Adult T-cell leukemia/lymphoma: a retroviral malady.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive leukemia/lymphoma of mature T-lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). At a tertiary healthcare center in South India, a 58-year-old female presented with multiple erythematous, crusted, and umbilicated papules over the body along with cervical lymphadenopathy. The skin biopsy was consistent with cutaneous T-cell lymphoma. Although she responded initially to chemotherapy, the disease relapsed after 3 months, and she developed disseminated infiltrated skin lesions, generalized lymphadenopathy, and leukemia. Due to the unusual clinical findings we did HTLV-1 Enzyme-linked immunosorbent assay (ELISA), which turned out to be positive in high titers. Her mother had died at an early age from a hematological malignancy and her daughter was also found to be seropositive. To the best of our knowledge, this is the first case to be reported from India of the chronic type of ATLL associated with mother-to-child transmission of HTLV-1 in two generations. This case also emphasizes that the chronic type of ATLL can occur in nonendemic areas like India and should be suspected in nonresponding cases of mycosis fungoides. It should be kept in mind that the chronic type often presents without hypercalcemia or the characteristic 'flower cells' in the peripheral smear.

Introduction

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive leukemia/lymphoma of mature T-lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). The virus is endemic in southwestern Japan, the Caribbean, sub-Saharan Africa, and certain areas of southern America and the Middle East. In nonendemic areas of the world like India the seroprevalence is below 0.03%, with most positive individuals being immigrants from endemic areas or intravenous drug abusers.[1] To the best of our knowledge this is the first case of the chronic type of ATLL associated with mother-to-child transmission of HTLV-1 in two generations to be reported from India.

Case Report

A 58-year-old lady residing in South India presented with multiple pruritic skin lesions over the scalp, face, and forearm of 2 weeks’ duration. History of risk factors for ATLL such as immigration from endemic area, intravenous drug abuse, blood transfusion, and extramarital or premarital sexual exposure was negative. The only significant family history was early demise of her mother at the age of 45 years due to some hematological malignancy.

Clinical examination revealed multiple erythematous papules – some umbilicated and crusted – over the scalp, forehead, and extensor aspect of forearms [Figure 1]. There was associated lymphadenopathy, with multiple firm, nontender, cervical lymph nodes. Skin biopsy revealed sheets of large cells with pleomorphic dark nuclei irregularly infiltrating the dermis with epidermotropism, consistent with cutaneous T-cell lymphoma (CTCL). Lymph node biopsy showed infiltration of sinusoids with atypical lymphocytes. Hemogram, peripheral smear, biochemical parameters, and imaging studies were normal. With the diagnosis of mycosis fungoides stage IV A, the patient was treated with six cycles of the CHOP regimen (cyclophosphamide, adriamycin, vincristine, and prednisone).

Figure 1

Multiple umbilicated and crusted papules (a) over the scalp and forehead and (b) over the forearm

Though there was an initial response the disease relapsed after 3 months, with the development of disseminated papules and annular plaques [Figure 2a], which progressed to nodules [Figure 2b] accompanied by generalized lymph node enlargement and bilateral pitting pedal edema. Repeat investigation revealed an elevated total leukocyte count of 45900 cells/mm3 (with the differential count showing 74% lymphocytes and 25% polymorphs), elevated serum lactate dehydrogenase (LDH) of 783 IU/L, elevated blood urea nitrogen, and lowered serum albumin. Serum calcium and alkaline phosphatase levels remained normal. HIV ELISA test was negative. The peripheral smear revealed atypical cells with indented nuclei constituting more than 5% of the peripheral lymphocytes [Figure 3]. Repeat biopsy from the nodules revealed infiltration of skin with innumerable pleomorphic cells showing epidermotropism with the formation of Pautrier's microabscesses [Figure 4]. Immunohistochemistry revealed the cells to be CD3 and CD4 positive but CD20 negative, thus confirming its T-cell lineage. The bone marrow aspiration and trephine biopsy were however normal.

Figure 2

Papules and annular plaques over the hands (a) and legs (b), which progressed to nodules

Figure 3

Peripheral smear revealing atypical cells with indented nuclei (hematoxylin and eosin; ×100)

Figure 4

Biopsy from the nodules revealed infiltration of skin with innumerable pleomorphic cells showing epidermotropism and Pautrier's microabscess formation (arrow) (hematoxylin and eosin; ×100)

At this stage we suspected the possibility of ATLL and asked for HTLV-1 ELISA; this was found to be positive in very high titers (1:8192). She was thus diagnosed to have the chronic form of ATLL. Despite treatment with interferon-α and zidovudine she died 3 months after diagnosis. When the family members of the patient were screened, her 32-year-old daughter was found to be seropositive for HTLV-1 in high titers (1:2048). She was advised against prolonged breastfeeding of her children and is currently under regular follow-up.

