1. Abstract Adult T Cell Leukaemia/Lymphoma (ATLL) is a rare T cell lymphoproliferative disease associated with Human T Cell Lymphotropic Virus-1 (HTLV1) endemic in some parts of the world and therefore has a distinct demographic distribution. There are no cases of ATLL reported in Sri Lanka thus far hence this is the first reported case. Renal parenchymal infiltration in ATLL is extremely rare. Due to the rarity of the disease, evidence-based standard therapeutic options are lacking. The outcome of patients with ATLL is poor, particularly in the relapsed and refractory settings. Here we report a case of ATLL with renal involvement that initially responded to combined chemotherapy but later regressed to refractory disease with poor response to combined immunotherapy and antiviral therapy.
Keywords: Adult T Cell Lymphoma/Leukaemia; Sri Lanka; Renal infiltration; HTLV-1
2. Introduction Adult T Cell Leukaemia/Lymphoma (ATLL) is a highly aggressive T cell neoplasm caused by a retrovirus named Human T Cell Lymphotropic Virus-1 (HTLV-1) which is endemic in Japan, the Caribbean islands, Central and South America, Central and South Africa, a part of the Middle East and Melanesia, and Aboriginal regions in Australia [1]. It is extremely rare in Southeast Asia and there have been no reported cases in Sri Lanka according to our knowledge. It is estimated that approximately 20 million people to be infected by HTLV-1 globally [2]. Over 90% of them remain asymptomatic carriers during their lives and silent transmission may occur sexually, via breastfeeding, and through blood transfusions [3]. We report a case of an acute subtype ATLL presented with renal infiltration. Due to its rarity in this part of the world, unusual renal parenchymal involvement at presentation, absence of solid treatment guidelines in management, unavailability certain diagnostic tests including serological or molecular tests for HTLV-1 and certain therapeutic options in this resource-restricted setting, we think it is important to report this case.
3. Case Presentation A 62-year-old lady presented with a history of cervical and axillary lymphadenopathy and intermittent low-grade fever for 3 weeks. There were no skin lesions, unintentional weight loss, excessive night sweats or bleeding manifestations. ECOG performance status (PS) at diagnosis was 1. There was no hepatosplenomegaly. She had hypertension for which she was on multiple antihypertensives and triple vessel disease for which she had undergone coronary artery by-pass graft surgery (CABG) a year ago with normal cardiac functions at baseline. Her renal functions had been previously normal. Results of some of the important blood investigations at diagnosis are depicted in table 1. There were 25% small to medium sized abnormal lymphoid cells in peripheral blood and the majority of them showed irregular nuclei with nuclear clefts. Serological investigations for CMV, EBV, toxoplasma were negative.Bone marrow aspirate revealed a population of small to medium sized lymphoid cell with irregular and clefted nuclei representing 50% cells. Cytoplasmic blebs were also noted in some of these cells. There were no central nucleoli. Flowcytometry gated 25% of cells at high CD45 region in CD45/SSC out of which 90% were CD3 positive T lymphocytes and 5% CD19 positive B lymphocytes. CD3 positive cell population was negative for CD4, CD7, CD8, CD19, CD94, CD99, HLADR, CD56, CD16, CD30, CD 7 and MPO and was positive for CD 2, CD5 and T-cell receptor αß while a subset of cells was CD 10 positive. CD 25 was diffusely and strongly positive (Figure 1). Fluorescent in situ Hybridization (FISH) detected T cell rearrangements (TCRA/D 14q11). Left axillary lymph node excision biopsy revealed effaced nodal architecture with a diffuse infiltrate of monomorphic small, mature lymphoid cells. They showed condensed chromatin and irregular nuclear contours. A few scattered medium sized cells and plasmacytoid cells were also seen. There was marked dilatation of sinuses and prominent high endothelial proliferation infiltrated with atypical lymphocytes. Perinodal spread of atypical lymphocytes was also noted. Immunohistochemistry revealed diffuse, strong positivity of atypical lymphocytes for CD3 (membrane and cytoplasmic) and CD5. These cells were weakly positive for CD30 and BCL 2. Atypical lymphoid cells were negative for CD7, CD20, CD23, Tdt, CD34, CD15, ALK-1 and S-100. Ki-67 proliferative index was around 35%. CD20 highlighted the residual lymphoid follicles.
4. Discussion Based on the Shimoyama criteria, ATLL is classified into four categories based on organ involvement, lactate dehydrogenase (LDH) and calcium values, namely, chronic (5%), smouldering (15%), lymphoma (20%) and acute (60%) [4]. According to these criteria, our patient belonged to the acute subtype. Diagnosis is based on clinical features, morphological and immunophenotyping characteristics of the abnormal lymphoid population and evidence of HTLV-1 infection. The latter is not available in Sri Lanka and peripheral blood samples were sent to India for serology and PCR. ATLL is characterized by the clonal expansion of mature activated T cells generally CD3+ CD4+ CD5+ CD7– CD8– CD25+ [5]. However, the present case was unusually CD4 negative but was strongly positive for CD25. The acute form of ATLL is the most aggressive, characterized by marked leucocytosis with atypical lymphocytes, skin lesions (erythematous rash, nodules or papules), constitutional symptoms, hepatosplenomegaly and massive lymphadenopathy that spare mediastinum [6]. Hypercalcemia and elevated LDH are frequently present. While, the index case showed severe leucocytosis with nearly 15x109 /L atypical lymphoid cells in peripheral blood, raised LDH which was more than 3 times the upper limit of normal range and lymphadenopathy sparing mediastinum although not massive, she did not have any skin manifestations, hypercalcaemia or hepatosplenomegaly. Lymph nodes, skin, liver, spleen, lung, GI tract, bone marrow, bone, and CNS are the frequent sites involved in ATLL [7]. In our patient, lymph nodes and bone marrow were involved. The PET scan showed bilateral renal parenchymal infiltration with renal impairment at presentation. Although lymphomatous infiltration of renal parenchyma is not uncommon with B-cell lymphomas, only a few reports of infiltration of T-cell lymphomas with renal infiltration exist in the literature. Renal involvement with ATLL is reported extremely rarely [8]. The survival rate varies depending on the subtype, with 4 to 6 months for the acute variant [4]. A multivariate analysis of 854 patients identified advanced performance status, elevated LDH level and ß2-microglobulin, age above 40 years, presence of more than three involved lesions and hypercalcemia to be associated with shortened survival [9]. In addition, thrombocytopenia, eosinophilia, bone marrow involvement, high interleukin-5 serum level, C-C chemokine receptor 4 expression, lung resistance-related protein, p53 mutation, and p16 deletion have also been shown to fare poor prognosis [7]. Our patient clearly had poor prognostic factors.
5. Conclusions ATLL is a rare T cell lymphoproliferative malignancy with a spectrum of clinical manifestations and is extremely rare in Sri Lanka. Clinical, morphological, immunophenotypical, serological and genetic information is vital in establishing the diagnosis but can be extremely challenging in this resource-restricted setting. The aggressive acute variant of ATLL has a dismal prognosis with disappointing results with combined chemotherapy regimens and remains an unmet clinical need with no satisfying therapy at present.
6. Acknowledgements We are grateful to Dr Ng Chin Hin MD, MRCP, Consultant Haematologist, National University Cancer Institute of Singapore for his guidance and advice in managing this case.
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UABP Somawardana. Adult T Cell Lymphoma/Leukaemia with Renal Infiltration: A Case Report from Sri Lanka. Annals of Clinical and Medical Case Reports 2021