Case Report: HTLV-1–Induced Adult T-Cell Leukemia and Tropical Spastic Paresis

ABSTRACT.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic in many areas around the world. HTLV-1 can induce the development of adult T-cell leukemia (ATL) or myelopathy/tropical spastic paraparesis (HAM/TSP). We report a patient who presented to our outpatient clinic with massive splenomegaly, weight loss, urinary retention, and lower extremity weakness for the previous 3 years. The patient was found to have positive HTLV-1 by ELISA and Western blot from peripheral blood. Evaluation of the spleen demonstrated T-cell large granular lymphocyte leukemia consistent with ATL. In addition to progressive lower extremity weakness, hyperreflexia and clonus, cerebral spinal fluid was positive for HTLV-1 by ELISA and had a reversed CD4-to-CD8 ratio consistent with HAM/TSP. These findings suggest HTLV-1 induced ATL and HAM/TSP presenting simultaneously in the same patient.

INTRODUCTION

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic to areas of Iran, Japan, Africa, the Caribbean Islands, South America, and several East Asian countries. In 2015, an estimated 5 to 10 million individuals were infected with HTLV-1 globally, although this number is likely underreported.¹ HTLV-1 is transmitted through sexual intercourse, intravenous drug use, breastfeeding, and blood transfusions. Complications related to HTLV-1 are rare, but approximately 2.5% to 5.0% of those infected with HTLV-1 will develop adult T-cell leukemia (ATL) and 0.3% to 2.0% will develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).² These two clinical entities represent distinct pathophysiologic mechanisms of HTLV-1 disease progression, with ATL being a lymphoproliferative disorder and HAM/TSP an autoimmune inflammatory disease. We report a case of HTLV-1 in a patient who presented with both ATL and HAM/TSP simultaneously.

CASE REPORT

A 58-year-old man from Iran currently living in the United States with travel history to Iran, Thailand, and Indonesia presented with splenomegaly in addition to weight loss of more than 50 pounds, urinary incontinence, and bilateral lower extremity weakness progressing over the previous 3 years. On presentation, the patient was afebrile. Neurologic examination demonstrated reduced proprioception and hyperreflexia with clonus in the bilateral lower extremities and abdominal exam revealed splenomegaly. There was no evidence of skin, bone, or central nervous system (CNS) involvement. Laboratory values were unremarkable, with a serum lactate dehydrogenase of 245 u/L and a calcium level of 10.3 mg/dL at time of presentation. Peripheral blood smear demonstrated no atypical cells. Computed tomography imaging revealed massive splenomegaly (24.5 cm in length) without lytic bone lesions or lymphadenopathy. Magnetic resonance imaging of the spine was normal except for mild degenerative changes in T3–T4. Bone marrow biopsy with flow cytometry was completed and no evidence of neoplasia was detected. The patient underwent a splenectomy and tissue was sent to for histopathologic evaluation. Immunohistochemistry of splenic tissue showed diffuse T-lymphocyte infiltrate (predominantly CD8⁺ T cells) in the red pulp with preservation of the white pulp (Figure 1). Malignant lymphocytes were small with some nuclear irregularity; however, there was no loss of T-cell marker expression. The CD57 and TIA stain highlighted an increased amount of diffusely scattered cytotoxic T cells and CD4⁺/CD8⁺ stain demonstrated dominance of CD8⁺ T cells. T-cell receptor gene rearrangement revealed a clonal T-cell receptor gamma (TCRγ) population consistent with T-cell large granular lymphocyte leukemia (T-LGL). A lumbar puncture was performed at that time and showed no evidence of aberrant T-cells by flow cytometry, but a reversed CD4-to-CD8 ratio of 0.5 suggesting a proliferation of CD8⁺ cytotoxic T lymphocytes. Peripheral blood antibodies for HTLV-1 were detected on ELISA assay and confirmed with a Western blot. The patient was diagnosed with HTLV-1 induced ATL and presumed HAM/TSP based on clinical exam findings.

Figure 1.

Histopathology of spleen noting infiltration and expansion of the red pulp cords and sinusoids by T-cell large granular lymphocyte leukemia with relative sparing of the white pulp. Inset demonstrating neoplastic cells. This figure appears in color at www.ajtmh.org.

The patient returned to his home in Iran for 2 years for treatment, which included interferon (IFN)-α, zidovudine, arsenic, prednisone, and intrathecal methotrexate; however, due to side effects and progressive disease, all medications were discontinued except prednisone (5 mg daily) and intrathecal methotrexate every 1.5 months during his stay in Iran. The patient returned to the United States due to progressive neurologic symptoms, including limited ambulation requiring a walker and severe urinary dysfunction requiring intermittent self-catheterization. A lumbar puncture was performed, revealing lymphocytic pleocytosis in the cerebrospinal fluid (CSF). ELISA and Western blot confirmed the presence of HTLV-1 antibodies in the CSF. Flow cytometry again did not show aberrant cell populations but did demonstrate a reversal of the CD4-to-CD8 cell ratio of 0.59. The patient was continued on prednisone while evaluating potential clinical trials for both HTLV-1 induced-ATL and HAM/TSP.

