Long-term incidence in hepatocellular carcinoma and intrahepatic bile duct cancer in Denmark, Finland, Norway and Sweden, role of Thorotrast?

We analyzed long-term incidence trends in liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma) with an aim to interpret the changes in terms of known risk factors and hypothesize that historical exposure to Thorotrast, a radiographic contrast medium emitting alpha particles, has changed population rates. The NORDCAN database was used to collect cancer registry data from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE), which we used from 1953 (DK, FI and NO) and 1960 (SE) through 2019. Thorotrast, which caused a 100-fold risk of liver cancer was used in DK and SE, and probably also in FI between 1930 and 1950, but not in NO. The incidence trend for liver cancer showed a broad maximum at around 1980, most prominent and statistically significant in SE and DK men and women, and in all countries, a steadily increasing trend towards the end of follow-up. Incidence for NO was lower than for the other countries and the rates showed no peaking at around 1980. Birth cohort analysis identified a transient risk which could be dated to a period between 1930 and 1950 in countries other than NO. Considering a lag time between Thorotrast use and liver cancer appearance, the large incidence peak around 1980 in DK and DE was probably contributed by Thorotrast but considering the ecological nature of the findings, the association should be considered cautiously as hypothesis generating. The late increase in liver cancer risk is most likely lifestyle related and largely preventable.

Radiation pathology: from thorotrast to the future beyond radioresistance.

The effects of radiation on human health have been a major concern, especially after the Fukushima Daiichi Nuclear Power Plant (FNPP) accident. We can determine these effects only from radiological disasters. The radiological contrast medium Thorotrast is known to induce hepatic cancers decades after injection. Using archival materials from Thorotrast patients, we performed molecular pathological studies to elucidate carcinogenic mechanisms of internal radiation exposure. It is emphasized here that radiation-induced cancers are a complex consequence of biological response to radiation and ingested radionuclides. We further expanded the study to establish clinically relevant radioresistant cancer cells in order to develop more effective and less harmful radiation therapy. We also found that cancer cells can acquire radioresistance by low-dose fractionated radiation within one month. The FNPP accidents prompted us to collect tissue samples from animals in and around the evacuation zone in order to construct a tissue bank. The final goal of the bank is to enable research that will contribute to the common understanding of radioprotection.

[The medical management of high risk individuals. Experiences with persons exposed to chronic internal irradiation]. / Über den ärztlichen Umgang mit Hochrisikopersonen. Erfahrungen bei Personen mit chronischer interner Strahlenexposition.

The medical management and counseling of persons at high risk due to exposure to chemicals or radiation or due to personal disposition, present an additional challenge for physicians and especially radiologists involved. This article is based on own experiences with patients who had been exposed to Thorotrast. They had been injected with the contrast medium Thorotrast, which was in use world-wide until around 1950. Thorotrast caused a chronic alpha irradiation mainly of the liver (up to 0.4 Gy/a), spleen (1.2 Gy/a) and bone marrow (0.1 Gy/a). For the Thorotrast patients and their physicians the most worrying problem was the risk of primary malignant liver tumors which occurred in more than 20% of the exposed persons, i.e. 100 times more frequently than in a non-exposed control group. The medical and especially radiological experiences with the management of these patients summarize a general aspect of the problem and can be referred to when managing other high risk groups.

Histological type of Thorotrast-induced liver tumors associated with the translocation of deposited radionuclides.

Exposure to internally deposited radionuclides is known to induce malignant tumors of various histological types. Thorotrast, a colloidal suspension of radioactive Thorium dioxide ((232)ThO(2)) that emits alpha-particles, was used as a radiographic contrast during World War II. Thorotrast is known to induce liver tumors, particularly intrahepatic cholangiocarcinoma (ICC) and angiosarcoma (AS), decades after injection. Therefore, patients injected with Thorotrast comprise a suitable study group to understand biological effects of internal ionizing radiation injury. Autoradiography and X-ray fluorescence spectrometry (XRF) were carried out on non-tumorous liver sections from Thorotrast-induced ICC (T-ICC) and Thorotrast-induced AS (T-AS). Autoradiography revealed that the slope of the regression line of the number of alpha tracks for the amount of deposited Thorium ((232)Th) was higher in non-tumorous parts of the liver with T-ICC than those with T-AS. XRF showed that the intensity ratio of Radium (Ra) to Thorium (Th) in non-tumorous liver tissue with T-ICC was significantly higher than that with T-AS. Furthermore, the mean (228)Ra/(232)Th radioactivity ratio at the time of death calculated was also significantly higher in T-ICC cases than in T-AS cases. These suggest that the metabolic behavior of radionuclides such as relocation and excretion, as well as the content of deposited radionuclides, is a major factor in determining the histological type of Thorotrast-induced liver tumors.

