Acute pulmonary complications in the setting of high risk gestational trophoblastic neoplasia and induction of chemotherapy.

Gestational trophoblastic neoplasia (GTN) consists of rare malignancies of the placenta with a known propensity to metastasize to the lungs. GTN is treated with chemotherapeutic agents known to cause lung injury, further placing patients at risk for serious pulmonary events. In the literature, only a few reports of these complications and their management have been described. Here, we present two cases of GTN with pulmonary complications in the hopes of providing guidance in management. Management of these acute complications had to be balanced between continuation of life-saving therapy to reduce disease burden versus further exacerbation existing pulmonary disease. A review of the English language literature on pulmonary complications in GTN and chemotherapy was performed. In these two cases, we identified key steps that were critical in management: inpatient chemotherapy, early intervention and transfer to an intensive unit when needed, multidisciplinary teams, and altering regimens to reduce lung toxicity. Sequelae of pulmonary injury secondary to chemotherapy can be similar to those secondary to metastases. Because consistent criteria for chemotherapy-induced lung injury has not been established, the true incidence of lung injury that is directly related to chemotherapy versus metastatic disease cannot always be parsed out, making management of these complications difficult. There is also a lack of centralized care for a rare disease like GTN and regional differences in incidence, which can lead to inconsistent treatment decisions. It therefore remains important to illuminate rarely seen complications and their management in the hopes of providing guidance to future clinicians.

Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer.

Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.

A case of placenta previa with increta with a history of pelvic radiation.

BACKGROUND: Prior pelvic radiation increases risks of pregnancy complications that can be life threatening. No documented pregnancy has successfully occurred with pelvic radiation dosing of >45 Gy. This case report describes a successful conception after receiving 54 Gy with subsequent severe pregnancy complications.Case34 yo G4P2012 with a history of pelvic radiation who presented with painless vaginal bleeding at 12w6d gestation resulting from a donor egg embryo transfer. She was subsequently diagnosed with a subchorionic hemorrhage, complete placenta previa, and placenta increta leading to a gravid hysterectomy at 23w0d due to concern for hemodynamic instability. CONCLUSION: History of pelvic radiation increases risk of severe life-threatening pregnancy complications. This case report details the complications that can arise to provide assistance for counseling and management for future providers.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study.

PURPOSE: Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS: Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS: Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION: This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

A case of a unique presentation of a primary vaginal endometrioid adenocarcinoma arising in the setting of a recurrent peritoneal inclusion cyst fistulized to the vagina.

Primary vaginal endometrioid adenocarcinoma is a rare cancer that is often associated with chronic endometriosis. We present the case of a 72-year-old female who underwent right salpingo-oophorectomy followed by hysterectomy with benign pathology 25 years prior to her cancer diagnosis. She had an extensive surgical history in the intervening years and several complicating factors including a history of endometriosis as well as a recurrent peritoneal inclusion cyst treated with ethanol sclerotherapy, followed by formation of a peritoneal-vaginal fistula. Endometriosis is associated with malignant transformation to endometrioid adenocarcinoma through genomic alteration, oxidative stress, inflammation, and hyperestrogenism. Frequency of surveillance examinations and imaging prior to diagnosis were based on patient symptoms, and ultimately a vaginal cuff mass was detected with invasion of the rectosigmoid colon, bladder and levators at time of diagnosis, necessitating infralevator total pelvic exenteration for removal.

Cervical Stratified Mucin-Producing Intraepithelial Lesion: A Systematic Review of Diagnosis and Management.

OBJECTIVES: The aims of the study were to synthesize reported associations of stratified mucin-producing intraepithelial lesion (SMILE) of the cervix with other dysplasia lesions and immunohistochemical (IHC) stains, compare expected patterns of IHC staining to other lesions in the differential diagnosis, and assess follow-up pathology. METHODS: This systematic review includes all case reports and case series of cervical lesions consistent with SMILE based on the histologic diagnosis described in the original case series. MEDLINE, EMBASE, and Cochrane Database were searched through June 2019. