E-IJD CASE SERIES
|Year : 2015 | Volume
| Issue : 1 | Page : 103
|Multifaceted adult T-cell leukemia/lymphoma in India: A case series
Anza Khader1, Mohamed Shaan2, Sunitha Balakrishnan3, Betsy Ambooken1, Kunnummel Muhammed1, Uma Rajan1
1 Department of Dermatology, Government Medical College, Calicut, Kerala, India
2 Department of Medicine, Government Medical College, Calicut, Kerala, India
3 Department of Pathology, Government Medical College, Calicut, Kerala, India
|Date of Web Publication||26-Dec-2014|
Department of Dermatology and Venereology, Government Medical College, Calicut-673 008, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background : Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell lymphotropic virus type-1 (HTLV-1). India is considered as a nonendemic region for HTLV-1. Recent upsurge of cases have been noted in southern parts of India. Aims and objectives: The objective was to describe skin manifestations in various types of ATL. Materials and Methods: Clinical examination, blood investigations, skin biopsies, lymph node biopsies, and immunohistochemistry were performed in five patients. Flow cytometry was performed in two cases. Results: Serological testing was positive for HTLV-1 in all patients. All patients presented with skin lesions. Rare presentations of molluscum contagiosum like papules, purpuric macules and plaques, hypopigmented macules and verrucous papules were seen. Dermatophytic infections occurred in two patients. Mucosal lesion was seen in one patient. Histological features include dermal lymphoid infiltrate with or without epidermotropism. Presence of epidermotropism did not correlate with the severity of disease. All patients except one succumbed to illness within few months to 1 year period. Conclusions: ATL manifest in myriad presentations and skin lesions are often the earliest manifestation. Cutaneous manifestations of ATL vary from subtle hypopigmented macules to florid nodular lesions, and HTLV-1 screening need to be carried out in all doubtful cases.
Keywords: Adult T-cell leukemia/lymphoma, India, skin lesions
|How to cite this article:|
Khader A, Shaan M, Balakrishnan S, Ambooken B, Muhammed K, Rajan U. Multifaceted adult T-cell leukemia/lymphoma in India: A case series. Indian J Dermatol 2015;60:103
|How to cite this URL:|
Khader A, Shaan M, Balakrishnan S, Ambooken B, Muhammed K, Rajan U. Multifaceted adult T-cell leukemia/lymphoma in India: A case series. Indian J Dermatol [serial online] 2015 [cited 2020 Feb 21];60:103. Available from: http://www.e-ijd.org/text.asp?2015/60/1/103/147846
What was known?
- ATL is rarely reported from India.
- ATL is known to cause skin lesions.
| Introduction|| |
Adult T-cell leukemia/lymphoma (ATL) was first recognized in 1977 in Kyoto, Japan by Uchiyama and coworkers as an aggressive leukemia/lymphoma of mature T lymphocytes.  Human T-cell lymphotropic virus type-1, the pathogen of ATL, was first isolated from a patient with an aggressive variant of mycosis fungoides only 3 years later. HTLV-1 is endemic in southwestern Japan, especially Kyushu and Okinawa, in the Caribbean Islands, and in central Africa. Majority of HTLV-1 transmission occurs via one of three routes, all of which require the passage of virus-infected cells. HTLV-1 carrier mothers transmit the virus to newborns mainly through breast milk. HTLV-1 can be transmitted from individual to individual by sexual contact especially males to females, through blood transfusions and sharing of contaminated intravenous needles.  After infection by HTLV-1, only a subpopulation of carriers (6% male and 2% female subjects) develop ATL after a long latent period. 
India is a nonendemic region for HTLV-1. ATL has been rarely reported from India. We at a tertiary health care center in northern Kerala observed an upsurge of ATL recently. We describe five cases of ATL of varied types: Acute, chronic, lymphomatous, and smoldering forms; all presented initially with skin lesions. HTLV-1 screening needs to be done in dubious skin lesions with or without lymph node enlargement.
| Materials and Methods|| |
A detailed history was obtained and thorough clinical examination was done in five patients. Blood samples were tested for HTLV-1 antibodies by enzyme linked immunosorbent assay (ELISA). Skin biopsy was done in all patients and lymph node biopsy in those with lymphadenopathy and subjected to tissue microscopy and immunohistochemistry for CD3, CD4, CD8, and CD20. Flow cytometry was performed on peripheral blood lymphocytes in relevant cases.
| Results|| |
A 58-year-old lady whose mother died of some unknown malignancy, presented with multiple pruritic disseminated erythematous papules - some umbilicated and crusted, annular plaques and nodules over the scalp, forehead, and extensor aspect of forearms accompanied by generalized lymph node enlargement and bilateral pitting pedal edema. Investigations revealed an elevated total leukocyte count, serum lactate dehydrogenase (LDH), blood urea nitrogen, and low serum albumin 2.1 g. Serum calcium and alkaline phosphatase (ALP) levels remained normal. ELISA test for human immunodeficiency virus (HIV) was negative. The peripheral smear showed atypical cells with indented nuclei constituting more than 5% of the peripheral lymphocytes. Biopsy from the nodules revealed infiltration of dermis with innumerable medium sized pleomorphic cells showing epidermotropism with the formation of Pautrier's microabscesses. The cells were CD3+, CD4+ but CD8- and CD20- on immunohistochemistry. Skull X-ray and bone marrow trephine biopsy were normal. HTLV-1 ELISA was positive. Chronic type ATL was diagnosed in view of skin lesions, histopathological and immunohistochemical features, and normal calcium levels. Despite treatment with interferon-α and zidovudine she died 1 year after the initial presentation.
A 32-year-old male with history of hypopigmented macules over chest and trunk of 1 year duration, presented with pruritic purpuric macules and plaques over face, trunk, and extremities and purpuric annular plaque over medial aspect of thighs of 20 days duration [Figure 1]. Wet purpura was present over hard palate and buccal mucosa [Figure 2]. Patient had submandibular, cervical, epitrochlear, and inguinal lymph node enlargement. Scraping for fungus from the annular purpuric plaque revealed plenty of hyphae. His total leukocyte count was elevated and peripheral smear revealed large number of atypical lymphocytes with cleaved nucleus [Figure 3] which were CD3+, CD5+, CD 25+, and CD7- by flow cytometry. Serum calcium, serum LDH, blood urea, and serum ALP were elevated. Platelet count was 2.04 lakhs/mm 3 and serum albumin 2.7 g. Dense infiltrate of medium sized atypical lymphocytes occupied the dermis with epidermotropism [Figure 4] in skin biopsy and similar infiltrate in lymph node biopsy which showed CD3+, CD4+, CD8-, and CD20- on immunohistochemistry. Patchy infiltrate of atypical lymphoid cells with irregular nuclei were found in the bone marrow trephine biopsy. Ultrasonography of abdomen showed bilateral bulky kidneys with raised echoes and loss of sinus fat and bilateral pleural effusion. Skull X-ray showed lytic lesions. HTLV-1 antibody was positive by ELISA and screening for HIV negative.
|Figure 1: Purpuric tinea corporis in patient 2 with acute adult T-cell leukemia/ lymphoma|
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|Figure 3: Peripheral smear of patient 2 showing atypical lymphoid cells with indented nuclei (hematoxylin and eosin stain (H and E), magnification 100× )|
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|Figure 4: Skin biopsy showing dense lymphoid infiltrate in the dermis with epidermotropism in patient 2 (H and E, magnification × 10)|
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Acute type of adult T-cell leukemia was diagnosed on the basis of skin lesions, histopathological and immunohistochemical features, leukemia with more than 5% atypical cells, osteolytic lesions, hypercalcemia, and pleural effusion.
The patient received two cycles of CHOP (cyclophosphamide, adriamycin, oncovin, prednisolone), succumbed to illness due to tumor lysis after second dose, 3 months after initial presentation.
A 62-year-old male whose mother died of lymphoma presented with pruritic skin lesions of 1 year duration and fever of 3 weeks duration. On examination, there were multiple verrucous and crusted papules [Figure 5] and plaques over forearm, dorsum of right hand and legs, cervical and axillary lymph node enlargement, and hepatosplenomegaly. He had elevated total leukocyte count with numerous atypical cells with cleaved nucleus in the peripheral smear and similar infiltrate in the bone marrow trephine biopsy which were CD3+, CD5+, CD25+ and CD7- by flow cytometry. Serum calcium, LDH, blood urea, serum uric acid, and serum ALP were elevated and serum albumin was low as 2.3 g. Skull X-ray was normal in spite of hypercalcemia. Skin biopsy revealed infiltrate of atypical lymphocytes in the dermis without epidermotropism and similar infiltrate in lymph node biopsy which showed CD3+, CD4+, CD8-, and CD2O- on immunohistochemistry. HTLV-1 antibody was positive by ELISA and screening for HIV negative.
Acute type ATL was diagnosed and patient received single dose CHOP. However, his condition deteriorated and he succumbed to illness, 1 month after diagnosis.
A 52-year-old male presented with pruritic erythematous annular plaque over right thigh and neck swelling of 3 months duration. On examination he had enlarged firm to hard nontender cervical, axillary, and inguinal lymph nodes and hepatosplenomegaly. Fungal hyphae were seen in the KOH smear from the thigh lesion and skin biopsy confirmed dermatophytosis. His total leukocyte count was normal with occasional atypical cells in peripheral smear. Lymph node biopsy revealed CD3+, CD4+, CD8-, and CD20- T-cell neoplasm with pleomorphic cells. Serum calcium, albumin, and blood urea nitrogen were normal. Serum LDH showed marked elevation. HTLV-1 antibody was positive by ELISA and screening for HIV negative.
Massive lymph node enlargement with T-cell infiltrate, without hypercalcemia and leukemia, lymphomatous type of ATLL was diagnosed and treated with six cycles of CHOP. While during chemotherapy size of lymph nodes regressed and patient was under follow-up for 3 months. Later patient developed rapid increase in size of lymph nodes and expired 10 months after the diagnosis.
A 30-year-old male with history of recurrent eczematous lesions in childhood presented with pruritic hypopigmented scaly macules [Figure 6] over back of 4 months duration. There was cervical lymph node enlargement without hepatosplenomegaly. The total leukocyte count showed mild elevation and few atypical cells in the peripheral smear. Serum calcium, albumin, and blood urea nitrogen were normal. Serum LDH was markedly elevated. Skin biopsy revealed infiltrate of CD3+, CD4+, CD8+, and CD20- atypical lymphocytes in the dermis with epidermotropism. HTLV-1 antibody was positive by ELISA and screening for HIV negative. Smoldering form of ATL was diagnosed in view of skin lesions, absence of hepatosplenomegaly, few atypical cells, and normal serum calcium. The patient denied treatment and is under follow-up for last 12 months.
| Discussion|| |
ATL has been classified into four clinical subtypes according to the clinical features: Acute, chronic, smoldering, and lymphomatous. 
The low incidence of ATL in Indian population may be due to the rarity of HTLV-1 infection. An analysis of blood donors from Mumbai showed a 1.9% prevalence of HTLV infection. A study from south India showed HTLV-1 prevalence of 3.7% among HIV-positive patients, while the rate was 0.3% in the HIV negative population.  Studies in Kerala found a lack of seroreactivity to HTLV-1 in cases of hematological malignancy. 
About nine cases of ATL have been reported from India of which four cases are from Kerala, south India. All cases presented with leukemia, however the exact subtype has not been mentioned except one which was reported as chronic form of ATL. ,,,,
Our case series include four different types of ATL so far described at a single center. We had two acute and one each of chronic, lymphomatous, and smoldering types of ATL [Table 1]. Two patients were in their 30's and others around 60. Males outnumbered females in a ratio of 4:1. Two patients had a history of fatal malignancies in their mothers, reflecting a mother to child transmission.
|Table 1: Clinical, investigative findings, and diagnosis of the patients|
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The mucocutaneous lesions observed included umbilicated and verrucous papules, annular plaques, nodules, hypopigmented and purpuric macules, purpuric tinea corporis, and wet purpura.
Cutaneous manifestations of ATL fall into any of the three following categories: (a) Lesions independent of ATL, (b) lesions prodromal to ATL, and (c) lesions subsequent to ATL. Crusted scabies, infectious dermatitis, pruritus, and prurigo may herald the onset of ATL.  Various types of specific cutaneous manifestations like macules, hypo- and hyperpigmentation erythematous, purpuric or flesh colored papules, plaques with or without ulceration, purpura, nodules, subcutaneous induration, erythroderma, ichthyosis, pompholyx like, granuloma annulare like, lichen planus like, vasculitic, angiodestructive, and acanthosis nigricans like have been described in ATL. ,,,, Vesiculobullous lesions are uncommon, but may occur resulting from marked epidermotropism and rapid disease onset.  Widespread dermatophytosis, viral, parasitic, and bacterial infections have been associated with the immunosuppressive nature of HTLV-1. All our patients presented with skin lesions, irrespective of the type of ATL. Rare presentations of molluscum contagiosum like papules, purpuric macules and plaques, hypopigmented macules, and verrucous papules were seen. Lymphomatous type had tinea corporis and no specific skin lesions. Acute type presented with purpuric tinea cruris and wet purpura which has not been reported earlier. It has been reported that the type of skin eruption is an independent prognostic factor for ATL. Patch or plaque type eruptions exhibited good prognosis. On the other hand multipapular, nodulotumoral, erythrodermic, or purpuric type eruptions showed poor prognosis.  Cutaneous-type, which is defined as cases of smoldering type predominantly involving skin with or without peripheral blood involvement has been proposed as a distinct clinical subtype. Prognosis of cutaneous-type ATL was reported to be poorer than that of smoldering-type without cutaneous involvement. 
Epidermotropism similar to that in mycosis fungoides is commonly present in ATL.  We noted epidermotropism in three of our cases (patients 1, 2, and 5). The chronic form (patient 1) had characteristic Pautrier's microabscess, and the other two lacked the same. Patient 3 with acute ATL had no epidermotropism. Presence of epidermotropism therefore need not correlate with the severity of the disease.
Infiltration and destruction of cutaneous blood vessels have been reported in ulcerated and purpuric skin lesions.  However, our patient with purpuric macules and plaques lacked any infiltration or damage to blood vessels. A characteristic immunophenotypic feature of ATL is increased expression of CD25, the interleukin-2 receptor.  Flow cytometry of blood and bone marrow aspirate of patients 2 and 3, respectively revealed CD25 expression in majority of cells.
In ATL patients, parathyroid hormone related peptide (PTH-rP) is frequently increased which induces receptor activator for nuclear factor (B (RANK) ligand expression on osteoblasts causing differentiation to osteoclasts accelerating bone resorption, resulting in hypercalcemia.  Despite hypercalcemia in two cases of acute ATL, only one of them developed osteolytic lesions of skull.
Bad prognostic factors in ATL include age > 40, high LDH, high blood urea nitrogen, low albumin, and hypercalcemia.  One of our acute ATL was in his 30s who succumbed to illness 3 months after diagnosis. Serum LDH levels was highest in smoldering form. High blood urea nitrogen, low albumin, and hypercalcemia was seen in both patients with acute ATL.
Liver invasion by ATL cells and impaired hepatic functions are frequent in HTLV-1 infection.  Serum ALP was found to be elevated in both acute and lymphomatous cases and not in chronic and smoldering variants. Mean survival time for acute, chronic, and lymphomatous types are 6, 24, and 10 months, respectively.  Our patients followed the same pattern in spite of treatment. None of our patients could afford allogenic stem cell transplantation which is thought to be curative. Survival is quite long for smoldering type and our only surviving patient continues to show no signs of systemic involvement for past 1 year.
Clinicians need to be aware of the varied cutaneous manifestations of ATL ranging from subtle hypopigmented macules to large nodular lesions, and HTLV-1 screening need to be carried out in all doubtful cases. Treatment of ATL is largely unsatisfactory to date, and therefore, we should target at preventive strategies to check the transmission of dreaded virus to forthcoming generations [Table 1].
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What is new?
- There is a clustering of ATL in south India.
- ATL presents with both skin and mucosal lesions.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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