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On-line version ISSN 1678-9946
Rev. Inst. Med. trop. S. Paulo vol.43 no.5 São Paulo Sept./Oct. 2001
ADULT T-CELL LEUKEMIA/LYMPHOMA ASSOCIATED WITH HTLV-1 INFECTION IN A BRAZILIAN ADOLESCENT
Antonio Carlos Francesconi do VALLE(1), Maria Clara Gutierrez GALHARDO(1), Ana Claudia Celestino LEITE(1), Abelardo Queiroz Campos ARAÚJO(1), Tullia CUZZI-MAYA(1), Juan Piñeiro MACEIRA(2) & Jane de Almeida DOBBIN(3)
We present the case of a 15-year-old patient infected with HTLV-1 who developed a cutaneous T-cell lymphoma, confirmed by histopathological and immunohistochemical examination, as well as clinically and hematologically confirmed leukemia. The patient died 3 months after initial presentation of the disease. The rarity of the disease in this age group justifies the present report.
KEYWORDS: HTLV-1; Leukemia; T-cell lymphoma; Adult T-cell leukemia/lymphoma
Human T-cell lymphotropic (HTLV) viruses are retroviruses classified in 2 groups, HTLV-1 and HTLV-2, which predominantly infect CD4 and CD8 cells, respectively.
HTLV-1 mainly infects inhabitants of southern Japan16,41, equatorial Africa8, Malasia50, the Caribbean6, South America (Brazil34, Colombia51, Peru19, Chile44, Argentina14, and Uruguay28), and the southern United States5,46. In Brazil, since the introduction of HTLV-1 screening tests in blood centers, the virus has been found among blood donors with a prevalence varying from state to state. The highest rate is in Bahia (1.8%) and the lowest in Santa Catarina (0.08%)2.
HTLV-1 is transmitted by the following routes: sexual21,29; parenteral, by way of blood product transfusion17; contaminated needles and syringes35 and vertically, through maternal milk27,29.
HTLV-1 has been associated thus far with adult T-cell leukemia/lymphoma (ATLL)32 and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)12. The possible association of HAM/TSP with ATLL was reported by KAWANO et al.20 and SHARATA et al.40, but simultaneous presentation of the two diseases in the same individual is rare. Other diseases may be associated with HTLV-1, including arthropathies, pneumopathies, uveitis11,30, and dermatologic diseases, including xerosis, eczematoid seborrhea15, crusty scabies37, balding folliculitis decalvans1, infective dermatitis24, and prurigo39. However, most HTLV-1-infected individuals do not develop any disease, thus constituting asymptomatic carriers.
The first reference to ATLL was by UCHIYAMA et al. in 197743 and POIESZ et al.32. HINUMA et al.16 later observed the association between ATLL and HTLV-1. Subsequent studies have confirmed this association34,49. ATLL is more common in areas where HTLV-1 is endemic. Patients with ATLL are usually infected before the age of 20 years, and their relatives have a high prevalence of HTLV-1 infection. The disease does not usually appear in more than one member of the family14. Epidemiological studies focusing on ATLL demonstrate that some 2 to 4% of infected patients develop neoplasias after a latent period of 20 to 30 years, thus making it an adult disease. Sexual contact and breastfeeding are the main infection routes in these patients14. The cutaneous manifestations of ATTL are common and have different types of lesions7,10.
We present the case of a 15 year-old HTLV-1-infected patient who developed a cutaneous lymphoma of T-cell origin, confirmed by histopathological and immunohistochemical examination, and clinically and hematologically verified leukemia.
T.C.S., male, 15 year-old, student, mixed-race, born in Rio de Janeiro, with HTLV-1 infection diagnosed in July 1997. The patient's parents were known to be infected since 1997, and the patient denied prior sexual contact and drug use. The patient came to the Evandro Chagas Hospital/FIOCRUZ because of a erythematous infiltrating lesion on his face (Fig. 1) and papulotuberous pruriginous cutaneous lesions on the upper limbs and torso (Fig. 2) which had appeared one month previously. Two skin biopsies were performed. Histopathological examination showed dermal infiltration of medium-to-large-sized lymphocytes with hyperchromatic nuclei that varied in size and shape with moderately pleomorphic lymphoid cells (Fig. 3a). These cells were more intensely and diffusely distributed in material from the ear (Fig. 3b) and mainly located around vessels in material from the upper limb. Discrete epidermotropism was present in addition to nuclear dust and rare mitotic figures (< 1/10 high power field), particularly in the sample in which the cellular infiltrate was more exuberant. Neither multinuclear tumor cells nor Pautrier microabscesses were observed. Using the immunohistochemical technique, at least half of the cellular infiltrate presented the CD45-RO antigen (Fig. 4) . In the setting of positive HTLV-1 serology and a clinical picture involving skin lesions, the histopathological findings were considered compatible with ATLL. The patient soon developed adynamia and fever. The cutaneous lesions became infiltrated, and hard loose cervical lymph nodes appeared, in addition to hepatosplenomegaly. Blood cell count showed a hematocrit of 45.1% with a white cell count of 57,800, platelet count of 152,000, and lymphoid lineage with a convoluted or clover-like nuclear contour (polymorphism). Given these findings, the diagnosis of HTLV-1 associated with ATLL was made. Rapid disease progression was observed with a worsening of the skin lesions, bent and salient sternum, splenomegaly, and enlargement of the superior mediastinum. Further tests revealed LDH of 1035 U/I and calcium of 10.7 mg/l. The patient was classified as acute-type ATLL and began treatment with alpha-interferon associated with zidovudine. No clinical response was observed, and peripheral lymphocyte levels increased. Systemic chemotherapy was begun. There was an approximately 30% reduction in the size and number of the skin lesions, although the leukemia persisted. The patient developed abdominal pain and sepsis and died after 73 days, probably due to pulmonary hemorrhage.
HTLV-1 is endemic in some areas of Brazil, but prevalence of ATLL is still unknown. HTLV-1 infection was demonstrated in 11 patients out of a series of 14 with ATLL, using serological and/or DNA methods34. Another study in Brazil had also detected HTLV-1 infection in 26% of 188 patients with T-cell lymphoma33. The age bracket for onset of lymphoma is 40-60 years, although in a review of 28 cases of ATLL in the state of Bahia, 6 cases were found under 30 years of age3.
Our patient had no history of blood transfusion, drug use, or sexual contact, and was probably infected by breastfeeding, with a latent period of 15 years. Development of this neoplasia appears to be associated with this transmission route42. A literature review shows that ATLL is quite rare in patients under 16 years of age3,9,13,22,26, 34,45,48. The term "adult T cell leukemia/lymphoma" may be inappropriate insofar as it does not occur only in adults.
In relation to the patient's family, the mother was an HTLV-1 carrier and the father, despite being the case index for HTLV-1 infection through blood donation, refused to be investigated for the disease. The patient's sister had negative HTLV-1 serology. It has been reported that individuals receiving blood transfusions with HTLV-1 develop paraparesis rather than ATLL. In a recent cohort study that included this patient, no HTLV-1 tax polymorphism was associated with specific manifestations of the infection36.
Concerning the patient's ethnic group, higher prevalence has been observed among black or mixed-race individuals34.
Our patient presented papulotuberous pruriginous cutaneous lesions in the upper limbs and torso and erythematous infiltrated lesions in the face, the differential diagnosis of which included lepromatous leprosy, secondary syphilis, drug-induced eruption, and T-cell cutaneous lymphoma. The diagnosis of acute subtype ATLL was made later with the aggravation of the skin lesions and the onset of systemic leukemia symptoms detected by the blood count, hypercalcemia, increased blood LDH, and the aggressive course of the disease.
