New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma: human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types

Adult T-cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T-lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. We propose an entity of cutaneous ATLL, which has less than 5% abnormal T lymphocyte in peripheral blood, a normal lymphocyte count (i.e. <4 x 10(9)/L), no hypercalcemia and lactate dehydrogenase values of up to 1.5 times the normal upper limit. At least one of the histologically proven skin lesions should be present accompanying monoclonal integration of human T-cell lymphotropic virus type 1 (HTLV-1) proviral DNA in the skin lesion. Blood samples were collected from 41 HTLV-1-infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV-1 proviral loads, soluble interleukin-2 receptors and other parameters were examined in each case. HTLV-1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.     

Familial disposition of adult T-cell leukemia and lymphoma

Sixteen families, each with two or more cases of adult T-cell leukemia or lymphoma were found in the Nagasaki district. Eight of the families had a parent with lymphoma. In the other eight families siblings were involved. Four families with sibling cases are presented in detail. Antibody titres to adult T-cell leukemia associated antigen (ATLA) in cases of ATL, CTL, T-CLL, and pre-ATL cases in Nagasaki were all positive. Of the non-leukemic T-cell malignant lymphoma 62.5 per cent were positive for antibody. The positive rate in healthy spouses and siblings of ATLL patients for ATLA antibody was high (67.5 per cent and 40 per cent respectively). The possibility of ATLV infection through spouses or from mother to child and the meaning of the high familial incidence of ATLL is discussed.     

Rearrangement of human T cell receptor beta and gamma chain genes in adult T cell leukemia/lymphoma

We studied rearrangement of human T cell receptor genes (TCR) of C beta, C gamma, V gamma and J gamma in 34 cases of adult T cell leukemia/lymphoma (ATLL), consisting of 29 cases with monoclonally integrated HTLV-I proviral DNA (ATLL-W) and five without monoclonal integration (ATLL-O), in comparison with 12 cases of other peripheral T cell lymphomas (non-ATLL). All cases of both ATLL and non-ATLL showed some rearrangement of T cell receptor genes (TCRs) of C beta, C gamma, V gamma, or J gamma. Rearrangement of TCR beta was found in 28 of 29 cases of ATLL-W, all cases of ATLL-O, and eight of 12 cases of non-ATLL. Rearrangement of TCR gamma was observed in 21 of 22 cases of ATLL-W, and in all cases of ATLL-O and non-ATLL. In TCR gamma, rearrangement of C gamma was seen in six of 20 cases of ATLL-W, none of three ATLL-O cases and three of six cases of non-ATLL. V gamma rearrangement occurred in 14 of 18 cases of ATLL-W, one of two cases of ATLL-O, and three of six cases of non-ATLL. Rearrangement of J gamma was found in 16 of 22 cases of ATLL-W, two of five ATLL-O cases, and six of seven non-ATLL cases. Rearrangement was more frequent in ATLL-W than in ATLL-O and non-ATLL. The incidence rate of rearrangement of V gamma families of V gamma 1, V gamma 2, and V gamma 3 was nearly the same in each group, except for deletion of V gamma 3, which was often observed in ATLL but was absent in non-ATLL. These results indicate the usefulness of detection of TCR and HTLV-I proviral DNA to differentiate ATLL from other T cell malignancies.     

Cytological diagnosis of adult T‐cell leukemia/lymphoma in sputum

Adult T‐cell leukemia/lymphoma (ATLL) is a rare and often aggressive T‐cell leukemia/lymphoma that has been linked to infection by the human T‐cell lymphotropic virus type 1 (HTLV‐1). ATLL can involve multiple organs including the respiratory airway. A 53‐year‐old Trinidadian woman presented with productive cough and progressive shortness of breath. Her past medical history included duodenal strongyloidosis, skin rash, and hypercalcemia. Radiological studies showed increased interstitial markings. Sputum cytology showed atypical pleomorphic, small‐to‐medium‐sized, lobated lymphocytes with irregular and hyperchromatic nuclei resembling “flower cells” which were CD3±/CD20? by immunocytochemistry. A lung biopsy showed interstitial, peribronchiolar, and subpleural infiltration by a CD3±/CD25± atypical lymphocytic infiltrate. Together with peripheral blood findings and positive HTLV‐1 serology, the diagnosis of ATLL was made. We suggest that sputum evaluation in patients with ATLL risk factors can be diagnostic. Diagn. Cytopathol. 2016;44:416–418. © 2016 Wiley Periodicals, Inc.     

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.     

Inactivation of p14ARF as a key event for the progression of adult T cell leukemia/lymphoma

The INK4a/ARF locus encodes two different proteins, p16^INK4a and p14^ARF, which are crucial for two tumor suppressor pathways. We found that p14^ARF mRNA expression was suppressed in 13 of 37 cases, among which 9 cases showed the inactivation of both of p14^ARF and p16^INK4a, and 4 cases showed the inactivation of p14^ARF alone. The inactivation of p14^ARF and the mutation of p53 are mutually exclusive. The patients with the p14^ARF inactivation had shorter survival, similar to that of patients with the p53 mutation. These results indicate that the inactivation of p14^ARF plays a key role in the progression of ATLL.     

Regulatory T-cell function of adult T-cell leukemia/lymphoma cells

Adult T-cell leukemia/lymphoma (ATLL) patients are highly immunocompromised, but the underlying mechanism responsible for this state remains obscure. Recent studies demonstrated that FOXP3, which is a master control gene of naturally occurring regulatory T (Treg) cells, is expressed in the tumor cells from a subset of patients with ATLL. Since most ATLL cells express both CD4 and CD25, these tumors might originate from CD4(+)CD25(+)FOXP3(+) Treg cells, based on their phenotypic characteristics. However, whether ATLL cells actually function as Treg cells has not yet been clearly demonstrated. Here, we show that ATLL cells from a subset of patients are not only hypo-responsive to T-cell receptor-mediated activation, but also suppress the proliferation of autologous CD4(+) non-ATLL cells. Furthermore, ATLL cells from this subset of patients secrete only small amounts of IFN-gamma, and suppress IFN-gamma production by autologous CD4(+) non-ATLL cells. These are the first data showing that ATLL cells from a subset of patients function as Treg cells in an autologous setting. The present study provides novel insights into understanding the immunopathogenesis of ATLL, i.e., how HTLV-1-infected cells can survive in the face of host immune responses. It also adds to our understanding of ATLL patients' severely immunocompromised state.     

Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors

Patients with adult T-cell leukemia/lymphoma (ATLL) are in a severely immunocompromised state. Therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-) associated cytokines [IFN-gamma, TNF-alpha, and interleukin (IL)-2], Th2-associated cytokines (IL-4, -5 and -6) and regulatory T cell-associated cytokines (IL-10 and TGF-beta1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic virus type-1 (HTLV-1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-1 carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.