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.     

Cutaneous manifestations associated with HTLV-1 infection

Skin lesions are frequent in human T-cell lymphotropic virus type 1 (HTLV-1) infection and may constitute an alert for the diagnosis of this condition. The most severe skin diseases related to this virus are adult T-cell leukemia/lymphoma (ATLL), an aggressive form of leukemia/lymphoma that fails to respond to chemotherapy, and infective dermatitis associated with HTLV-1 (IDH), a severe and recurrent form of eczema occurring in childhood. ATLL affects the skin in 43-72% of cases. In this review, the clinical, histopathological and immunohistochemical aspects of ATLL and IDH will be discussed, as well as the differential diagnoses, giving particular focus to the primary cutaneous ATLL. IDH may progress to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and to ATLL. Adult onset IDH and reactional and inflammatory dermatoses found in carriers and also in patients with HAM/TSP will be considered. Other dermatological diseases that occur more frequently in HTLV-1-infected individuals such as xerosis, acquired ichthyosis, seborrheic dermatitis and infectious and parasitic dermatoses will also be discussed.     

Trichothiodystrophy without associated neuroectodermal defects

We report a case of adult T-cell leukaemia/lymphoma (ATLL) with prurigo as a prodromal skin manifestation. The patient was a 52-year-old woman with a 2-year history of a fluctuating skin condition consisting of pruritic papules and pigmentation on her lower legs and right buttock. Prurigo was diagnosed at her first visit in October 1995, and she was found to be seropositive for human T-cell lymphotropic virus type 1 (HTLV-1). Two years later, the skin lesions had spread over the patient's forearms and dorsa of the hands, and abnormal lymphoid cells had appeared in her peripheral blood. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus in the peripheral blood, but not in a skin lesion. Based on these results, a diagnosis of overt ATLL of the smouldering type was made. The findings in this case indicate that in healthy HTLV-1 seropositive carriers, prurigo requires careful follow-up as a cutaneous prodrome of ATLL.     

A Case of Adult T-cell Leukemia/Lymphoma (ATLL) with Angiocentric and Angiodestructive Features

This report describes a case of adult T-cell leukemia/lymphoma (ATLL) with angiocentric and angiodestructive features. The patient was a 66-year-old Japanese woman who began developing widespread skin lesions ten months prior to admission. The diagnosis of ATLL was made on the basis of her having an antibody to human T-cell lymphotropic virus type -1 (HTLV-1) and typical flower cells (ATLL cells) in peripheral blood smears. Once hospitalized, the course of her disease was very acute and severe, as is seen with angiocentric lymphoma. Based on histological features, this case was judged not to be angiocentric lymphoma; however, it may lie within the spectrum of angiocentric immunoproliferative lesions (AIL). The findings in this case strongly suggest that HTLV-1 can be a pathogenic factor in the expression of angiocentric and angiodestructive features in ATLL, as is Epstein-Barr virus (EBV) (1–4). To our knowledge, the present case is the sixth reported in the literature of lymphoma in which these features are associated with HTLV-1 infection (5–7).     

Crusted scabies in association with human T-cell lymphotropic virus 1

BACKGROUND: Human T-cell lymphotropic virus I (HTLV- 1) infection can lead to myelopathy/tropical spastic paresis and adult T-cell leukemia/lymphoma (ATLL). Infection with HTLV-1 has also been associated with clinically significant immunosuppression. Crusted scabies, also known as Norwegian scabies, is an uncommon presentation of scabies that may occur in conjunction with immunosuppression. Although crusted scabies has been reported in association with HTLV-1 infection, to our knowledge it has never been described in association with HTLV-1 associated myelopathy. OBJECTIVE: The aim is to describe a case of HTLV-1 associated myelopathy and concomitant crusted scabies. METHODS: This article includes a case report and a literature review. CONCLUSIONS: Crusted scabies is reported in association with HTLV-1 infection with or without concomitant ATLL. Crusted scabies should be considered in the differential diagnosis of a generalized cutaneous eruption in an HTLV-1 positive patient. Patients with crusted scabies from an HTLV-1 endemic population should be rested for a possible HTLV-1 infection. These patients may be at increased risk of progressing to ATLL.     

