Cervical adenocarcinoma in young women: possible relationship to microglandular hyperplasia and use of oral contraceptives.

Cervical adenocarcinoma in young women: Possible relationships to microglandular hyperplasia and use of oral contraceptives

Whether previous oral contraceptive (OC) use impacts on prognosis women who subsequently develops breast cancer is unclear. The aim was to study history of OC use in relation to breast cancer events in a prospective population-based cohort. Between 2002 and 2011, primary breast cancer patients without preoperative treatment were enrolled in Lund, Sweden and followed until December 2012. Tumor characteristics, clinical data, and date of death were obtained from pathology reports, patient charts, and population registries. History of OC use was obtained from preoperative questionnaires. Among the 948 patients with invasive cancer and no metastasis detected on the postoperative screen, 74% had ever used OCs. Patients were followed for up to nine years and 100 breast cancer events were recorded. Ever OC users had significantly smaller tumors than patients who never used OCs (Ptrend = 0.013). However, there was a significantly higher frequency of grade III tumors in patients with OCs use before age 20 (Ptrend = 0.013), compared to patients with later start or never use. Ever OC use was not associated with prognosis, irrespective of duration. However, any OC use before age 20 was associated with a 3-fold increased risk for breast cancer events in patients younger than 50 years at diagnosis (adjusted HR 3.26: 95% CI 1.06-10.01) adjusted for age, tumor size, axillary lymph node involvement, histological grade, estrogen receptor status, and body mass index, but not in patients 50 years or older at diagnosis (Pinteraction = 0.009). In conclusion, these findings warrant confirmation in an independent cohort. If confirmed, history of OC use may yield prognostic information in addition to currently used criteria. Citation Format: Louise Huzell, Mia Persson, Maria Simonsson, Andrea Markkula, Christian Ingvar, Carsten Rose, Helena C. Jernström. History of oral contraceptive use in breast cancer patients and risk for early breast cancer events. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 855. doi:10.1158/1538-7445.AM2015-855

The purpose was to study oral contraceptive (OC) use in relation to breast cancer events and endocrine treatment response in a prospective population-based cohort, because it is unclear whether history of OC use impacts on prognosis in breast cancer patients. Between 2002 and 2011, 994 primary breast cancer patients without preoperative treatment were enrolled in Lund, Sweden and followed until December 2012. History of OC use was obtained from preoperative questionnaires. Tumor characteristics, clinical data, and date of death were obtained from pathology reports, patient charts, and population registries. Among the 948 patients with invasive cancer and no metastasis detected on the post-operative screen, 74 % had ever used OCs. Patients were followed for up to nine years (median follow-up 3 years), and 100 breast cancer events were recorded. Ever OC use was not associated with prognosis, irrespective of duration. However, any OC use before age 20 was associated with a threefold increased risk for breast cancer events in patients <50 years but not in patients ≥50 years (P interaction = 0.009). In patients ≥50 years with estrogen receptor positive tumors, previous OC use at any age was associated with a significantly decreased risk of breast cancer events among patients who received aromatase inhibitors compared to patients who never used OCs (adjusted HR 0.37: 95 % CI 0.15-0.87). OC use was not associated with tamoxifen-response. If confirmed, history of OC use may yield valuable prognostic and treatment predictive information in addition to currently used criteria.

The histories of oral contraceptive (OC) use provided by women participating in a study of hepatocellular adenoma (HCA) were compared with records obtained from their physicians. In the HCA study two memory aids were used to assist women in their recall: a calendar of significant events during a woman's lifetime to which she might relate her use of OCs and a book of colour photographs of the 90 OC preparations available up to the time of the study. Using the number of months of a woman's history which could be checked against physician records (mean for all women of 33 months) as the denominator, the highest proportion of concordance was for month-specific duration of OC use (90%) with lower agreement for duration and brand (62%) and duration, brand, and dose (54%). Agreement was better for cases than for controls.

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In hepatic adenomatosis, a rare entity first described by Flejou et al. (1) in 1985, multiple liver cell adenomas (usually > 10) occur in patients with no prior history of oral contraceptive use, androgenic steroid use, or glycogen storage disease. So far, only 18 cases have been reported, including two cases in patients under 18 years of age (1-12). We report an adolescent with hepatic adenomatosis and briefly review the literature (Table 1). CASE REPORT A 17-year-old white girl was evaluated at a community hospital for complaints of afternoon headaches, which were relieved by acetaminophen, and sharp abdominal pains that occurred monthly, lasted 1-2 days, and resolved spontaneously. She had no history of prior illnesses or oral contraceptive use. A urinalysis showed hematuria and proteinuria, and culture was negative. Abdominal ultrasound showed hydronephrosis of the left kidney, a left ovarian mass, and multiple liver masses. Laparoscopic examination revealed hydronephrosis of the left kidney, normal uterus and fallopian tubes, and a cystic left ovary. No abnormal fluid or tumor implants were noted in the pelvis or peritoneum. The liver appeared markedly enlarged. On the surface of the right lobe was a tumor measuring about 6 cm in diameter. The tumor was yellowish, soft, and appeared to have markedly increased vascularity. A kidney biopsy showed minimal change, and prednisone was administered at a dose of 1 mg/kg/day for management of nephrotic syndrome. She was referred to our center for further evaluation of the liver masses. Physical examination showed that liver was palpable ≈ 14 cm below the right costal margin in the mid-clavicular line, with a total percussable span of 24 cm, and extended 5 cm to the left of the midline. The spleen was not palpable, and there were no signs of portal hypertension or chronic liver disease. Pertinent laboratory tests included the following: hemoglobin 9.8 g/dl (normal, 11.5-15.5), hematocrit 29.4% (normal, 36-47), albumin 4.0 g/dl (normal, 3.5-5.0), total bilirubin 0.4 mg/dl (normal, 0.1-1.2), alanine aminotransferase 41 IU/L (normal, 15-59), gamma glutamyl transpeptidase 432 IU/L (normal, 8-35), alkaline phosphatase 193 IU/L (normal, 150-650), and prothrombin time 12 s (normal, 11.0-13.4). A CT scan without intravenous contrast showed 20 low-density lesions within the liver, each with a dense rim. The density of all lesions enhanced after the infusion of intravenous contrast material. The largest of these lesions measured 6.5 cm in diameter (Fig. 1). The patient underwent a laparotomy for the purpose of an open liver biopsy. Histopathology showed hepatocytes arranged in cords with fatty metamorphosis but no significant nuclear pleomorphism. No normal portal structures—and in particular, no bile ducts—were identified within the tumors. Trichrome stain demonstrated perivenular fibrosis. No areas of hemorrhage or necrosis were seen (Fig. 2). A year later, the patient was clinically unchanged. Repeat CT scan of the liver showed minimal change in the size of the hepatic masses. DISCUSSION Liver cell adenoma (hepatocellular adenoma) is an uncommon liver tumor that is strongly associated with oral contraceptive use (1,2,13). Prior to the advent of oral contraceptive use in 1960, only four cases of hepatic adenomas had been described. When Benz and Bagenstoss reviewed necropsy material at the Mayo Clinic in 1922-51, they identified two patients with hepatic adenomas (14). Edmonson found only two hepatic adenomas among over 50,000 autopsies performed between 1918 and 1954 at Los Angeles County General Hospital (15). Baum et al. first described the association with oral contraceptives in 1973 (16). Although liver cell adenomas are usually solitary, in 21% of cases they are multiple, usually less than three. Because of the association with oral contraceptives, they have a female preponderance, but they have also been reported in patients receiving androgenic steroids and in patients with glycogen storage disease, especially type 1 (17,18). The liver parenchyma outside of the adenomas is usually normal, although both adenomas and focal nodular hyperplasia are rarely encountered in patients receiving oral contraceptives (5). Liver tests are normal in the majority of patients. There are case reports of malignant transformation within a hepatic adenoma, especially when associated with glycogen storage disease or oral contraceptive use (17-19). Adenomas appear to regress after discontinuing oral contraceptives or androgenic steroids (20,21). Hepatic adenomatosis is defined by the presence of numerous (> 10) hepatic cell adenomas in an otherwise normal hepatic parenchyma (1,3). The incidence is equal for men and women, and the disease is not associated with oral contraceptives, androgenic steroids, or glycogen storage disease. Extratumorous hepatic tissue is usually normal, although two patients with focal nodular hyperplasia and granulomatous hepatitis have been reported (5). There have been no reports of malignancy arising from hepatic adenomatosis, but this may reflect the rareness of the syndrome and the lack of long-term follow-up of the reported cases rather than the actual risk for malignant transformation. Clinical symptoms are mild to absent in most patients with hepatic adenomatosis; in most cases, the disorder probably goes unrecognized for many years. This is