Short Communication: Aggressive Adult T Cell Leukemia/Lymphoma: The Tip of the Iceberg of the Hidden Human T Cell Lymphotropic Virus Type 1 Infection Burden in Nonendemic Countries

Abstract

Adult T cell leukemia/lymphoma has only rarely been reported in Europe. We aimed to determine the clinical characteristics and outcome of adult T cell leukemia/lymphoma patients in a nonendemic country. Cases of adult T cell leukemia/lymphoma managed at Hospital Universitari Vall d'Hebron, Barcelona, Spain were reviewed. Information on the foreign population living in Spain, according to country of origin, was obtained using official published data from the National Statistics Institute. Three patients were diagnosed with adult T cell leukemia/lymphoma between 2003 and 2010. Two cases were of the acute subtype and one case of the lymphoma subtype. Two patients were female and the mean age at presentation was 41.3 years. Patients originated from three different countries. The characteristics of the attended patients include widespread enlargement of the lymph nodes, a variety of multiple extranodal involvements, bone marrow infiltration, and a high incidence of infections including latent parasitic infections. Prototypic adult T cell leukemia/lymphoma presenting with high white cell counts, flower cells, and hypercalcemia was not observed. Regarding therapy, one patient received chemotherapy alone and two subjects combined first-line therapy including antiviral drugs. Of the three patients, two are dead (mean survival time 6 months) and one has been lost to follow-up. We estimate that at least 15,000 people living in Spain are infected with human T cell lymphotropic virus type 1 (HTLV-1). Adult T cell leukemia/lymphoma is a heterogeneous disease that often presents without distinguishing or prototypical features. A high index of clinical suspicion is essential for diagnosis. Several epidemiological differences have been observed in different countries. Today, HTLV-1 infection is highly underdiagnosed.

A dult T cell leukemia/lymphoma (ATLL) is a malignancy of mature activated T cells caused by human T cell lymphotropic virus type 1 (HTLV-1), the first human retrovirus to be discovered.¹ ATLL usually occurs in people from HTLV-1 endemic regions, such as southern Japan, the Caribbean, Central and South America, central and western intertropical Africa, northern Iran, and Melanesia.² HTLV-1 infection and ATLL have only rarely been reported in Europe, usually limited to immigrants from HTLV-1 endemic areas.³

Approximately 90% of the infected individuals remain asymptomatic carriers during their lives and a subpopulation of carriers (2–6%) develops ATLL after a long latency period (>20 years).⁴ Additionally, HTLV-1 is the causative agent of an inflammatory neurodegenerative disorder called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM), as well as of the infective dermatitis.²

The main routes by which the HTLV-1 virus is transmitted in endemic areas are from mother to child (predominantly through breastfeeding),⁵ sexual intercourse (mainly from male to female), and to a lesser extent blood contact, including the transfusion of infected cellular products or sharing of needles.⁶

ATLL was first described in 1977 as a distinct clinicopathological entity.⁷ Subsequently, ATLL was clinically classified into four subtypes by Shimoyama et al.: acute (55%), lymphomatous (20%), chronic (20%), and smoldering (5%).⁸ Recently, new clinical cutaneous types had been proposed, namely cutaneous type and primary cutaneous tumoral.^9,10 Reaching an accurate diagnosis of ATLL in nonendemic areas can be challenging, owing to diverse manifestations and varying cell morphology.^11,12 We report our experience with this heterogeneous neoplasm, describing the clinical and laboratory data in three patients diagnosed with aggressive ATLL (two acute and one lymphomatous types) between 2003 and 2010, in Barcelona (Spain) a nonendemic area of HTLV-1 infection. We also analyzed our findings from an epidemiological perspective. The increase in migratory flows to Europe from endemic areas may bring about an increase in the incidence of infections by the HTLV-1 virus in the decades to come, as well as of the diseases associated with it.

A total of three patients were diagnosed with ATLL between 2003 and 2010 at Hospital Universitari Vall d'Hebron, Barcelona, Spain. The diagnosis was based on clinical features, hematological characteristics, immunophenotype, and the presence of serum antibodies to HTLV-1/2-associated antigens.¹³ HTLV-1/2 antibodies were screened using a commercial enzyme immunoassay Murex HTLV I+II (Murex Biotech Ltd, Dartford, England) and followed by a confirmatory INNO-LIA HTLV I/II Ab assay (Innogenetics, Ghent, Belgium). The molecular diagnosis of HTLV-1 infection in peripheral blood mononuclear cells was performed in a referral center (Hospital Carlos III, Madrid, Spain). The proviral load was expressed as the number of HTLV-1 DNA copies per 10,000 peripheral blood mononuclear cells (real-time polymerase chain reaction, RT-PCR). Pathological diagnostic criteria for ATLL were histological and/or cytological evidence of a CD4⁺, CD7⁻, CD25⁺ T cell malignancy (based on immunohistochemistry and/or flow cytometric analysis). Population data were obtained using official published data from the National Statistics Institute (INE).¹⁴ These statistics offer information on the foreign population living in Spain, according to country of origin (place of birth). The source of this information is the municipal population censuses on January 1 of each year.

Detailed information of the patients is provided in Table 1. According to the clinical presentation two cases had the acute ATLL subtype and one case a lymphoma subtype. Two patients were female and the mean age at presentation was 41.3 years. Patients originated from Bolivia, Peru, and Western Sahara. Investigation of HTLV-1 infection in relatives in one patient (six siblings) showed a prevalence of 50%, with the presence of confirmed infection in one brother and two sisters.

Table 1.

Patient Demographics and Clinical Characteristics

	Case 1	Case 2	Case 3
Age, years	49	40	35
Gender	Male	Female	Female
Native	Bolivia	Western Sahara	Peru
Visited countries	Brazil, Argentina
Marital status	Bachelor	Separated	NA
Anti-HTLV-1 antibody relatives	NA	NA/6 children	2 sisters and 1 brother positive/6
Initial consultation	Abdominal pain, rash, anorexia, weight loss	7×6-cm frontal tumor, 3×2-cm breast tumor	Asthenia, weight loss
Other diseases	Anti-Trypanosoma cruzi antibody positive		Neurocysticercosis
Anti-HTLV-1 antibody^a	Positive	Positive	Positive
Viral load (copies per 10,000 PMBC)	<60^b	2,522	2,067
White cell count per mm³ (4,100–9,900)	7,600	6,800	16,500
Lymphocytes per mm³ (1,200–3,400)	<200	1,200	8,320
Atypical lymphocytes PBS	No	Yes (no flower cells)	Yes (no flower cells)
Eosinophils, % (<0.7)	10.65	0.2	0.6
Erythrocyte sedimentation rate (<20 mm/h)	22	24	5
Lactate dehydrogenase (190–300 UI/liter)	1,963	1,694	725
β₂-Microglobulin (0.7–2.5 mg/liter)	4	2.2	2.5
Thymidine kinase (<10 U/liter)	19	40	34.8
Corrected calcium (8.8–10.2 mg/dl)	9.6	8.2	9.01
Serum protein electrophoresis	Normal pattern	Raised α₁ and α₂ globulins	Normal pattern
Total serum protein (6.61–8.01 g/dl)	4.76	5.64	6.4
Albumin (3.40–4.80 g/dl)	2.21	3.12	3.5
Lymphadenopathy	Yes^c	Yes	Yes
Extranodal involvement	Macular rash, lung, CNS, gastrointestinal tract, ascites, pleural effusion	Subcutaneous nodules, splenomegaly, breast, lung, bone (paranasal sinuses, jaw)	Hepatomegaly, ascites, pleural effussion
Bone marrow involvement	Yes	Yes	Yes
Disease subtype^d	Lymphomatous	Acute	Acute
Therapy	Zidovudine 600 mg/day, lamivudine 300 mg/day+CHOP×5 (1st plus alentuzumab)+intrathecal cytarabine	CHOP×2	Zidovudine 600 mg/day, lamivudine 300 mg/day+ interferon-α 5 MUI/m²/ day+CHOP×3; high-dose methotrexate (2nd line)
Antiparasitic therapy	Benznidazole, 60 days		Albendazole
Opportunistic infections	CMV reactivation, bacterial lymphadenitis	Herpes zoster
Response	Complete response 4th CHOP (6 weeks)	NA	Progressive disease
Survival	7 months	NA repatriate	5 months

Antihuman immunodeficiency virus antibody was negative in all cases.

Unusual. The combination of characteristic morphological and immunophenotypic features (CD4⁺ CD7⁻ CD25⁺) in the lymph node and bone marrow, in conjunction with the positive HTLV-1 serological studies, allowed for a conclusive diagnosis of ATLL.

Pleomorphic (medium and large cell) type; this type is a typical nodal lesion of ATLL. Immunophenotype: CD4⁺ CD7⁻ CD25⁺.

Shimoyama classification has been extremely useful for the standardization and comparison of the outcome of patients, although the clinical features and natural history of the lymphomatous type may overlap with the acute type. Patients with aggressive presentation and >1% circulating abnormal lymphocytes are labeled as acute adult T cell leukemia/lymphoma, even when the patients have bulky lymph nodes or visceral disease.

To convert the values for serum β₂-microglobulin to nanomoles per liter, multiply by 84.75. To convert the values for calcium to millimoles per liter, multiply by 0.25. To convert the values for total serum protein and albumin to grams per liter, multiply by 10.

HTLV-1, human T cell lymphotropic virus type 1; NA, not available; PMBC, peripheral blood mononuclear cells; PBS, peripheral blood smear; CNS, central nervous system; CMV, cytomegalovirus; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Two cases had other diseases or infections at the time of diagnosis; one patient was seropositive for Tripanosoma cruzi and in the other neurocysticercosis was observed. These two patients also showed opportunistic infections during therapy, namely cytomegalovirus reactivation and cervical lymphadenitis (Streptococcus anginosus), and herpes zoster, respectively. The mean value of the white blood cell count and lymphocyte count at presentation was 10.3×10⁹/liter and 3.24×10⁹/liter, respectively. Examination of peripheral blood smear showed atypical lymphocytes in two patients, some presenting convoluted nuclei; however, polylobulated nuclei characteristics of flower cells were not observed. Blood tests showed significant elevations in serum lactate dehydrogenase levels and serum thymidine kinase levels, normal corrected calcium levels, and decreased total serum protein levels. Stool examination did not reveal the presence of larvae of Strongyloides stercoralis. Computed tomography scans and other imaging test showed widespread lymphadenopathy in our patients, and a highly variable multiorgan involvement (skin, lungs, liver, spleen, gastrointestinal tract, ascites, pleural effusions, breast, and bone).

Regarding therapy, one patient received chemotherapy alone (cyclophosphamide, adriamycin, vincristine, and prednisone) and two subjects combined first-line therapy (with the first cycle of chemotherapy) including antiviral drugs. All patients received prophylaxis of opportunistic infections during chemotherapy and proper treatment was administered in patients who developed infections or had latent parasitic infections. Of the three patients, two are dead (mean survival time 6 months) and one has been lost to follow-up and is presumed to have died.

In 2010, the total number of residents in Spain was 47,021,034 inhabitants and 5,730,667 were foreign population, representing 12.2% of the total number registered. In terms of distribution by group of countries of origin, the European Union (EU-27) is the most numerous (40.9%) and South America, Africa, and Central America and the Caribbean accounted for 26,7%,18.4%, and 3.5% of the total foreign population, respectively. We estimate that at least 15,000 people living in Spain are infected with HTLV-1. The estimation of the prevalence of HTLV-1 in Spain was obtained by applying a prevalence rate of 1% for those who were born in endemic countries¹⁵ and the prevalence found among immigrant pregnant women in Spain (0.2%)¹⁶ for immigrants born in nonendemic areas but with HTLV-1-infected individuals detected in Spain. This approach may underestimate the true prevalence of HTLV-1 in Spain.

It is important to note that geographically defined environments may alter the natural history of this disease.¹⁷ Our patients with ATLL resemble Brazilian and Caribbean patients in terms of age, although we observed a female predominance. In Japan, the annual incidence of ATLL is comparatively high, peaks around age 60, and is approximately three times greater in men than in women. The incidence of ATLL among Caribbean carriers is less than one-third the rate in Japan, peaks in the forties, and does not vary by gender.¹⁷ This suggests the presence of still unknown cofactors in the pathogenesis of this disease in areas of different ethnical origin and environmental and cultural conditions. It has long been proposed that the risk of ATLL is strongly related to very early HTLV-1 infection.⁴ The mean age of presentation was 41.3 years in our patients, suggesting an early life exposure to the virus possibly by maternal-to-child transmission, with a high possibility in the third case, a female with one brother and two sisters HTLV-1 infected.

Patients originated from three different countries (one African and two Latin American countries). In Central America and the Caribbean, the overall seroprevalence of infection from population-based surveys ranges between 1% and 10% in most studies. All 13 South American countries have reported the presence of HTLV-1, but the prevalence varies greatly (from less than 0.1% to over 5%) among and within the countries and population groups. The highest proportions of infection among the general population (1% to 5%) have been described in Brazil, Colombia, and Peru.¹⁵ Unfortunately, information from several African countries is either lacking (e.g., Western Sahara) or unrepresentative.