Discussion

ATLL was first recognized in 1977 by Uchiyama and coworkers as an aggressive leukemia/lymphoma of mature T-lymphocytes.[2] Currently, according to the Lymphoma Study Group in Japan, ATLL can be classified into four clinical types based on clinical features and cell morphology: acute type, chronic type, lymphoma type, and smoldering type. Chronic ATLL patients develop lymphadenopathy, skin involvement, and absolute lymphocytosis (>4×109/L), with more than 5% of T-cells in the peripheral blood being abnormal. The frequent expression of chemokines CCR-4 receptor on the surface of tumor cells accounts for the cutaneous involvement in ATLL.[3] LDH may be increased to more than two times the normal upper limit. There is no hypercalcemia or involvement of bone, central nervous system, or gastrointestinal system in the chronic type.[4] Skin lesions reported with ATLL are localized or diffuse; there may be erythematous, crusted or purpuric, papules, plaques, nodules, ulcerative lesions, pompholyx-like and ichthyosis-like lesions, and erythroderma. Umbilicated papules similar to that in our case has been rarely seen.[5]

The three major routes of transmission of HTLV-1 are mother-to-child transmission (especially through breastfeeding), sexual transmission, and transmission by blood transfusion. The intravenous route of infection, though the most efficient mode of HTLV-1 transmission, is associated with a higher risk of developing tropical spastic paraparesis rather than ATLL. The lifetime risk of development of ATLL in HTLV carriers is estimated to be 1–4%. The latent period from infection to the actual development of disease is estimated to be 30–50 years.[3] In our case, mother-to-child transmission is the most probable mode, considering the absence of other risk factors, seronegativity in the husband, and prolonged breastfeeding by her mother who died at an early age due to a hematological malignancy. Since our patient's daughter was also seropositive, HTLV-1 transmission had occurred in at least two generations via the mother-to-child route.

The skin biopsy findings in the chronic type of ATLL can be confused with that of mycosis fungoides (MF), in which also there may be dermal and epidermal infiltration with malignant lymphocytes, with or without Pautrier's microabscesses. Both these disorders have similar cutaneous manifestations, show malignant T-cells in peripheral blood, and have identical skin biopsy findings. It is now well accepted that HTLV-1 is not involved in the pathogenesis of MF but that MF-like lesions may be a clinical presentation of ATLL.[6]

In the chronic variant of ATLL, peripheral smear reveals atypical cells with nuclear indentations, unlike the lobulated ‘flower cells’ seen in acute ATLL. The bone marrow is involved in only 35% of cases and the infiltrates are usually patchy, sparse, or moderate. Practically all patients with ATLL have serological antibodies to HTLV-1, which can be screened using ELISA and confirmed by means of the Western blot technique.[7] The presence of high LDH, high blood urea nitrogen, or low serum albumin is considered to indicate poor prognosis in the chronic type of ATLL.[8] All the three parameters were present in our patient, thus predicting a poor outcome.

Various regimens of cytotoxic chemotherapy have been used to treat patients with ATLL but the rates of complete response are below 30%. The CHOP regimen still remains the standard first-line therapy for ATLL. Zidovudine, arsenic trioxide, interferon-α as well as its nucleoside analog deoxycoformycin, and allogeneic hematopoietic stem-cell transplantation are the new therapeutic options in ATLL. Potential strategies under investigation include targeted therapies like monoclonal antibodies against CD25, CD2, CD52, and chemokine receptor 4; histone deacetylase inhibitors such as vorinostat; a novel antifolate pralatrexate; a purine nucleotide phosphorylase inhibitor forodesine; combination of the proteasome inhibitor bortezomib with high-dose CHOP chemotherapy; and antiangiogenic therapy.[8]

Mandatory screening of blood donors and pregnant women for HTLV-1 should be considered since prevention of transmission is of paramount importance in HTLV infection. Seropositive mothers should be advised to avoid prolonged breastfeeding of infants so as to reduce the risk of transmission to the next generation.[9] Studies evaluating strategies to prevent ATLL development in HTLV-1 carriers are also ongoing.[8]

Conclusion

Our case emphasizes that adult T-cell leukemia/lymphoma can occur in nonendemic areas like India and may exhibit an aggressive course. Chronic type of ATLL is to be suspected in nonresponding cases of MF, as they often present without hypercalcemia or the characteristic ‘flower cells.’ Timely diagnosis and early initiation of treatment with the new therapeutic regimens may offer better 5-year survival rates in future.[8]