The patient initially responded well to chemotherapy, although presenting pancreatitis as a complication. He did not respond favorably to the association of alpha-interferon and AZT, contrary to the results reported by BAZARBACHI & HERMINE4, in which that regimen was beneficial in 8 of 10 patients. Three months later he developed a sudden neurological complication and he died of probable pulmonary hemorrhage.
Histologically, skin involvement in ATTL is characterized by the presence of atypical lymphocytes in focal clusters or dispersed in the dermal tissue. Epidermotropism is seen in varying degrees18,25,31,47. In one of our samples, the neoplastic cells showed a clear perivascular distribution, but without destruction of vessel walls; it has been shown that different infiltration patterns can be present when several tissue samples are obtained from different lesions in the same patient47. Since the histological alterations can be similar to those found in fungoid mycosis25, detection of HTLV-1 by tissue polymerase chain reaction can be used to diagnose these cases23,38.
In endemic areas for HTLV-1 infection, several inflammatory skin conditions can mimic ATLL, making early diagnosis and immediate treatment extremely important in light of the infection's aggressive course. In this case we identified precisely such an association, and at an early age.
Leucemia/linfoma de células T do adulto associado a infecção pelo HTLV-1 em adolescente brasileiro
Apresentamos o caso de um adolescente de 15 anos de idade com infecção pelo HTLV-1 que desenvolveu linfoma cutâneo de células T, confirmado por exame histopatológico e imunohistoquímico, assim como leucemia, diagnosticada por exame clínico e avaliação de sangue periférico. O paciente morreu 3 meses após o início da doença. A raridade da doença nesta faixa etária justifica o relato de caso.
The authors wish to thank Laboratório de Produção e Tratamento de Imagens/Instituto Oswaldo Cruz.
1. ARAÚJO, A.Q.C.; ANDRADA-SERPA, M.J.; PAULO-FILHO, T.A.; RODRIGUES, M.T. & PRADO, L.A.F. - Folliculitis decalvans and HTLV-1 associated myelopathy/tropical spastic paraparesis. Clin. infect. Dis., 20: 696-699, 1995. [ Links ]
2. ARAÚJO, A.Q.C. - Tropical spastic paraparesis in Brazil. In: ZANIZOVIC, V., ed. Human Virology. Cali, Fund. Mar., 1996. [ Links ]
3. BARBOSA, H.S., BITTENCOURT, A.L.; BARRETO DE ARAUJO, I. et al. - Adult T-cell leukemia/lymphoma in northeastern Brazil: a clinical, histopathologic, and molecular study. J. Acquir. Immune Defic. Syndr., 21: 65-71, 1999. [ Links ]
4. BAZARBACHI, A. & HERMINE, O. - Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J. AIDS hum. Retrov., 13(suppl): S186-S190, 1996. [ Links ]
5. BLAYNEY, D.W.; BLATTNER, W.A.; ROBERT-GUROFF, M. et al. - The human T-cell leukemia-lymphoma virus in the southeastern United States. J. Amer. med. Ass., 250: 1048-1052, 1983. [ Links ]
6. DE THÉ, G.; GESSAIN, A.; GAZZOLO, L. et al. - Comparative seroepidemiology of HTLV-I and HTLV-III in the French West Indies and some African countries. Cancer Res., 45(suppl. 9): S4633-S4636, 1985. [ Links ]
