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Adult T‐cell leukaemia/lymphoma in Brazil: A rare disease or rarely diagnosed?

2019; Wiley; Volume: 188; Issue: 4 Linguagem: Inglês

10.1111/bjh.16318

1365-2141

Carolina Rosadas, Marzia Puccioni‐Sohler, Augusto César Penalva de Oliveira, Jorge Casseb, Maísa Silva de Sousa, Graham P. Taylor,

Animal Disease Management and Epidemiology

Adult T-cell leukaemia/lymphoma (ATL), caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection has a median survival of 6–8 months. In Japan the incidence of ATL is about 10 times higher than HTLV-1-associated myelopathy (HAM) whilst in other regions the incidence of these consequences is similar. Brazil has a high prevalence of HTLV-1 with HAM cohorts described, but reports of ATL are sparse, leading to the concept that the incidence of ATL is low. Here, the number of ATL cases in Brazil was estimated and compared with cases in the national registry of cancer (RHC) (Ministério da Saúde do Brasil, 2012). Whether the incidence of ATL is genuinely low or ATL is under-diagnosed is discussed. First, using published estimates of HTLV-1 infected individuals in Brazil: 800,000 (Gessain & Cassar, 2012) – 2,500,000 (Carneiro-Proietti et al., 2002) and a life-time ATL risk of 4% (Iwanaga et al., 2012), 32,000–100,000 can be expected to develop ATL. Based on 75 years life expectancy in Brazil, 427–1,333 cases of ATL/year are expected. Second, ATL development is linked with mother-to-child transmission. Only 12 % of infections were considered to be acquired through this route but these 96,000–300,000 infant infections carry as much as 20% life-time ATL risk (Nunes et al., 2017). Thus, 19,200–60,000 carriers would develop ATL resulting in 256–800 cases/year. Third, ATL cases were estimated accounting for differences in HTLV-1 prevalence between Brazil`s regions, age and gender, resulting in 856 ATL cases/year (Table 1 and Table S1). However, from 1986–2016 only 369 ATL cases were reported in RHC an average of 12 per year (https://irhc.inca.gov.br/RHCNet/visualizaTabNetExterno.action) (Fig 1). Their age ranged from months to >85 years, with 8·4% of cases in paediatric patients; 51·8% were females. The states of São Paulo, Rio de Janeiro, Bahia, Minas Gerais and Pernambuco had the most registrations. The average time from initial investigation to diagnosis was 0·2 years (maximum 7 years) and to treatment was 0·27 years (maximum 10 years). In Japan, with a similar number of HTLV-1-infected carriers as Brazil, 800–1000 cases of ATL are diagnosed annually (Iwanaga et al., 2012). If the life-time risk of ATL in Brazil is the same as in Japan or the Caribbean the expected number of cases is ~100-fold higher than those reported but similar to the three estimates presented. Why then are reported cases so few? Since 1993, RHC was implemented in all units with procedures of high complexity in oncology, reaching 268 hospitals in 2012. The data obtained guides public health policies regarding cancer (Ministério da Saúde do Brasil, 2012). Despite that, the number of ATL notified cases is extremely low compared to the expected cases. However, 195 cases were identified over four years (48 cases/year) (Pombo De Oliveira et al., 1999) whilst 287 cases have been published in Brazil (Oliveira et al., 2017). Similarly, only three cases were reported in Pará during 31 years, whereas, a hospital-based study identified four patients with HTLV-1 and Non-Hodgkin lymphoma over 6 years, with 3·2% (4/126) HTLV-1 seroprevalence among patients with leukaemia/lymphoma (Barbosa, 2012). Even in research settings the definitive diagnosis of ATL was hampered by lack of resources. In an HTLV specialised centre in São Paulo, the number of diagnosed ATL cases increased 10-fold after an awareness campaign among clinicians. Most cases were cutaneous with at least one year of disease and with good overall health (personal communication APO). This suggests that acute ATL, the most severe presentation, remains undiagnosed or un-referred to specialised centres. Moreover, the states that reported the most ATL cases were those where the main HTLV research groups are stablished. In Japan there is a male predominance of ATL; in other regions, e.g. Jamaica, ATL occurs more frequently in females (Iwanaga et al., 2012). In Brazil no gender predominance was observed. The median age at ATL presentation in Brazil is lower than in Japan (44 vs. 68 years) (Iwanaga et al, 2012) and despite its name, there are reports of ATL in paediatric patients from different countries (Oliveira et al., 2018). In the RHC 31 cases (8·4%) occurred in children (<18 years old, including infants). These observations are important since long duration of infection, with acquisition of mutations during a life-time period, is considered important to the oncogenesis of ATL. It also highlights the necessity of routine surveillance for ATL in paediatric oncology. In the other hand, the relatively high percentage of paediatric cases also points to under diagnosis amongst adults. The time between the first consultation to diagnosis and treatment can be up to 7 and 10 years. This reflects the difficulty in the diagnosis even when we consider that those reported cases were seen in reference oncology units. This time can be essential for a better prognosis. The clinical manifestation of ATL is diverse, varying from very aggressive acute forms which are most common to chronic, indolent presentations (Carneiro-Proietti et al., 2002) although these constitute 15% of cases. Acute presentations with hypercalcaemia or opportunistic infections result in patients dying precipitously without a proper diagnosis. The data presented indicate that acute cases are rarely diagnosed in Brazil. The necessity of more studies regarding ATL in Brazil is clear. Medical training is essential. Many doctors in the country do not know about HTLV-1 despite its high prevalence (Zihlmann et al., 2012). Indeed, when HTLV-1 patients and their relatives listed their main difficulties in Brazil, the lack of knowledge about HTLV-1 among health professionals was the second most important complaint (data not published). Considering the complexity of clinical manifestation and diagnosis of ATL, the lack of knowledge among health professionals and difficult access to public health care in Brazil, especially in low-income areas, together with the evidence presented here, it is plausible that the reported low incidence of ATL is due to misdiagnosis rather than to low incidence. Further studies are urgently needed to understand the real scenario of this high mortality disease. Furthermore, public health policies aiming to reduce mother-to-child transmission are essential to prevent the majority of ATL cases and should be implemented in the country. The authors declare no conflict of interest. The authors received no specific funding for this work. JC has received scholarship from CNPq and Fapesp. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.