A clinicopathologic study of steroid-related liver tumors.

A registry of liver tumors was started in late 1973 in an attempt to assess the relationship of these tumors to oral contraceptives or to other environmental factors. This report is concerned with the pathological aspects and the possible pathogenesis of the first 101 tumors accessioned. There were 44 instances of focal nodular hyperplasia, 40 adenomas, four unclassified but probably benign tumors, and 13 hepatocellular carcinomas. Eighty-one patients took oral contraceptives; six were associated with pregnancy; three had taken estrogens for long periods of time; one had a thecoma; four never took sex steroids; and in five the history was unknown. Tumor rupture and intrahepatic hemorrhage were frequent complications. It is possible that the vascular lesions associated with focal nodular hyperplasia could play a part in their pathogenesis as well as with rupture. Foci of adenomatous hyperplasia may be related to the development of adenomas. The association of these tumors with sex steroids could be coincidental. The fact that none of the patients had cirrhosis of liver fibrosis, and that androgenic anabolic steroid therapy has been associated with hepatocellular carcinomas in males, suggests that further study of the problem is necessary.

Malignant trophoblastic tumors with massive hemorrhage presenting as liver primary. A report of two cases.

Two women, aged 29 and 27, presented with evidence of recent hemorrhage and large tumors of the liver. One tumor was successfully resected; the other patient died of blood loss. Both lesions were almost identical and were indistinguishable from choriocarcinoma. Both patients had markedly elevated serum human chorionic gonadotropin (hCG) levels and positive pregnancy tests. Examination of the endometrium showed only proliferative endometrium, and the pelvic organs were found to be normal. Immunoperoxidase stains of the liver tumors were strongly positive for hCG and human placental lactogen. Alpha-1-antitrypsin and alpha-fetoprotein tests were weakly positive, and one patient tested positive for carcinoembryonic antigen.

Human liver tumors in relation to steroidal usage.

Since 1973 a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material we have examined the histology of over 250 cases of hepatic neoplasia, most in patients receiving steroid medications. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for focal nodular hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in patients who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Of significance is the young age of these patients and lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophilic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations.

PIP: Since 1973, a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material, we have examined the histology of over 250 cases of hepatic neoplasia, mostly in patients receiving steroids. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for nodular focal hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of the patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in those who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Significant is the young age of these patients and the lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophillic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations.

Dysplasia, carcinoma in situ, and microinvasive carcinoma of the uterine cervix.

Carcinoma in situ is defined as the early stage of cancer and must therefore be initiated by an as yet unknown carcinogen(s). Progression of the lesion to invasive carcinoma is reported to occur in a high proportion of nontreated cases. Reserve cell proliferations are frequently associated with both dysplasia and carcinoma in situ, and it is suggested that these are the cells from which both lesions arise. Dysplasia may result from both carcinogenic and noncarcinogenic stimuli. Since dysplasia usually either regresses or remains stabilized over a prolonged period, it is suggested that it is more frequently associated with noncarcinogenic stimuli. Microinvasive carcinoma is limited to lesions with no more than 5 mm. of stromal invasion as measured from the surface. Confluence of growth and lymphatic-like space invasion should not interdict the diagnosis. Microinvasive carcinoma thus defined rarely gives rise to lymph node metastasis or eventuates in death. The diagnosis cannot be made from punch biopsy specimens. Only if pathologists adhere to a standard nomenclature can follow-up studies be used successfully to identify the natural behavior of each type of lesion in this spectrum.

Glassy cell carcinoma of the endometrium.

A variant of mixed adenosquamous carcinoma of the endometrium was encountered in 5 of 68 patients (7.4 per cent) with mixed adenosquamous carcinomas of the endometrium. A sixty patient had an isolated area of glassy cell carcinoma in an otherwise typical adenosquamous carcinoma. The ground-glass appearance of the cytoplasm, the distinctive nucleus with prominent nucleoli, the numerous mitoses, and the similarity of this tumor to previously described glassy cell cervix cancers all suggest that the tumor is glassy cell carcinoma. Four of the five tumors behaved in an aggressive manner.

Carcinoma of the endometrium. II. Papillary adenocarcinoma: a clinical pathological study, 46 cases.

Forty-six patients with papillary carcinoma of the endometrium were studied. Forty-five were followed for at least five years or until death, and 41 were followed for 10 years. The remaining patient was alive at four years. The survival rate was 51.1% at five years and 46.3% at 10 years. At five years one-third had died of their disease. The median age at time of diagnosis was 63 years, and the age at diagnosis was an important determinant of survival. None of the seven black women survived for five years. Tumor grade was an important predictor of the course of disease and nuclear grading was a significantly more accurate indicator than was the histologic grading of the World Health Organization. Papillary carcinoma should be distinguished from the papillary type of clear cell carcinoma of the endometrium. While it has a somewhat better prognosis than mixed adenosquamous carcinoma or clear cell carcinoma, it appears to be more aggressive with a lower survival rate and higher rate of death from disease than the usual type of endometrial adenocarcinoma or adenoacanthoma.

Carcinoma of the endometrium. IV. Mixed adenosquamous carcinoma. A clinical-pathological study of 68 cases with long-term follow-up.

In a histologic review of 989 cases of invasive endometrial carcinomas there were 68 mixed adenosquamous carcinomas. Sixty were followed for at least five years, or until death. The other eight were diagnosed in 1976 and were ineligible for five-year status evaluation. Twenty-eight of the 60 patients or 46.7% were alive at five years. Twenty-five or 41.7% died of their cancer. Stage of disease, depth of myometrial invasion, vascular invasion, age, and method of treatment all had an impact on end results. By comparison, the absolute five-year survival rate for 200 women with adenocanthoma was 87.0%. Thirty patients with atypia of the squamous portion of the adenoacanthoma had an identical survival rate as those without atypia. Combined irradiation and hysterectomy end results were superior to hysterectomy only, or to radiation therapy only. Although one examination of time trends revealed a significant increase in the percentage of all tumors that were diagnosed as adenoacanthoma, there was no increase in the relative frequency of mixed adenosquamous carcinoma.

Alpha1-antitrypsin, protein marker in oral contraceptive-associated hepatic tumors.

Tissue specimens from a series of 46 hepatic tumors occurring in young female oral contraceptive users were tested for alpha1-antitrypsin deposition, utilizing immunocytochemical and histochemical methods. In two instances serum alpha1-antitrypsin phenotyping was also performed. Immunoreactive alpha1-antitrypsin deposits were demonstrated in benign lesions, including 56% of cases of focal nodular hyperplasia and 68% of cases of liver-cell adenoma, and in 89% of cases of malignant hepatoma. There was good correlation between alpha1-antitrypsin deposits and variable amounts of finely granular, or globular, diastase-resistant periodic acid-Schiff positivity within tumor cells. While quantitative differences in alpha1-antitrypsin deposits between benign and malignant cell proliferations were not observed, a qualitative continuum that linked all tumors in the study group was found. The findings suggest that alpha1-antitrypsin deficiency is not related to the hepatic tumors developing in oral contraceptive users. The tumor tissue deposits of alpha1-antitrypsin observed represent a marker protein, the significance of which is undefined.

Cervix cancer precursors in young offspring of low-income families.

The revolutionary changes in the mores and practices of adolescent sexuality have not as yet resulted in a significant increase in the rates of cervical cancer precursors in a study of 29,600 young women under age 21. The study represents women from families of low socioeconomic status. Over a 21-year period no cases of carcinoma in situ nor of invasive cervix cancer occurred. The dysplasia rate was low (0.9/1000), and when prerevolutionary and revolutionary periods were compared, there were no significant differences in the rates. Cryocautery was successful in ablating dysplasia, as was follow-up without treatment. An attempt will be made to continue to monitor these young women of the sexual revolution since the effects of their past and current participation might not be discernible for years to come.

Carcinoma of the endometrium. III. Analysis of 865 cases of adenocarcinoma and adenoacanthoma.

Eight hundred sixty-five patients with confirmed adenocarcinoma of the endometrium were studied. Eight hundred eleven were followed up for at least 5 years or until death, and 537 were followed up for 10 years. The survival rate was 77.1% at 5 years and 61.0% at 10 years. Age at diagnosis was the single most important clinical determinant of survival. Tumor grade was an important predictor of the course of disease, and nuclear grade was a significantly more accurate indicator than was histologic grade. Stage and depth of invasion were also important predictors of survival. The 5-year survival rate for black women was only 41.9%. Stage for stage and grade for grade, women undergoing hysterectomy alone and with radiation had similar survival rates. Adenoacanthoma had a better prognosis that did adenocarcinoma without squamous metaplasia; there were no deaths at 5 to 10 years in women diagnosed before age 50. The subtype of carcinoma was found to be a highly significant predictor of prognosis.

