Hydatidiform mole: clinicopathologic associations with the development of postevacuation trophoblastic disease.

Clinical information and histopathologic material for 165 patients with hydatidiform mole referred to the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School during one year were reviewed in order to identify characteristics more likely to be associated with the development of gestational trophoblastic tumors. Twenty-nine patients (18%) required chemotherapy for invasive mole or choriocarcinoma. Patients with uterine enlargement beyond that expected for dates and patients with ovarian theca-lutein cysts were much more likely to require treatment after molar evacuation (47% vs. 18% and 40% vs. 16%, respectively). There was no correlation between the initial human chorionic gonadotropin level, gestational age, uterine size per se, maternal age or gravidity and the subsequent clinical course. Histologically, the following factors were associated with an increased incidence of postmolar gestational trophoblastic tumor: (1) progressive nuclear atypia (26.7% if atypia present vs. 40% if absent); (2) necrosis and hemorrhage (39.1% if extensive vs. 12.8% if limited); (3) decreased trophoblast maturation (48% if less than 20% mature vs. 8.7% if greater than or equal to 20% mature); (4) trophoblast proliferation (50% if marked vs. 13.9% if limited); (5) increased ratio of cytotrophoblast to syncytium (33.3% if greater than 1 vs. 6.4% if less than 1); and (6) absence of Nitabuch's layer (21.4% if absent vs. 11.6% if present). Hydatidiform moles which demonstrate clinical or histopathologic evidence of excessively abnormal proliferative activity, as indicated by these features, are more likely to develop invasive mole or choriocarcinoma and should be considered for prophylactic chemotherapy.

The immune response in two populations of wild badgers naturally infected with bovine tubercle bacilli.

This study describes the immune responses of two defined badger populations; one from East Sussex and another from Staffordshire. The mean in vitro lymphoproliferative response, of all infected badgers from both areas, to Glaxo BCG, was significantly greater than that of healthy animals. The infected badgers had significantly higher antibody levels against mycobacterial antigens, especially New Tuberculin, than did the healthy animals. All the healthy and tuberculous badgers from the Staffordshire area were invariably unreactive to the various preparations used for skin-testing. However, in the East Sussex area, positive reactions were obtained in 10 out of 37 healthy and 7 out of 10 infected animals. This is the first account of positive skin tests in free living badgers. These results support the concept that badgers infected with bovine tubercle bacilli pass through an immunological spectrum throughout much of which they are unlikely to be important sources of infection. In the early stages, tubercle bacilli are excreted from infected wounds, whereas in the later stages, failure of cell-mediated immunity results in excretion of tubercle bacilli from other sites and the badger becomes a potent source of infection.

Experimental infection of badgers (Meles meles) with Mycobacterium bovis.

The intradermal inoculation of four badgers with small numbers of Mycobacterium bovis resulted in localized lesions with ulceration which slowly healed by 5 months after inoculation. Lesions of generalized tuberculosis were seen in three badgers, one of which died at 17 months post-inoculation and in the remaining two killed 22 months post-inoculation. In the fourth badger lesions were confined to the draining lymph node of the inoculation site but M. bovis was isolated from the liver. Monthly clinical sampling of faeces, urine, tracheal aspirate and inoculation site exudates detected only the excretion of M. bovis from the inoculation site of one badger. There were marked seasonal variations in body weight but significant weight loss was observed during the second year in all four badgers, particularly prior to death. Four badgers inoculated intratracheally with a similar inoculum of M. bovis and another two control badgers showed no evidence of infection with M. bovis.

Tuberculosis in East Sussex. II. Aspects of badger ecology and surveillance for tuberculosis in badger populations (1976-1984).

Following the disclosure of Mycobacterium bovis infection in badgers in East Sussex in 1976, badgers have been examined from and around farms on which cattle have become infected, but with no other attributable source of infection. These farms are confined to the downland of the south-west of the county and M. bovis has been confirmed in badger populations utilising their land. The available evidence indicates that M. bovis infection in badgers is also confined to this area. A detailed study in one area on the South Downs suggested that M. bovis is endemic in the badger population and therefore presents a continued risk for cattle occupying the area.

Tuberculosis in East Sussex. IV. A systematic examination of wild mammals other than badgers for tuberculosis.

A detailed investigation of the possible role of wild mammals, other than badgers, in the maintenance of Mycobacterium bovis in an area on the South Downs of East Sussex was carried out over 3 years. Estimates of population sizes were made where possible and minimum sample sizes were selected to be 95% certain of including at least one infected animal if the prevalence was at least 5%. Samples of wild mammals were taken from populations which had the highest potential direct or indirect contact rate with known infected badgers. M. bovis was not isolated from any of the 15 species of wild mammals. It was concluded that badgers are able to maintain M. bovis in an area independently of other species, and that in the area studied other species were not a source of infection for the cattle herds.

Tuberculosis in East Sussex. III. Comparison of post-mortem and clinical methods for the diagnosis of tuberculosis in badgers.

Following epidemiological and ecological studies of a defined badger population in an area of East Sussex, removal of all badgers by cage trapping was attempted. Trapping was incomplete due to the activities of protesters. Forty-seven badgers were caught from the eight social groups. All badgers were examined clinically and samples of faeces, urine and tracheal aspirate were taken, together with swabs from any bite wounds, for bacteriological examinations. Forty-five animals were skin tested using whole killed cells of Mycobacterium bovis strain AN5, bovine PPD Weybridge and new human tuberculin. Skin test results were recorded after 24 and 72 h. All badgers were killed and subjected to a post-mortem and bacteriological examination. M. bovis was detected in 10 (21.3%) badgers at post-mortem and in 2 badgers from clinical samples. Four social groups were infected. Positive skin test results were recorded at 72 h with bovine PPD (2 micrograms and 20 micrograms/ml), strain AN5 (1 mg/ml) and human tuberculin (2 micrograms/ml), but not with human tuberculin at 20 micrograms/ml. Histological sections of the skin test reactions showed the cellular types typical of delayed-type hypersensitivity. The skin test reactions observed were neither sensitive nor specific enough to be of practical value.

Choriocarcinoma associated with ectopic pregnancy.

Eight patients with choriocarcinoma associated with ectopic pregnancy were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1981. This represented 4% of the 197 patients with documented choriocarcinoma or 1.7% of all 459 patients with gestational trophoblastic disease treated with chemotherapy at the center during this 20-year period. The presenting signs and symptoms were similar to those classically outlined for ectopic pregnancies: amenorrhea and abdominal pain (88%), irregular vaginal bleeding (75%), positive pregnancy test (100%), and adnexal mass (50%). Six patients (75%) had metastatic disease and four of these six had one or more high-risk factors. Two patients (25%) died of metastatic disease, both of whom had received chemotherapy elsewhere before referral to the center.

Treatment of high-risk gestational trophoblastic disease with methotrexate, actinomycin D, and cyclophosphamide chemotherapy.

Seventy-three patients with metastatic high-risk gestational trophoblastic disease were treated with methotrexate, actinomycin D, and cyclophosphamide chemotherapy at the Brewer Trophoblastic Disease Center between 1968 and 1982. Forty-six patients were treated primarily with methotrexate, actinomycin D, and cyclophosphamide because of the presence of one or more high-risk factors. Twenty-seven additional patients who had not responded to initial single-agent chemotherapy with methotrexate and/or actinomycin D were subsequently treated with methotrexate, actinomycin D, and cyclophosphamide. Adjuvant surgery and radiotherapy were used in selected patients. The overall cure rate was 51% (37 of 73): 63% (29 of 46) for primary treatment and 30% (eight of 27) for secondary treatment (P less than .01). Several factors that influenced response to primary treatment with methotrexate, actinomycin D, and cyclophosphamide chemotherapy were determined: 1) clinicopathologic diagnosis of choriocarcinoma versus invasive mole (59 versus 100%), 2) metastases to sites other than the lung and/or vagina (44 versus 74%), 3) antecedent term gestation compared with hydatidiform mole or abortion (50 versus 75%), and 4) presence of three or more high-risk factors (27 versus 74%). There were no significant differences in cure rates during the course of the study period.

Choriocarcinoma associated with term gestation.

Fifty-one patients with choriocarcinoma associated with term pregnancy were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1981. An overall remission rate of 61% was achieved: 65% for 43 patients who received all of their treatment at the center and 38% for eight patients who received treatment elsewhere before referral to the center. This remission rate was significantly less (P less than 0.005) than the 87% remission rate obtained in patients with choriocarcinoma after hydatidiform mole, abortion, or ectopic pregnancy combined. Three factors were determined which significantly influenced response to treatment in these patients: (1) time from delivery to treatment greater than 4 months (41% versus 80%, P less than 0.0005); (2) presenting symptomatology other than abnormal uterine bleeding (40% versus 87%; P less than 0.001); and (3) metastases to sites other than the lung and/or vagina (22% versus 72%, P less than 0.01). There appeared to be no advantage to treating all patients with choriocarcinoma after term pregnancy with initial multiple-agent chemotherapy unless other high-risk characteristics were present.

Repeat gestational trophoblastic disease.

During a ten-year period from 1969 through 1979, 22 of 1648 patients referred to the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School had repeat gestational trophoblastic disease, an incidence of 1.33%. A total of 52 trophoblastic disease episodes occurred in these 22 patients. Invasive mole or choriocarcinoma occurred as the first trophoblastic disease episode in only three patients (14%), whereas one of these sequelae was the second trophoblastic disease event in seven patients (32%). Seventeen patients (77%) had consecutive trophoblastic disease episodes. After a second trophoblastic disease episode, the risk for a subsequent event rose to 28%; however, 44% of these patients delivered viable infants. There was no difference in outcome of subsequent pregnancies with respect to previous chemotherapy.

Urinary nucleic acid breakdown products as markers for trophoblastic diseases.

A feasibility study on the use of urinary nucleoside markers for the management of trophoblastic disease is presented. The markers return to normal rapidly after effective therapy, whereas the human chorionic gonadotropin levels remain elevated longer before reaching normal. If this finding is valid in a larger number of patients, it may spare patients with trophoblastic disease needless continuation of chemotherapy.

Natural history of hydatidiform mole after primary evacuation.

From 1962 to 1978, 738 patients with hydatidiform mole were referred to the John I. Brewer Trophoblastic Disease Center of Northwestern University for follow-up and human chorionic gonadotropin (hCG) testing after evacuation. There was spontaneous regression of trophoblastic disease in 596 (80.8%) of the 738 patients. Of these 596 patients, regression occurred in 11 (1.8%) by day 10 after evacuation, in 124 (20.8%) between days 11 and 30, in 255 (42.8%) between days 31 and 60, and in 206 (34.6%) between days 61 and 170. Treatment with chemotherapeutic agents was required in 142 (19.2%) of the 738 patients; 125 (16.9%) of these had invasive mole (107 nonmetastatic and 18 metastatic) and 17 (2.3%) had choriocarcinoma (13 nonmetastatic and four metastatic). All 596 patients whose hCG titers declined spontaneously to normal levels have remained well and free of disease. All 142 treated patients experienced permanent remission. Thus, all 738 patients are well and free of disease 4 to 18 years after evacuation of the hydatidiform mole. The follow-up regimen described in this report furnishes information on natural history of molar pregnancies after evacuation and provides an excellent means by which all patients can be safely managed following termination of a hydatidiform mole.

Observation of an organism found in patients with gestational trophoblastic disease and in patients with toxemia of pregnancy.

This is an initial descriptive report of observations of multiple forms of an organism found in patients with gestational trophoblastic disease and in patients with preeclampsia-eclampsia. The worm-like forms most frequently observed have an average length of 1.0 to 1.5 mm. Larva-like forms have an average length of 150 mu; primordial eggs and egg-like forms in developmental stages range from 7 to 43 mu in diameter; and sperm-like forms are 3.5 mu or slightly smaller in size. These forms have been observed in contact smears prepared from 3 ml samples of peripheral circulating blood from both groups of patients, from trophoblastic tumor tissue, from contact smears prepared from placentas of patients with preeclampsia-eclampsia, and from umbilical cord blood of infants delivered of patients with preeclampsia-eclampsia. The various forms of this organism share morphologic characteristics of several orders of helminths, i.e., hookworms, roundworms and tapeworms. The taxonomy of these forms has not yet been determined. Until the time of taxonomic classification, the various forms will be referred to as Hydatoxi lualba. We have experimental evidence that this organism has biologic activity in BALB/c mice and in beagle dogs.