probably the case in our patient, for example, considering the size of the tumors at the time of diagnosis and their subsequent growth rate. Modest to extreme hepatomegaly can be detected in most patients. Hepatomegaly is sometimes accompanied by dull abdominal pain or a sense of fullness in the right upper quadrant. No reported patient has exhibited clinical evidence of parenchymal insufficiency or portal hypertension. Forty-six percent of the reported cases of hepatic adenomatosis have experienced intratumorous or intraperitoneal bleeding, which is higher than the 25-35% occurrence in patients with hepatic adenomas (1,19). The bleeding is secondary to rupture of the very vascular adenomas either spontaneously or following trivial abdominal trauma (1). Acute epigastric or right upper quadrant abdominal pain can accompany bleeding and may be the first symptom of disease. In one case, pruritis persisted even after excision of the tumors (1). Radiologic imaging is useful in the diagnosis of hepatic adenomatosis. The tumors may be hyperechoic or hypoechoic when imaged by ultrasound (1,4). Hyperechoic tumors are usually fatty. Most lesions are less dense than surrounding parenchyma in CT scans performed without intravenous contrast. A high-density rim may be seen around the low-density lesions, possibly due to compression of the surrounding normal liver parenchyma, and entire nodules may rarely be hyperdense. After infusion of intravenous contrast, there is enhancement of the lesions from center to the periphery related to their increased vascularity. These typical changes were also seen in our case. There has been one case report of intratumoral calcification seen on CT scan, most likely secondary to prior hemorrhage (4). Magnetic resonance imaging (MRI) usually shows the lesions as well defined, relatively homogenous, high-intensity masses (3). Arteriogram shows a hypervascular tumor in the arterial phase, while in the venous phase, intrahepatic veins are displaced without signs of obstruction or invasion (1). Patients with hepatic adenomatosis usually have normal liver tests except for modest elevations of gamma glutamyl transpeptidase and alkaline phosphatase (1,5,22). The cause for elevated cholestatic enzymes is not known, but it may be secondary to localized intrahepatic cholestasis caused by obstruction of regional bile ducts. Histopathologic changes are similar in liver cell adenoma and adenomatosis. The tumors consist of fairly normal or enlarged hepatocytes without nuclear pleomorphism arranged in one to two cell thick cords. The adenoma cells may contain fat and glycogen. Numerous prominent venous outflow channels are seen, occasionally with closely related branching small arterioles (22). Biliary structures and portal triads are absent. Sinusoidal dilatation, peliosis, hemorrhage, and necrosis may be observed. The tumors are usually nonencapsulated (1,2,5,22). The prognosis and evolution of adenomatosis is generally uncertain. The main concerns of long-term follow-up are the potential for malignant transformation and hemorrhagic complications. There have been no reports of malignant transformation. Serum α-fetoprotein values are usually normal at the time of diagnosis and are of questionable value in long-term follow-up. A review by Neuberger et al. of seven patients with hepatic adenoma associated with oral contraceptive use and with malignant transformation showed no rise in serum α-fetoprotein levels in any patient (17). Surgical intervention is mainly reserved for the management of acute emergencies following hemorrhage. Although an open biopsy or surgical excision of an isolated adenoma is frequently performed to establish an initial diagnosis, surgical excision of all the tumors often is not possible, given the number and location of these lesions. Large adenomas (>10 cm in diameter) have been excised to reduce the risk of hemorrhage (23). Liver transplantation is also an option, but it seems unwarranted given the benign biologic nature of the adenomas. Percutaneous ethanol injections following contrast-enhanced ultrasound is an alternative therapy that needs to be explored. Although this treatment modality has never been used before for hepatic adenomatosis, it has been successful in inducing tumor necrosis in hepatocellular carcinoma (20). Tanaka et al. (24) have also used combination therapy, consisting of pretreatment with transcatheter arterial embolization and subsequent percutaneous ethanol injections, for solitary large primary hepatocellular carcinoma lesions. These options are being considered for our patient. A conservative approach to the management of hepatic adenomatosis seems to be the most reasonable option. This entails close monitoring of the clinical status and repeated radiological studies to assess any change in the size of the tumors. Rapid growth, hemorrhage, or encroachment on vital structures would justify surgical intervention, including orthotopic liver transplantation.FIG. 1.: Anterior view of a contrast enhanced CT scan of the liver showing multiple well-defined areas of low attenuation. The areas show ringlike peripheral enhancement with irregular central enhancement.FIG. 2.: A low-power view of one of the lesions showing sheets of hepatocytes with macrovesicular steatosis. Several thin-walled vessels are visible, but no portal tracts are present in the entire tissue. (H&E, approximate final magnification × 300)

OBJECTIVE: Oral contraceptive (OC) use is common in the United States and high-profile articles have renewed research interest in OC use and cancer risk. Several mechanisms have been proposed to explain how OC use influences postmenopausal cancer risk; one of the leading hypotheses is that OC use fundamentally alters feedback in the hypothalamic-pituitary-gonad axis, leading to long term changes in sex steroid hormone metabolism. However, women who use OCs are also unique with respect to factors that may affect both hormone metabolism and cancer risk. No studies have comprehensively commented on hormone levels in postmenopausal women who did and did not use OCs. DESIGN: We examined differences in circulating markers of sex steroid hormone metabolism associated with prior use of OCs among a subcohort of postmenopausal women from the Women’s Health Initiative Observational Study (983 women with at least one intact ovary and not currently using menopausal hormone therapy). MATERIALS AND METHODS: Using highly sensitive liquid chromatography–tandem mass spectrometry assays, we measured over 30 markers of estrogen and androgen metabolism in study serum samples. We used linear regression (adjusted and weighted) to estimate geometric mean hormone levels, which were then converted into relative percent differences. We controlled for potential confounders and stratified by: lifetime ovulatory cycles, body mass index, and parity (the focus of this abstract). RESULTS: Women with a history of OC use (n=346) had lower levels of estrogen metabolites than women who never used OCs (n=637), particularly when limiting this comparison among parous women (n=158 nulliparous women, n=825 parous women). In parous women, OC use was associated with reductions in total estrone (-18.5%, 95% confidence interval [CI] -31.1, -3.7%) and in estrogen metabolism overall: 2-hydroxylation metabolites were reduced by -18.5% (CI -28.2, -7.7%), 4-hydroxylation metabolites by -19.9% (CI -29.4, -9.1%), and 16-alpha-hydroxylation metabolites by -24.0% (CI -34.2, -12.2%). Hormone differences associated with OC use among nulliparous women were imprecise. When we made comparisons to nulliparous women who did not use OCs, women who both used OCs and were parous had lower testosterone (-21.2%, CI -33.1, -7.2%) and higher dihydrotestosterone relative to testosterone (its metabolic precursor; 16.5%, CI% -0.6, 36.6). However, aside from lower total estrone (-25.5%, CI -44.6, 0.2%), estrogen metabolism was not different between these groups. CONCLUSIONS: We saw evidence suggesting estrogen metabolism, as reflected in circulating markers, may be lower in postmenopausal women who previously used OCs. These effects were strongest among parous women, likely due to sufficient sample size, rather than any synergistic effect attributable to both using OCs and giving birth. These results support the idea that OC users have lower estrogen levels, but this should be evaluated in other age groups, as differences in hormone metabolism early in the lifecourse may lead women to use OCs. Citation Format: Kara A. Michels, Sally B. Coburn, Garnet Anderson, Louise A. Brinton, Chu Chen, Roni T. Falk, Margery L. Gass, Ashley M. Geczik, JoAnn E. Manson, Ruth M. Pfeiffer, Kerryn Reding, Gloria E. Sarto, Nicolas Wentzensen, Robert A. Wild, Xia Xu, Britton Trabert. Oral contraceptive use and postmenopausal sex steroid hormone metabolism [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO029.

Reproductive history and pregnancy outcomes in women with endometriosis findings from the national health and nutrition examination surveys (NHANES) 1999–2002

Introduction/BackgroundIn our study, the factors determining persistence and clearance were questioned by cytology and HPV testing in cervical cancer screening. We tried to determine the relationship between persistence and variables...

Introduction: Hepatocellular adenomas (HCA) are benign tumors with possible complications of bleeding and malignant transformation. Oral contraceptive us in women of childbearing are most frequently associated with hepatocellular development. This study investigates the multifactorial role of oral contraceptive use and its effect on mutation frequency, mutation count, and nodule size in patients with HCA. Methods: Using the cBioPortal platform and systematic bioinformatical analysis of the Cancer Genome Atlas (INSERM) Cancer Cell 2014 data for hepatocellular adenoma, 30 HCA patients were included in this study. Of which twenty-one patients had used oral contraception for greater than two years, four patients < 2 years, and five patients had no reported history of oral contraceptive use. Results: The mutational landscape of the lack of oral contraceptive use associated with HCA was distinct with statistically significant alterations in ACY1, APOA1, APOB, ARHGAP22, ARNTL2, BICRAL, C3ORF70, CASR, CD247, CDH9 mutation frequency (See Figure). Further, the mutation count was statistically significant as patients with oral contraceptive use < 2 years had the lowest mutation count of 6, (See Table). Additionally, the nodule size (mm) in patients with HCA was statistically significant as patients with a history of oral contraceptive use < 2 years had the smallest median nodule size of 37.5 mm (See Table). Conclusion: The findings in this study highlight the complex multifactorial role of oral contraceptive use in HCA. Further studies are essential for understanding the molecular and pathophysiologic impact of oral contraceptive use on functions of critical genes that exert carcinogenic potential.Figure 1.: The mutational landscape among oral contraceptive use in hepatocellular adenoma Table 1. - Mutation count and nodule size in hepatocellular adenoma with relation to oral contraceptive use No OCP use OCP < 2 years OCP use > 2 years P-value Mutation count 19 6 11 0.03 Nodule size (mm) 70 mm 37.5 mm 70 mm 0.03

Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis

Oral contraceptive (OC) use is weakly associated with breast cancer risk in the general population, but the association among women with a familial predisposition to breast cancer is less clear. To determine whether the association between OC use and risk of breast cancer is influenced by family history of the disease. Historical cohort study of 426 families of breast cancer probands diagnosed between 1944 and 1952 at the Tumor Clinic of the University of Minnesota Hospital. Follow-up data on families were collected by telephone interview between 1991 and 1996. A total of 394 sisters and daughters of the probands, 3002 granddaughters and nieces, and 2754 women who married into the families. Relative risk (RR) of breast cancer associated with history of OC use by relationship to proband. After accounting for age and birth cohort, ever having used OCs was associated with significantly increased risk of breast cancer among sisters and daughters of the probands (RR, 3.3; 95% confidence interval [CI], 1.6-6.7), but not among granddaughters and nieces of the probands (RR, 1.2; 95% CI, 0.8-2.0) or among marry-ins (RR, 1.2; 95% CI, 0.8-1.9). Results were essentially unchanged after adjustment for parity, age at first birth, age at menarche, age at menopause, oophorectomy, smoking, and education. The elevated risk among women with a first-degree family history of breast cancer was most evident for OC use during or prior to 1975, when formulations were likely to contain higher dosages of estrogen and progestins (RR, 3.3; 95% CI, 1.5-7.2). A small number of breast cancer cases (n = 2) limited the statistical power to detect risk among women with a first-degree relative with breast cancer and OC use after 1975. These results suggest that women who have ever used earlier formulations of OCs and who also have a first-degree relative with breast cancer may be at particularly high risk for breast cancer. Further studies of women with a strong family history who have used more recent lower-dosage formulations of OCs are needed to determine how women with a familial predisposition to breast cancer should be advised regarding OC use today. JAMA. 2000;284:1791-1798.

History of oral contraceptive use and risk of spontaneous abortion

To analyze the associations between oral contraceptive (OC) use and markers of iron deficiency, objectively measured using hemoglobin and soluble transferrin receptor. A secondary data analysis was performed of a population-based cross-sectional study using data from the 2010 Tanzania Demographic and Health Survey. Weighted percentages were calculated. Multivariable logistic regression was used to examine the associations between OC use and iron deficiency, anemia, and iron deficiency anemia. Of the 4336 participants, only 7.3% reported a history of OC use. The prevalence rates of iron deficiency, anemia, and iron deficiency anemia were 30.3%, 40.9%, and 15.1%, respectively. Use of OCs was negatively associated with anemia and iron deficiency anemia, independent of potential confounders. Compared with OC nonusers, the multivariable-adjusted odds ratio among OC users was 0.44 (95% confidence interval 0.32-0.59; P<0.001) for anemia and 0.43 (95% confidence interval 0.27-0.68; P<0.001) for iron deficiency anemia. A longer duration of OC use was negatively associated with iron deficiency (P=0.003 for trend), anemia (P<0.001 for trend), and iron deficiency anemia (P<0.001 for trend). The significant association between OC use and iron status has important implications for educating healthcare providers and women about additional nutritional benefits of the use of OCs.

ObjectivesThe relationship between reproductive factors and breast cancer (BC) risk has been investigated in previous studies. Considering the discrepancies in the results, the aim of this study was to estimate the causal effect of reproductive factors on BC risk in a case-control study using the double robust approach of targeted maximum likelihood estimation.MethodsThis is a causal reanalysis of a case-control study done between 2005 and 2008 in Shiraz, Iran, in which 787 confirmed BC cases and 928 controls were enrolled. Targeted maximum likelihood estimation along with super Learner were used to analyze the data, and risk ratio (RR), risk difference (RD), andpopulation attributable fraction (PAF) were reported.ResultsOur findings did not support parity and age at the first pregnancy as risk factors for BC. The risk of BC was higher among postmenopausal women (RR = 3.3, 95% confidence interval (CI) = (2.3, 4.6)), women with the age at first marriage ≥20 years (RR = 1.6, 95% CI = (1.3, 2.1)), and the history of oral contraceptive (OC) use (RR = 1.6, 95% CI = (1.3, 2.1)) or breastfeeding duration ≤60 months (RR = 1.8, 95% CI = (1.3, 2.5)). The PAF for menopause status, breastfeeding duration, and OC use were 40.3% (95% CI = 39.5, 40.6), 27.3% (95% CI = 23.1, 30.8) and 24.4% (95% CI = 10.5, 35.5), respectively.ConclusionsPostmenopausal women, and women with a higher age at first marriage, shorter duration of breastfeeding, and history of OC use are at the higher risk of BC.