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1.
Cancer Sci ; 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33426772

RESUMO

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (e.g., PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs. 14.6%, P = 0.044; RHOA, 24.4% vs. 6.3%, P = 0.032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = 0.027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.

2.
Photodiagnosis Photodyn Ther ; : 102087, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33160062

RESUMO

Cutaneous angiosarcoma is a rare neoplasm. One important predictor of recurrence is the resection margin; however, identifying the tissue area containing the malignant cells is difficult. Indocyanine green fluorescence angiography (ICG-FA) has been used to identify superficial malignancies, including malignant tumors in the liver and sentinel lymph node metastasis of breast cancer. ICG-FA is also used to identify and define the resection margin of cutaneous angiosarcomas. However, there are currently only a few reports on the application of ICG-FA for detecting cutaneous angiosarcomas. We experienced a case of cutaneous angiosarcoma in the scalp in which one lesion, located in the parietal scalp, and showed high fluorescence intensity corresponding exactly with the lesion defined by physical examination, whereas the malignant area of the second lesion, located in the occipital scalp, was revealed more accurately by ICG-FA than by physical examination. Further, the second lesion was the first case diagnosed as angiosarcoma by the limited-area biopsy for a high-intensity area of ICG-FA. By determining where ICG is located within cutaneous angiosarcomas and quantitating the ICG intensity level corresponding to the malignant area, ICG-FA will be a promising tool for identifying cutaneous angiosarcomas.

3.
Pathol Int ; 70(11): 893-898, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32881147

RESUMO

Although cases with metachronous or synchronous co-occurrence of classic Hodgkin lymphoma (CHL) and B-cell non-Hodgkin lymphoma (B-NHL) have been reported, few reports have analyzed the clonal relationship between both lesions in detail, especially in Epstein-Barr virus (EBV)-positive settings. Here, we report a case of a 38-year-old male with CHL, followed by the recurrence of EBV-positive mucocutaneous ulcers of the large intestine and EBV-positive diffuse large B-cell lymphoma in the liver. Surprisingly, polymerase chain reaction analysis for immunoglobulin heavy chain gene rearrangement revealed that all lesions were clonally distinct. We further reviewed the literature on synchronous and metachronous co-occurrence of CHL and B-NHL in EBV-positive settings. In contrast to EBV-negative settings, all evaluable cases showed clonally distinct multiple lesions. These findings suggest that histologically and clonally distinct B-cells could simultaneously proliferate in EBV-associated settings, providing a new insight into the pathogenesis of EBV-associated lymphoproliferative disorders.

4.
Mod Pathol ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32801340

RESUMO

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.

5.
Int J Surg Pathol ; : 1066896920946835, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32772757

RESUMO

BACKGROUND: Thyroid transcription factor-1 (TTF-1) is a useful marker for identifying thyroid and lung cancers in diagnostic pathology, particularly for the investigation of unknown primary cancers. However, some other tumors such as colorectal cancer might aberrantly express TTF-1, particularly with the less specific clone SPT24. Occasional diffuse large B-cell lymphoma (DLBCL) cases have been reported to be TTF-1-positive, yet there is no information on TTF-1 expression in peripheral T-cell lymphoma (PTCL). METHODS: We investigated a series of PTCL and DLBCL by immunohistochemistry for TTF-1 expression using 2 commercially available clones. RESULTS: We found that 33% (5/15) adult T-cell leukemia/lymphomas (ATLLs) and 25% (2/8) angioimmunoblastic T-cell lymphomas (AITLs) were positive by clone SPT24 and only 2ATLL cases were positive by clone 8G7G3/1. Overall TTF-1 expression rates of PTCL by SPT24 and 8G7G3/1 were 16% (7/43) and 5% (2/43), respectively. All DLBCLs were negative. CONCLUSION: Although TTF-1 is a relatively specific marker for thyroid and lung cancers, it might be expressed in some lymphomas, particularly PTCL when using clone SPT24. Pathologist should be aware of this possible diagnostic pitfall when using TTF-1 in investigating tumors of unknown origin.

8.
Cancer Sci ; 111(9): 3367-3378, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619037

RESUMO

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).


Assuntos
Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
11.
Histopathology ; 77(1): 133-143, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32162348

RESUMO

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.

12.
Blood Adv ; 4(6): 1062-1071, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32196559

RESUMO

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.

14.
Appl Immunohistochem Mol Morphol ; 28(4): 316-324, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30653030

RESUMO

Granulomatous reaction is not uncommon in histopathology, with various etiologies in different organs and geographic regions. Lymphoma is one of the underlying causes of granuloma; and sometimes the neoplastic cells may be masked by the granulomatous reaction. In this report, we present our experience with 7 lymphoma cases of various histologic types with coexisting granuloma to show the diagnostic challenges. In all cases, a granulomatous reaction was simultaneously present with the neoplastic cells. The 7 cases included 3 cases of adult T-cell leukemia/lymphoma in the lymph node or skin including one coexisting with mycobacterial infection, 2 cases of classical Hodgkin lymphoma involving the liver, and 1 case each of systemic Epstein-Barr virus-positive peripheral T-cell lymphoma and a hepatic inflammatory pseudotumor-like follicular dendritic cell sarcoma. Three cases were initially misdiagnosed as reactive change or mycobacterial infection instead of lymphoma, and a wrong histologic lymphoma type was diagnosed in 1 case. In this report, we showed that granulomatous reaction might mask lymphomas of various histologic types; and a diagnosis of mycobacterial infection or sarcoidosis could not exclude the possibility of an underlying lymphoma. We emphasized the importance of detailed histologic examination with the aid of ancillary studies to reach a correct diagnosis and to avoid inappropriate management of the patients. Our study also broadened the spectrum of lymphoma types coexisting with granuloma.

15.
Bone Marrow Transplant ; 55(1): 233-241, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31534195

RESUMO

Outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T cell leukemia/lymphoma (ATL) are not satisfactory, particularly in patients in non-complete remission at transplantation (Pt-non-CR). We conducted a regional retrospective study in the ATL endemic area of Okinawa, Japan. Of 62 ATL patients, 21 received allo-HSCT in CR and 41 in non-CR. The 3-year overall survival (3yOS) rate and median survival time for the whole cohort was 25.6% and 7.7 months, respectively. The 3yOS of Pt-non-CR was significantly lower than that of patients in CR (Pt-CR) (16.8% vs. 43.6%, P = 0.005). Transplant-related mortality (TRM) was significantly higher in Pt-non-CR than in Pt-CR (46.3% vs. 15.7%, P = 0.025), while there was no significant difference in disease-associated mortality (DAM) between Pt-non-CR and Pt-CR. Multivariable analysis for Pt-non-CR revealed that poor performance status (poor-PS) and higher sIL-2R level (high sIL-2R) adversely affected OS. Poor-PS was associated with higher TRM, but not with higher DAM in Pt-non-CR. High sIL-2R did not affect TRM or DAM in Pt-non-CR. Overall, high TRM rates rather than DAM contribute to the poor outcomes of Pt-non-CR, suggesting that not only disease control but also management of transplant-related complications is required for allo-HSCT in ATL patients.

16.
Oncol Lett ; 18(3): 2777-2788, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452756

RESUMO

The occurrence of second primary tumor (SPT)following malignancy treatment is common. In patients with head and neck (H&N) cancer, SPTs principally occur in the H&N region, lungs or esophagus. Therefore, patient follow-up after cancer treatment is important in order to detect recurrence, metastasis and new primary tumors. However, no standard guidelines on lifelong follow-up imaging are available. Herein, we report a patient who presented with three metachronous primary tumors-squamous cell carcinoma (SCC) of the tongue, SCC of the lip and type A thymoma. The third tumor was incidentally detected during follow-up using contrast-enhanced computed tomography (CT) 9 years following resection of the second tumor. To the best of our knowledge, this specific combination of metachronous tumors has not yet been reported. Based on the literature review, we observed that thymoma occurs following H&N cancer treatment. Therefore, to ensure that the presence of subsequent thymomas is not overlooked, we suggest regular lifelong follow-up using contrast-enhanced CT in patients who had previously been diagnosed with H&N cancer. The literature review revealed that thymomas occur in patients with H&N cancer and should be detected at the earliest convenience.

18.
Cancer Sci ; 110(9): 2982-2991, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237072

RESUMO

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.


Assuntos
Leucemia-Linfoma de Células T do Adulto/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/patologia , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Fosforilação , Prognóstico , Intervalo Livre de Progressão , Fator de Transcrição STAT3/genética
19.
Transpl Immunol ; 55: 101205, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30946889

RESUMO

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics.


Assuntos
Doenças da Medula Óssea , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Tecido Adiposo , Aloenxertos , Animais , Doenças da Medula Óssea/etiologia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Células-Tronco Mesenquimais/patologia , Camundongos
20.
Cancer Sci ; 110(1): 443-457, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30417470

RESUMO

Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.


Assuntos
Antígenos de Superfície/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Proteoglicanas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Heterólogo , Carga Tumoral
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