7. DICAUDO, D.J.; PERNICIARO, C.; WORRELL, J.T.; WHITE Jr., J.W. & COCKERELL, C.J. - Clinical and histologic spectrum of human T-cell lymphotropic virus type I-associated lymphoma involving the skin. J. Amer. Acad. Derm., 34: 69-76, 1996. [ Links ]
8. FLEMING, A.F.; MAHARAJAN, R.; ABRAHAM, M. et al. - Antibodies to HTLV-I in Nigerian blood-donors, their relatives and patients with leukaemias, lymphomas and other diseases. Int. J. Cancer, 38: 809-813, 1986. [ Links ]
9. FOUCAR, K.; CARROLL Jr., T.J.; TANNOUS, R. et al. - Nonendemic adult T-cell leukemia/lymphoma in the United States: report of two cases and review of the literature. Amer. J. clin. Path., 83: 18-26, 1985. [ Links ]
10. FOUCHARD, N.; MAHE, A.; HUERRE, M. et al. - Cutaneous T cell lymphomas: mycosis fungoides, Sezary syndrome and HTLV-I associated adult T cell leukemia (ATL) in Mali, West Africa: a clinical, pathological and immunovirological study of 14 cases and review of the African ATL cases. Leukemia, 12: 578-585, 1998. [ Links ]
11. FURUYA, T.; NAKAMURA, T.; GOTO, H. et al. - HTLV-I associated myelopathy associated with multi-organ inflammatory disease: a case report. J. neurol. Sci., 157: 109-112, 1998. [ Links ]
12. GESSAIN, A.; BARIN, F.; VERNANT, J.C. et al. - Antibodies to human T lymphotropic virus type 1 in patients with tropical spastic paraparesis. Lancet, 2: 407-410, 1985. [ Links ]
13. GILL, P.S.; HARRINGTON Jr., W.; KAPLAN, M.H. et al. - Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. New Engl. J. Med., 332: 1744-1748, 1995. [ Links ]
14. GIOSEFFI, O.N.; NUCIFORA, E.; FANTL, D. et al. - Leucemia-linfoma T del adulto HTLV-1 positiva en Argentina. Sangre (Barcelona), 40: 421-424, 1995. [ Links ]
15. HASHIGUSHI, T.; OSAME, M. & ARIMURA, K. - Skin manifestations in HTLV-I associated mielopaty (HAM): xerosis and erythema. In: ROMAN, C.G.; VERNANT, J.C. & OSAME, M. HTLV-I and nervous system. New York, Alan L. Liss, 1989. p. 443-448. [ Links ]
16. HINUMA, Y.; KOMODA, H.; CHOSA, T. et al. - Antibodies to adult T-cell leukemia-virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide sero-epidemiology study. Int. J. Cancer, 29: 631-635, 1982. [ Links ]
17. JASON, J.M.; Mc DOUGAL, J.S.; CABRADILLA, C.; KALYANARAMAN, V.S. & EVATT, B.L. - Human T-cell leukemia virus (HTLV-I) p24 antibody in New York City blood product recipients. Amer. J. Hemat., 20: 129-137, 1985. [ Links ]
18. JIMBOW, K. & JEWELL, L.D. - Lymphoid proliferation and lymphoma associated with human retroviruses (HTLV and HIV). Int. J. Derm., 30: 605-613, 1991. [ Links ]
19. JOHNSON, R.T.; GRIFFIN, D.E.; ARREGUI, A. et al. - Spastic paraparesis and HTV-1 infection in Peru. Ann. Neurol., 23(suppl.): S151-S155, 1988. [ Links ]
20. KAWANO, F.; TSUKAMOTO, A.; SATOH, M. et al. - HTLV-I associated myelopathy/tropical spastic paraparesis with adult T-cell leukemia. Leukemia, 6: 66-67, 1992. [ Links ]
