CASE REPORT. Abstract. Case Report. Introduction

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1 CASE REPORT Polymyositis as a Paraneoplastic Syndrome in Cytotoxic Molecule-positive and Epstein-Barr Virus-associated Peripheral T-cell Lymphoma, Not Otherwise Specified Hiroko Tsunemine 1, Hayato Maruoka 2, Hiroshi Akasaka 1, Kengo Udaka 1, Kazuyo Yamamoto 1, Emiko Ishikawa Sakane 1, Nobuhiro Hiramoto 1, Kiminari Ito 1, Taiichi Kodaka 1, Tomoo Itoh 3 and Takayuki Takahashi 1 Abstract We encountered a rare case of cytotoxic molecule-positive and Epstein-Barr virus (EBV)-associated peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), which was clinically preceded by polymyositis. A 50-year-old woman with a 4-year history of steroid-refractory polymyositis developed ulcerative skin swelling on her left arm. A diagnosis of cytotoxic molecule (TIA-1)-positive and EBV-associated PTCL-NOS was made on the basis of immunohistochemical and molecular examinations of the biopsied brachial muscle. Combination chemotherapies were ineffective, with a fatal outcome. Reassessment of the biopsy specimens of the muscle taken at the age of 46 years showed that the PTCL was already present, indicating that the polymyositis was likely a paraneoplastic manifestation. Key words: polymyositis, paraneoplastic syndrome, cytotoxic molecule, Epstein-Barr virus, peripheral T-cell lymphoma, not otherwise specified (Intern Med 52: , 2013) () Introduction Polymyositis or dermatomyositis often manifests as a paraneoplastic syndrome due to occult malignancies (1, 2). Many types of malignancy have been reported in association with polymyositis/dermatomyositis; however, the involvement of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) has rarely been reported. We herein describe a rare case of cytotoxic molecule (TIA-1)-positive and Epstein-Barr virus (EBV)-associated PTCL-NOS complicated by polymyositis. This PTCL case initially manifested as polymyositis and showed a long-lasting and smoldering clinical course for four years, which then transformed to an aggressive lymphoma. Case Report A 50-year-old woman was referred to our hospital because of ulcerative skin swelling on her left arm in August She had intermittently exhibited liver dysfunction and swelling of the eyelids and lips due to an unknown cause since the age of 44. She had no history of hypersensitivity to mosquito bites. At the age of 46, she developed muscle weakness of the upper extremities with a high serum concentration of creatine phosphokinase (CK) (3,500 IU/L; normally 30 to 190 IU). A diagnosis of polymyositis was made on the basis of the muscle weakness, high serum CK levels and a histological picture that was compatible with polymyositis in the biceps muscle (Fig. 1A) biopsied at another hospital. The effect of treatment with prednisolone and methotrexate on polymyositis was transient, and persistent Department of Hematology, Shinko Hospital, Japan, Department of Laboratory Medicine, Kobe City Medical Center General Hospital, Japan and Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Japan Received for publication July 5, 2012; Accepted for publication December 6, 2012 Correspondence to Dr. Hiroko Tsunemine, htsunemine@shinkohp.or.jp 901

2 Figure 1. The histopathologic findings of a biopsy specimen obtained from the biceps brachii muscle at the time of initial diagnosis of polymyositis (in 2004). Mild infiltration of small lymphocytes among the muscle fiber bundles and regeneration and degeneration of muscle fibers without necrosis were present (A, 100). On reexamination of this specimen (in 2008), the lymphocytes were revealed to be positive for CD3 epsilon (B, 400), CD8 (data not shown), TIA-1(C, 400) and EBER-1 (D, 400). Figure 2. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging revealed abnormal accumulation in the left brachial, deltoid and right rectus muscles, the biceps muscles of the thigh and the left oral cavity. lymphocytopenia (around /L) occurred one and a half years after the initiation of the immunosuppressive therapy. At the age of 50, she developed the above-mentioned ulcerative skin swelling on her left arm. The serum aldolase concentration was also elevated to 15.1 IU/mL (normally below 5.9 IU) in addition to the high CK level. A biopsy from the brachial muscle was again performed, and malignant lymphoma was histopathologically suspected. She was thus admitted to our hospital. At the time of admission, she was orally administered 20 mg/day prednisolone for the polymyositis. A physical examination revealed mild bilateral eyelid swelling, oral ulcers, swelling of the left thigh and a tumor with a diameter of 2 cm in the left breast. The biopsy site of the left arm formed a deep edematous ulcer with exposed brachial muscle. Superficial lymphadenopathy or hepatosplenomegaly was not noted. A neurological examination did not show any obvious muscle weakness in the extremities. Laboratory tests showed a white blood cell count of /L with 74.7% segmented neutrophils, 17.7% lymphocytes, 0.3% atypical lymphocytes, 1.3% basophils and 4.3% monocytes, a hemoglobin concentration of 12.4 g/dl and a platelet count of /L. The C-reactive protein level was 0.36 mg/dl (normally below 0.3 mg). A blood chemistry analysis showed elevated serum concentrations of aspartate aminotransferase at 63 IU/L (normally 5 to 40 IU/L), alanine aminotransferase at 69 IU/L (normally 3 to 40 IU/ L), total bilirubin at 1.6 mg/dl (normally 0.2 to 1.3 mg/dl), alkaline phosphatase at 376 IU/L (normally 115 to 360 IU/ L), lactate dehydrogenase at 539 IU/L (normally 120 to 230 IU/L), CK at 330 IU/L (normally 30 to 190 IU/L) and ferritin at 4,200 ng/ml (normally 10 to 85 ng/ml). The levels of blood urea nitrogen and creatinine were within the normal limits. Serological tests gave negative results for antinuclear and anti-jo-1 antibodies. The serum concentration of soluble interleukin-2 receptor (sil-2r) was elevated to 3,300 U/mL (normally 220 to 530 U/mL). Serological examinations for EBV-specific antibodies showed that the anti-viral capsid antigen (VCA) IgG titer was 8.3 (normally below 1.0), anti-vca IgM was 0.3 (normally below 1.0), anti-early antigen (EA) IgG was 0.2 (normally below 1.0) and anti- EBV nuclear antigen (EBNA) IgG was 0.7 (normally below 1.0), as determined by enzyme-linked immunosorbent assays. The genome copy number of EBV was copies/ 902

3 Figure 3. The histopathologic findings of a biopsy specimen obtained from the left brachial muscle (Hematoxylin and Eosin staining). Extensive intramuscular necrosis (A, 100) and massive infiltration of abnormal lymphocytes (B, 100) were observed. The atypical lymphocytes partially exhibited angiocentric infiltration (C, 200). Figure 4. Immunohistochemical staining of abnormal lymphocytes. These cells were positive for CD3 epsilon (A, 400), CD8 (B, 400) and TIA-1, a cytotoxic molecule (C, 400), but negative for CD4 and CD56 (data not shown). These lymphocytes were also positive for EBV-encoded RNA-1 (EBER-1) (D, 400) circulating mononuclear cells, as measured by quantitative real-time PCR. A bone marrow aspirate showed neither abnormal cells nor hemophagocytes. Fluorine-18 fluorodeoxyglucose-enhanced positron emission tomography (FDG-PET) revealed abnormal accumulation in the left brachial muscle, deltoid muscle, rectus and biceps muscles, and of the right thigh and left oral cavity (Fig. 2). Swelling of the left brachial muscle and deltoid muscle was also observed by FDG-PET. A biopsy specimen from the same brachial muscle revealed extensive necrosis (Fig. 3A) and massive intramuscular (Fig. 3B) and partially angiocentric infiltration of abnormal lymphocytes (Fig. 3C). On immunohistochemistry, these abnormal lymphocytes were positive for CD3 epsilon (Fig. 4A), CD5 (data not shown), CD8 (Fig. 4B), TIA-1, a cytotoxic molecule (Fig. 4C) and EBVencoded RNA (EBER-1) (Fig. 4D), but negative for CD56 and CD4. To determine the monoclonality of the brachial muscleinfiltrated lymphocytes, we performed multiplex PCR (3) on formalin-fixed, paraffin-embedded tissue from the muscle. As shown in Fig. 5, monoclonal rearrangement of both the T-cell receptor (TCR)-γ chain and immunoglobulin heavy chain (IgH) genes was observed. Nevertheless, we considered that the muscle-infiltrated lymphocytes were clonal T- cells because a T-cell phenotype was shown by the immunohistochemical analysis. In addition, the frequency of dual genotypes of T- and B-cells in T-cell lymphomas was 11% in a previous study (4). Therefore, an additional diagnosis of 903

4 Figure 5. Rearrangement of the TCRγ chain and immunoglobulin heavy chain (IgH) genes assessed by use of multiplex PCR (3) on formalin-fixed, paraffin-embedded tissues of the brachial muscle biopsied at the time of admission to our hospital at 50 years of age. Lane 1: size marker (100 bp); lane 2: Vγlf, Vγ10-Jγ1.1/2.1, and Jγ1.3/2.3 ( bp); lane 3: Vγ9,11-Jγ1.1/2.1, and Jγ1.3/2.3 ( bp); lane 4: positive control gene (DH7-JH). TCRγ chain PCR shows a single product of a 230 bp (white arrow, lane 2), indicating the presence of a clonal T-cell population (right lane). IgH PCR also shows a single band of a bp, thus indicating monoclonality of the B-cell lineage (lane 4). cytotoxic molecule-positive and EBV-associated CD8 + PTCL-NOS was made. Furthermore, lymphoma cells with the same phenotypes had infiltrated the oral mucosa and the breast mass (data not shown). Although combination chemotherapy with dexamethasone, etoposide, ifosfamide and carboplatin (DeVIC) normalized the serum CK levels, liver dysfunction and further elevation of the serum sil-2r level were observed. The chemotherapy regimen was therefore changed to ProMACE/CytaBOM (prednisolone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine and methotrexate) and then modified SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide). However, the effects of these chemotherapies were only transient, and the patient died of multiple organ failure four months after the diagnosis. Reassessment of the biopsy specimens of the muscle and lip taken from the patient at the age of 44 revealed that infiltrating lymphocytes were positive for CD3epsilon, TIA-1 and EBER-1 (Fig. 1B-D), although the muscle was free of massive lymphomatous invasion and necrosis (Fig. 1A). These findings indicated the existence of the PTCL at this time, and the association of polymyositis as a paraneoplastic syndrome of the PTCL. Discussion The association of polymyositis/dermatomyositis with malignancies is well known. Hill et al. reported that polymyositis was associated with an increased risk of non- Hodgkin s lymphoma (2). Marie et al. reported that the hematological malignancies most commonly associated with polymyositis/dermatomyositis were B-cell lymphomas, but not T-cell lymphomas, which comprise 7.8 to 12.5% of such malignancies (5). The association of polymyositis with T- cell lymphoma appears to be less common, and only two cases of Ki-1 lymphoma associated with polymyositis have been reported (6, 7). To the best of our knowledge, the present patient may be the first case of PTCL-NOS complicated by polymyositis after the 2008 WHO classification. PTCL-NOS is heterogeneous, and it does not correspond to any of the specifically defined types of mature T-cell lymphomas (8). However, in recent years, nodal cytotoxic molecule-positive and EBV-associated PTCL-NOS has been supposed to be distinct from the current category of mature T/natural killer (NK) cell lymphomas, because of its unique immunophenotypes and aggressive clinical course (9). The present case, therefore, would be categorized into this type of PTCL-NOS, due to its similar phenotype and clinical picture, although our case was an extra-nodal type. The present case also showed similar characteristics to extra-nodal NK/ T-cell lymphoma because of the presence of EBV and cytotoxic molecules (10). In the present patient, a reassessment of the biopsy preparations of the muscle and lip taken from the patient at the age of 46 revealed the infiltration of EBER-1-positive lymphocytes, indicating the existence of PTCL at this time. Therefore, whether or not the polymyositis was caused by PTCL-related abnormal immunity, that is, whether it was a paraneoplastic syndrome of PTCL, or by mechanical muscle damage due to lymphoma cell invasion is important. As shown in Fig. 1A, the muscle fiber bundle showed anisocytosis and eosinophilic changes despite the mild and nondestructive infiltration of lymphoma cells. The infiltrative patterns of lymphoma cells in the lip were similar. Furthermore, the present patient did not have any signs of overt lymphoma, such as ulcerative skin lesions or tumoral lesions, during the same period. Therefore, these findings suggest that the polymyositis was caused by a PTCL-related immunological response, such as an autoantibody or T-cell response against the muscle, not due to a destructive intramuscular invasion of lymphoma cells. The PTCL in the present patient initially showed a smoldering clinical picture for four years, and then transformed into an aggressive lymphoma. This transformation might have been caused by the lymphocytopenia and subsequent impaired immune surveillance due to long-term immunosuppressive therapies. In conclusion, muscle-infiltrating lymphocytes should be precisely characterized if the clinical picture of polymyositis/dermatomyositis is atypical and its response to immunosuppressive treatments is poor. The authors state that they have no Conflict of Interest (COI). 904

5 Acknowledgement We are grateful to Professor Shigeo Nakamura in the Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan for valuable suggestions regarding the histopathological analysis of the biopsied specimens in the present patient. References 1. Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. A populationbased study. N Engl J Med 326: , Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a populationbased study. Lancet 357: , van Dongen JJM, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Cocerted Action BMH4-CT Leukemia 17: , Vergier B, Dubus P, Kutschmar A, et al. Combined analysis of T cell receptor γ and immunoglobulin heavy chain gene rearrangements at the single-cell level in lymphomas with dual genotype. J Pathol 198I: , Marie I, Guillevin L, Menard JF, et al. Hematological malignancy associated with polymyositis and dermatomyositis. Autoimmun Rev 11: , Bouscary D, Tulliez M, Dreyfus F, et al. Polymyositis associated with Ki-1 lymphoma. Leuk Lymphoma 17: , Onodera J, Hayashi T, Chida K, Shiga Y, Mochizuki H, Itoyama Y. A case of Ki-1 lymphoma-associated eosinophilic polymyositis. Rinsho Shinkeigaku 37: , 1997 (in Japanese, Abstract in English). 8. Swerdlow SH CE, Harris NL, Jaffe ES, et al. World Health Organization classfication of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, France, Kato S, Takahashi E, Asano N, et al. Nodal cytotoxic molecule (CM)-positive Epstein-Barr virus (EBV)-associated peripheral T cell lymphoma (PTCL): a clinicopathological study of 26 cases. Histopathology 61: , Suzuki R, Takeuchi K, Ohshima K, Nakamura S. Extranodal NK/ T-cell lymphoma: diagnosis and treatment cues. Hematol Oncol 26: 66-72, The Japanese Society of Internal Medicine 905