The risk of second malignant tumors and its consequences for the overall survival of Hodgkin's disease patients and for the choice of their treatment at presentation: analysis of a series of 1524 cases consecutively treated at the Florence University Hospital.

PURPOSE: To quantify the incidence of second malignant tumors (SMT) as a whole and that of second "solid" tumors (SST) and leukemia (L) in a large series of 1524 Hodgkin's disease (HD) patients (pts) treated at the Florence University Hospital (UFH); to define the clinical and therapeutic features possibly related with SMT occurrence; to evaluate the consequences of SMT for the overall survival of the series studied and for the choice of the treatment of HD at presentation. METHODS AND MATERIALS: From 1960 to 1991, 1524 pts with HD, Clinical Stage (CS) I--IV have been treated at the UFH. Overall treatment consisted of radiation alone (RT, 36%), chemotherapy alone (CHT, 21%), or both (RT + CHT, 43%). The cumulative probability (CP) of SMT, SST, and L was calculated for the whole series and for the different clinical and therapeutic subgroups, and the results compared with uni- and multivariate analysis ("internal" comparison, IC). Standardized incidence ratios (SIR) for different SMT types (estimated on the basis of gender, age, period specific incidence rates of the general population) have been also calculated ("external" comparison, EC). The impact of the SMT-related mortality on the survival of the entire series has been estimated. RESULTS: A 14.9% 20-year CP of SMT was registered, along with a SIR of 2.04 (95% confidence interval [CI]: 1.2--2.5). Both IC and EC showed a statistically significant relationship between L incidence and treatment with CHT, alone or in combination with RT. A significant excess of breast cancers has been observed in RT-treated patients with longer follow-up (SIR, 2.9); an excess of other common SST (lung, non-Hodgkin's lymphomas) is evident in pts treated with either RT, RT + CHT, or CHT. The actuarial long-term survival of the series would have been better of about 3%, in absence of the SMT mortality possibly due to HD treatment, which is almost equally divided between patients treated with RT alone, CHT alone, and RT + CHT. CONCLUSIONS: SMT represent an important late event in HD long-term survivors. The relationship between L and treatment with CHT seems to be the most clearly defined. The effect of SMT on the survival of the entire series, although not negligible, does not seem to justify by itself substantial alterations in the current standards for the treatment of HD at presentation.

Haematopoietic cancer and medical history: a multicentre case control study.

BACKGROUND: Viruses (such as Epstein-Barr virus) and pathological conditions (mainly involving immunosuppression) have been shown to increase the risk of haematolymphopoietic malignancies. Other associations (diabetes, tonsillectomy, autoimmune diseases) have been inconsistently reported. METHODS: The association between different haematolymphopoietic malignancies (lymphomas, myelomas and leukaemias) and the previous medical history has been studied in a population-based case-control investigation conducted in Italy, based on face to face interviews to 2669 cases and 1718 population controls (refusal rates 10% and 19%, respectively). Controls were a random sample of the general population. RESULTS: Previous findings were confirmed concerning the association between non-Hodgkin's lymphoma (NHL) and lupus erythematosus (odds ratio, OR=8.4; 95% CI 1. 6, 45), tuberculosis (OR=1.6; 1.05, 2.5) and hepatitis (1.8; 1.4, 2. 3). An association was found also between NHL and maternal (OR=2.8; 1.1, 6.9) or paternal tuberculosis (OR=1.7; 0.7, 3.9). Odds ratios of 4.0 (1.4, 11.8) and 4.4 (1.1, 6.6) were detected for the association between NHL and Hodgkin's disease, respectively, and previous infectious mononucleosis, but recall bias cannot be ruled out. No association was found with diabetes, tonsillectomy and adenoidectomy. An association with malaria at young age and "low grade" lymphatic malignancies is suggested. One interesting finding was the observation of four cases of poliomyelitis among NHL patients, one among Hodgkin's disease and one among myeloid leukaemia patients, compared with none among the controls (Fisher's exact test for NHL and Hodgkin's disease, p= 0.03, one tail). CONCLUSIONS: Some of these findings are confirmatory of previous evidence. Other observations, such as the putative role of the polio virus and of malaria are new. A unifying theory on the mechanisms by which previous medical history may increase the risk of haematolymphopoietic malignancies is still lacking.

Delayed infection, family size and malignant lymphomas.

