Published Papers - Sakihama Shugo

A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma.

Tamaki T, Karube K, Sakihama S, Tsuruta Y, Awazawa R, Hayashi M, Nakada N, Matsumoto H, Yagi N, Ohshiro K, Nakazato I, Kitamura S, Nishi Y, Miyagi T, Yamaguchi S, Nakachi S, Morishima S, Masuzaki H, Takahashi K, Fukushima T, Wada N

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   36 ( 8 ) 100169 - 100169   2023.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-β and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.

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Spindle cell tumor with histiocytic and myogenic marker expression in the lymph node of a human T-cell leukemia virus type 1 carrier.

Kubo T, Hirayama Y, Sakihama S, Kikuchi T, Hirohashi Y, Tsujiwaki M, Karube K, Hasegawa T, Torigoe T

Pathology, research and practice ( Pathology Research and Practice )  234   153935   2022.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Genetic Alterations in Adult T-Cell Leukemia/Lymphoma: Novel Discoveries with Clinical and Biological Significance.

Sakihama S, Karube K

Cancers ( Cancers )  14 ( 10 )   2022.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Acute type adult T-cell leukemia cells proliferate in the lymph nodes rather than in peripheral blood.

Mizuguchi M, Takatori M, Sakihama S, Yoshita-Takahashi M, Imaizumi N, Takahashi Y, Hasegawa H, Karube K, Fukushima T, Nakamura M, Tanaka Y

Cancer gene therapy ( Cancer Gene Therapy )    2022.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma.

Morichika K, Karube K, Sakihama S, Watanabe R, Kawaki M, Nishi Y, Nakachi S, Okamoto S, Takahara T, Satou A, Shimada S, Shimada K, Tsuzuki T, Fukushima T, Morishima S, Masuzaki H

The American journal of surgical pathology ( American Journal of Surgical Pathology )  45 ( 6 ) 832 - 840   2021.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV-1 strains.

Sakihama S, Morichika K, Saito R, Miyara M, Miyagi T, Hayashi M, Uchihara J, Tomoyose T, Ohshiro K, Nakayama S, Nakachi S, Morishima S, Sakai K, Nishio K, Masuzaki H, Fukushima T, Karube K

Cancer science ( Cancer Science )  112 ( 3 ) 1300 - 1309   2021.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Clinicopathological features of adult T-cell leukemia/lymphoma with HTLV-1-infected Hodgkin and Reed-Sternberg-like cells.

Karube K, Takatori M, Sakihama S, Tsuruta Y, Miyagi T, Morichika K, Kitamura S, Nakada N, Hayashi M, Tomori S, Nakazato I, Ohshiro K, Imaizumi N, Kikuti YY, Nakamura N, Morishima S, Masuzaki H, Fukushima T

Blood advances ( Blood Advances )  5 ( 1 ) 198 - 206   2021.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A new diagnostic algorithm using biopsy specimens in adult T-cell leukemia/lymphoma: combination of RNA in situ hybridization and quantitative PCR for HTLV-1.

Takatori M, Sakihama S, Miyara M, Imaizumi N, Miyagi T, Ohshiro K, Nakazato I, Hayashi M, Todoroki J, Morishima S, Masuzaki H, Fukushima T, Karube K

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc ( Modern Pathology )  34 ( 1 ) 51 - 58   2020.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Histopathological distinction between adult T-cell leukemia/lymphoma (ATLL) and other T-cell neoplasms is often challenging. The current gold standard for the accurate diagnosis of ATLL is the Southern blot hybridization (SBH) assay, which detects clonal integration of human T-cell leukemia virus type I (HTLV-1) provirus. However, SBH cannot be performed with small biopsy or formalin-fixed paraffin-embedded (FFPE) tissue samples because this assay requires a large amount of DNA without degradation. Here we developed a new diagnostic algorithm for the accurate diagnosis of ATLL using FFPE samples. This method combines two HTLV-1 detection assays, namely, ultrasensitive RNA in situ hybridization using RNAscope for HTLV-1 bZIP factor (HBZ-RNAscope), and quantitative PCR targeting the tax gene (tax-qPCR). We analyzed 119 FFPE tissue specimens (62 ATLL, and 57 non-ATLL, including 41 HTLV-1 carriers) and compared them with the SBH results using the corresponding fresh-frozen samples. As a result, tax-qPCR had a higher ATLL identification rate than HBZ-RNAscope (88% [52/59], and 63% [39/62], respectively). However, HBZ-RNAscope clearly visualized the localization of HTLV-1-infected tumor cells and its identification rate increased to 94% (17/18) when the analysis was limited to samples up to 2 years old, indicating its usefulness in the daily diagnosis. The diagnostic algorithm combining these two assays successfully evaluated 94% (112/119) of samples and distinguished ATLL from non-ATLL cases including HTLV-1 carriers with 100% sensitivity and specificity. This method is expected to replace SBH and increase the accuracy of the diagnosis of ATLL.

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Dermatopathic reaction of lymph nodes in HTLV-1 carriers: a spectrum of reactive and neoplastic lesions.

Chinen S, Miyagi T, Murakami Y, Takatori M, Sakihama S, Nakazato I, Kariya Y, Yamaguchi S, Takahashi K, Karube K

Histopathology ( Histopathology )  77 ( 1 ) 133 - 143   2020.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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AIMS: Dermatopathic reaction is a histopathological finding of lymph nodes that usually occurs in patients with inflammatory pruritic cutaneous lesions. However, it is sometimes seen in patients with cutaneous T cell lymphoma. Adult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV-1), which is frequently accompanied by cutaneous lesions. However, the detailed clinicopathological characteristics of the dermatopathic reaction of lymph nodes in ATLL patients and HTLV-1 carriers, addressed in this study, remains to be clarified. METHODS AND RESULTS: We retrospectively analysed 18 nodal lesions with dermatopathic reaction in HTLV-1 carriers. Axillary and inguinal lymph nodes were the primary affected tissues. Three cases with atypical lymphoid cell infiltration were defined as ATLL with dermatopathic reaction (ATLL-D), showing an abnormal T cell immunophenotype and T cell monoclonality. Two of the three ATLL-D patients died 14 and 7 months after diagnosis (the third case had a very short follow-up). The other 15 patients were indistinguishable from reactive lesions and were defined as HTLV-1-associated lymphadenitis with dermatopathic reaction (HAL-D). They showed an indolent clinical course, with only one case eventually transforming to aggressive disease. CONCLUSIONS: Lymph node lesions accompanied by dermatopathic reaction in HTLV1 carriers represent a spectrum that includes reactive and neoplastic conditions. HAL-D should be distinguished from ATLL-D, especially to avoid overtreatment.

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Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL.

Guerrero CLH, Yamashita Y, Miyara M, Imaizumi N, Kato M, Sakihama S, Hayashi M, Miyagi T, Karimata K, Uchihara J, Ohshiro K, Todoroki J, Nakachi S, Morishima S, Karube K, Tanaka Y, Masuzaki H, Fukushima T

Blood advances ( Blood Advances )  4 ( 6 ) 1062 - 1071   2020.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.

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Intestinal helminth infections in HIV-infected patients in Savannakhet after establishment of an HIV registration network in Lao People's Democratic Republic.

Kaneshiro Y, Sourinphoumy K, Imaizumi N, Rasaphon M, Kuba-Miyara M, Sakihama S, Guerrero CLH, Nhativong K, Nonaka D, Pongvongsa T, Kobayashi J, Kounnavong S, Fukushima T

Tropical medicine and health ( Tropical Medicine and Health )  47 ( 1 ) 14 - 14   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: In Lao People's Democratic Republic (PDR), which borders China, Vietnam, Cambodia, Thailand, and Myanmar, the number of HIV-infected patients has increased in recent years. HIV-infected patients diagnosed in Lao PDR are enrolled in a registration network and receive antiretroviral therapy (ART) covered by governmental financial support. Based on the registration network, we investigated intestinal helminth infections and coinfection with HTLV-1 in HIV-infected patients treated with an early intervention using ART in Lao PDR. Methods: This cross-sectional study of all 252 HIV-infected patients at Savannakhet Provincial Hospital, located in the southern part of Lao PDR, was conducted between February and March 2018. Socioepidemiological information and clinical information were collected from a registration network database and by questionnaire administered to participants. Microscopic examination of intestinal helminth infections in stool samples and particle agglutination for anti-HTLV-1 antibody in plasma were performed. Results: The median age of all 252 participants was 39 years old (range, 18-59). Based on the registration network database, there were 156 (61.9%) HIV-infected patients with a CD4-positive cell count ≥ 200 cells/μL and 146 (57.9%) with an HIV viral load < 250 copies/mL. Among 212 stool samples, 75 (35.4%) were found to contain one or more intestinal helminth species, including Opisthorchis viverrini (16.5%), Strongyloides stercoralis (10.8%), hookworm (10.4%), and Taenia saginata (3.3%). This rate of intestinal helminth infections was lower than that of a previous report conducted before the establishment of the registration network for HIV-infected patients in Lao PDR. There was no significant association between intestinal helminth infections and a lower CD4-positive T cell count or higher HIV viral load. HIV-infected patients with anti-HTLV-1 antibody positivity were not found in this cohort. Conclusion: The registration network and an early intervention using ART may provide good medical care and improve the clinical course of HIV-infected patients in Lao PDR. However, the incidence of intestinal helminth infections remains high at 35.4%. The development of a specific medical care system for helminth infection for HIV-infected patients is necessary.

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Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T-cell leukemia/lymphoma.

Sakihama S, Saito M, Kuba-Miyara M, Tomoyose T, Taira N, Miyagi T, Hayashi M, Kinjo S, Nakachi S, Tedokon I, Nishi Y, Tamaki K, Morichika K, Uchihara JN, Morishima S, Karube KN, Tanaka Y, Masuzaki H, Fukushima T

Leukemia research ( PERGAMON-ELSEVIER SCIENCE LTD )  61   18 - 24   2017.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL.

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