Treatment of adult T-cell leukemia/lymphoma: past, present, and future

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell lymphotrophic virus type I. Clinical manifestations of ATLL range from smoldering to chronic, lymphoma and acute. Patients with acute and lymphoma type ATLL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATLL patients, but the therapeutic outcomes of acute and lymphoma type ATLL remain very poor. Promising results of allogeneic stem cell transplantation (SCT) for ATLL patients have recently been reported and the treatment outcome might be improved for some ATLL patients. Besides conventional chemotherapy and SCT, interferon, zidovudine, arsenic trioxide, targeted therapy against surface molecule on ATLL cells, retinoid derivatives, and bortezomib have been administered to ATLL patients in pilot or phase I/II studies. Further studies are required to confirm the clinical benefits of these novel therapeutics. This article reviews the current status and future directions of ATLL treatment.     

A refractory human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patient with lymphoma-type adult T-cell leukemia/lymphoma: A case report and review of the literature

Rationale:Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%.Patient concerns:A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened.Diagnoses:Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system.Interventions:Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL.Outcomes:Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient''s exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells.Lessons:This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background.     

Cutaneous plaque in adult T cell leukemia/lymphoma: A case report

Rationale:The rarity of adult T cell leukemia/lymphoma (ATLL) in China, coupled with its clinicopathologic mimicry of primary skin disease, poses a diagnostic challenge. The method of diagnosis and mechanism of immune regulation in ATLL are discussed in the present report.Patient concerns:A 51-year-old Chinese man was admitted to the hospital with 2-years history of systemic plaque lesions and 1-year history of left ankle joint pain.Diagnoses:The patient was diagnosed with ATLL based on the results of flow cytometry immunophenotype and human T-cell lymphotropic virus type 1 (HTLV-1) serology.Interventions:The patient received 3 cycles of cyclophosphamide, epirubicin/ vinorelbine, and dexamethasone (CHOP) chemotherapy. However, he relapsed and did not respond to epirubicin, vindesine, etoposide, dexamethasone (EPOCH) chemotherapy.Outcomes:His family discontinued the treatment and opted for hospice care.Lessons:Patch and plaque ATLL types exhibits a better survival rate, but atypical skin patches delays the diagnosis of ATLL and negatively affects the patient survival. Based on the present findings, we suggest that patients with petal-like nuclear lymphocytes in blood smears, a high CD4: CD8 ratio, and strong CD25 expression should undergo HTLV-1 serology testing.     

Adult T-cell leukemia/lymphoma presenting multiple lymphomatous polyposis

Multiple lymphomatous polyposis （MLP） is an unusual form of non-Hodgkin＇s lymphoma characterized by polyps throughout the gastrointestinal tract. It has been reported that most MLP are observed in cases with mantle cell lymphoma of B-cell type. We herein present a case of a 66-year-old man with adult T-cell leukemia/lymphoma （ATLL）. Colonoscopy revealed MLP throughout the colon and histopathological findings of ATLL cell infiltration. The patient died despite combination of chemotherapy. The literature of manifestations of colonic involvement of ATLL isreviewed and the importance of endoscopic evaluation to differentiate ATLL intestinal lesions from opportunistic infectious enterocolitis is discussed.     

Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma

Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.     

Acute liver failure as a rare initial manifestation of peripheral T-cell lymphoma

Acute liver failure (ALF) is an uncommon disease in the United States, affecting more than 2 000 people each year. Of all the various causes, malignant infiltration is one of the least well known and carries with it a high mortality. We describe a case of ALF as the presenting manifestation of peripheral T-cell lymphoma in an elderly woman. By reporting this case, we hope to increase early recognition of this disease process in order to potentially improve treatment outcomes.     

Chromosomal abnormalities in adult T-cell leukemia/lymphoma (ATL)

Summary Chromosomal studies were performed on six patients with adult T-cell leukemia (ATL). Structural abnormalities of chromosome 3 were the most common. In one case a complete loss of the short arm of chromosome 10 (10 p-) was noted while in another case a balanced translocation involving chromosome 10 p and 4q was found. These abnormalities have not been previously reported. After reviewing the literature, it was concluded that chromosomes 3, 6, 10, 13, 14, and X were most frequently involved in abnormalities. Specific and consistent chromosomal abnormalities were noted in each study. Therefore, it is hypothesised that the mutation rate for this virus may be higher than first expected. Furthermore, the relative consistency of heterogenous findings in different localities may reflect a geographic clustering of specific chromosomal abnormalities which may in turn be related to specific and geographically associated viral mutations. To support these suggestions not only are more cytogenetic data required but a molecular evaluation of these patients must be carried out to establish a relationship, it any, between genetic abnormalities and the epidemiology of ATL.     