BACKGROUND: The annual incidence of non-Hodgkin's lymphomas (NHL) is increasing by 3%-4% in different parts of the developed world. Excesses of NHL have been observed in populations exposed to immunosuppressants and to HIV, but these causes do not explain the increasing trends. It is suggested that delayed infection could explain NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. METHODS: In a population-based study on 1388 patients with NHL, 354 with Hodgkin's disease (HD) and 1718 healthy controls, the age of first occurrence of bacterial and viral diseases was investigated. Clinical records were perused in one centre to check the anamnestic data. FINDINGS: The age of occurrence of bacterial and viral diseases was significantly higher among NHL patients than in the controls. The association between later age at first bacterial or viral disease was limited to small families (OR= 1.95; 95% confidence intervals 1.26, 3.00, for age 4-8 at first infection; OR=1.91; 1.19, 3.06, for age 9+, compared with less than 4). The association was more obvious for bacterial diseases (possibly for the lower degree of misclassification). High grade lymphomas showed the strongest association. The later age of occurrence of bacterial or viral diseases in NHL patients is consistent with a higher incidence of lymphomas observed in higher social groups. No clear association was found between HD and age at first bacterial or viral diseases. INTERPRETATION: It is proposed that delayed infection could explain the increasing NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. The model of delayed infection has been proposed also to explain increasing prevalence rates of asthma.

Aplastic anemia, leukemia and other cancer mortality in a cohort of shoe workers exposed to benzene.

Benzene is a well documented carcinogen for the hematic and lymphopoietic system, and experimental research confirms its carcinogenicity for tumors of other sites. This report presents the results of a historical cohort study in a shoe manufacturing plant in Florence where cases of aplastic anemia and leukemia were reported in the 1960s. A total of 1008 men and 1005 women were considered eligible members of the cohort. For total mortality, comparing the rates of the cohort with the national rates, the standardized mortality ratio (SMR) was 79 for the women and 95 for the men. For the men excesses of risk for aplastic anemia [SMR 1566; 95% confidence interval (95% CI) 547-3264] and leukemia (SMR 400, 95% CI 146-870) were observed. The increased risk occurred among workers first employed during the period in which benzene was used, but the expected number of cases in the subsequent period was too small to evaluate whether any reduction in risk had occurred. No increasing pattern with duration of employment was discernible.

[The epidemiology and risk factors, in particular environmental, of malignant non-Hodgkin's lymphomas. The Working Group on the Epidemiology of Tumors of the Hemo- and Lymphopoietic Systems in Italy]. / Epidemiologia e fattori di rischio, in particolare ambientali, dei linfomi maligni non Hodgkin. Gruppo di lavoro sull'epidemiologia dei tumori del sistema emolinfopoietico in Italia.

Malignant non-Hodgkin's lymphomas (NHL) represent a category of neoplasms that includes several types of tumours with different hystological and clinical characteristics. No large differences exist in incidence and mortality for the whole category of lymphomas among different countries. On the other hand data concerning different subclassifications of lymphomas in different countries are not available. The incidence of NHL increased in recent years in USA and in the European countries. Data from the Cancer Registry in the province of Varese, the registry with the longest high-quality registration period in Italy, indicate the same tendency. Also mortality rates show an increasing trend in Europe and in the USA. The cause of changing in incidence and in mortality rates for NHL are unknown. Anyhow many factors, viral, chemical and immunological are known to be associated to the occurrence of lymphomas. Risk factors and in particular environmental factors are reviewed. Problematic aspects, in relation to methodologies adopted in these studies, are focused.

[An Italian multicenter case-control study on malignant neoplasms of the hematolymphopoietic system. Hypothesis and preliminary results on work-related risks. WILL (Working Group on Hematolymphopoietic Malignancies in Italy)]. / Studio caso-controllo multicentrico italiano sulle neoplasie maligne del sistema emolinfopoietico. Ipotesi in studio e risultati preliminari sui rischi associati alle attività lavorative. WILL. Working Group on Hematolymphopoietic Malignancies in Italy.

A multicenter case-control study was conducted in Italy in twelve areas covering a population of 7 million persons with the aim of verifying the hypothesis of an association between exposure to herbicides and to organic solvents and occurrence of lymphoma, leukaemia and multiple myeloma. 3420 cases were recruited in a three-year period (1991-1993), through periodical surveys in the main hospitals in each area. A random sample of the general population (2317 subjects) constitutes the control group. Cases and controls were face to face interviewed by trained personnel. A questionnaire was used asking about personal habits, residential and occupational history, past health status. Preliminary analyses, concerning a total of 1388 cases and 1718 controls, focused risks by occupation. Elevated risks of non Hodgkin's lymphoma (OR: 1.7; IC 95%: 0.92-3.02; based on 28 exposed cases), and of multiple myeloma (OR: 3.6; IC 95%: 1.51-8.63; based on 9 exposed cases) were shown for welders. Among female hairdressers there were elevated risks of non Hodgkin's lymphoma (OR: 1.8; IC 95%: 0.76-4.30; based on 8 exposed cases), multiple myeloma (OR: 3.3; IC 95%: 0.77-14.15; based on 3 exposed cases) and Hodgkin's disease (OR: 2.0; IC 95%: 0.93-4.47; based on 16 exposed cases).

Studying cancer among female workers: methods and preliminary results from a record-linkage system in Italy.

In the context of a national program for occupational health surveillance, we examined cancer mortality among women from two study populations. The Torino Longitudinal Study includes 159,039 women, resident in Torino, northern Italy, 18 to 64 years old and economically active at the 1981 census. The Italian Cross-sectional Study includes 2,038 deaths among 6,073,071 Italian women, 18 to 64 years old and economically active at the 1981 census. Preliminary results indicate that women in higher socioeconomic classes showed excess overall cancer mortality. This excess was almost entirely explained by increased breast cancer among teachers, managers, and public officials. Metal, wood, and clothing manual workers showed a significantly increased risk of ovarian cancer. Some excesses of lung and digestive cancers were noticeable among women in the textile and clothing industry and in the restaurant, bar, and hotel trade. Further study is under way.

Cancer mortality among workers in the Tuscan tanning industry.

The mortality of 2926 male workers at the tanneries in the "leather area" of Tuscany was examined from 1950 to 1983 comparing it with the national mortality. Cancer mortality was of particular concern because of the many chemicals known to be definite or suspected carcinogens used in the tanning cycle, in particular chromate pigments, benzidine based dyes, formaldehyde, and organic solvents. There was no excess of deaths for cancers of all sites but slight increases in deaths from cancer of the lung (SMR = 131, CI 95% = 88-182), bladder (SMR = 150, CI 95% = 48-349), kidney (SMR = 323, CI 95% = 86-827), pancreas (SMR = 146, CI 95% = 39-373), and leukaemias (SMR = 164, CI 95% = 53-382) occurred. Two cases of soft tissue sarcomas were observed versus 0.09 expected (SMR = 2178, CI 95% = 250-8023).

Cancer mortality among shoe manufacturing workers: an analysis of two cohorts.

OBJECTIVES: To examine the cancer risk of shoe manufacturing workers and evaluate whether the risk was associated with exposure to leather dust and solvents. METHODS: Data from two historical cohort studies of shoe workers were expanded and analysed in parallel. A total of 4215 shoemakers from England contributing 103 726 person-years at risk and 2008 shoemakers from Florence, Italy, contributing 54,395 person-years at risk were included in the analysis. Exposure to leather dusts and solvents from glues was evaluated on the basis of job title information. Standardised mortality ratios (SMR) were calculated as ratios of observed deaths (Obs) over expected derived from national mortalities. RESULTS: Overall mortality was lower than expected in both cohorts (English cohort: Obs 3314, SMR 81, 95% confidence interval (95% CI) 78-84; Florence cohort: Obs 333, SMR 87, 95% CI 78-97). An increased risk of nasal cancer was found (English cohort: Obs 12, SMR 741; Florence cohort: Obs 1, SMR 909). 10 of the 13 cases occurred among English workers employed in the manufacture of welted boots (SMR 926, 95% CI 444-1703), a sector of the industry thought to have had the highest exposure to leather dust. Mortality from leukaemia was not increased in the English cohort (Obs 16, SMR 89), but was increased in the Florence cohort (Obs 8, SMR 214, 95% CI 92-421); and the highest risk was found among shoe workers in Florence who were first exposed between 1950 and 1959 when exposure to benzene was substantial (Obs 3, SMR 536, 95% CI 111-1566). Some evidence for an excess risk of stomach, bladder, and kidney cancer, as well as multiple myeloma and non-Hodgkin's lymphoma was also found in the Florence cohort only among workers employed in jobs with the highest exposure to solvents. CONCLUSIONS: These findings confirm the associations between exposure to leather dust and nasal cancer and between exposure to benzene and leukaemia in the shoe manufacturing industry and suggest that the risk of other cancers may be increased among workers exposed to solvents or glues.

Pleural malignant mesothelioma in Tuscany, Italy (1970-1988): II. Identification of occupational exposure to asbestos.

