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3. HTLV IandATLLBlood Manifestation A.Shirdel MD Associated Prof. Of MUMSGhaemHaspital

5. Human T cell Leukemia Virus type I (HTLV-I) • Associated with 2 fatal human diseases • Adult T cell leukemia (ATL) • clonal malignancy of infected mature CD4+ T cells • Tropical spastic paraparesis/HTLV-1 associated myelopathy • neurodegenerative disease

6. Human T cell Leukemia Virus type I (HTLV-I) • Endemic in parts of Japan, South America, Africa, Caribbean and the Iran. • With an estimated 10-20 million people infected worldwide • Asymptomatic in majority of individuals with approximately 2-5% of HTLV-I carriers developing disease 20-40yrs post infection. • The long clinical latency and low percentage of individuals who develop leukemia suggest that T-cell transformation occurs after a series of cellular alterations and mutations. • Infects primarily CD4+ T cells.

7. HTLV 1 Transmission • Extended close contact (cell-associated virus) • Sexual (60% male to female versus 1% female to male transmission) • Blood products (screening of blood supply since 1988) • Mother to child (breast feeding: 20% children with seropositive mothers acquire virus)

8. Epidemiology of HTLV-I • HTLV-I infection occurs in clusters in certain geographic locations around the world. • It is endemic in Southern Japan (15-30%), Caribbean (3-6%), Papua New Guinea and some parts of Africa Iran

9. Epidemiology of HTLV-I • Appears to be transmitted sexually and through blood. • Vertical transmission is thought to play an important role in the maintenance of virus in areas of high endemicity.

10. Epidemiology of HTLV-I • Transmission through breast milk is implicated as a major route for the maintenance of infection in high prevalence areas. • Seroprevalence of HTLV-I increases with age • Is twice as high in females than males.

11. Epidemiology of HTLV-II • Is particularly common in : • IV drug abusers, • Has been found in clusters among certain South American Indians.

12. Manifestations of HTLV-I Adult T-cell leukaemia An incubation period of 15 to 20 years have been suggested for the development of ATL.

13. In the United States as a whole, the incidence of ATLL is approximately 0.05 cases per 100,000 population ATLL is more common in Black Americans than White Americans and there is a slight male predominance overall The median age at diagnosis is in the sixth decade However, median age at diagnosis can vary with geographic location

14. infection with this virus can indirectly cause many other diseases via the induction of immunodeficiency, such as : chronic lung disease, chronic renal failure opportunistic lung infection, strongyloidiasis cancer of other organs, monoclonalgammopathy, non-specific dermatomycosis, HTLV-I-associated lymphadenitis, HTLV-I uveitis HTLV-I-associated myelopathy-tropical spastic paraparesis (HAM/TSP)

15. PATHOGENESIS   Adult T-cell lymphoma/leukemia (ATLL) is associated with HTLV-I infection of the tumor clone in 100 percent of cases In all malignant cells in an affected individual, the HTLV-I pro-viral genome is incorporated into an identical location of the genome Whether the particular insertion location affects the phenotype of the cell is unclear

16. The long-term risk of developing ATLL following infection with HTLV-I in endemic areas has been estimated to be 4 to 5 percent, usually after a latency period of several decades Exposure to the virus early in life increases the risk of eventual development of ATLL. A shorter latency period has been noted in infected patients receiving treatment with immunosuppressive agents for other reasons

17. The exact mechanism by which HTLV-I contributes to tumor development is unknown. However, increasing evidence suggests that the viral regulatory gene tax (transactivating gene of the X region) encodes an oncoprotein, named tax protein The gene product induces cellular proliferation, promotes cellular survival, and impairs DNA damage repair mechanisms

18. Clinical Syndromes Reported in Association with Human T-Cell Lymphotropic Virus Types I and II (HTLV-I and HTLV-II) Adult T-cell leukemia/lymphoma Atypical hairy cell leukemia? Large granular lymphocytic leukemia? HTLV associated myelopathy Myelopathy, cerebellar ataxia Mycosis fungoides? Mycosis fungoides? Increased susceptibility to infections Increased susceptibility to infections Polymyositis Myositis Uveitis Arthropathy Sjogren's syndrome Pulmonary syndrome, alveolitis Infectious dermatitis HTLV-I HTLV-II

19. ATLL according to the most recent (WHO) classification of lymphoid neoplasms Defined as a peripheral T-cell neoplasm associated with infection by the HTLV-I

20. Other T cell lymphomas include: • Mycosis fungoides • T cell large granular lymphocytic leukemia • T cell prolymphocytic leukemia • Anaplastic large cell lymphoma • Peripheral T cell lymphoma • Precursor T cell lymphoblastic leukemia ( These disorders are not caused by HTLV-1)