Smoldering HTLV-1-induced T-cell lymphoma localized within the skin; a radiation-resistant tumor

BACKGROUND: Human T-cell lymphotrophic virus type 1 (HTLV-1)-induced lymphoproliferative disease occurs in approximately 3-5% of people in endemic areas who have been HTLV-1 positive for decades. Lymphoproliferative disease may present as four subtypes, including an acute adult T-cell leukemia/lymphoma (ATLL), an aggressive HTLV-1 lymphoma, chronic ATLL, and smoldering ATLL. MATERIALS AND METHODS: A 72-year-old HTLV-1+ Haitian woman presented with a 2-year history of a cutaneous eruption localized to the right arm. The eruption had evolved into multinodular lesions over the past 6-7 months. Peripheral blood and cutaneous biopsy specimens were evaluated. Immunohistochemical studies for lymphoid markers were performed on the cutaneous biopsy material, and polymerase chain reaction (PCR) and Southern blot assay were evaluated for the presence and integration of HTLV-1 within the genome. RESULTS: The biopsy specimen showed a pleomorphic T-cell infiltrate with epidermotrophism, and an immunohistochemical phenotype showing CD3+, CD4+, CD8-, CD25, CD30-, HLDA-DR+ cells. PCR and Southern blot assay evaluation showed a single clonal integration of HTLV-1 provirus within a monoclonal tumor cell population. The patient had no abnormal lymphoid forms on peripheral smear at presentation, and no evidence of other organ involvement. CONCLUSIONS: Smoldering HTLV-1-induced lymphoma is uncommon even in endemic areas. In previously reported cases, the smoldering variant was accompanied by abnormal forms in the peripheral blood and/or by other signs of systemic disease. This case illustrates that smoldering disease may be localized to the skin with no detected morphologic abnormalities on peripheral smear.     

Expression of human T-cell lymphotropic virus type-1 gene products in the short-term cultured skin tissues of an adult T-cell leukemia/lymphoma patient with cutaneous manifestations.

Adult T-cell leukemia/lymphoma (ATLL) is recognized as a disease etiologically associated with human T lymphotropic virus type-1 (HTLV-1) infection, but, neither viral replication nor specific virus antigen expression have been detected on ATLL cells distributed in organs, including skin. To examine the latent expression of HTLV-1 in the cutaneous lesions of ATLL patients, we cultured the lesional skin tissues in vitro and applied immunofluorescence staining with mouse monoclonal antibodies Lt-4, GIN-14, and F10, which react with p40tax, p19 and gp21, respectively. We recognized HTLV-1 specific antigens on clustered ATLL cells only in the deeper dermis of the skin after 24 hrs cultivation of the lesional skin tissue from an ATLL patient in RPMI-1640 medium supplemented with 20% fetal calf serum. In the electron microscope, we observed HTLV-1 like particles, 80-140 nm in diameter with envelope and core structures, in the same tissue specimen. These findings suggest that HTLV-1 gene products may be expressed in the skin lesions of ATLL patients and involved in the pathogenesis of skin eruptions in cutaneous type ATLLs. To our knowledge, this is the first report that envisages the potency of intracutaneous HTLV-1 expression in vivo.     

HTLV-I-associated granulomatous T-cell lymphoma in a child

Adult T-cell leukemia/lymphoma (ATLL) is a T-cell malignancy closely associated with human T-cell lymphotropic virus-1 (HTLV-I). Because of its long latency period, ATLL occurs almost exclusively in adults. We report a case of a 13-year-old boy with an 8-year history of skin eruptions. After complete evaluation, a diagnosis of HTLV-I-associated lymphoma/leukemia was made. The T-cell lymphoma exhibited a granulomatous histomorphology. There have been very few reports of ATLL presenting in childhood and none, to our knowledge, demonstrating granulomatous histology. We conclude that ATLL may rarely present as a chronic granulomatous eruption in a child.     

Human T-lymphotropic virus 1 (HTLV-1) infection--dermatological implications

Human T-lymphotropic virus type 1 (HTLV-1) is a type C retrovirus primarily endemic to Japan, Central and South America, the Middle East, regions of Africa, and the Caribbean. Currently, an estimated 10-20 million people worldwide are infected with this virus. Although the majority of infected individuals remain asymptomatic, HTLV-1 is the causative agent of a number of disorders, notably adult T-cell leukemia/lymphoma (ATLL) and a progressive demyelinating neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to ATLL and HAM/TSP, HTLV-1 has been associated with a spectrum of skin disorders, such as infective dermatitis associated with HTLV-1, crusted scabies, and leprosy. The understanding of the interaction between virus and host response has improved markedly, but there are still few treatment options.     

A Clinicopathological Analysis of Primary Cutaneous Lymphomas: A 6-year Observational Study at a Tertiary Care Center of South India

Background:Little data are available concerning clinical and pathological patterns of cutaneous lymphomas in India.Aim:To analyze the clinical and histopathological characteristics of cutaneous lymphomas in Indian patientsResults:Among 35 cases, 33 (94.3%) were T-cell, and 2 (5.7%) were B-cell lymphomas. The mean age was 52.66, and the male to female ratio was 2.5:1. The most common types of T-cell lymphomas included mycosis fungoides (MF) (57.1%) followed by adult T-cell lymphoma/leukemia (ATL) (17.1%). Primary cutaneous peripheral T-cell lymphoma not otherwise specified was diagnosed in 17.1% and anaplastic large cell lymphoma in 2.9%. The morphological types of MF included polymorphic, poikilodermatous, folliculotropic, hypopigmented, hyperpigmented, mixed, and purpuric. Skin manifestations of ATL included ulcerated plaques and erythroderma. Epidermotropism was very marked in ATL (83.3%) than in MF (70%). Larger Pautrier''s microabscess was noted in ATL compared to smaller ones in MF. Markedly dense, diffuse infiltrate of atypical cells was noted in ATL in contrast to mild to moderate nodular or perivascular infiltrate in MF. ATL had an extremely poor prognosis.Limitations:Identification of DNA integration of HTLV-1 by Southern blot could not be analyzed, and the number of cases studied is limited.Conclusions:The study showed unique patterns of subtypes of cutaneous lymphomas in our country. Variations in the clinical pattern and histopathological analysis will help to differentiate T-cell lymphoma types which have prognostic implications.     

Adult T-cell leukemia/lymphoma in a patient from Romania: a case report and review of the literature

Adult T-cell leukemia/lymphoma (ATLL) is a rare malignancy caused by human T-cell leukemia virus-1. ATLL is endemic to Japan, and to date, there are only four case reports of patients from Romania who have developed ATLL. Here, we describe a woman living in Madison, Wisconsin, originally from Romania, who presented with an atypical papulosquamous eruption and was ultimately diagnosed with smoldering ATLL. Narrow-band ultraviolet-B (UV-B) therapy and mid-potency topical steroids resulted in skin clearing for approximately 5 months after diagnosis; however, she subsequently relapsed with disease refractory to both narrow band UV-B and psoralen plus ultraviolet A (PUV-A), progressed to acute ATLL and expired secondary to complications.     

Adult T-Cell Leukemia/Lymphoma and Cutaneous T-Cell Lymphoma Are They Related?

Comparative studies were performed on clinical and laboratory features of four patients with different types of T-cell lymphoma of the skin; adult T-cell leukemia/lymphoma (ATLL), Sézary syndrome, mycosis fungoides, and Ki-1-positive lymphoma. All neoplastic cells studied showed a helper-inducer T-cell phenotype. A Ki-1-positive lymphoma is distinct from other types of cutaneous lymphomas because of unique morphologic and phenotypic features. Clonal proliferation of lymphocytes infected by human T-cell lymphotrophic virus (HTLV)-1 distinguishes ATLL from other T-cell lymphomas of the skin, especially in the endemic area of ATLL. From the pathogenic point of view, ATLL should not be included in a group with mycosis fungoides and Sézary syndrome.     