Primary adrenal adult T-cell leukemia/lymphoma: a case report and review of the literature

Primary adrenal lymphoma (PAL) is very rare; the majority of cases reported previously were of B-cell origin. We report a rare case of primary adrenal adult T-cell leukemia/lymphoma (primary adrenal ATLL). ATLL is a highly aggressive T-cell type non-Hodgkin's lymphoma and etiologically associated with human T-cell lymphotropic virus 1 (HTLV-1). Most ATLL patients present with leukemia and widespread lymphadenopathy. A 37-year-old Japanese woman presented with back pain in January 2004. Examination showed no peripheral lymphadenopathy, circulating lymphoma cells, hepatosplenomegaly, and skin lesions. Imaging studies demonstrated large adrenal masses bilaterally. Subsequently, she underwent open adrenal biopsy and pathological diagnosis was confirmed as T-cell lymphoma. The serum antibody to HTLV-1 was positive. Southern blot analysis detected monoclonal integration of proviral DNA of HTLV-1 into host genome in the biopsy specimen. The diagnosis of ATLL arising in adrenal glands was established. Despite repeated systemic chemotherapy, the patient died of progressive disease in December 2004. ATLL could primarily involve the adrenal gland and this disease entity should be included in the differential diagnosis of adrenal mass lesions.     

An unusual extranodal natural killer/T-cell lymphoma presenting as chronic laryngitis: A case report

Rationale:Nasal-type, extranodal natural killer (NK)/T-cell lymphoma is a rare lymphoma. The tumor usually shows ulcerative and necrotic lesions in the nasal cavities and sinuses. Tissue involvement outside the nasal cavity is uncommon.Patient concern:We describe a 30-year-old man with a 2-month history of hoarseness, weight loss, and dyspnea.Diagnosis:Magnetic resonance image (MRI) showed edema of the larynx with obliteration of the airway. Laryngoscopic examination described necrotic tissue in the glottis and larynx. The biopsy showed chronic, necrotizing laryngitis, with no granulomas, vasculitis, or atypical cells. The immunologic and microbiologic study was negative. Later, after immunosuppressive therapy, the patient presented erythema and diffuse enlargement of the right arm. MRI showed myositis of the biceps and brachial muscles. Infection was rule out, and direct microscopy showed an extensive muscle infiltration by mononuclear cells and abundant mitosis. Immunohistochemistry was positive for CD3, CD8, Ki 67 (90%), and CD56 compatible with extranodal NK/T cell lymphoma.Interventions:The patient initially received immunosuppression treatments (corticoids, cyclofosfamide, and Rituximab) with relapsing episodes. When lymphoma was diagnosed, chemotherapy was started.Outcomes:The patient died during chemotherapy.Lessons:Nasal-type, extranodal NK/T-cell lymphoma should be suspected even when there are no classical findings of neoplasms on histology. Immunohistochemistry is mandatory to rule it out.     

Pericardial effusion: a rare presentation of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) has a wide variety of clinical presentations. The most common ones include leukemia, hypercalcemia, lymphadenopathy, hepatosplenomegaly, and skin lesions. We report a case of ATLL in a 73-year-old woman who presented initially with chest discomfort and shortness of breath. The patient had no peripheral lymphadenopathy, circulating lymphoma cells, hepatosplenomegaly, or skin lesions. CT scan showed small mediastinal lymph nodes and pericardial effusion. Diagnosis was established by cytomorphologic evaluation and flow cytometric analysis of the pericardial fluid. Cardiac involvement is a rare event in ATLL and, when present, usually is a late finding in the setting of disseminated disease. This case was unusual because the patient lacked all common clinical features of ATLL. We present this case so as to increase awareness that ATLL could initially present with pericardial effusion. The pathophysiologic mechanisms of cardiac involvement are also discussed.     

