Stereotactic Body Radiation Therapy: A Versatile, Well-Tolerated, and Effective Treatment Option for Extracranial Metastases From Primary Ovarian and Uterine Cancer.

PURPOSE: Single extracranial metastases from ovarian and uterine malignancies have historically been treated with surgery or conventional radiation. We report mature local control (LC), overall survival (OS), progression free survival (PFS), and toxicity for patients who completed 5-fraction stereotactic body radiation therapy (SBRT). METHODS: Patients with biopsy-proven, single extracranial metastases from primary ovarian and uterine malignancies treated with 5-fraction SBRT were included. Patients were stratified based on tumor volume (small < 50 cc or large ≥ 50 cc) and dose (low dose < 35 Gy or high ≥ 35 Gy). Kaplan-Meier method was used to estimate LC, OS, and PFS. RESULTS: Between July 2007 and July 2012, 20 patients underwent SBRT to a single extracranial metastasis. Primary site was divided evenly between ovarian and uterine (n = 10 each). Metastases involved the liver (30%), abdominal lymph nodes (25%), lung (20%), pelvic lymph nodes (10%), spine (10%), and extremity (5%). The median gross tumor volume (GTV) was 42.5 cc (range, 5-273 cc) and the median dose to the GTV was 35 Gy (range, 30-50 Gy). At a median follow-up of 56 months, the 5-year LC and OS estimates were 73 and 46%. When stratified by tumor volume, the 5-year LC and OS for small tumors were significantly better at 100% (p < 0.01) and 65% (p < 0.02). When stratified by dose, the 5-year LC was 87.5% with high dose and 53.6% with low dose (p = 0.035). The 5-year PFS for the entire cohort was 20%. Four patients with small metastases who had complete response remained disease free at study completion and were considered cured (median PFS > 10 years). Treatment was generally well tolerated, and only one patient experienced a late grade III musculoskeletal SBRT related toxicity. CONCLUSIONS: SBRT is a versatile, well-tolerated, and effective treatment option for single extracranial metastases from ovarian and uterine primary tumors. 35 Gy in five fractions appears to be a practical minimum effective dose. Four patients with small metastases were disease free at the study completion and considered cured. However, patients with larger metastases (≥50 cc) may require higher SBRT dosing or alternative treatments.

Diagnostic evaluation of metastatic placental site trophoblastic tumor.

BACKGROUND: Placental site trophoblastic tumor, a type of gestational trophoblastic disease, is a rare tumor composed of intermediate trophoblasts. CASE: We report the case of a 47-year-old woman with 1 year of amenorrhea who presented with cough in the absence of gynecologic symptoms. She was found to have diffuse pulmonary metastases that were nonhypermetabolic on positron emission tomography (PET) scan. She was diagnosed with Stage 3 metastatic placental site trophoblastic tumor 12 years after her most recent pregnancy. CONCLUSION: Placental site trophoblastic tumor is an unusual malignancy that may present remotely from antecedent gestational events. The relatively slow growth rate of this tumor may explain the lack of PET findings in our case.

Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: results from two studies conducted in Costa Rica and the United States.

Previous work suggests that cervical cancer may aggregate in families. We evaluated the association between a family history of gynecological tumors and risk of squamous cell and adenocarcinomas of the cervix in 2 studies conducted in Costa Rica and the United States. The Costa Rican study consisted of 2,073 women (85 diagnosed with CIN3 or cancer, 55 diagnosed with CIN2 and 1,933 controls) selected from a population-based study of 10,049 women. The U.S. study consisted of 570 women (124 with in situ or invasive adenocarcinomas, 139 with in situ or invasive squamous cell carcinomas of the cervix and 307 community-based controls) recruited as part of a multicentric case-control study in the eastern part of the United States. Information on family history of cervical and other cancers among first-degree relatives was ascertained via questionnaire. Information on other risk factors for cervical cancer was obtained via questionnaire. Human papillomavirus (HPV) exposure was assessed in both studies using broad spectrum HPV L1-based PCR testing of exfoliated cervicovaginal cells and in Costa Rica by additional testing of plasma collected from participants for antibodies against the L1 protein of HPV types 16, 18, 31 and 45 by ELISA. A family history of cervical cancer in a first-degree relative was associated with increased risk of squamous tumors in both studies (odds ration [OR] = 3.2 for CIN3/cancer vs. controls; 95% confidence interval [CI] = 1.1-9.4 in Costa Rica; OR = 2.6 for in situ/invasive squamous cell carcinoma cases vs. controls, 95% CI = 1.1-6.4 in the Eastern United States study). These associations were evident regardless of whether the affected relative was a mother, sister or daughter of the study participant. Furthermore, observed effects were not strongly modified by age. In Costa Rica, the effect persisted in analysis restricted to HPV-exposed individuals (OR = 3.0; 95% CI = 1.0-9.0), whereas in the Eastern United States study there was evidence of attenuation of risk in analysis of squamous carcinoma cases restricted to HPV positive women (OR = 1.4; 95% CI = 0.29-6.6). No significant association was observed between a family history of cervical cancer in a first-degree relative and adenocarcinomas (OR = 1.3; 95% CI = 0.43-3.9). History of gynecological tumors other than cervical cancer in a first-degree relative was not significantly associated with risk of disease in either study. These results are consistent with a role of host factors in the pathogenesis of squamous cell cervical cancer, although familial aggregation due to shared environmental exposures cannot be ruled out.

Distribution of human papillomavirus types 16 and 18 variants in squamous cell carcinomas and adenocarcinomas of the cervix.

The distributions of human papillomavirus (HPV) types detected in cervical adenocarcinomas and squamous cell tumors differ. However, whether the distributions of intratypic HPV variants seen in these two histological forms of cervical disease differ is unknown. Our objective was to compare the distribution of HPV intratypic variants observed in squamous cell carcinomas (SCC) and cervical tumors of glandular origin (e.g., adenocarcinomas; AC) for two HPV types commonly observed in cervical tumors, HPV16 and HPV18. Participants in a multicenter case-control study of AC and SCC conducted in the eastern United States were studied. A total of 85 HPV16 and/or HPV18 positive individuals (31 diagnosed with AC, 43 diagnosed with SCC, and 11 population controls) were included. For HPV16-positive individuals, both the noncoding long control region and the E6 open reading frame were sequenced, and classified into phylogenetic-based lineage groups (European, Asian-American, African1, and African2). For HPV18-positive individuals, the long control region region only was sequenced and classified into known intratypic lineages (European, Asian-Amerindian, and African). The distribution of these different intratypic lineages among AC cases, SCC cases, and population controls was compared using standard methods. Non-European HPV16 and/or HPV18 intratypic variants were observed in 42% of ACs compared with 16% of SCCs and 18% of population controls (P = 0.04). Intratypic variants from the Asian-American lineage of HPV16 accounted for the differences seen between histological groups. The differences observed between AC and SCC cases were strongest for HPV16, and persisted in analysis restricted to Caucasian women, suggesting that the effect cannot be explained by differences in the ethnic make-up of AC versus SCC cases. Cervical AC and SCC differ not only with respect to the distribution of HPV types detected but also with respect to intratypic variants observed. Non-European HPV16 and/or HPV18 variants are commonly seen in AC. A possible hormonal mechanism is suggested to explain the observed findings.

Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix.

BACKGROUND: Hormonal factors may play a more prominent role in cervical adenocarcinoma than squamous cell carcinoma. The authors evaluated whether obesity, which can influence hormone levels, was associated with adenocarcinoma and squamous cell carcinoma. METHODS: This case-control study included 124 patients with adenocarcinoma, 139 matched patients with squamous cell carcinoma, and 307 matched community control participants. All participants completed interviews and provided cervicovaginal samples for human papillomavirus (HPV) testing. Polytomous logistic regression-generated odds ratios (ORs) and 95% confidence intervals (95% CIs) for self-reported height and weight, body mass index (BMI; kg/m(2)), and measured waist-to-hip ratio (WHR) for both histologic types were adjusted and stratified for HPV and other confounders. RESULTS: Height, weight, BMI, and WHR were positively associated with adenocarcinoma. BMI >or= 30 kg/m(2) (vs. BMI < 25 kg/m(2); OR, 2.1 and 95% CI, 1.1-3.8) and WHR in the highest tertile (vs. the lowest tertile; OR, 1.8 and 95% CI, 0.97-3.3) were associated with adenocarcinoma. Neither height nor weight was found to be associated with squamous cell carcinoma, and associations for BMI >or= 30 kg/m(2) (OR, 1.6) and WHR in the highest tertile (OR, 1.6) were weaker and were not statistically significant. Analyses using only HPV positive controls showed similar associations. The data were adjusted for and stratified by screening, but higher BMI and WHR were associated with higher disease stage at diagnosis, even among recently and frequently screened patients with adenocarcinoma. Thus, residual confounding by screening could not be excluded as an explanation for the associations. CONCLUSIONS: Obesity and body fat distribution were associated more strongly with adenocarcinoma than with squamous cell carcinoma. Although questions about screening remain, obesity may have a particular influence on the risk of glandular cervical carcinoma.

Comparison of human papillomavirus genotypes, sexual, and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma: Northeastern United States.

OBJECTIVE: Although human papillomavirus causes essentially all cervical carcinoma, cofactors may differ by cancer histologic type. We examined human papillomavirus genotypes and sexual and reproductive risk factors for cervical adenocarcinoma and squamous cell carcinoma. STUDY DESIGN: One hundred twenty-four women with adenocarcinoma, 139 women with squamous cell carcinoma, and 307 control subjects participated in this case-control study. Logistic regression analyses were performed to calculate odds ratios and CIs. RESULTS: Human papillomavirus 18 was associated most strongly with adenocarcinoma (odds ratio, 105; 95% CI, 23-487). Human papillomavirus 16 was associated most strongly with squamous cell carcinoma (odds ratio, 30; 95% CI, 12-77). More than three lifetime sexual partners was a risk factor for adenocarcinoma (odds ratio, 2.1; 95% CI, 1.1-4.0) and squamous cell carcinoma (odds ratio, 3.0; 95% CI, 1.6-5.9). Even being pregnant was associated inversely with adenocarcinoma (odds ratio, 0.4; 95% CI, 0.2-0.8). Five or more pregnancies was associated with squamous cell carcinoma (odds ratio, 2.2; 95% CI, 0.9-5.4). CONCLUSION: The relative importance of human papillomavirus genotypes 16 and 18 and the reproductive co-factor differences suggest distinct causes for cervical adenocarcinoma and squamous cell carcinoma.

Comprehensive analysis of human leukocyte antigen class I alleles and cervical neoplasia in 3 epidemiologic studies.

To comprehensively explore the relationship between human leukocyte antigen (HLA) class I alleles and cervical neoplasia, a subset of participants from 3 large US and Costa Rican cervix studies were typed for HLA class I alleles. Study subjects were women with cervical cancer or high-grade squamous epithelial lesions (HSILs; n=365) or low-grade squamous epithelial lesions (LSILs; n=275) or who were cytologically normal (control subjects; n=681). Allele-disease associations were assessed by logistic regression analysis. Consistent associations across all studies were observed for HLA-CW*0202 with a combined odds ratio of 0.53 (95% confidence interval [CI], 0.29-0.89) for cancer or HSILs and 0.58 (95% CI, 0.37-1.04) for LSILs, compared with control subjects and adjusted for study. This finding supports the hypothesis that a single allele may be sufficient to confer protection against cervical neoplasia. Given the relationship between HLA-C and its receptors on natural killer (NK) cells, a role is proposed for NK function in human papillomavirus infection and cervical neoplasia.

Detection and quantitation of human papillomavirus DNA in the plasma of patients with cervical carcinoma.

Human papillomaviruses (HPVs) play a central role in the development of cervical carcinoma. Plasma DNA from 232 patients taken at diagnosis or after treatment for invasive cervical cancer (n = 175) or carcinoma in situ (n = 57) and 60 normal controls were examined for HPV-16 or HPV-18 E7 DNA by conventional and real-time quantitative PCR assays. We found HPV-16 or HPV-18 E7 DNA in 6.9% (11 of 175) of invasive cervical cancer cases (18.1% of cases positive for HPV-16 or HPV-18 at the genital tract), 1.8% (1 of 57) of carcinoma in situ, and 1.7% (1 of 60) of normal controls by conventional PCR. Quantitative PCR identified the highest concentrations of HPV DNA (copy number of HPV/ml of plasma) in patients with invasive cervical cancer (mean, 11,163; median, 183.5), followed by a level of 8 in the single carcinoma in situ case and 0 copies in the normal control initially positive by conventional PCR. HPV DNA can be detected in the plasma of some patients with HPV-positive cervical tumors. It remains to be demonstrated whether quantitative PCR analysis of HPV DNA in plasma may have utility in patients at high risk of recurrent disease.

Identificación de papilomavirus en cáncer de cervix recurrente postradioterapia / Papillomaviruses identification in cervix neoplasm postradiotherapy recurrent

Utilizando la técnica de hibridización in situ, se investigó la presencia de papilomavirus humano (PVH) en el material biópsico proveniente de 10 pacientes con cáncer del cuello uterino con recurrencia pelviana luego de radioterapia. Se utilizaron sondas de ácido ribonucleico (ARN) marcado con el radioisótopo S35 para los tipos de PVH 6, 11, 16 y 18. Nueve de estas pacientes tenían también biópsias del tumor primario antes de la radioterapia. Se detectó el PVH 16 en el tumor primario y recurrente en cuatro pacientes, y solamente en el primario en un caso. También se encontró PVH 16 en un cáncer recurrente que no tenía biópsias evaluables del tumor primario. La comparación del tumor primario y recurrente evidenció que la radioterapia no altera la señal de hibridización. La persistencia del PVH 16 en el cáncer recurrente del cérvix dá fundamento a la teoría que el PVH jugaría un rol en el mantenimiento del estado maligno