Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan

Authors


Abstract

The incidence of adult T-cell leukemia/lymphoma (ATL) and its impact on that of total non-Hodgkin lymphoma (NHL) were evaluated in Nagasaki, an area in southwestern Japan where human T-cell lymphotropic virus type I (HTLV-I) is endemic. The first study area comprised 4 towns located on the K Islands, which had a population of 26,870 in 1990. The overall HTLV-I seroprevalence estimated from the serologic survey of 18,485 subjects was 16.2%. By using the data from the Nagasaki Prefectural Cancer Registry (NPCR) and reviewing clinical and laboratory information, we identified 40 cases of ATL and 35 cases of other NHL diagnosed between 1985 and 1995. The crude annual incidence of ATL among 100,000 HTLV-I carriers aged 30 or older was estimated at 137.7 for men and 57.4 for women, with a significant sex difference after adjustment for age (rate ratio = 2.50, 95% confidence interval 1.32–4.73). The cumulative risk from 30 to 79 years of age was estimated at approximately 6.6% for men and 2.1% for women. Among the entire population, ATL accounted for 51 to 59% of the total NHL incidence, showing the strong impact of HTLV-I infection. The second study area comprised the whole of Nagasaki Prefecture (total population in 1990 = 1.56 million). Between 1985 and 1995, 989 cases of ATL and 1,745 cases of other NHL were registered in the NPCR. The world age-standardized annual incidence rate of ATL per 100,000 persons aged 30 or older was estimated at 10.5 for men and 6.0 for women, which accounted for approximately 37 to 41% of the total NHL incidence. Int. J. Cancer 85:319–324, 2000. ©2000 Wiley-Liss, Inc.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T cells which is endemic in several regions of the world, including southwestern Japan, the Caribbean basin, Central and West Africa, and South America (IARC, 1996). ATL develops exclusively among persons infected with human T-cell lymphotropic virus type-I (HTLV-I). It is believed that mother-to-child HTLV-I infection early in life constitutes an essential factor in the multi-step process of oncogenesis, although the precise molecular mechanisms and the environmental risk co-factors for development of the disease are still unclear.

Several epidemiologic studies have reported the mortality rates, incidence rates and the cumulative risks of ATL among HTLV-I carriers in various countries in the world (Tajima et al.,1987; Murphy et al.,1989; Tokudome et al.,1989; Kondo et al.,1989; Iwata et al.,1994; Cleghorn et al.,1995; Gerard et al.,1995). However, most of the earlier studies on the incidence rates were based on seroprevalence data from only a small proportion of the population examined or from voluntary blood donors. Moreover, there is still a more than 3-fold difference in the point estimates of the ATL incidence reported in Japan (Kamihira et al.,1992).

Epidemiologic data are also limited as to the accurate number of cases and the incidence of ATL among geographically defined populations or ethnic sub-populations in HTLV-I endemic areas, because of the scarcity of population-based cancer registries. Such descriptive data are important to assess the burden of the disease and to evaluate the beneficial effect of prevention programs. Nagasaki Prefectural Cancer Registry (NPCR) (Soda and Ikeda, 1997), which covers approximately 1.56 million people in an HTLV-I endemic area in southwestern Japan, provides a unique opportunity to obtain such data, since ATL has been registered as a separate diagnostic group in this registry since 1985.

The purpose of the present study was 2-fold. First, the incidence and the lifetime risk of ATL among HTLV-I carriers were re-evaluated in the K Islands in Nagasaki Prefecture. In addition, the data from the K Islands were used to determine the validity of the diagnosis of ATL in the NPCR. Second, the impact of ATL on the total incidence of non-Hodgkin lymphoma (NHL) was assessed in the K Islands and all of Nagasaki Prefecture between 1985 and 1995.

MATERIAL AND METHODS

Evaluation of ATL and total NHL incidence in the K Islands

Study area and population.

The study area consisted of 4 towns (K, S, A and N) located on the K Islands, Nagasaki Prefecture, the total population of which included 12,820 men and 14,050 women in 1990 (Statistics Bureau, Management and Coordination Agency, 1990) (Table I). According to the results of the national census of 1990, the main industries in this area were the service (23.4%), fishery (22.4%) and wholesale, retail and restaurant (18.1%) industries.

Table I. NUMBER OF SUBJECTS EXAMINED, PREVALENCE OF HTLV-I SEROPOSITIVITY AND TOTAL POPULATION IN 1990 ACCORDING TO SEX AND AGE, IN 4 TOWNS OF THE K ISLANDS, NAGASAKI, JAPAN
Age1Town 1Town 2Town 3Town 4
Number tested2Positive (%)3Total populationNumber testedPositive (%)Total populationNumber testedPositive (%)Total populationNumber testedPositive (%)Total population
  • 1

    Age as of October 1, 1990.

  • 2

    Number of subjects examined between 1985 and 1996. Persons born after October 1, 1990 were excluded.

  • 3

    Prevalence of HTLV-I seropositivity was calculated assuming that HTLV-I serostatus did not change over time.

Men
    0–94172.36341416.13741613.6597687.1262
   10–195633.46272525.74912514.26481047.4283
   20–294575.93862277.62513106.23401004.8161
   30–396049.162827511.93664449.863213613.4274
   40–4952810.648622415.533936216.5494989.8272
   50–5952919.856125926.435337621.857411522.6326
   60–6940324.842024831.033526736.44808928.1273
   70–7921527.722012833.816413133.12014824.1134
   80–999034.2773016.0462333.5471420.664
   Total3,80612.14,0391,78416.92,7192,32515.94,01377214.32,049
Women
    0–93771.56121253.13651664.65684810.0219
   10–195743.46082593.04512805.2615732.6249
   20–295995.04273015.42154676.03951596.1163
   30–3962210.456132010.53404698.859016015.0250
   40–4949416.251123519.233231420.255810221.7299
   50–5951927.454426825.943835928.465710829.4347
   60–6951233.856230335.945530339.76138235.2345
   70–7934137.234917735.327215344.73744641.8216
   80–9915750.91558146.31315952.21681739.696
   Total4,19517.24,3292,06918.62,9992,57018.54,53879518.82,184

Assay of serum antibodies to HTLV-I.

Between January 1985 and August 1996, serum antibodies to HTLV-I were assayed in 8,771 men and 9,714 women living in the study area, using a particle agglutination (PA) assay. These subjects had been admitted to the K Hospital or had participated in free, government-sponsored annual health check-ups. Informed consent was obtained verbally. The assay kits used were Serodia ATLA (Fuji Rebio, Tokyo, Japan) until April 1990 and the modified version, Serodia HTLV-I, after May 1990.

To assess the validity of the antibody assay, serum samples from 106 PA-positive and 101 PA-negative subjects, whose HTLV-I serostatus had been examined between 1985 and 1996 (169 during 1985–April 1990 and 38 during May 1990–1996), were obtained in 1998 and blindly tested for HTLV-I antibodies by the PA assay (Serodia HTLV-I) and the indirect immunofluorescence [IF] assay on a 1:4 mixture of HTLV-I producing MT-2 and non-infected CEM cells. All discordant or borderline samples were tested again by the PA and the IF assay, and confirmation was obtained by Western blot assay (Problot HTLV-I, Fuji Rebio). Using the results of 1998 as standard, the positive and the negative predictive value of the PA assay during 1985–1996 was estimated at 102/106 (96.2%) and 99/101 (98.0%), respectively. Both subjects whose results of the HTLV-I antibody assay had changed from negative to positive were females over 40 years. Thus, the possibility of seroconversion by sexual transmission could not be excluded in these 2 individuals.

Calculation of person-years at risk among HTLV-I carriers and the entire population.

The person-years at risk among HTLV-I seropositive subjects were calculated as follows. First, the HTLV-I seroprevalence for each town-, sex- and 5-year-age-specific category in each year was computed using the results of the serologic survey of all 18,485 subjects examined during 1985–1996. In this calculation, it was assumed that the HTLV-I antibody status in the same individual did not change over time. The seroprevalence was corrected by multiplying the positive predictive value of the PA assay (96.2%). By multiplying the number of people in the population by the prevalence of HTLV-I seropositivity, the number of HTLV-I carriers in each year was estimated for each town-, sex- and 5-year-age-specific category. Then the sex- and 10-year-age-specific person-years at risk of HTLV-I carriers were computed by summing the number of seropositive subjects from 1985 to 1995. Similarly, the sex- and 10-year-age-specific person-years at risk of the entire population were also calculated.

Incident cases of ATL and NHL.

We selected all cases of lymphoid malignancies [1st version of the International Classification of Diseases for Oncology-Morphology (ICDO-M) = 9590–9701, 9750–9825 and ATL], diagnosed between January 1985 and December 1995 in subjects living in the study area at the time of diagnosis, from the file of the NPCR. Separately, we obtained information on symptoms, signs and laboratory data by reviewing medical records or by sending questionnaires to the hospital where the diagnosis was made. In addition, our results of the HTLV-I antibody assay were used for diagnosis. Whenever possible, histological or cytological specimens were also re-examined.

Subjects who satisfied the following 4 conditions were considered to have ATL: (i) histologically or cytologically confirmed cases of lymphoid malignancy; (ii) presence of antibodies to HTLV-I detected by PA, IF, enzyme-linked immunosorbent assay or Western blot; (iii) T-cell surface marker (+) of lymphoma cells or leukemic cells proven by immunohistochemistry or flow cytometry; and (iv) exclusion of smoldering ATL and other distinct disease categories such as follicular lymphoma and Hodgkin's disease. Even if condition (iii) has not been met, subjects were considered to have ATL when the characteristic signs of ATL, such as the presence of atypical lymphocytes in the peripheral blood (>2%), hypercalcemia (corrected serum calcium levels >= 5.5 mEq/l) and/or skin lesions, were present. Smoldering ATL was excluded because of the difficulty in distinguishing it from the healthy carrier state with monoclonal proliferation of HTLV-I infected T-lymphocytes (pre-ATL), which accounts for approximately 2% of all HTLV-I carriers and does not always transform to overt ATL (Ikeda et al.,1993). Furthermore, the time at onset of smoldering ATL was often unclear. According to the proposed point-score system for identification and international comparison of ATL (Levine et al.,1994a), our criteria were essentially equal to at least possible cases (>= 3 points), except that smoldering ATL was excluded. The diagnostic criteria for ATL used in this study did not include the monoclonal integration of the HTLV-I proviral DNA into the genome, the only confirmatory test for differential diagnosis of HTLV-I-associated T-cell leukemia/lymphoma (Yamaguchi et al.,1984). This was because molecular biological techniques such as Southern blotting and polymerase chain reaction are not routinely used in clinical settings. All NHL cases that did not satisfy the criteria for diagnosis of ATL were classified as other NHL.

Estimation of ATL and total NHL incidence in the whole of Nagasaki Prefecture

The total population of Nagasaki Prefecture included 736,729 men and 826,230 women in 1990. The person-years at risk were calculated as for the K Islands. All incident cases of ATL and NHL (ICDO-M = 9590–9642, 9690–9701, 9750) diagnosed between January 1985 and December 1995 were chosen from the file of the NPCR. In the NPCR, ATL cases have been registered using a unique ICDO-M code. The criteria used were (i) T-cell malignancy with seropositivity to HTLV-I or (ii) clinical diagnosis of ATL. NHL cases not satisfying the above criteria were classified as other NHL. Those subjects who were registered by death certificates only and whose primary cause of death was malignant lymphoma were classified as other NHL, since Hodgkin's disease accounted for less than 5% of all histologically confirmed cases of malignant lymphomas (excluding ATL) in the study area.

Statistical analysis

The rates of incidence of ATL and total NHL were calculated by dividing the number of cases by person-years at risk. Because of the small number of ATL cases in the younger age group, the calculation was limited to the age range 30 or older. The exact confidence intervals (CI) for crude and age-specific incidence rates were computed assuming that the number of cases followed the Poisson distribution. The age-standardized incidence rates and their CI were calculated by conventional methods, using the weights of the world population. The cumulative risks were computed by the following equation: cumulative risk (%) = 100[1 − exp (−CR)], where CR denotes a cumulative rate, i.e., the sum of the age-specific incidence rates over each 10-year age category (Plummer, 1997). Using the same equation, the confidence limits of cumulative risks were also calculated from those of CR. In the present study, the lifetime risk was defined as the cumulative risk of the disease from 30 to 79 years of age. Poisson regression analysis (SAS GENMOD procedure) was used to estimate the age-adjusted rate ratios of developing ATL associated with gender. All p values reported were 2-tailed, and the level of statistical significance was set at α = 0.05.

RESULTS

Evaluation of the incidence of ATL and total NHL in the K Islands

Table I shows the number of subjects examined, the prevalence of HTLV-I seropositivity and the total population at the mid-point of the study period (in 1990), according to town, sex and age. In some town-, sex- and age-specific categories, the number of persons examined exceeded that of the total population, owing to the dynamic nature of the study population; there were individuals who entered or exited the study area between 1985 and 1996. In general, the prevalence of HTLV-I seropositivity increased with age in men and in women. The seroprevalence was significantly higher in women than in men aged 40 years or older (Chi-squared test, p < 0.01). The overall HTLV-I seroprevalence was 14.3% for men and 17.9% for women. The total person-years at risk of HTLV-I carriers was 20,457 for men and 30,292 for women. For the entire population, the person-years at risk was 145,514 for men and 156,125 for women.

During 1985–1995, a total of 82 cases of lymphoid malignancies were registered in the study area. We could obtain clinical and laboratory data for 76 of these 82 cases. After excluding 2 acute lymphocytic leukemias (one in a 3-year old boy and one HTLV-I antibody negative case), one B-chronic lymphocytic leukemia, 3 cases of Hodgkin's disease and one patient who had been diagnosed as ATL without an assay of HTLV-I antibody, there were 75 cases in which the diagnosis was NHL or ATL (Table II). When HTLV-I antibody negative, B-cell positive, or follicular lymphoma cases were further excluded, 50 cases remained. Finally, 40 of these 50 cases met the diagnostic criteria of ATL. The median age at the onset of ATL in men and in women was 62.5 (range 35.3–76.3) and 65.5 (range 53.2–81.8) years respectively. In neither sex were there patients with ATL under 30 years of age. One male and 3 females with a diagnosis of NHL were HTLV-I antibody positive, but there was no information for them on the surface marker of tumor cells, though no characteristic symptom of ATL was present in these patients. There were also 2 patients (one in each sex), diagnosed as NHL, who had hypercalcemia, but for whom HTLV-I antibody was not determined. Of the 6 subjects, 5 were aged from 70 to 79 years. Thus, it was speculated that a precise differential diagnosis between ATL and other NHL had not always been performed for elderly patients.

Table II. NUMBER OF INCIDENT CASES OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND OTHER NON-HODGKIN'S LYMPHOMAS IN 4 TOWNS OF THE K ISLANDS, NAGASAKI, JAPAN BETWEEN 1985 AND 1995
Age1MenWomen
ATLNHLTotalATLNHLTotal
  • 1

    Age at onset.–ATL, adult T-cell leukemia/lymphoma; NHL, non-Hodgkin's lymphoma.

0–9000000
10–19011000
20–29000000
30–39101000
40–49123022
50–598412415
60–6988168210
70–796511257
80–99055202
Total242549161026

Of the 36 cases of ATL in which the patient died, the primary cause of death listed on the death certificate was ATL in 30, malignant lymphoma in 4 and other causes in 2. Of the 22 deceased patients with NHL (excluding 2 cases registered by death certificate only), the primary cause of death was malignant lymphoma in 16 and other causes in 6.

In the NPCR, only one of the 40 cases with ATL had been classified into the other disease category. This case (HTLV-I seropositive T-cell lymphoma) had been registered as NHL. However, it was not clear whether this case was a true ATL or a non-HTLV-I-associated T-cell lymphoma that occurred spontaneously in an HTLV-I carrier, since molecular analysis of the tumor cells had not been performed. There was also only one case that had been registered as ATL but did not meet the diagnostic criteria used in this study. This patient had characteristic symptoms of ATL (jaundice and abnormal lymphocytes in the peripheral blood), but the very rapid clinical course hampered an assay of HTLV-I antibody. These results suggested that the diagnosis of ATL in the NPCR was valid, though this may not be directly applicable to other areas within the prefecture.

The sex- and age-specific incidence rates of ATL are presented in Table III. The point estimate of the incidence rate was highest in the 70s for men and in the 60s for women. However, because of the small number of cases, the 95% CI were wide and overlapped. The crude annual incidence rate of ATL among 100,000 HTLV-I carriers aged 30 or over was estimated at 137.7 (95% CI 88.3–204.9) for men and 57.4 (95% CI 32.8–93.2) for women. In other words, the number of HTLV-I carriers that yielded one case of ATL annually was approximately 726 for men and 1,742 for women. Men were at significantly higher risk for developing ATL than women (age-adjusted rate ratio = 2.50, 95% CI 1.32–4.73). To determine whether the lower incidence among women resulted from the dilution of HTLV-I carriers due to transmission after adolescence, the age-specific seroprevalence among men was applied to women. In this calculation, the crude incidence rate among women slightly increased (74.1 cases/100,000 person-years), but was still significantly lower than in men (age-adjusted rate ratio of males vs. females = 1.96, 95% CI 1.04–3.71). The lifetime risk of the disease was estimated at approximately 6.6% (95% CI 3.8–9.2) for men and 2.1% (95% CI 1.0–3.1) for women.

Table III. SEX- AND AGE-SPECIFIC INCIDENCE RATES AND LIFETIME RISK OF ADULT T-CELL LEUKEMIA/LYMPHOMA AMONG HTLV-I CARRIERS IN 4 TOWNS OF THE K ISLANDS, NAGASAKI, JAPAN, BETWEEN 1985 AND 1995
Age1Men2Women2
  • 1

    Age at onset.

  • 2

    Cases/100,000 person-years. Numbers in parentheses are 95% confidence intervals.

  • 3

    Cumulative risk from 30 to 79 years of age (%).

  • 4

    Age-adjusted rate ratio using Poisson regression analysis.

30–3944.6 (1.1–248.4)0 (0–173.1)
40–4939.3 (1.0–218.8)0 (0–103.1)
50–59174.0 (75.1–342.9)64.9 (17.7–166.1)
60–69162.9 (70.3–321.0)105.8 (45.7–208.5)
70–79257.1 (94.3–559.5)36.4 (4.4–131.5)
80–990 (0–461.5)67.9 (8.2–245.1)
Total (crude)137.7 (88.3–204.9)57.4 (32.8–93.2)
Lifetime risk36.6 (3.8–9.2)2.1 (1.0–3.1)
Rate ratio42.50 (1.32–4.73)1.0

Among the entire population, the world age-standardized incidence rate of ATL per 100,000 person-years (>= 30 years old) was estimated at 23.7 (95% CI 14.1–33.2) for men and 11.5 (95% CI 5.7–17.4) for women (Table IV). The lifetime risk was estimated at approximately 1.7% (95% CI 1.0–2.4) for men and 0.7% (95% CI 0.3–1.1) for women. The age-standardized total NHL incidence among men and women aged 30 or older was 46.8 (95% CI 33.4–60.2) and 19.4 (95% CI 11.5–27.3) respectively. Therefore, ATL accounted for 51 to 59% of the total NHL incidence in the study area.

Table IV. SEX- AND AGE-SPECIFIC INCIDENCE RATES AND LIFETIME RISK OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND NON-HODGKIN'S LYMPHOMA AMONG THE ENTIRE POPULATION IN 4 TOWNS OF THE K ISLANDS, NAGASAKI, JAPAN, BETWEEN 1985 AND 1995
Age1MenWomen
ATL2ATL + NHL2ATL2ATL + NHL2
  • 1

    Age at onset.

  • 2

    Cases/100,000 person-years. Numbers in parentheses are 95% confidence intervals.

  • 3

    Age-standardized rate based on world population aged 30 or older.

  • 4

    Cumulative risk from 30 to 79 years of age (%).–ATL, adult T-cell leukemia/lymphoma; NHL, non-Hodgkin's lymphoma.

30–394.7 (0.1–25.9)4.7 (0.1–25.9)0 (0–19.3)0 (0–19.3)
40–495.3 (0.1–29.8)16.0 (3.3–46.8)0 (0–19.5)10.6 (1.3–38.2)
50–5939.8 (17.2–78.3)59.6 (30.8–104.2)18.4 (5.0–47.0)23.0 (7.5–53.6)
60–6948.7 (21.0–95.9)97.3 (55.6–158.0)37.9 (16.4–74.6)47.3 (22.7–87.0)
70–7974.2 (27.2–161.5)136.0 (67.9–243.4)14.6 (1.8–52.8)51.2 (20.6–105.5)
80–990 (0–136.1)184.5 (59.9–430.5)33.2 (4.0–120.0)33.2 (4.0–120.0)
Total (crude)27.4 (17.6–40.8)54.8 (40.4–72.7)15.9 (9.1–25.8)25.9 (16.9–37.9)
Total (adjusted)323.7 (14.1–33.2)46.8 (33.4–60.2)11.5 (5.7–17.4)19.4 (11.5–27.3)
Lifetime risk41.7 (1.0–2.4)3.1 (2.1–4.1)0.7 (0.3–1.1)1.3 (0.8–1.8)