22. CLINICAL FEATURES include evidence of: • Generalized lymphadenopathy • Hepatosplenomegaly • Immunosuppression • Hypercalcemia • Lytic bone lesions • Skin lesions

23. Clinical variants Several clinical variants of ATLL have been described: • Acute • Lymphomatous • Chronic • Smoldering

24. Progression from chronic and smoldering disease to aggressive disease resembling the acute variant eventually occurs in up to 25 percent of cases

25. Acute • The most common presentation of ATLL • Occurring in about 60 percent of cases • Has a generally poor prognosis with survival measured in months to a year

26. Patients most frequently present with systemic symptoms: • Organomegaly • Lymphadenopathy • Hypercalcemia • Elevated lactate dehydrogenase (LDH) • Circulating malignant cells.

27. Common presenting signs or symptoms include: • A high WBC is common due to the presence of circulating lymphocytes with highly abnormal convoluted nuclei • Bone marrow involvement is observed in approximately 35 percent of cases. • Generalized lymphadenopathy is seen in almost all cases. • Hepatosplenomegaly is present in approximately 50 percent. • One-half will have hypercalcemia with or without lytic bone lesions at presentation • Additional third will develop hypercalcemia at some point during the course of their disease • Approximately 50 percent will have skin lesions at diagnosis

28. Less common clinical features may include: • Interstitial pulmonary infiltrates, which may be due to pneumocystis jirovecii pneumonia • Central nervous system involvement with mass lesions on imaging

29. Lymphomatous • Accounts for approximately 20 percent of cases • Characterized by prominent lymphadenopathy without blood involvement. • Patients frequently have an elevated LDH level and hypercalcemia. • Prognosis is poor with a survival similar to that of patients with the acute variant

30. Chronic • Approximately 15 percent of cases are a chronic variant • Characterized by an: • Increased white blood cell count with absolute lymphocytosis which may be stable for months to years • Skin lesions • Mild lymphadenopathy. • These patients have no hepatosplenomegaly or hypercalcemia • Normal or only slightly increased LDH level (less than twice the upper limit of normal). • This variant has a better prognosis than the acute and lymphomatous variants with survival measured in years

31. Smoldering • Is least common: • Accounting for approximately 5 percent of cases • These patients are often asymptomatic • Skin and/or pulmonary lesions are common. • Normal blood lymphocyte counts with <5 percent circulating neoplastic cells and normal calcium levels. • Median survival is more than five years.

32. CUTANNEUS MANIFESTATION OF ATL • Erythematous patches • Erythroderma • Maculopapular • Papules • Plaques • Tumors • Ulcer

33. Hypercalcemia and lytic bone lesions • In the acute variant, approximately 70 percent of patients will have hypercalcemia at some point in their disease course • 40 percent will have lytic bone lesions . Hypercalcemia can be severe with calcium levels as high as 21 mg/dL (5.25 mmol/liter). • Signs and symptoms related to hypercalcemia such as renal dysfunction or neuropsychiatric disturbances may be prominent

34. Hypercalcemia seen in ATLL is paraneoplastic in origin, and thought to arise from cytokines liberated from the malignant cells. • Their exact nature is not known • The following have been proposed: • Constitutive production of parathyroid hormone related protein (PTH-RP) • Tumor necrosis factor-beta or interleukin-1 These factors may also be the genesis of : • Lytic bone lesions • Increased bone turnover • Increased serum alkaline phosphatase

35. Immunosuppression Patients are immunosuppressed and at risk of developing opportunistic infections including : • Pneumocystis jirovecii pneumonia • Cryptococcus meningitis • Disseminated herpes zoster • Infestation by and dissemination of strongyloides stercoralis

36. Analysis of 818 patients with ATLL found that 213 (26 percent ) had infection at the time of diagnosis • Infection were more common in patients with the ACUTE , CHRONIC or SMOULDERING variant than in LYMPHOMATOUS

37. Of 465 patients with Acute ATLL following infections were found at diagnosis: • Bacterial (mostly pneumonia) in 12 percent • Fungal (mostly cutaneous) in 8 percent • Protozoal (mostly strongyloidiasis) in 5 percent • Viral (mostly herpes zoster ) in 3 percent • 339 patients were without infection at diagnosis (73 percent)

38. DIAGNOSIS Is based upon a combination of : • Characteristic clinical features • Morphologic and immunophenotypic changes of the malignant cells • Confirmation of HTLV – 1 • Identification of at least five percent tumor cells is often sufficient to make the diagnosis in acute , chronic , or smoldering type ATLL • In lymphomatous lesions should undergo an excisional biopsy and molecular analysis for HTLV 1 provirus integration.

39. My God!