Diagnosis and management of gestational trophoblastic disease: 2021 update.

Gestational trophoblastic disease (GTD) arises from abnormal placenta and is composed of a spectrum of premalignant to malignant disorders. Changes in epidemiology of GTD have been noted in various countries. In addition to histology, molecular genetic studies can help in the diagnostic pathway. Earlier detection of molar pregnancy by ultrasound has resulted in changes in clinical presentation and decreased morbidity from uterine evacuation. Follow-up with human chorionic gonadotropin (hCG) is essential for early diagnosis of gestational trophoblastic neoplasia (GTN). The duration of hCG monitoring varies depending on histological type and regression rate. Low-risk GTN (FIGO Stages I-III: score <7) is treated with single-agent chemotherapy but may require additional agents; although scores 5-6 are associated with more drug resistance, overall survival approaches 100%. High-risk GTN (FIGO Stages II-III: score ≥7 and Stage IV) is treated with multiagent chemotherapy, with or without adjuvant surgery for excision of resistant foci of disease or radiotherapy for brain metastases, achieving a survival rate of approximately 90%. Gentle induction chemotherapy helps reduce early deaths in patients with extensive tumor burden, but late mortality still occurs from recurrent treatment-resistant tumors.

Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial.

OBJECTIVE: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). METHODS: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. RESULTS: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). CONCLUSIONS: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

Successful management of stage IV epithelioid trophoblastic tumor using multimodality treatment: A case report.

Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia (GTN) that develops from chorionic-type intermediate trophoblast, is more resistant to chemotherapy than choriocarcinoma, and presents with metastatic disease in 25-35% of cases. We report a case of a 32-year-old who presented one week postpartum with severe abdominal pain and was found to have profound anemia and an elevated hCG level. CT scans and MRI revealed bleeding from hepatic masses, multiple hemorrhagic pulmonary nodules, a 7 cm uterine mass, and brain metastases. She underwent emergent hepatic embolization, was started on induction chemotherapy with weekly low-dose etoposide and cisplatin followed by a transition to etoposide, high-dose methotrexate, actinomycin D, etoposide, and cisplatin (HD EMA-EP), received stereotactic brain radiotherapy, and subsequently underwent minimally-invasive hysterectomy. She remains disease free over one year after the completion of treatment. An aggressive multimodal treatment approach employing etoposide/cisplatin-based chemotherapy as well as surgical procedures to control hemorrhage or excise resistant disease, and radiotherapy for brain metastases can result in successful treatment of stage IV ETT.

Placental site trophoblastic tumor: Successful treatment of 13 cases.

Placental site trophoblastic tumor (PSTT) is a rare variant of gestational trophoblastic neoplasia (GTN) that is characterized by slow growth resulting in mostly uterine-confined disease, low human chorionic gonadotropin (hCG) levels, and resistance to chemotherapy. Our objective was to update our center's experience with PSTT with respect to presentation, prognostic factors, treatment, and outcomes from 2003 to 2019. Thirteen women with PSTT were identified. Mean age was 32 years. The most frequent presenting symptom was abnormal uterine bleeding (69%). A uterine mass was noted in 62%. The diagnosis was usually established by endometrial biopsy or curettage (62%). Nonmolar pregnancy was the preceding gestation in 85%. Median time from last pregnancy to diagnosis was 13 months (range 0-240 months). Serum hCG levels at diagnosis ranged from 1 to 2606 mIU/mL (median 98 mIU/mL). Three women (23%) presented with metastatic disease. All 13 women underwent surgery: 12 had a hysterectomy, 1 had a fertility-sparing hysteroscopic resection, and 2 underwent pulmonary metastatectomy. Nine women (69%) also received chemotherapy for persistently elevated hCG levels after hysterectomy (2), high-risk factors (4), or metastatic disease (3). Overall survival was 100% with a median survival of 65 months (range 30-167 months). Survival for PSTT increased from 57% to 100%, including from 33% to 100% for metastatic disease, at our center from 1982 to 2003 to 2003-2017. Surgery is the most important component in the treatment of women with PSTT. Multidrug platinum/etoposide- chemotherapy should be used in women with metastatic disease and considered in women with nonmetastatic disease with high-risk features.

Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.

Update on the diagnosis and management of gestational trophoblastic disease.

Gestational trophoblastic disease (GTD) arises from abnormal placenta and is composed of a spectrum of premalignant to malignant disorders. Changes in epidemiology of GTD have been noted in various countries. In addition to histology, molecular genetic studies can help in the diagnostic pathway. Earlier detection of molar pregnancy by ultrasound has resulted in changes in clinical presentation and decreased morbidity from uterine evacuation. Follow-up with human chorionic gonadotropin (hCG) is essential for early diagnosis of gestational trophoblastic neoplasia (GTN). The duration of hCG monitoring varies depending on histology type and regression rate. Low-risk GTN (FIGO Stages I-III: score <7) is treated with single-agent chemotherapy but may require additional agents; although scores 5-6 are associated with more drug resistance, overall survival approaches 100%. High-risk GTN (FIGO Stages II-III: score >7 and Stage IV) is treated with multiple agent chemotherapy, with or without adjuvant surgery for excision of resistant foci of disease or radiotherapy for brain metastases, achieving a survival rate of approximately 90%. Gentle induction chemotherapy helps reduce early deaths in patients with extensive tumor burden, but late mortality still occurs from recurrent resistant tumors.

Surgery and Platinum/Etoposide-Based Chemotherapy for the Treatment of Epithelioid Trophoblastic Tumor.

OBJECTIVE: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia that develops from chorionic-type intermediate trophoblast, simulates carcinoma, presents years after a pregnancy event, is associated with low or normal human chorionic gonadotropin levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in combination with platinum/etoposide-based chemotherapy in the management of both localized and metastatic ETT. METHODS: A retrospective review was performed of women with ETT treated at a gestational trophoblastic disease center from 2010 to 2016. RESULTS: Five patients were identified who had complete records. Mean age was 38.0 years. Three women presented with abnormal uterine bleeding, 2 women presented with respiratory complaints, and 1 woman was asymptomatic. Two women had no identifiable antecedent pregnancy, 2 women had spontaneous abortions, and 1 woman had a normal term delivery before diagnosis. Four (80%) of 5 women had metastatic pulmonary disease. All 5 women underwent hysterectomy, and 3 women had resection of metastatic pulmonary disease. The 4 women with metastatic disease were also treated with chemotherapy. All 5 women are currently without evidence of disease. CONCLUSIONS: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum/etoposide-containing regimen should be used in women with metastatic disease. All 5 women with ETT in this series were cured using this approach, including the 4 who had metastatic disease.

Role of adjuvant external beam radiotherapy and chemotherapy in one versus two or more node-positive vulvar cancer: A National Cancer Database study.

BACKGROUND AND PURPOSE: Inguinal lymph node involvement is considered the most important prognostic risk factor for survival in vulvar cancer. However, controversy exists concerning the optimal adjuvant therapy for node-positive disease. This study sought to identify the optimal adjuvant therapy for each subset of women with node-positive disease. MATERIAL AND METHODS: The National Cancer Database (NCDB) was queried to identify women with inguinal node positive vulvar cancer. Survival analysis was performed using log-rank test, the Kaplan-Meier estimates, and Cox proportional hazards to both clarify prognosis and identify the benefit of each treatment modality in individual subsets of women. RESULTS: A total of 2779 women with inguinal node positive vulvar cancer were identified. On multivariate Cox model hazard ratio, radiotherapy yielded a survival advantage for women with one positive node (HR 0.81, p = 0.027) and two or more positive nodes (HR = 0.59, p < 0.001). The addition of chemotherapy to radiotherapy yielded an incremental improvement in survival for women with 2 or more positive nodes (HR = 0.79, p = 0.022) but not women with 1 positive node (HR = 0.93, p = 0.605). CONCLUSIONS: All patients with node positive disease benefited from radiotherapy. By contrast, only those with 2 or more positive nodes benefited from the addition of chemotherapy to radiotherapy.

Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

Advanced small cell carcinoma of the cervix - Successful treatment with concurrent etoposide and cisplatin chemotherapy and extended field radiation: A case report and discussion.

The purpose of this article is to present a case of successful treatment of a patient with stage IVB small cell carcinoma of the cervix (SCCC) who was treated with concurrent chemoradiotherapy (CCRT) consisting of etoposide/cisplatin (EP) chemotherapy, external beam radiation therapy (EBRT), and brachytherapy. The patient has since remained without evidence of disease for nearly six years. This report reviews and summarizes the existing case literature on SCCC.

The selected biomarker analysis in 5 types of uterine smooth muscle tumors.

Uterine smooth muscle tumors (USMTs) consist of a group of histologically heterogeneous and clinically diverse diseases ranging from malignant leiomyosarcoma (LMS) to benign leiomyoma (ULM). The genetic alterations in LMS are complex, with some genetic alterations present in both LMS and other atypical histologic variants of USMT. In this study, we reviewed 119 USMTs with a diagnosis of LMS, smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, and cellular leiomyoma, as well as 46 ULMs and 60 myometrial controls. We selected 17 biomarkers highly relevant to LMS in 4 tumorigenic pathways including steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]), cell cycle/tumor suppressor genes, AKT pathway markers, and associated oncogenes. ER and PR expression was significantly lower in LMS than smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, cellular leiomyoma, and ULM (P < .01). Sixty-five percent of LMSs showed complete loss of ER, and 75% of LMSs showed complete loss of PR. All cell cycle genes were differentially expressed in different types of tumor, but significant overlap was noted. More than 75% of LMSs had Ki-67 index greater than 33%, and only 5% in all other types of USMT. Expression of the selected oncogenes varied widely among different types of USMT. PR positivity and p53 had a borderline association with progression-free survival (P = .055 for PR and P = .0847 for p53). Furthermore, high PR expression was significantly associated with a longer overall survival (P = .0163, hazard ratio 0.198). Cell proliferative indices (Ki-67) and sex steroid hormone receptors were the most valuable markers in differentiating LMS from other USMT variants.

The "hook effect" causing a negative pregnancy test in a patient with an advanced molar pregnancy.

•At high hCG levels in molar pregnancies, a "hook effect" can cause an artificially negative value.•Delay in diagnosis of a molar pregnancy due to the "hook effect" can lead to severe complications.•Suspicion of a molar pregnancy should be communicated so a diluted sample is used to quantify hCG.

Vulvar Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

Synuclein-γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.

Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Data Base study.

BACKGROUND: Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power. METHODS: Women with surgically staged IA or IB endometrial adenocarcinoma who were treated with total hysterectomy between 2003 and 2011 were identified in the National Cancer Data Base. Chi-square tests and multivariate logistic regression were performed to analyze factors associated with the treatment type. A survival analysis was performed with log-rank testing, Cox proportional hazards regression, and Kaplan-Meier estimates. RESULTS: A total of 44,309 eligible women were identified (33,380 at stage IA and 10,929 at stage IB): 88.4% of the women with stage IA tumors and 51.6% of the women with stage IB tumors received no RT. Older age, comorbid disease, a higher histologic grade, and a larger tumor size were independently associated with an increase in mortality. The receipt of vaginal brachytherapy (VB) was independently associated with a reduction in mortality for both stage IA disease (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.67-0.97) and stage IB disease (HR, 0.62; 95% CI, 0.51-0.74). CONCLUSIONS: Analyses of this large database support the utility of postoperative VB for many women with stage I endometrial cancer. Unfortunately, RT appears to be underused in this population. Greater adherence to consensus guidelines may lead to improved outcomes. Cancer 2016;122:3724-31. © 2016 American Cancer Society.

Follow-Up After Molar Pregnancy Evacuation: Feasibility of Using Semi-Quantitative Urine Pregnancy Tests.

OBJECTIVE: To evaluate human chorionic gonadotropin (hCG) trends after evacuation of complete hydatidiform moles to determine if urinary semiquantitative pregnancy tests (SQPTs) could replace blood draws. while still detecting early postmolar gestational trophoblastic neoplasia. STUDY DESIGN: A retrospective review of complete hydatidiform moles at a safety-net hospital from 2003-2013 was performed. hCG curves were used to extrapolate expected SQPT results over timefor a resolving hydatidiform mole. RESULTS: Of 61 complete moles, 37 had an uncomplicated hCG decline and at least 4 serum hCG results. All of those patients had hCG < 10,000 mIU/mL within 15 days, < 2,000 within 64 days, < 500 within 70 days (92.2% within 1 month), < 100 within 89 days (90% within 2 months), and < 25 within 152 days (95.2% within 3 months). After reaching levels < 25, hCG rose only in cases of new pregnancies. CONCLUSION: Based on this retrospective analysis, SQPT monitoring could have avoided 90% of blood draws while still flagging all patients with subsequent postmolar GTN within 45 days by limiting blood draws to (1) patients with SQPT levels of > 10,000, > 500, and >100 mIU/mL at 15, 30, and 45 days, respectively, (2) hCG > 25 after 60 days, or (3) increasing SQPT levels.