Estimation of the incidence of ATL and total NHL in the whole of Nagasaki Prefecture

In the NPCR, 989 cases of ATL and 1,745 cases of other NHL were registered between 1985 and 1995 (Table V). The proportion of cases registered by death certificate only was 13.3% for ATL and 9.1% for other NHL. The male-to-female ratio was 1.34 for ATL and 1.46 for other NHL. The mean age at the onset of ATL in men and in women was 63.3 (SD 11.4) and 64.0 (SD 12.9), respectively. Both in men and in women, the age-specific incidence rate of ATL increased until 70 to 79 years, followed by a decrease after 80 (Table VI), while the age-specific incidence of total NHL increased monotonously with age. The age-standardized annual incidence rate of ATL per 100,000 persons aged 30 or older was 10.5 (95% CI 9.6–11.4) for men and 6.0 (95% CI 5.4–6.6) for women, which accounted for approximately 37 to 41% of the total NHL incidence rates (28.1/100,000/year for men and 14.8/100,000/year for women).

Table V. NUMBER OF INCIDENT CASES OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND OTHER NON-HODGKIN'S LYMPHOMAS IN NAGASAKI PREFECTURE, JAPAN, BETWEEN 1985 AND 1995
Age1MenWomen
ATLNHLTotalATLNHLTotal
  • 1

    Age at onset.–ATL, adult T-cell leukemia/lymphoma; NHL, non-Hodgkin's lymphoma.

0–9066066
10–1902020088
20–29121223710
30–39123749141933
40–4962691314555100
50–5913019132191100191
60–69196304500124164288
70–79133257390103210313
80–993313116442140182
Total5671,0361,6034227091,131
Table VI. SEX- AND AGE-SPECIFIC INCIDENCE RATES AND LIFETIME RISK OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND NON-HODGKIN'S LYMPHOMA IN NAGASAKI PREFECTURE, JAPAN, BETWEEN 1985 AND 1995
Age1MenWomen
ATL2ATL + NHL2ATL2ATL + NHL2
  • 1

    Age at onset.

  • 2

    Cases/100,000 person-years. Numbers in parentheses are 95% confidence intervals.

  • 3

    Age-standardized rate based on world population aged 30 or older.

  • 4

    Cumulative risk from 30 to 79 years of age (%).–ATL, adult T-cell leukemia/lymphoma; NHL, non-Hodgkin's lymphoma.

30–391.0 (0.5–1.8)4.1 (3.1–5.5)1.1 (0.6–1.9)2.7 (1.8–3.8)
40–495.4 (4.1–6.9)11.4 (9.5–13.6)3.7 (2.7–4.9)8.1 (6.6–9.9)
50–5912.7 (10.6–15.1)31.3 (28.0–35.0)7.8 (6.3–9.6)16.3 (14.1–18.8)
60–6923.2 (20.1–26.7)59.2 (54.1–64.6)11.6 (9.7–13.8)27.0 (23.9–30.3)
70–7929.4 (24.6–34.9)86.3 (77.9–95.3)14.7 (12.0–17.9)44.8 (40.0–50.1)
80–9919.2 (13.2–27.0)95.5 (81.5–111.3)11.9 (8.6–16.1)51.7 (44.4–59.7)
Total (crude)11.7 (10.8–12.7)32.2 (30.6–33.9)7.3 (6.6–8.0)19.2 (18.1–20.4)
Total (adjusted)310.5 (9.6–11.4)28.1 (26.7–29.5)6.0 (5.4–6.6)14.8 (13.9–15.7)
Lifetime risk40.71 (0.65–0.78)1.90 (1.80–2.01)0.39 (0.35–0.43)0.98 (0.92–1.05)

DISCUSSION

In the 4 towns of the K Islands, the prevalence of HTLV-I seropositivity increased with age, and was significantly higher in women than in men aged 40 or older. This pattern of age- and sex-specific seroprevalence was similar to those reported by other researchers (Tajima et al.,1987; IARC, 1996). Prospective studies conducted in other HTLV-I endemic areas of Japan have shown that the frequencies of seroconversion were very low in recent years, and the age-dependent rise in HTLV-I seropositivity has been considered as a result of the birth cohort effect (Morofuji-Hirata et al.,1993; Stuver et al.,1993). For instance, among 534 married couples enrolled in the Miyazaki Cohort Study (overall HTLV-I seropositivity at baseline = 26.9%), only 7 subjects (0.9%) seroconverted during a 5-year follow-up (Stuver et al.,1993). Although the number of subjects examined was small, our validation study on the reliability of the PA assay (median time between the 2 assays 9.9 years) also suggested that HTLV-I serostatus was stable in the present study population. Shorter duration of breast-feeding (<1 year) (Morofuji-Hirata et al.,1993), more frequent condom use (Stuver et al.,1993) and improved socio-economic conditions may have contributed to the lower frequency of HTLV-I infection in the later birth cohorts.

The crude annual incidence rate of ATL among 100,000 HTLV-I carriers aged 30 or older was estimated at 137.7 for men and 57.4 for women. The lifetime risk was estimated at approximately 6.6% for men and 2.1% for women. These figures may have been slightly underestimated, since it was possible that some patients with ATL were misclassified as other NHL, or were missed. There were 4 cases of HTLV-I seropositive NHL with no information on the cell-surface marker and 2 cases of NHL with hypercalcemia but with no information on HTLV-I seropositivity. There was also one patient who had characteristic symptoms of ATL but whose HTLV-I serostatus was unknown. If all of these 7 cases were included as ATL, the crude annual incidence rate and the lifetime risk became slightly higher (men, 154.9/100,000/year and 7.5%; women, 71.8/100,000/year and 2.7%). However, whether or not these cases were included, the present results were in good agreement with those reported for other HTLV-I-infected populations in Japan (Tokudome et al.,1989; Kondo et al.,1989). These results suggest that the incidence rates of ATL are quite similar among different HTLV-I-infected Japanese populations. One study reported 3 to 5 times higher incidence rates in a 4-year follow-up of 403 HTLV-I carriers (Kamihira et al.,1992). It should be noted, however, that the 95% CI for incidence were wide, reflecting a small number of cases (2 for each sex), and still included the estimates from the above 3 studies.

When the age-specific HTLV-I seroprevalence among men was applied to women, the incidence of ATL among women was still approximately 0.5 times that in men. This suggests that the lower morbidity of ATL among women cannot be explained by the higher prevalence of HTLV-I seropositivity, which has been considered the result of more frequent sexual HTLV-I transmission from males to females than vice versa (Tajima et al.,1987; Stuver et al.,1993). Instead, the result may indicate that female carriers are less susceptible to ATL. Hisada et al. (1998) reported that female HTLV-I carriers had a significantly lower number of abnormal lymphocytes that resemble malignant cells of ATL in the peripheral blood. Another explanation might be that the proportion of smokers is much lower in women than in men among the Japanese population. A case-control study reported that smoking was a significant risk factor for ATL among HTLV-I carriers (Tokudome et al.,1993). In Jamaica and Trinidad, the annual incidence rate and the lifetime risk among childhood-acquired HTLV-I carriers has been reported to be 44.5/100,000 person-years and 3–4.5%, respectively, with no sex difference (Cleghorn et al.,1995). Thus, male predominance of ATL incidence appears to be characteristic of endemic areas in Japan.

The median or mean ages at the onset of ATL both in the K Islands and in Nagasaki Prefecture exceeded 60 years, and were approximately 5 years higher than the mean ages reported by the 1988–1993 nationwide surveys of ATL in Japan (58–59 years) (T- and B-Cell Malignancy Study Group, 1996). One reason for this may be that our case series represent almost all cases that occurred in geographically defined populations. The registration proportions of the nationwide surveys have been estimated to be lower than 50%, and to decrease with age (Takezaki et al.,1997). Therefore, ATL cases in the present study may better reflect the true distribution of age at the onset. The average age at diagnosis of ATL in Nagasaki Prefecture significantly increased from 62.6 years (SD 12.2) during 1985–1990 to 64.5 years (SD 11.8) during 1991–1995 (t-test, p < 0.05). However, the increase in the onset ages may not be the reason for the difference, since the mid-points of the study periods were similar. The results from the present study may indicate that age at onset in Japanese patients with ATL is later than previously thought. Another reason might be the regional difference in the age distribution of HTLV-I carriers. It has been noted that ATL cases among Japanese or Japanese Americans in the United States are diagnosed at much older ages compared with those in other parts of the world (Levine et al.,1994b; IARC, 1996), probably owing to the effects of genetic and/or environmental co-factors. The precise reason for this is unknown. However, difference in the immune status should be considered as a possible co-factor, since infective dermatitis, an immunosuppressed state at high risk for ATL, has been reported among Jamaican but not Japanese children infected with HTLV-I (LaGrenade et al.,1990).

In the whole of Nagasaki Prefecture, the world age-standardized annual incidence rate of ATL per 100,000 persons aged 30 or older was estimated at 10.5 for men and 6.0 for women. In considering the mortality from ATL in Nagasaki Prefecture, Takezaki et al. (1997) indirectly estimated that the rate per 100,000 person-years (>= 20 years), adjusted to the 1985 Japanese model population, was 10.3 for men and 4.7 for women between 1988 and 1992, on the basis of the difference in lymphoid-malignancy mortality between Kyushu district and the rest of Japan. When the same standard was applied, our estimate (>= 20 years) in men and in women was 8.6/100,000/year and 5.0/100,000/year respectively. We believe that these 2 methods, using the cancer registry and vital statistics, contribute to an evaluation of the true incidence of ATL, since the sources of error differ for each method. In the former, a small number of patients aged over 70 or those registered by death certificate only may be misclassified as other NHL or missed, as suggested by the data from the K Islands, while the latter is based on information from death certificates alone, and assumes that the mortality rates in districts other than Kyushu are equal to zero. Among the total population in the K Islands, the age-standardized rate was estimated at 23.7/100,000/year for men and 11.5/100,000/year for women. This incidence rate in men was as high as that reported for the Noir Marron population in French Guiana (Gerard et al.,1995), with a very high seroprevalence of HTLV-I (25% among adults over 20 years) (Plancoulaine et al.,1998), and was among the highest in the world. The results from the present study also indicated a strong impact of HTLV-I endemy on total NHL incidence in the study areas. ATL accounted for approximately 37–41% and 51–59% of the total NHL incidence in Nagasaki Prefecture and the K Islands respectively.

An intervention program to prevent mother-to-child transmission of HTLV-I has been operating in Nagasaki Prefecture since 1987 (Hino et al.,1996). This program has consisted of screening more than 90% of pregnant women and recommending HTLV-I-carrier mothers not to breast-feed their babies. Consequently, the risk of vertical HTLV-I infection has decreased from approximately 20% to 3%. In addition, there is a natural declining tendency in HTLV-I seroprevalence because of the birth-cohort effect, especially among the younger generation in endemic areas of Japan (Oguma et al.,1992). A relatively low frequency of HTLV-I seropositivity was also noted among the young generation in the K Islands in this study. Thus, the incidence of ATL is expected to decrease in the future, as the proportion of HTLV-I carriers in the age range at high risk for developing ATL decreases. However, monitoring for several decades may be required to evaluate the secular trend in the ATL incidence and the beneficial effect of the intervention program.

Acknowledgements

We are grateful to Drs. S. Ikeda (Sasebo City General Hospital), T. Amenomori (Nagasaki Atomic Bomb Hospital), K. Nagai (Nagasaki University Hospital), S. Momita (National Nagasaki Central Hospital), S. Koga (St. Francisco Hospital), K. Taira (Michinoo Hospital), M. Shiraishi (Arikawa Hospital), M. Yatsugi, Y. Matsuo (Goto Central Hospital), M. Kimura, S. Okamura, (Kyushu University Hospital), N. Uike (Kyushu Cancer Center Hospital), A. Notomi (Hakujyuji Hospital), N. Makino (Hyogo Prefectural Amagasaki Hospital) and A. Horiuchi (Kinki University Hospital) for their kind cooperation in this study. We also thank Ms. M. Yokoo for technical assistance.

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