During chemotherapy, the prevention of opportunistic infections is essential in the management of ATLL patients, nearly half of whom develop severe infections.⁸ Infestation by Strongyloides stercoralis is frequent in ATLL patients and it is hypothesized that this parasite plays a role in the development of ATLL in healthy carriers¹⁸; although it was not detected in our cases, all but one showed other latent parasitic infections.

Prototypic ATLL presenting with high white cell counts (with the presence of flower cells), skin lesions, hepatosplenomegaly, lymphadenopathy, and hypercalcemia was not observed in our patients. The characteristics of attended patients include widespread enlargement of the lymph nodes, a variety of multiple extranodal involvements, bone marrow infiltration, and a high incidence of opportunistic infections. Although ATLL often presented a leukemic feature, marked leukocytosis was not observed and peripheral blood smears showed pleomorphic lymphocytes with convoluted nuclei, without the characteristic hyperlobulated nuclei known as flower cells.

Another common and distinguishing feature of aggressive ATLL, hypercalcemia, was absent. To the best of our knowledge, clinical breast involvement in patients with ATLL has been previously reported only in a male patient and in four Afro-Caribbean female patients.¹⁹

Despite advances in the support and development of novel treatment agents, the prognosis for ATLL remains poor.²⁰ A recent study supports the use of low-dose zidovudine/interferon-α with chemotherapy as a first-line treatment of acute and lymphoma ATLL.²¹ Two of our patients received combined first-line therapy including chemotherapy and antiviral drugs; however, the mean survival was 6 months. This mean survival time was similar to that reported from Japan.⁸

On the other hand, ATLL patients are the sentinels to the health problem in their country of origin and the tip of the iceberg of the hidden HTLV-1 infection burden in Europe. In the 1990s, it was estimated that around 10–20 million people were infected with HTLV-1 worldwide.²² In 1999, the world population passed the six billion mark and latest official current world population estimate is seven billion. The large immigration flows from Latin America and Africa during the past decade may have changed the prevalence and distribution of HTLV-1, therefore the former estimate may no longer reflect the global epidemiology.

Good surveillance systems for HTLV-1 infection are crucial for measuring the magnitude of the problem. Spain has had a national registry for retroviral infections other than human immunodeficiency virus since 1989. Up to December 2009, a total of 144 cases of HTLV-1 infection have been reported.²³ HTLV-1 infection occurs predominantly in adults, with a mean age at the time of diagnosis of 41 years (4–78 years). It is more common in females (female:male ratio 1.4:1). Most patients infected with HTLV-1 are immigrants from Latin America (54%) and sub-Saharan Africa (18%) or Spaniards who had traveled to, or had sexual contacts with natives from endemic areas (26%). A total of 34 patients had presented or developed diseases associated with HTLV-1: 21 TSP/HAM and 13 ATLL. Furthermore, the seroprevalence of HTLV infection among immigrant pregnant women in Spain is 0.2%,¹⁶ with all cases found among women from Latin America and Africa; in recently arrived sub-Saharan immigrants the seroprevalence is 0.96%.²⁴ The overall prevalence of HTLV-1 infection in Spain remains low. Although an increase in the detection of new cases has occurred in recent years, officially observed cases clearly underestimate the expected cases.

HTLV-1 is a transmissible infection with identifiable risk factors; prevention must inevitably be linked to early diagnosis and screening of the relatives of newly diagnosed HTLV-1 cases. Although the rate of sexual transmission of HTLV appears to be low, it is the main route of infection in Spain.²³ The prevention of virus transmission is advantageous not only at the individual level but also in the public health setting.

The findings summarized above raise several questions of particular interest in nonendemic countries. (1) ATLL is a heterogeneous disease that often presents without distinguishing or prototypical features. A high index of clinical suspicion is essential for diagnosis. Investigation of HTLV-1 infection needs to be extended to all patients with T cell malignancy, regardless of ethnic/geographic origin. (2) Much of the knowledge of ATLL is based on studies conducted in Japan and several epidemiological differences have been observed in different countries. These facts highlight the importance of geographic/social environment in the natural history of HTLV-1 infection. (3) Further investigation is warranted on the subject of persistent parasitic coinfections (other than S. stercoralis), which may increase the risk of ATLL in HTLV-1 carriers, and presents a potential for risk reduction with parasite treatment and control. (4) Since there is no effective treatment for ATLL, the reduction of mortality may have to rely on successful prevention of HTLV-1 infection. (5) HTLV-1 infection remains highly underdiagnosed. Further efforts should be made at intensifying physician awareness on HTLV-1 infection and its associated diseases.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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