21. KHABBAZ, R.F.; DARROW, W.W.; HARTLEY, J. et al. - Seroprevalence and risk factors for HTLV-I/II infection among female prostitutes in the United States. J. Amer. med. Ass., 263: 60-64, 1990. [ Links ]
22. KINOSHITA, K.; KAMIHIRA, S.; IKEDA, S. et al. - Clinical, hematologic, and pathologic features of leukemic T-cell lymphoma. Cancer, 50: 1554-1562, 1982. [ Links ]
23. KIKUCHI, A.; OHATA, Y.; MATSUMOTO, H.; SUGIURA, M. & NISHIKAWA, T. Anti-HTLV-I antibody positive cutaneous T-cell lymphoma. Cancer, 79: 269-274, 1997. [ Links ]
24. LENZI, M.E.R.; ARAÚJO, A.Q.C.; CUZZI-MAYA, T. et al. - Dermatite, «ïnfectiva» associada ao HTLV-I. Relato de caso. An. bras. Derm., 71: 115-118, 1996. [ Links ]
25. LESSIN, S.R.; VOWELS, B.R. & ROOK, A.H. - Retroviruses and cutaneous T-cell lymphoma. Derm. Clin., 2: 243-253, 1994. [ Links ]
26. LIN, B.T.Y.; MUSSET, M.D; SZÉKELY, A.M. et al. - Human T-cell lymphotropic virus-1-positive T-cell leukemia/lymphoma in a child. Report of a case and review of the literature. Arch. Path. Lab. Med., 121 : 1282-1286, 1997. [ Links ]
27. MANNS, A. - Natural history of HTLV-I infection: relationship to leukemogenesis. Leukemia, 7(suppl. 2): S75-S77, 1993. [ Links ]
28. MUCHINIK, G.; BOUZAS, M.; ZAPIOLA, I. et al. - HTLV-I and HTLV-II infection in Uruguay. J. Acquir. Immune Defic. Syndr., 5: 743-744, 1992. [ Links ]
29. MURPHY, E.L.; FIGUEROA, J.P.; GIBBS, W.N. et al. - Sexual transmission of human T-lymphotropic virus type I (HTLV-I). Ann. intern. Med., 111: 555-560, 1989. [ Links ]
30. NEVES, E.S.; ARAÚJO, A.Q.C.; LEITE, A.C.C.B. et al. - Espectro clínico da infecção pelo HTLV-I. Arq. bras. Med., 70: 137-141, 1996. [ Links ]
31. OHTAKE, N.; SETOYAMA, M.; FUKUMARU, S. & KANZAKI, T. - A case of adult T-cell leukemia/lymphoma (ATLL) with angiocentric and angiodestructive features. J. Derm., 24: 165-169, 1997. [ Links ]
32. POIESZ, B.J.; RUSCETTI, F.W.; GAZDAR, A.F. et al. - Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. nat. Acad. Sci. (Wash.)., 77: 7415-7419, 1980. [ Links ]
33. POMBO DE OLIVEIRA, M.S.; MATUTES, E.; SCHULZ, T. et al. - T-cell malignancies in Brazil. Clinico-pathological and molecular studies of HTLV-I positive and negative cases. Int. J. Cancer, 60: 823-827, 1995. [ Links ]
34. POMBO DE OLIVEIRA, M.S.; MATUTES, E.; FAMADAS, L.C. et al. - Adult T-cell leukaemia/lymphoma in Brazil and its relation to HTLV-I. Lancet, 336: 987-990, 1990. [ Links ]
35. ROBERT-GUROFF, M.; WEISS, S.H.; GIRON, J.A. et al. - Prevalence of antibodies to HTLV-I, -II, and III in intravenous drug abusers from an AIDS endemic region. J. Amer. med. Ass., 255: 3133-3137, 1986. [ Links ]
36. SAMBOR, A.M.; POMBO DE OLIVEIRA, M.S.; FARHADI, A. et al. - Human T-lymphotropic virus type I tax polymorphisms in a transmission cohort: no association between sequence variation and disease manifestations. J. hum. Virol., 2: 308-314, 1999. [ Links ]
37. SANTOS, I.; SANTOS, I.B.; PEREIRA, T. dos S.; VASCONCELOS, G.B. & LIMA, R.A.S.A. - Sarna crostosa em paciente portador do retrovírus HTLV -1. An. bras. Derm., 70: 49-51, 1995. [ Links ]