DISCUSSION

More than 95% of people infected with HTLV-1 remain asymptomatic. Rarely, individuals with high viral loads will induce aberrant clonal expansion of infected CD4⁺ T cells, which leads to ATL or HAM/TSP. Given the inherent differences in the immunopathogenesis of these disease processes, the presence of both clinical manifestations, as in this case, represents an extraordinarily rare presentation of HTLV-1. A review of the literature reveals one additional case report in which both complications were present in the same individual;³ however, this patient had an indolent subtype of ATL and less aggressive disease progression compared with current patient. Additionally, in the previous case report, the patient had HTLV-1 complications occurring sequentially and not concurrently. In a more recent HTLV-1 cohort in Japan, approximately 3% of patients who had HAM/TSP developed ATL and the development of ATL was associated with a worse prognosis.⁴ The current case describes for the first time simultaneous, progressive ATL and HAM/TSP in a patient with HTLV-1 and further demonstrates the importance of understanding the underlying immunopathology associated with HTLV-1 to inform disease monitoring strategies and therapeutic drug development.

HTLV-1 is endemic in several regions worldwide, including Japan, the Caribbean, and rare foci in the South Gabon, Australia, Colombia, French Guyana, and the Middle East, specifically in Iran. Despite the patient’s extensive travel history to several countries, only Iran has reported ongoing HTLV-1 transmission. The seroprevalence of HTLV-1 infection in Iran is on the decline, dropping from 0.13% in 2007 to 0.07% in 2013; however, there are regional hotspots within Iran where the seroprevalence is significantly higher.⁵ The mode of transmission of HTLV-1 occurs most commonly by blood transfusions, IV drug use and sharing of needles, or sexual intercourse. Additionally, mother-to-infant transmission can be as high as 20%, with a particularly high risk associated with breastfeeding. Interestingly, the route of infection has been linked to HTLV-1 complications. Patients with ATL most commonly acquire HTLV-1 by vertical transmission, specifically breastfeeding, whereas patients with HAM/TSP more commonly acquire infection via blood transfusions.⁶ The patient denied IV drug use or high-risk sexual behaviors; additional family history was unknown.

HTLV-1 induced ATL can present as four distinct subtypes according to the Shimoyama Classification: acute, lymphoma, chronic, and smoldering. In this case, the massive splenomegaly, lack of leukemic or atypical cells in the peripheral blood, and normal serum lactate dehydrogenase level suggested that the neoplasm was of the chronic subtype of ATL.⁷ Notably, the median survival time of the chronic subtype of ATL is approximately 24.3 months, whereas our patient survived more than 4 years.⁷ The pathophysiology of ATL involves infected memory T cells producing Tax and HTLV-1 basic leucine zipper (HBZ) factor oncoproteins following integration of the viral genome into the infected cell’s genome. The expression of the Tax protein leads to immune evasion and proliferation, while the HBZ factor performs a similar function and aids in T-cell transformation.⁸ This uncontrolled T-cell proliferation leads to disease progression and the immunosuppressive state typically seen in ATL. Conversely, HAM/TSP is an inflammatory, autoimmune-like disorder driven by infected clonal CD4⁺ T cells expressing the Tax protein and translocating across the blood brain barrier into the CNS. Infected CD4⁺ T cells release IFN-γ, which stimulates astrocytes to produce CXCL10, a chemokine that recruits additional T cells into the CSF, including CD8⁺ cytotoxic T cells. The influx of CD8⁺ T cells into the CNS causes chronic inflammation and neural tissue damage manifesting clinically as paraparesis.⁹

Currently there are no approved treatment options to prevent HTLV-1 viral replication. Given the similarity to HIV, another human retrovirus, antiretroviral therapies (ART) have been evaluated for HTLV-1. However, to date, the outcomes of these studies have remained inconclusive and are not currently standard of care.⁸ Novel therapies, such as the anti-CCR4 monoclonal antibody mogamulizumab, which has been shown to reduce HTLV-1 proviral load levels, are approved for use in HTLV-1 in other countries, such as Japan. At this time, mogamulizumab is approved in the United States for the treatment of mycosis fungoides and Sézary syndrome, but it is not approved for the treatment of HTLV-1 viral replication.¹⁰ As a result, no treatment is currently recommended for patients with HTLV-1 who remain asymptomatic.

For individuals who develop HTLV-1-associated conditions, treatment strategies are limited as well. There is currently no standard treatment of the lymphoproliferative effects of ATL.⁸ Although treatment of asymptomatic disease is not recommended, treatment regimens for symptomatic individuals typically consist of a combination of chemotherapy agents and in some cases initiation of antiretroviral therapies, which has shown some benefit in the leukemic classification of ATL.⁸ Promising new therapies are currently under development, including allogenic hematopoietic stem cell transplantation, purine analogues, histone deacetylase inhibitors, and monoclonal antibodies targeting ATL cell surface proteins.¹¹ Current available HAM/TSP treatment strategies target symptom mitigation rather than reversal of disease progression. Corticosteroids, which blunt the inflammatory response in HAM/TSP, can be associated with a transient improvement in HAM/TSP symptom severity. Immunomodulators, such as tumor necrosis factor-α and INF-α, are also frequently used to slow the short-term progression of the disease.¹² Mogamulizumab has demonstrated initial promise in reducing spasticity in patients with HAM/TSP but requires further investigation.⁹ The patient described in this case report had progressive disease despite use of available therapeutic options. As a result, there is a critical need for the development of effective treatment options to provide virologic control and minimize symptoms in patients with HTLV-1 associated HAM, ATL, or both.