Ionizing radiation: a risk factor for mesothelioma.

In the majority of mesothelioma cases worldwide, asbestos is a likely causal factor, but several alternative factors, such as ionizing radiation, have been recognized. We reviewed ionizing-radiation evidence from epidemiology studies of (1) patients exposed to the diagnostic X-ray contrast medium "Thorotrast," (2) patients undergoing radiation therapy (i.e., to treat cancer), and (3) atomic energy workers chronically exposed to lower levels of radiation. The results from these populations are also supported by case reports of mesothelioma following therapeutic radiation. Statistically significant associations were found in many, but not all, epidemiology studies (particularly those of Thorotrast- and radiation-treated patients). Given the low mesothelioma rate in the general population, the consistently increased risk among these radiation-exposed individuals is noteworthy. Many studies were limited by the lack of a uniform manner in which mesothelioma was reported prior to introduction of a uniform classification system (ICD-10). Future studies that rely on ICD-10 should have greater power to detect an association. While the evidence falls short of a definitive causal link, considering studies in which statistical significance was achieved, the case reports, and the plausible mode of action, we conclude that the evidence is supportive of a causal link between ionizing radiation exposure and mesothelioma risk.

Long incubation period for the induction of cancer by thorotrast is attributed to the uneven irradiation of liver cells at the microscopic level.

Irradiation from internally deposited radionuclides induces malignant tumors. Ingested long-lived radionuclides accumulate in specific organs that are irradiated throughout life. To elucidate why the development of malignant tumors requires long-term internal exposure, of the order of decades, despite the fact that irradiation is continuous over this period, we analyzed intrahepatic cholangiocarcinoma in Thorotrast patients (Th-ICC). Autoradiography showed that the density of alpha-particle tracks was 50 times more concentrated than would be expected if Thorotrast were evenly distributed throughout the liver. The age-incidence curves revealed that while the incidence of hepatobiliary cancer in Japan increased in proportion to the 7th power of age, that of Th-ICC increased to the 6th power. Internal radiation significantly increased the randomness of hepatocyte distribution but not the density. Three major factors are considered to be responsible for the long incubation time: the uneven distribution of radionuclides, the limited range of radiation, and the movement of tumor precursor cells. Target cells susceptible to malignant transformation may undergo one event and may then migrate outside of the range of alpha particles, thereby avoiding immediate induction of successive additional events that would lead to cell death or neoplastic changes.

Radiation databases and archives - examples and comparisons.

Studies of ionizing radiation effects through the archiving of data began with standardizing medical treatments in the early 1900s shortly after the discovery of X-rays. Once the breadth of the delayed effects of ionizing radiation was recognized, the need for long-term follow up became apparent. There are now many human archives of data from nuclear disasters and accidents, occupational exposures, and medical procedures. Planned animal irradiation experiments began around the time of the Cold War and included a variety of doses, fractions, dose rates, and types of ionizing radiation. The goal of most of these studies was to supplement information coming from human data through carefully planned experimental conditions and immediate and uninterrupted data collection. This review aims to highlight major archives and databases that have shaped the field of radiation biology and provide a broad range of the types of datasets currently available. By preserving all of these data and tissue sets, radiation biologists can combine databases and conduct large-scale analyses of detailed existing data and perform new assays with cutting edge scientific approaches.

Mortality among Thorotrast-exposed patients and an unexposed comparison group in the German Thorotrast study.