Hemophagocytic syndrome as a presenting sign of transformation of smoldering to acute adult T-cell leukemia/lymphoma: efficacy of anti-retroviral and interferon therapy

A 55-year-old Caribbean woman with a 6-year history of smoldering adult T-cell leukemia/lymphoma presented with clinical and biological symptoms of hemophagocytic syndrome. An extensive search for infectious diseases was negative. A lymph node biopsy showing large T-cell lymphoma (CD4-, CD25+) and findings of high LDH count and severe lymphocytosis led to the diagnosis of acute adult T-cell leukemia/lymphoma. Anti-retroviral therapy combining zidovudine, lamivudine, and interferon-alpha was started, resulting in rapid control of both hemophagocytic syndrome and symptoms of acute adult T-cell leukemia/lymphoma. Thus, we propose that adult T-cell leukemia/lymphoma must be added to the spectrum of etiologies of hemophagocytic syndrome.     

Adult T-cell leukemia/lymphoma with two distinct clones in the peripheral blood and lymph node

A case of adult T-cell leukemia/lymphoma (ATL) with two different clones in the peripheral blood and lymph nodes is reported here. When cellular DNA from the lymph node was digested with EcoRI, one band larger than 9 Kb was detected. Digestion of the cellular DNA with PstI resulted in one clear band in addition to three internal fragments. In contrast, when cellular DNA from malignant peripheral blood lymphocytes (PBL) was digested with the same endonucleases, distinct bands at positions different from those observed in the lymph node were detected, indicating two separate malignant clones in the patient. Monoclonality of the tumor cells was shown by T-cell receptor-β (TCR-β) gene rearrangement in both PBL and lymph node. Furthermore, there was a difference in the surface phenotype between tumor cells taken from peripheral blood (CD4+, CD8–) and lymph node (CD4+, CD8+). These findings suggest the presence of two different ATL clones in PBL and lymph node in a single patient simultaneously, which is distinguishable by the integration pattern of human T-cell leukemia virus type I (HTLV-I) proviral DNA.     

Osteitis fibrosa cystica generalizata with adult T-cell leukaemia: a case report

We report on a 62-year-old female initially suffering from extreme pain in both her lower extremities. Plain radiographs revealed multiple osteolytic lesions. Laboratory analyses indicated high levels of serum calcium and parathyroid hormone related protein (PTHrP) and detected HTLV-1 antibody. Histological examination of biopsied specimens which were obtained from osteolytic lesions indicated osteitis fibrosa cystica (OFC) without tumour cells. After the initial biopsy, a subcutaneous mass developed in the left thigh. Microsections of the biopsied mass disclosed adult T-cell leukaemia (ATL) neoplastic cells. Immunohistochemical findings revealed that PTHrP secreted from ATL neoplastic cells induced the OFC.     

Acute myeloid leukemia with T-cell receptor gamma gene rearrangement occurring in a patient with chronic lymphocytic leukemia: a case report

The association of chronic lymphocytic leukemia (CLL) and acute leukemia, either lymphoid or myeloid is a rare event. Our review of the medical literature revealed only 6 cases of CLL transformation to acute myeloid leukemia (AML) (M0, M1 and M2) with no other associated malignancy. We report a similar case but with occurrence of AML-M4 associated with normal cytogenetic analysis and molecular testing but with positive T-cell receptor gamma gene rearrangement rather than the usual Vbeta rearrangement.     

Development of Acute Adult T-cell Leukemia Following PD-1 Blockade Therapy for Lung Cancer

Immune checkpoint inhibitors (ICIs) are widely used for the treatment of various cancers. However, paradoxical exacerbation of neoplasms, referred to as “hyperprogressive disease,” has been reported in a proportion of patients treated with anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) blockade. We herein report a case of acute adult T-cell leukemia (ATL) that developed shortly after the administration of nivolumab, a PD-1 inhibitor, to treat non-small-cell lung cancer. There were no signs of ATL before the administration of nivolumab, and seropositivity for human T-cell leukemia virus type-1 (HTLV-1) was confirmed after the development of acute ATL. We speculate that nivolumab likely contributed to the development of acute ATL.