Experimental induction of a toxemia-like syndrome in the pregnant beagle.

A toxemia-like syndrome was induced in pregnant beagles by intraperitoneal inoculation of concentrates prepared from placentas of patients with preeclampsia-eclampsia and hydatidiform mole, which contained an agent, Hydatoxi lualba, that stained in a unique fashion with toluidine blue-O-. The pregnant dogs inoculated with either of these concentrates progressively developed hypertension, eyeground changes consistent with hypertensive retinopathy, proteinuria, disseminated intravascular coagulation, and hepatic dysfunction in addition to intrauterine growth retardation and intrauterine fetal death. Hepatic periportal hemorrhage and glomeruloendotheliosis, lesions usually seen in preeclampsia-eclampsia, were also noted to occur in pregnant beagles inoculated with these concentrates. A significant increased sensitivity to angiotensin II infusion was also noted. The toxemia-like syndrome did not develop in pregnant beagles when inoculated in a similar fashion with concentrates prepared from placentas from normal term pregnancies which were free of Hydatoxi lualba or in nonpregnant beagles inoculated with concentrates containing Hydatoxi lualba. Although the agent was not injected in pure form, the inoculation of concentrates containing Hydatoxi lualba appears to be required for the manifestation of the toxemia-like syndrome.

Fatal gestational choriocarcinoma. Clinicopathologic study of patients treated at a trophoblastic disease center.

We studied 31 autopsied cases of gestational choriocarcinoma encountered at the Northwestern University Trophoblastic Disease Center in the past two decades to learn if the clinical and morphologic aspects of these cases have been altered by therapy. These cases were analyzed for cause of death, distribution of tumor and histologic patterns in relation to the amount of chemotherapy. Tumor hemorrhage and/or pulmonary insufficiency were the most common causes of death, irrespective of the amount of therapy although other factors including drug toxicity, sepsis, and uremia led to death in six cases. The amount of chemotherapy generally did not affect the number or distribution of metastases. Histologically, nine cases showed extensive or complete necrosis. Eighteen of the remaining tumors had typical biphasic patterns, but four patients who received multiple courses of chemotherapy had atypical patterns with a marked predominance of cytotrophoblast and infiltrative growth. These atypical patterns do not appear to be a direct result of chemotherapy but may represent a more aggressive form of this tumor. This study shows that fatal gestational choriocarcinoma can have a variety of clinicopathologic features which reflect not only the biologic capabilities of the neoplasm but also the effects of chemotherapy and prolonged disease.

Fatal gestational trophoblastic disease: an analysis of treatment failures.

Forty-eight of 399 patients referred to the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 to 1979 for treatment of gestational trophoblastic disease (invasive mole or choriocarcinoma) died. All patients who died had histologically documented metastatic choriocarcinoma. The time from pregnancy event to treatment was greater than 4 months and/or the pretreatment human chorionic gonadotropin titer was greater than 100,000 IU/L in 64% of these patients. Seventy-one percent of fatal cases developed in association with term pregnancies, abortions, or ectopic pregnancies rather than hydatidiform moles. Fifty percent of patients who died had metastases to the liver, brain, and/or peritoneal cavity when they first presented for treatment. The most common causes of death were hemorrhage from one or more metastatic sites (42%) and pulmonary insufficiency (31%). Factors primarily responsible for the treatment failures in these patients were: (1) presence of extensive disease at the time of initial treatment; (2) inadequate initial treatment; and (3) failure or presently used chemotherapy protocols in advanced disease. Secondary chemotherapy, radiation therapy to sites other than the brain, and adjuvant surgical procedures failed to improve survival in these high-risk patients.