Thorotrast was the brand name of a stabilised colloidal solution of thorium dioxide which was used preferentially as an X-ray contrast medium for arteriography between 1930 and 1950. The administration of the medium led to lifelong chronic alpha-particle irradiation by thorium decay products, mainly in the organs of deposition. Several epidemiological follow-up studies were set up after recognition of these side-effects among which the German study was the largest. After an extended follow-up, by 2004 only nine out of 2326 originally exposed subjects were still alive (while 151 of the comparison group, which originally numbered 1890 subjects, survived) and partially more than 70 years observation and chronic exposure time could be studied allowing for further observations to be made about long-term mortality effects of Thorotrast exposure. Median life-expectancy was shortened by 14 years and mortality increased, affecting total mortality SMR=287 for males, SMR=387 for females) as well as cause-specific, especially liver cancer (SMR=16,695 and SMR=12,680, respectively), and the haematopoietic system (SMR=556 and SMR=504, respectively), but not lung cancer. Mortality (total and selected cause-specific) increased with cumulative time since first exposure.

Thorium dioxide-related haemangiosarcoma of the liver.

Rare tumours of the liver are occasionally seen; thorium dioxide-related haemangiosarcoma of the liver, with an estimated frequency of 0.14 to 0.25 per million in the normal population, is one of these. Causes, epidemiology and pathobiology are described related to a clinical case of angiosarcoma. A differentiation of hepatic tumours with imaging techniques is presented. Last, a short review on up-to-date treatment of haemangiosarcoma is discussed. Lessons can always be learned from history: will the contrast agent gadolinium be the Th232 of this era?

[Electrophoretic and immunochemical research of rat urine proteins in dynamics after intravenous injection of thorium dioxide (thorotrast)].

Rats were treated with a single intravenous injection of thorotrast (thorium dioxide)--the source of alpha-rays. Dynamic investigation of urine protens of rats by methods of electrophoresis and immunoelectrophoresis was carried out during 22 months after thorotrast injection. Already the month after drug injection the selectivity of tubular reabsorbtion was disturbed. Three months after thorotrast injection the content of urinal proteins of tissue (in particular renal) origin was decreased. Finally the selectivity of renal filtration of proteins was damaged 4-6 months after thorotrast introduction. Serum proteins which were absent in normal urine (for example transferrin and lipoproteins) appeared in urine of affected rats. The urine proteins of serum origin were less degraded than those in normal urine. The alterations of glomerular filtration was increased up to 20-22 months when the spectrum of urine proteins became similar to the spectrum of serum proteins. The death of treated rats was occurred in this period. Thus the monitoring of urine proteins of rats treated with alpha-ray producing preparation throtrast allows to register the successive alterations of reabsorbtion, excretion and filtration functions of kidney.

Effects of preconceptional irradiation on mortality and cancer incidence in the offspring of patients given injections of Thorotrast.

BACKGROUND: Findings from a British case-control study suggest that a preconceptional paternal external radiation dose of more than 100 mSv (10 rem) is significantly related to risk for leukemia and non-Hodgkin's lymphoma in offspring. The suggestion, however, has not been supported by experimental or other epidemiologic studies. PURPOSE: The purpose of this study was to investigate if preconceptional irradiation of males and females from internally deposited radionuclides affects mortality and risk of developing cancer in their offspring. METHODS: The offspring of 260 females (n = 143) and 320 males (n = 226) who lived longer than 1 year after receiving Thorotrast (a compound no longer in use) for cerebral arteriography were studied for mortality rate and the risk for developing cancer. Thorotrast was used as a contrast medium containing a 20% colloidal solution of thorium dioxide-Th 232, an alpha particle-emitting radionuclide, which is retained lifelong in nearly all organs. The offspring of the exposed patients were identified by manual linkage with the municipal population registers and followed-up for vital status by computerized linkage with the Danish National Central Population Registry and for incidence of cancer by computerized linkage with the Danish National Cancer Registry. The standardized mortality/morbidity ratios (SMRs) for death and for site-specific incidence of cancer in the offspring were calculated as ratios of the observed rates in the study population to the expected rates in the general population. RESULTS: After a median follow-up of 40 years, four cases of cancer (breast [one], uterine cervix [one], melanoma of skin [one], and retinoblastoma [one]) versus 2.9 cases expected, developed among 143 children born to mothers who received injections of Thorotrast (SMR = 1.4; 95% confidence interval [CI] = 0.4-3.5), while six cases of cancer (one case each of cancer of lung, testis, thyroid, and Hodgkin's lymphoma and two cases of melanoma of skin), versus 4.5 expected, occurred among 226 children of exposed fathers (SMR = 1.3; 95% CI = 0.5-2.9). No case of leukemia or non-Hodgkin's lymphoma occurred in any of the offspring studied. Mortality was lower than expected both for children of exposed mothers (SMR = 0.7; 95% CI = 0.3-1.5) and of exposed fathers (SMR = 0.5; 95% CI = 0.2-1.0). CONCLUSIONS: This study does not support the previously proposed association between parental exposure to radiation and the risk of childhood leukemia and lymphoma. Furthermore, since mortality from all causes was not increased in any offspring, our results do not support the belief that preconceptional parental low-dose exposure to alpha radiation increases the incidence of cancer or mortality in the offspring.

Survey of thorotrast-associated liver cancers in Japan.

Data on 93 autopsy cases (group A) of thorotrast-associated liver cancers were obtained from the "Annual of Pathological Autopsy Cases in Japan" from 1958 to 1979, and data on 78 autopsy cases (group B) of thorotrast-associated liver cancers were obtained from the Japanese literature from 1953 to 1980. Cholangiocarcinoma (CLC) constituted 58% of group A and 55% of group B. The curve of the cumulative numbers of patients with CLC versus year in group A was almost linear, showing an increasing risk per surviving patients with advancing time. Angiosarcoma (AGS) occurred in 25% of group A and 24% of group B. The number of patients with AGS increased significantly after 1969 in both groups (P less than 0.05). In group B, age and years after thorotrast injection of patients with AGS were statistically higher than those of patients with CLC (age: P less than 0.05; years after thorotrast injection: P less than 0.0001). Hepatocellular carcinoma (HPC) accounted for 17 and 21% of groups A and B, respectively. When yearly distribution, age, and time after thorotrast injection of patients with HPC were correlated with those of patients with other liver cancers, the only statistically significant difference between patients with HPC and patients with CLC (P less than 0.02) was in the years after thorotrast administration. Since 1977 multiple primary liver cancers including AGS developed in thorotrast-administered patients in both groups.

Cancer among epileptic patients exposed to anticonvulsant drugs.

Cancer incidence among 8,004 patients hospitalized for epilepsy between 1933 and 1962 in the Filadelfia treatment community in Denmark was compared to that of the general population. Patients received powerful and prolonged treatment with phenobarbital, phenytoin, and other anticonvulsants. This new survey extends the follow-up from 1976 through 1984. Among 7,864 patients with epilepsy not known to have received radioactive Thorotrast, record linkage with national cancer incidence files identified 789 cancers, compared to 664 expected [relative risk (RR) = 1.19; 95% confidence interval = 1.11-1.27]. Significant risks were found for cancers of the brain and central nervous system (RR = 5.7; n = 118) and the lung (RR = 1.4; n = 106). The excess numbers of brain cancer were concentrated within 10 years of hospitalization (RR = 20.7; n = 80) and decreased significantly over time, which suggests that brain tumors account for the seizure disorder and are not due to phenobarbital exposure as suggested by some epidemiologic studies. No overall risk was apparent when brain cancers were excluded (RR = 1.03). Because bladder cancer was significantly decreased (RR = 0.6; n = 18), the excess risk of lung cancer may not have been related to the "anecdotal" heavy smoking reported among confined groups of epileptic patients in the early years of the study period. The incidence of malignant melanoma was also significantly low (RR = 0.5; n = 7), which suggested limited exposure to sunlight among confined patients. The risk of non-Hodgkin's lymphoma was increased, but not significantly (RR = 1.4; n = 16), which is interesting in view of previous reports suggesting an association with phenytoin. Overall, these data provide little evidence that phenobarbital and phenytoin are carcinogenic to humans, but the excess risks of lung cancer and non-Hodgkin's lymphoma among epileptic patients in our study deserve further evaluation.

Cancer incidence among Danish Thorotrast-exposed patients.

BACKGROUND: Studies of groups of patients given injections of the alpha-emitting x-ray contrast medium Thorotrast may provide information on human alpha-ray carcinogenesis. PURPOSE: We re-established a formerly identified cohort of neurological patients receiving injections of Thorotrast for cerebral arteriography and assessed their incidence of cancer. METHODS: Using the national population register, the Danish Cancer Registry, and other registers, we determined the incidence of cancer among Thorotrast-injected patients. Incidence ratios were standardized to the general population and computed for different cancer sites. RESULTS: The cumulative risk for cancer at all sites (excluding brain tumors where the standardized incidence ratio [SIR] was 28) reached 86% 50 years after Thorotrast injection. SIR was greatly elevated at all sites except the brain and CNS (3.3, 95% confidence interval = 3.0-3.7), mainly because of liver cancers (SIR = 126) as well as leukemia (SIR = 10) for which a relationship was found between the time since injection and the estimated dose (but not the age at injection). Other sites with significantly increased risks of cancer included the gallbladder and extrahepatic bile ducts (SIR = 14), peritoneum (SIR = 8.6), sites of multiple myeloma (SIR = 4.6), metastatic sites (SIR = 12), and unspecified sites (SIR = 11). Cancers of the lung and breast also occurred in significant excess, but no relationship between SIR and volume of injected Thorotrast or time since injection was observed. Cancer risk was increased at most other sites, although this increase was not statistically significant. CONCLUSION: Alpha radiation may account for the increased risk of tumors of the liver, gallbladder, and peritoneum as well as leukemia and multiple myeloma, whereas confounding factors most probably contribute to the increased risks at other sites.

Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma.

The possible influence of phenobarbital and phenytoin treatment on cancer risk was investigated in a case-control study nested in a cohort of 8004 epileptic patients in Denmark. Information on anticonvulsive treatments was abstracted for 95% of 60 patients with cancers of the liver and biliary tract or malignant lymphoma and for 94% of 171 cancer-free control patients. Use of anticonvulsive drugs was correlated with angiographic procedures that used Thorotrast, a well-known human liver carcinogen. After exclusion of study subjects exposed to Thorotrast, no association was seen between treatment with phenobarbital and cancer of the liver (odds ratio, 1.0; 95% confidence interval, 0.1-8.0) or biliary tract (odds ratio, 0.8; 95% confidence interval, 0.1-4.2). Furthermore, a histopathological evaluation of slides from 7 of 9 liver cancer patients not treated with Thorotrast revealed that 3 of the 4 cases of hepatocellular carcinoma involved cirrhosis of the liver, which suggested an etiological role for alcohol or viral hepatitis. A possible link was observed between use of phenytoin and risk for non-Hodgkin's lymphoma (1.8; 0.5-6.6), with a rising trend in risk with increasing dose. Our results suggest that the increased risk for cancers of the liver and biliary tract among Danish epileptic patients is likely to be due to Thorotrast administration and factors associated with cirrhosis of the liver rather than to anticonvulsive treatment.

The clinical features of hepatic angiosarcoma: a report of four cases and a review of the English literature.

Four cases of hepatic angiosarcoma are reported with a review of 99 other cases in the English literature. Angiosarcoma of the liver is associated with chronic exposure to thorotrast, vinyl chloride, arsenicals, radium and possibly copper and with chronic idiopathic hemochromatosis. Although 40% of patients have hepatic fibrosis or cirrhosis at autopsy, the nature of the association between chronic liver disease and hepatic angiosarcoma is unknown. The clinical presentation of hepatic angiosarcoma is nonspecific with abdominal pain, weakness and weight loss common complaints and with hepatomegaly, ascites and jaundice common findings. Liver function tests are usually abnormal but there is no one liver function test or set of tests specific for the tumor. The occurrence of thrombocytopenia and disseminated intravascular coagulation is characteristic of hepatic angiosarcoma and may be related to local consumption of clotting factors and formed blood elements in the tumor. Catastrophic intraabdominal bleeding is also characteristic and occurs in one-fourth of all cases. This complication is likely related to the high incidence of clotting abnormalities and the vascular nature of the neoplasm. Selective hepatic arteriogram and open liver biopsy are the foundations of diagnostic evaluation. Percutaneous liver biopsy should be avoided. Failure to appreciate the possibility of hepatic angiosarcoma in the proper clinical setting, leading to blind percutaneous biopsy, may result in failure to make the diagnosis at the cost of significant morbidity and mortality. Survival of patients with hepatic angiosarcoma is brief; only 3% live longer than 2 years. Treatment of the tumor to date is empirical. There are probably a few patients who might benefit from radical surgery with curative intent. For all others chemotherapy is indicated. Adriamycin is active against hepatic angiosarcoma, but optimal dose and mode of administration require further investigation. Further study is also required to delineate the cause of hepatic angiosarcoma in the 60% of cases without definite epidemiologic association.

Mutations in the tumor suppressor gene p53 in human liver cancer induced by alpha-particles.

The p53 tumor suppressor gene is mutated in varying fractions of almost all tumor types studied. The rate of mutations and the mutational spectrum in some tumors are specific for environmental mutagens assumed to be involved in the carcinogenic process. Thus, hepatocellular carcinomas supposedly induced by aflatoxin exposure often contain a specific point mutation in codon 249, and in lung cancers of miners with heavy radon exposure, another specific point mutation in codon 249 suggestive of an alpha-particle-specific mutation has been shown. The interpretation of studies linking the mutational spectrum with specific environmental exposures is complicated by the multifactorial or unknown genesis of most tumors. However, people given injections of the X-ray contrast medium Thorotrast (Th) in the past have experienced an enormous risk of liver tumors, and virtually all of these are supposedly induced by alpha-particles from the decay of 232Th. The examination of these tumors may provide evidence as to whether specific p53 point mutations are relevant in alpha-particle carcinogenesis. Therefore, we collected paraffin-embedded, formalin-fixed archival tissues from 18 hepatocellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients. The tissues were analyzed for p53 protein expression by immunohistochemical staining by using the mAb DO-7 and for mutations of exons 5-8 by PCR and constant denaturant gel electrophoresis. G --> T transversions of the third base of codon 249 of the p53 gene were specifically screened for by restriction enzymes. No high score for p53 protein expression (i.e., positive staining of >20% of examined cells) was observed; lower scores were seen in 5 of 18 (28%) hepatocellular carcinomas, 1 of 9 (11%) cholangiocarcinomas, and 0 of 8 (0%) hepatic angiosarcomas. Only one p53 mutation, a heterozygous T --> G transversion of the first base codon 176, occurred in a hepatocellular carcinoma. The rate of p53 point mutations in alpha-particle-induced liver tumors seems to be lower than in European hepatocellular carcinomas in general. The study does not exclude the possibility that alpha-particle carcinogenesis may involve inactivation of p53 by gross deletions of the gene, but it speaks against the proposed specificity of point mutations of codon 249 in cancer supposedly induced by alpha-particles from radon progeny.

Phenobarbital, drug metabolism, and human cancer.

To investigate the possible influence of anticonvulsant treatment on cancer risk, a nested case-control study of 104 lung cancers, 18 bladder cancers, and 322 cancer-free controls was conducted. The background for the study was previous observations among 8004 epileptics in Denmark with a significantly high risk for lung cancer and a significantly low risk for bladder cancer. Cigarette smoking appears to explain the lung cancer excess but not the low risk for bladder cancer, another tobacco-related disease. Information was abstracted on 94 and 95% of the cases and controls, respectively. Lung cancer was not associated with any anticonvulsant drug, but bladder cancer was inversely related to use of phenobarbital (PB). The apparent protective effect of PB was further evaluated in a study of rats given 4-aminobiphenyl (ABP), a bladder carcinogen. The levels of 4-aminobiphenyl adducts in hemoglobin and in bladder and liver DNA were significantly lower in rats given PB prior to 4-aminobiphenyl, compared to controls. These studies suggest that PB may induce drug-metabolizing enzymes of the liver that deactivate bladder carcinogens found in cigarette smoke and provide clues to the role of activation and detoxification of carcinogens in humans.

Cytobiologic and clinical aspects in a patient with chronic neutrophilic leukemia after thorotrast exposure.

A patient with fairly typical chronic neutrophilic leukemia, as represented by some two dozen such reported cases, had been given Thorotrast more than 20 years before. Typical myeloblastic crisis developed with remarkable terminal leukocytosis. Mature blood neutrophils had normal function with respect to phagocytosis, bacterial killing, metabolic activation, and chemotactic response. The number of cells producing colonies of neutrophils and monocytes in in vitro semisolid cultures was normal in the blood and increased in marrow. Colony size was smaller than is usually observed in normal patients or in typical patients with chronic myeloid leukemia. Termination in blast crisis, also seen in a few other patients with chronic neutrophilic leukemia, indicates that this is indeed a form of leukemia and not a "leukemoid" reaction of obscure cause. The differential diagnosis of extreme neutrophilia is discussed.