PIT group 3/4 8/14 (57) 33/43 (77) 0.18 Hb <13g/dL (male) or <11g/dL 8/14 (57) 27/45 (60) 1.0 (female) Platelets <130×10⁹/L 1/14 (7) 26/45 (58) 0.001 Serum LDH > normal 8/14 (57) 38/44 (86) 0.052 CRP > normal 6/8 (75) 18/26 (69) 1.0 History of autoimmune disease 0/10 (0) 1/28 (4) 1.0 ENKTL, extranasal NK/T-cell lymphoma of nasal type; PS, performance status; GI tract, gastrointestinal tract; CNS, central nervous system; BM, bone marrow; PB, peripheral blood; IPI, International Prognostic Index; PIT, prognostic index for PTCL; Hb, hemoglobin; LDH, lactate dehydrogenase; CRP, C-reactive protein

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Stage Ⅰ 76 (59-89) 75 (47-89)

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Primary or secondary extranodal site Skin (n=24) GI tract (n=11)

P 0.012 0.27

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ENKTL, extranasal NK/T-cell lymphoma of nasal type; GI tract, gastrointestinal tract

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Table 3 Differences in the clinicopathological characteristics of stage Ⅰ ENKTL between primary cutaneous and non-cutaneous disease Non-cutaneous PCNKTL ENKTL (n=7) (n [%]) (n=7) (n [%]) P Age at diagnosis (median 76 (59-89) 61 (21-89) 0.37 [range]) (y) Age at diagnosis >50 yr 7/7 (100) 5/7 (71) 0.46 Sex (male/female) 2/5 7/0 0.021 PS>1 0/7 (0) 3/4 (75) 0.024 B symptoms present 0/7 (0) 2/6 (33) 0.19 Extranodal sites Skin 7/7 (100) 0/7 (0) <0.001 GI tract 0/7 (0) 5/7 (71) 0.021 CNS 0/7 (0) 2/7 (29) 0.46 PIT group 3/4 4/7 (57) 4/7 (57) 1.0 Serum LDH > normal 5/7 (71) 3/7 (43) 0.59 Major morphological criteria centroblastoid 1/7 (14) 1/7 (14) 1.0 pleomorphic 3/7 (43) 5/7 (71) 0.59 mixed 2/7 (29) 0/7 (0) 0.27 unspecified 1/7 (14) 1/7 (14) 1.0 Immunophenotype TIA-1 6/6 (100) 6/7 (86) 1.0 Granzyme B 4/6 (67) 6/7 (86) 0.56 CD4 0/7 (0) 0/5 (0) CD8 1/6 (17) 3/5 (60) 0.24 CD56 6/7 (86) 4/7 (57) 0.56 T-cell type* 1/6 (17) 2/4 (50) 0.50 TCRβ + 1/6 (17) 0/4 (0) 1.0 TCRγ and/or δ + 0/6 (0) 2/4 (50) 0.13 TCR silent† 0/6 (0) 0/4 (0) NK-cell type‡ 5/6 (83) 2/4 (50) 0.50 Treatment 5/7 (71) 0/7 (0) 0.021 RT alone 2/7 (29) 7/7 (100) 0.021 CT Response 4/7 (57) 1/6 (17) 0.27 CR 3/7 (43) 3/6 (50) 1.0 PR 0/6 (0) 2/6 (33) 0.46 NR

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PCNKTL, primary cutaneous ENKTL; ENKTL, extranasal NK/T-cell lymphoma of nasal type; PS, performance status; PIT, prognostic index for PTCL; LDH, lactate dehydrogenase; RT, radiotherapy; CT, chemotherapy *Patients with T-cell type showed positivity for T-cell receptor (TCR) protein expression or TCRγ gene rearrangement. †TCR-silent cases were negative for TCRβ, γ, and δ expression, but positive for clonal TCRγ gene rearrangement. ‡Patients with NK-cell type did not have any of the TCR protein expression or clonal TCRγ gene rearrangement.

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Table 4 Clinicopathological data of PCNKTL

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+

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Mixe d

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Pleo morp hic

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67 M Ey eli d and for ehe ad 71 F Rig ht che ek 76 M Lef t lo we r leg 81 F Rig ht lo we r leg 82 F Ne ck

Cytol ogical featur e Centr oblast oid Pleo morp hic

Fol low Pla up H tele tim b t e (g (x1 Trea (m /d 04/ tme ont l) μl) nt hs) 1 30. CH 23. 4. 5 OP 8 9 9. 27. THP 6.3 3 3 -CO P

Res pon se CR PR

Sur viv al A NE D D OL

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1 0. 8

29. 7

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Lo cati on Ne ck

RT+ 100 CR DE XA

A NE D

+

NK 0 + *

1 4. 7

18. 6

RT

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PR

D OL

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NK 1 + *

9. 4

26. 8

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15. 4

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A ge (y ea r) 59

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Se ru m L D H Cel > C l no D typ P rm 56 e S al − TC 1 + Rβ + + NK 1 + *

NA

Pleo + − + NA 0 1 14. RT 44. CR A morp 2. 6 2 NE hic 3 D 7 89 F Lef Mixe + − + NK 0 1 16. RT 43. CR D t d * 5. 5 1 OL elb 3 ow F, female; M, male; NA, not available; PS, performance status; LDH, lactate dehydrogenase; Hb, hemoglobin; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; THP-COP, pirarubicin, cyclophosphamide, vincristine, prednisolone; RT, radiotherapy; DEXA, dexamethasone; CR, complete remission; PR, partial remission; ANED, alive no evidence of disease; DOL, died of lymphoma. *Patients with NK-cell type did not have any of the TCR protein expression or clonal TCRγ gene rearrangement. 6