Clinicopathologic analysis of 124 cases of adult T-cell leukemia/lymphoma with cutaneous manifestations: the smouldering type with skin manifestations has a poorer prognosis than previously thought

Adult T-cell leukemia/lymphoma (ATLL) commonly involves the skin as well as peripheral blood and lymph nodes. During the last 15 years we have studied 124 cases of ATLL with specific skin manifestations. Twenty-one patients (16.9%) were classified as acute, 21 (16.9%) as chronic, 26 (21.0%) as lymphoma, and 56 (45.2%) as smouldering according to Shimoyama's classification. Many patients had nodules/tumors (34.7%), erythematous plaques (22.6%), and erythematous papules (19.4%) similar to those occurring with other cutaneous T-cell lymphomas. Some patients displayed characteristic skin manifestations resembling non-neoplastic cutaneous disorders. The median survival time (MST) of all patients was 12.0 months. The MSTs of individual clinical types were: acute type, 4 months; chronic type, 14 months; lymphoma type, 7 months; and smouldering type, 16 months. In the smouldering type, cases with a deeper infiltration pattern (MST, 14 months) had a more aggressive course than those with a superficial infiltration pattern (MST, 24 months) (p < 0.05). The results indicate that smouldering type ATLL with skin manifestations may have a worse prognosis than without skin manifestations. Moreover, some cases of the smouldering type with specific skin lesions should be classified into another group with a much poorer prognosis.     

中国人皮肤型成人T细胞白血病/淋巴瘤一例报道

目的 报道1例皮肤型成人T细胞白血病/淋巴瘤(cATLL)。方法 检测皮肤损害的组织病理、直接免疫荧光和免疫表型的特点,同时应用酶联免疫吸附试验、蛋白印迹法以及聚合酶链反应分别检测患者外周血中嗜人T淋巴细胞病毒Ⅰ型(HTLV-Ⅰ)抗体和淋巴样细胞的HTLV-Ⅰ前病毒DNA。结果 此例患者的皮肤损害多形,除表现丘疹、斑块外,并发生疱壁紧张或松弛的大疱。组织病理检查示表皮下水疱,疱底真皮乳头和疱边缘处小至中等大不典型淋巴样细胞浸润。不典型淋巴样细胞示CD45⁺、CD45RO⁺,直接免疫荧光检查阴性。外周血中HTLV-Ⅰ抗体阳性;淋巴样细胞中HTLV-Ⅰ前病毒DNA阳性。患者最后死亡,病程1年10个月。结论 ATLL在我国并非极罕见,cATLL也存在,应加以警惕。     

Cutaneous involvement in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive non-Hodgkin's nodal peripheral T-cell lymphoma characterized by general lymphadenopathy, night sweats, fever, hepatosplenomegaly, polyclonal hypergammaglobulinemia, and cutaneous involvement. We present a rare case of AITL cutaneous involvement mimicking toxic erythema recurring with AITL relapse and suggesting a precursor of disease progression.     

Epstein-Barr virus-associated primary central nervous system lymphoma in a patient with adult T-cell leukemia / lymphoma

We present a case of Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma (PCNSL) arising from a patient with cutaneous-type adult T-cell leukemia/lymphoma (ATLL). Extranodal sites affected by ATLL include the skin, lung, liver, gastrointestinal tract and central nervous system (CNS). CNS involvement usually occurs as an acute and lymphoma-type ATLL. PCNSL is a rare type of tumor and the vast majority of PCNSL are of B-cell lineage. Individuals with acquired, iatrogenic or congenital immunodeficiency are at increased risk of PCNSL, which is commonly associated with EBV. In our patient, the expression of latent infection membrane protein 1 (LMP1), EBV nuclear antigen 2 (EBNA2), and EBV-encoded small RNA (EBER) in tumor cells confirmed a type III latency of EBV infection. Human T-cell lymphotropic virus type I (HTLV-I) can induce immunodeficiency before the overt development of ATLL. The HTLV-I infection led to suppression of the immune system and the development of EBV-associated PCNSL. This is the first reported case of the clinicopathological features of EBV-associated PCNSL arising from a patient with ATLL.     