Liver tumors in women on contraceptive steroids.

The possible association between oral contraceptives and benign liver tumors has recently been reported. To date the majority of cases have been diagnosed as benign hepatomas (liver cell adenomas). We have had the opportunity to study 13 such cases. Eight have been examples of focal nodular hyperplasia of the liver; however, in addition, there were examples of hepatocellular carcinoma, liver cell adenoma, and possible liver cell hamartoma; all were in women on "the pill." Gynecologists are alerted to the fact that many of the patients present with symptoms of acute abdomen, syncope or shock, and intrahepatic or intraperitoneal bleeding. Prompt diagnosis and treatment may be lifesaving.

Estrogens and endometrial carcinoma.

A group of 205 women with endometrial carcinoma was matched for age, parity, and year of operation with a group of 205 women who had had hysterectomies for benign disease. In the former group, 32 patients had used conjugated estrogens, while in the latter group 12 had used this hormone, yielding a relative risk of 3.1 (P = 0.0008). Users of other forms of systemic estrogens showed similar elevations in relative risk. Relative risk was related to duration of use, progressing from no evidence of risk among those using the hormone for less than 5 years to an 11.5-fold greater risk for those using it for 10 years or more. Risk was also related to the strength of the medication. The relative risk for users of the 1.25-mg tablets was 12.7 as compared to a two- to fourfold greater risk among users of lesser strength tablets.

PIP: 205 patients with endometrial carcinoma, excluding carcinoma in situ, were seen in 1 private practice between 1947-1976. A control for each case was chosen from patients who had had a hysterectomy for a benign condition. Average age of patients with cancer was 56.5 years and parity 1.5. The cancer patients weighed significantly more than controls. A history of diabetes was recorded for 8 study patients, and 1 control. Of the 205 cancer patients, 55, and of the control patients, 31, had used some form of estrogen-containing medication. The relative risk (RR) for all users of systemic estrogens was 2.6. Most had used conjugated estrogens giving an RR of 3.1 for this form of the drug. There was no increased risk associated with vaginal estrogenic preparations or oral contraceptives. The RR increased with increasing duration of use, with no appreciable increase in the risk for those using the medication for less than 5 years. Those using these drugs for 5-9 years had a risk 11.5 times that of nonusers. Those using the 1.25 mg tablet had a risk markedly above that for users of the .3 or .625 mg tablets. The study group had more frequent histories of abnormal uterine bleeding than the control group. The lifetime risk of developing endometrial cancer is estimated as 2.2% for whites and 1.1% for blacks. A 70.9% 5-year survival rate and a 55.8% 10-year survival rate have been recorded. With early diagnosis, the cure rate may approach 95%. Many of the symptoms of women in the manopause may be alleviated by estrogenic therapy. Many of these women will have had a hysterectomy and no longer be at risk of endometrial cancer. Therefore, such therapy seems justified.

Primary duodenal choriocarcinoma.

We report a case of nongestational extragenital choriocarcinoma arising in the duodenum of a 29-year-old woman. Immunohistochemical stains of the tumor were positive for human chorionic gonadotropin and human placental lactogen.

Trends in mortality from uterine cancer in relation to mass screening.

Mortality rates from cancer of the cervix uteri, as well as for all uterine cancer, have shown a remarkable decrease in recent years in Louisville, Kentucky. For women ages 30-39 the decrease was 70.8 per cent, and for ages 50-59, 69 per cent. No change in rates was noted for women ages 70 years and over. These changes correlate well with the success of recruitment for screening of women according to age. The high degree of success in screening the low socioeconomic quartile is thought to be of prime importance. The average annual age adjusted mortality for uterine cancer other than cervix also fell impressively. In contrast to Louisville, mortality from cervical cancer in England and Wales, with the exception of the younger age group, has remained fairly constant over the past decade. Denmark showed no mortality decline between 1961 and 1971. Like England and Wales and unlike Louisville, screening there had not achieved high population coverage and the screening as does exist was not commenced as early.