Bilateral ovarian fibromas as the sole manifestation of Gorlin syndrome in a 22-year-old woman: a case report and literature review.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is a rare autosomal dominantly inherited disorder that is characterized by multisystem disorder such as basal cell carcinomas, keratocystic odontogenic tumors and skeletal abnormalities. Bilateral and/or unilateral ovarian fibromas have been reported in individuals diagnosed with NBCCS. CASE PRESENTATION: A 22-year-old female, presented with low back pain, and was found to have bilateral giant adnexal masses on pelvic ultrasonography, which had been suspected to be malignant ovarian tumors. Positron emission tomography/computed tomography showed multiple intracranial calcification and skeletal abnormalities. The left adnexa and right ovarian tumor were resected with laparotomy, and pathology revealed bilateral ovarian fibromas with marked calcification. We recommended the patient to receive genetic testing and dermatological examination. No skin lesion was detected. Germline testing identified pathogenic heterozygous mutation in PTCH1 (Patched1). CONCLUSIONS: The possibility of NBCCS needs to be considered in patients with ovarian fibromas diagnosed in an early age. Skin lesions are not necessary for the diagnosis of NBCCS. Ovarian fibromas are managed with surgical excision with an attempt at preserving ovarian function. Follow-up regime and counseling on options for future fertility should be offered to patients.

Clinical features of uterine sarcomas presenting mainly with uterine masses: a retrospective study.

BACKGROUND: Uterine sarcomas are uncommon mesenchymal tumors of the uterus. The clinical problem is that the features of uterine sarcomas can sometimes mimic uterine fibroids. This study aims to investigate the clinical characteristics of patients with uterine sarcomas who were preoperative presenting mainly with uterine masses. METHODS: A retrospective analysis of patients who underwent gynecological surgery for uterine sarcomas at the Obstetrics & Gynecology Hospital of Fudan University, between January 2016 and December 2021. RESULTS: Over the 5-year period, 277 patients were final diagnosed of uterine sarcomas. A total of 162 patients were preoperatively diagnosed as uterine fibroids for surgical treatment, the majority of whom were diagnosed of uterine leiomyosarcoma (uLMS) (49/162) and low-grade endometrial stromal sarcoma (LG-ESS) (100/162). Ninety people underwent total hysterectomy and bilateral salpingo-oophorectomy (TH + BSO), while 72 underwent myomectomy followed by supplemental TH + BSO. The group with direct hysterectomy had a higher average age than the group with prior myomectomy (47.20 ± 8.94 vs. 40.86 ± 5.88, p < 0.001). Among patients preoperatively diagnosed as uterine fibroids, patients with uLMS had a higher proportion of previous myomectomy (26.53% vs. 5.00%, p < 0.001), a larger uterine mass diameter on ultrasound (8.38 ± 3.39 cm vs. 6.41 ± 1.92 cm, p < 0.001), and richer hypervascularity (34.69% vs. 18%, p = 0.024) compared with LG-ESS. CONCLUSIONS: Analysis of our data showed that a large proportion of uterine sarcomas, especially uLMS and LG-ESS, present mainly with uterine masses. Ultrasound features including a large uterine mass diameter and rich hypervascularity, and with a history of myomectomy may alert clinicians in suspicion of uLMS when compared with LG-ESS.

Synergistic effects of a combined treatment of PI3K/mTOR dual inhibitor LY3023414 and carboplatin on human endometrial carcinoma.

OBJECTIVES: Our study aims to investigate whether PI3K/mTOR dual inhibitor LY3023414 has synergistic effects with carboplatin in suppressing endometrial cancer (EC), and explore the mechanisms and toxicity of combined therapy. METHODS: The effects of combined therapy of LY3023414 and carboplatin on cell viability, long-term survival and cell apoptosis were studied in vitro, and on subcutaneous xenograft model of HEC-1A cells and patient derived xenograft (PDX) models with different PI3K pathway mutational patterns in vivo. The synergistic mechanisms were explored on ATM/Chk2 and PI3K signaling pathway. The toxicity of combined therapy was also observed. RESULTS: Combined treatment of LY3023414 and carboplatin synergistically inhibited proliferation, colony formation, promoted apoptosis of EC cells, and significantly activated ATM/Chk2 signaling pathway. LY3023414 had synergistic anti-tumor effects with carboplatin in HEC-1A subcutaneous xenograft which harbors PIK3CA mutation. The sensitivity to LY3023414 and carboplatin differed in PDX of EC cases with different mutational patterns of PI3K pathway, and combined therapy exhibited distinct synergistic anti-tumor effects in those harboring different PI3K pathway mutations. No increased drug toxicity in nude mice was seen in combined groups. CONCLUSIONS: Combined therapy of PI3K/mTOR dual inhibitor LY3023414 and carboplatin had synergistic anti-tumor effects in EC cell line and some of the PDX EC models, without increasing the toxicity of single drug. Enhanced carboplatin-induced DNA damage response (DDR) and cell apoptosis may be the mechanisms of synergistic effects. The anti-tumor effects may correlate with the mutational pattern of PI3K pathway, which provides experimental basis of individual treatments of ECs in the future.

Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer.

BACKGROUND: Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC. METHODS: Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival. RESULTS: Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616-188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4. CONCLUSIONS: Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.

Endometrioid endometrial cancer "recurring" as high-grade serous adenocarcinoma in the inguinal lymph nodes in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

BACKGROUND: Inguinal metastasis of endometrial cancer (EC) is rare. The aims of the study were to identify whether the inguinal metastatic tumor was originated from EC and to present the management of the disease. METHODS: The clinical data of a case of endometrioid EC "recurring" as serous adenocarcinoma in the inguinal lymph nodes were collected and analyzed. Paired samples of primary and metastatic tumors were used for exome sequencing to determine whether the tumors are same origination and to identify potential gene mutations associated with the relapse. RESULTS: The patient presented with right inguinal lymphadenopathy and histopathology revealed metastatic serous adenocarcinoma. A germline MLH1 mutation was identified. A combination of bioinformatical methods and cancer-related gene exome sequencing assay identified that only 17 (0.1%) somatic gene mutations were shared by the primary EC and the metastatic inguinal tumor, suggesting that the metastasis did not originate from the primary EC. Postoperative radiation therapy followed by a combination of chemotherapy were performed. Thirty-four months after that, the patient was doing well without any evidence of recurrence. CONCLUSIONS: This is the first case of metastatic inguinal serous adenocarcinoma in a woman with Lynch syndrome shortly after surgical treatment of stage I endometrioid EC.

Ovarian preservation for premenopausal women with early-stage endometrial cancer: a Chinese retrospective study.

OBJECTIVE: This study aimed to retrospectively investigate the safety of ovarian preservation of premenopausal women with stage 1a endometrial carcinoma. METHODS: We performed a population-based study to identify surgically treated stage Ia endometrial cancer of premenopausal women who were diagnosed between August 1989 and December 2015 in our center. Survival outcomes and recurrence rate were examined for premenopausal women who underwent ovarian preservation. Recurrence-free survival rates were calculated following generation of Kaplan-Meier curves and were compared with the log-rank test. Cox regression analysis was performed to identify the independent factors affecting the recurrence rate. RESULTS: Patients with ovarian preservation tended to be significantly younger at diagnosis, have less myometrial invasion, and were less likely to undergo lymphadenectomy compared with women treated with bilateral salpingo-oophorectomy. There was no significant difference in recurrence-free survival between the two groups. In the Cox regression model, ovarian preservation remained an independent prognostic factor for improved overall survival. CONCLUSION: Ovarian preservation does not have a negative effect on oncological outcomes. Ovarian preservation can be applied to premenopausal women with stage Ia endometrial carcinoma.

Establishment of Patient-Derived Tumor Xenograft Models of High-Risk Endometrial Cancer.

OBJECTIVE: High-risk endometrial cancers (ECs), including high-grade EC, serous carcinoma (SC), clear cell carcinoma, and carcinosarcoma, account for 50% of deaths due to ECs. Therapies for these cancers are limited, and patient-derived tumor xenograft (PDTX) models are useful tools for preclinical drug evaluation, biomarker identification, and personalized medicine strategies. Here, we used and compared 2 methods to establish PDTX models. METHODS: Fresh tumor tissues collected from 18 primary high-risk EC patients (10 high-grade ECs, 6 SCs, 1 clear cell carcinoma, and 1 carcinosarcoma) were engrafted subcutaneously and in the subrenal capsule in NOD/SCID for establishment and Balb/c-nu/nu mice for expansion. Histology and cytokeratin, estrogen receptor, progesterone receptor, and P53 expression were evaluated to assess the similarity of primary tumors and different generations of PDTX tumors. Whole-exome sequencing (WES) and RNA sequencing were used in 2 high-grade EC models to verify whether the genetic mutation profiles and gene expression were similar between primary and PDTX tumors. RESULTS: The total tumor engraftment rate was 77.8% (14/18) regardless of the engraft method. The tumor engraftment rate was increased in subrenal capsule models compared with subcutaneous models (62.5% vs 50%, P = 0.464). The time to tumor formation varied significantly from 2 to 11 weeks. After subrenal capsular grafting, grafted tumors could be successfully transplanted to subcutaneous sites. We observed good similarity between primary tumors and corresponding different passages of xenografts. CONCLUSIONS: The combination of 2 engrafting methods increases the tumor engraftment rate. The high tumor engraftment rate ensures the establishment of a high-risk EC biobank, which is a powerful resource for performing preclinical drug-sensitivity tests and identifying biomarkers for response or resistance.

Whether intermediate-risk stage 1A, grade 1/2, endometrioid endometrial cancer patients with lesions larger than 2 cm warrant lymph node dissection?

BACKGROUND: Our research aimed to investigate whether lymphadenectomy was required in patients with intermediate-risk endometrioid endometrial cancer (EEC). METHODS: Between 1989 and 2015, 1009 patients with intermediate-risk EEC: grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter ≥ 2 cm and 818 low-risk patients with grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter < 2 cm were enrolled in this study. The rate and risk factors of node metastasis were evaluated and compared between the two risk groups. Survival data were analyzed in patients with intermediate-risk EEC with or without lymphadenectomy. RESULTS: In all, 624 of 1009 (61.8%) patients with intermediate-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 1.9% (12/624), whereas 394 of 818 (48.2%) patients with low-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 0.3% (1/394) (p = 0.021). Notably, intermediate-risk EEC patients with a microcystic, elongated and fragmented (MELF) pattern of invasion, lymphatic vascular space invasion (LVSI), diffuse lesions, or lesions located in the cornua were more likely to have node metastasis. The 5-year overall cancer-related survival and the recurrence-free survival rates of the 742 intermediate-risk EEC patients who were followed for more than 3 years were 99.4% and 94.7%, respectively. In intermediate-risk group, 6 patients (6/443, 1.4%) with lymphadenectomy and 9 patients (9/299, 3.0%) without lymphadenectomy recurred, with a mean recurrence time of 38.3 and 18.7 months respectively. The five-year overall and recurrence-free survival rates of intermediate-risk patients with and without lymphadenectomy were similar (100% vs 98.9%, p = 0.351; 95.2% vs 93.3%, p = 0.464). CONCLUSION: Patients with intermediate-risk EEC have low nodal metastasis rate and a favorable outcome whether lymphadenectomy is performed or not. Omission of lymphadenectomy may be a reasonable option in the surgical management of patients with intermediate-risk EEC.

Possible Risk Factors of Pulmonary Metastases in Patients With International Federation of Gynecology and Obstetrics Stage I Endometrioid-Type Endometrial Cancer.

OBJECTIVE: Limited data have been obtained in regard to pulmonary metastasis (PM) in patients with stage I endometrial cancer. The aims of the study were (1) to present the clinical and pathological characteristics of patients with PM in the setting of stage I endometrioid-type endometrial cancer (EEC) and (2) to define possible factors that may be used to predict PM. METHODS: Six hundred thirty patients with stage I EEC, including 12 with PM, 19 with extra-PM (EPM), and 599 with no recurrence, were observed. Paired samples of primary and metastatic tumors from a patient were used for exome sequencing to identify potential gene mutations associated with PM. RESULTS: There was no significant difference in the age, Ki-67, lymphatic vascular space invasion, and grade 3 among the 3 groups (P > 0.05). More squamous epithelial differentiation was observed in PM (7/12), as compared with patients with EPM (1/19) (P < 0.05) and no recurrence (20/599) (P < 0.05). The tumor size of the patients with PM was bigger than that of nonrecurrent patients (29.8 ± 16.6 vs 18.5 ± 16.3 mm, P < 0.05). More percentage of patients with deep myometrial invasion (IB) were found in PM (6/12) (P < 0.05) as compared with patients with EPM (3/19) (P < 0.05) and no recurrence (76/599). CDH10, ARID1A, and EMT-associated gene mutations were identified in metastatic tumor tissue but not in primary tumors from a patient with EEC and lung metastases. CONCLUSIONS: Squamous epithelial differentiation, large tumor size, and deep myometrial invasion might be risk factors for PM in patients with stage I EEC. CDH10, ARID1A, and EMT-associated gene mutation may promote the initiation of lung recurrence. However, further studies are needed to determine the precise mechanisms associated with lung metastasis in these patients.

Factors that influence persistence or recurrence of high-grade squamous intraepithelial lesion with positive margins after the loop electrosurgical excision procedure: a retrospective study.

BACKGROUND: In 5-20 % of patients with cervical high-grade squamous intraepithelial lesion (HSIL), a positive margin after the loop electrosurgical excision procedure (LEEP) is associated with persistence/recurrence, but the prognostic value of other clinico-pathological factors is less clear. METHODS: Among 4336 patients with HSIL who underwent an initial LEEP, 275 (6 %) had HSIL-positive margins, 37 of whom were lost to follow-up. We evaluated the remaining 238 patients. Persistence/recurrence was defined as histopathological HSIL during follow-up. RESULTS: The age of the patients ranged from 21 to 69 years (median: 40). The median follow-up period was 25 months (range: 6-43). Of the 238 patients, 211 (88.7 %) patients remained free of persistence/recurrence, while 27 (11.3 %) experienced persistence/recurrence. According to a univariate analysis, age (P = 0.03) and maximum specimen diameter (P = 0.043) were associated with persistence/recurrence, but number/location of involved margin sections and the pathology of the endocervical curettage were not (P > 0.10). The relative risk of the subjects (greater than or equal to 35 years ages) was 4.6 times of the subject less than 35 years, the difference was statistically significant (14 % vs. 3 %, P < 0.05). A multivariate analysis indicated that an age of 35 years or older was the only independent risk factor (OR 4.97, 95 % CI 1.14-21.62, P = 0.03). CONCLUSION: In patients with HSIL and HSIL-involved margins after an initial LEEP, age is a strong independent predictor of persistence/recurrence. Follow-up with screening cytology and/or biopsy may be considered in younger patients, whereas a secondary LEEP/hysterectomy may be considered in older patients.