Detection of human T-cell lymphotropic virus type-1 proviral DNA in the saliva of an adult T-cell leukaemia/lymphoma patient using the polymerase chain reaction

We report a case of adult T-cell leukaemia/lymphoma (ATLL), in whom the polymerase chain reaction (PCR) on genomic DNA from saliva demonstrated the monoclonal integration of human T-cell lymphotropic virus type-1 (HTLV-1) proviral DNA in lymphocytes in the saliva. These results provided evidence of the possibility of saliva-borne transmission of HTLV-1.     

The comparison of expression of cutaneous lymphocyte-associated antigen (CLA), and Th1- and Th2-associated antigens in mycosis fungoides and cutaneous lesions of adult T-cell leukemia/lymphoma

Mycosis fungoides (MF) is morphologically similar to cutaneous lesions of adult T cell leukemia/lymphoma (ATLL) of human T-cell lymphotropic virus-type I (HTLV-1). In addition, the Th1 or Th2 characteristic of MF and ATLL is still controversial. In the present study, to discriminate MF and cutaneous lesion of ATLL using immunohistochemical markers, and to elucidate Th1 or Th2 dominancy in both disorders, CLA (cutaneous lymphocyte associated antigen) was expressed on epidermotrophic lymphoma cells in all early stage MF. In contrast, all ATLL were negative for CLA. CXCR3 was especially expressed in epidermotropic small lymphoma cells of MF. CCR5 was expressed in both disorders with variable sized lymphoma cells. ST2 was expressed on large transformed lymphoma cells with ATLL, but not in any MF cases. OX40 was expressed in the large transformed cell population in both disorders. These findings suggest that CLA and ST2 could be potentially useful immunohistochemical markers for discrimination of mycosis fungoides and cutaneous lesions of ATLL. And OX40 could be a useful immunohistochemical marker for the histopathological progression of both disorders.     

Cutaneous Manifestations and Treatment Advances of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell lymphoma caused by the human T lymphotropic virus type-1. The skin is affected in approximately half of ATLL patients, and skin lesions may be the first manifestation of the disease. The skin lesions of ATLL are polymorphous, and depend on the type of skin eruption, which makes it possible for doctors to predict the prognosis of the disease based on the characteristics of skin lesions. In this review article, we describe th...     

Adult T-cell leukemia/lymphoma with follicular mucinosis: an unusual histopathological finding and a commentary

Follicular mucinosis is currently recognized as a histopathological finding characterized by the accumulation of mucin within follicular epithelium and is commonly associated with follicular mycosis fungoides (MF). We report the finding of follicular mucinosis in a cutaneous nodule of human T-lymphotropic virus type 1 (HTLV-1) associated adult T-cell leukemia/lymphoma (ATLL). The patient was a 69-year-old female of Caribbean descent with a history of ATLL who presented with erythematous nodules on the chest and abdomen. Histopathologic examination showed a pan-dermal infiltrate of medium-to-large sized atypical lymphocytes extending into follicular epithelium where they associated with large mucin deposits. Immunohistochemical stains showed that the atypical lymphocytes were positive for CD3, CD4 and CD25 and negative for CD30. Cutaneous lesions of ATLL, which often present histopathologically as an epidermotropic lymphoma with Pautrier-type collections, are often difficult to distinguish from MF. Until recently, lymphoma-associated follicular mucinosis seemed specific to MF and Sézary syndrome (SS), being reported only once in a lesion of ATLL. We report a second case of ATLL-associated follicular mucinosis to increase awareness of this possible association, and briefly review the literature of follicular mucinosis-associated hematologic malignancies, ultimately cautioning against the interpretation of all cutaneous lymphoma-related follicular mucinosis as MF/SS.