38. SETOYAMA, M.; KERDEL, F.A.; ELGART, G.; KANZAKI, T. & BYRNES, J.J. - Detection of HTLV-I by polymerase chain reaction in situ hybridization in adult T-cell leukemia/lymphoma. Amer. J. Path., 152: 683-689, 1998. [ Links ]
39. SETOYAMA, M.; MIZOGUCHI, S. & KANZAKI, T. - Prurigo as a clinical prodrome to adult T-cell leukaemia/lymphoma. Brit. J. Derm., 138: 137-140, 1998. [ Links ]
40. SHARATA, H.H.; COLVIN, J.H.; FUJIWARA, K.; GOLDMAN, B. & HASHIMOTO, K. - Cutaneous and neurologic disease associated with HTLV-I infection. J. Amer. Acad. Derm., 36: 869-871, 1997. [ Links ]
41. TAJIMA, K. & TOMINAGA, S. - Epidemiology of adult T-cell leukemia/lymphoma in Japan. Curr. Top. Microbiol. Immunol., 115: 53-66, 1985. [ Links ]
42. TSUJI, Y.; DOI, H.; YAMABE, T. et al. - Prevention of mother-to-child transmission of human T lymphotropic virus type 1. Pediatrics, 86: 11-17, 1990. [ Links ]
43. UCHIYAMA, T.; YODOI, J.; SAGAWA, K.; TAKATSUKI, K. & UCHINO, H. - Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood, 50: 481-492, 1977. [ Links ]
44. VASQUEZ, P.; SANCHEZ, G.; VOLANTE, C. et al. - Human T-lymphotropic virus type I: new risk for Chilean population. Blood, 78: 850-851, 1991. [ Links ]
45-VILMER, E.; LE DEIST, F.; FISCHER, A. et al. - Smouldering T lymphoma related to HTLV-1 in a Sicilian child. Lancet, ii: 1301, 1985. [ Links ]
46. WEINBERG, J.B.; SPIEGEL, R.A.; BLAZEY, D.C. et al. - Human T-cell lymphotropic virus 1 and adult T-cell leukemia: report a cluster in North Carolina. Amer. J. Med., 85: 51-58, 1988. [ Links ]
47. WHITTAKER, S.J.; NG, Y.L.; RUSTIN, M. et al. - HTLV-1 associated cutaneous disease: a clinicopathological and molecular study of patients from the U.K. Brit. J. Derm., 128: 483-492, 1993. [ Links ]
48. WILLIAMS, C.K.O.; ALEXANDER, S.S.; BODNER, A. et al. - Frequency of adult T-cell leukaemia/lymphoma and HTLV-I in Ibadan, Nigeria. Brit. J. Cancer, 67: 783-786, 1993. [ Links ]
49. YAMAGUCHI, K.; SEIKI, M.; YOSHIDA, M. et al - The detection of human T-cell leukemia virus proviral DNA and its application for classification and diagnosis of T cell malignancy. Blood, 63: 1235-1240, 1984. [ Links ]
50. YANGIHARA, R.; JENKINS, C.L.; ALEXANDER, S.S.; MORA, C.A. & GARRUTO, R.M. - Human T lymphotropic virus type infection in Papua New Guinea: high prevalence among the Hagahai confirmed by Western analysis. J. infect. Dis., 162: 649-654, 1990. [ Links ]
51. ZANINOVIC, V. & BIOJO, R. - El vírus HTLV-1 como posible causa de la paraparesia espastica del pacifico. Colombia méd., 17: 2-8, 1986. [ Links ]
Received: 13 March 2001
Accepted: 25 May 2001
(1) Centro de Pesquisa Hospital Evandro Chagas/Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
(2) Hospital Universitário Clementino Fraga Filho/Universidade Federal do Rio de Janeiro, RJ, Brasil.
(3) Instituto Nacional do Câncer
Correspondence to: Antonio Carlos Francesconi do Valle, Centro de Pesquisa Hospital Evandro Chagas/Fundação Oswaldo Cruz, Av. Brasil 4365, 22045-900 Rio de Janeiro, RJ, Brazil. Tel./fax: (55-21) 590-9988. e.mail: firstname.lastname@example.org