Following the finding of an unexpected cluster of mesotheliomas in textile workers, a surveillance system of malignant mesotheliomas was implemented in the region of Tuscany, Italy. This article reports on the investigation of 124 cases of mesothelioma diagnosed and reviewed by the Institutes of Morbid Anatomy and Histopathology at the Universities of Florence, Pisa, and Siena between 1970 and 1988. A complete occupational and asbestos exposure history was assessed through a semi-structured questionnaire directly administered to resident cases of Tuscany or, if deceased, to their closest living relatives, for a total of 100 interviews. The hypothesis of past occupational asbestos exposure was verified and documented. Seventy-two cases have been classified as occupationally exposed to asbestos; four were classified in the category of "possible domestic" exposure to asbestos. For two others, the role of other risk factors was stressed, and for 22 cases, either no asbestos exposure was found or the available data were not adequate to define it. The present study allowed identification of some unknown or scarcely known occupational asbestos exposures in the study area.

Delayed infection, late tonsillectomy or adenoidectomy and adult leukaemia: a case-control study.

In a population-based case-control study among adults in Italy, of 261 lymphoid and 313 myeloid leukaemias and 1718 controls, a later age at adenoidectomy and tonsillectomy (after age 10 years) increased considerably the risk of lymphocytic (but not myeloid) leukaemia (odds ratio 4.2, 95% confidence interval 1.1-16.2). We propose that late infection is a proliferative stimulus for B-cells.

Smoking and hematolymphopoietic malignancies.

OBJECTIVE: Tobacco use is the most prominent cause of respiratory cancers. Little is known, however, about the influence of smoking on hematolymphopoietic malignancies. To evaluate this relation, a population-based case-control study was carried out in 12 areas of Italy. METHODS: Detailed interviews on tobacco smoking habits were administered to 1450 non-Hodgkin's lymphoma (NHL), 365 Hodgkin's disease (HD), 270 multiple myeloma (MM), and 649 leukemia (LEU) patients occurring from 1990 to 1993, and 1779 population controls. RESULTS: We found a slightly increased risk for NHL in smokers (odds ratio 1.2, 95% confidence interval 1.0-1.4 for ever smokers), but a consistent positive association was shown only for follicular NHL. In this subtype, a significant excess risk was observed for ever versus never smokers, after adjustment for gender, age, geographic residence, education, and respondent (OR = 1.8, 95%, CI 1.3-2.7), with a positive exposure-response gradient for smoking duration (p < 0.01). The risk for follicular NHL was significantly elevated only among women, with ever smokers showing OR = 2.3 (CI 1.4-3.8), while for men we found OR = 1.3 (CI 0.69-2.3). No major differences were shown according to age. Female subjects also showed significant positive exposure-response trends for duration. CONCLUSION: Cigarette smoking could be a risk factor for follicular NHL among women. For HD, MM, or LEU, no clear association was observed.

A multicenter case-control study in Italy on hematolymphopoietic neoplasms and occupation.

We conducted a population-based, case-control study on hematolymphopoietic malignancies in 12 areas in Italy to investigate associations between different hematolymphopoietic malignancies and exposure to solvents and pesticides. We collected all incident cases 20-74 years of age from 12 areas, with a combined population of approximately 7 million residents. The control group was formed by a random sample of the study population. Data presented in this paper refer to 2,737 interviewed cases of 3,357 eligible cases and to 1,779 of 2,391 eligible controls. We analyzed risks associated with occupation using job-title information to evaluate disease pattern according to job category. An earlier publication presented results for women; here, we report the findings for men and discuss the overall patterns in both genders. The most consistent overall finding was an approximate doubling in relative risk for all four types of malignancies among male managers and related occupations. Several additional occupations were associated with elevated risk of one or more malignancies among men. These included cooks, waiters, and bartenders, and building caretakers and cleaners, for non-Hodgkin's lymphoma; textile workers and machinery fitters for Hodgkin's lymphoma; metal processors, material handlers, rubber workers, and painters for leukemia; and hairdressers, metal processors, tailors, electrical workers, and plumbers for multiple myeloma. The finding of increased risk of non-Hodgkin's lymphoma among both male and female cooks, waiters, and bartenders has not been previously reported; nor has the elevated risk of leukemia among material handlers. Among people engaged in agriculture, those employed as tractor drivers and as "orchard, vineyard, and related tree and shrub workers" appeared to be at increased risk for hematolymphopoietic malignancies.

Hematopoietic cancer and peptic ulcer: a multicenter case-control study.

Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL). In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H.pylori antibodies. The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8-8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0-1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1-4.2) after >/=20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0-9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity). The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2-10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects.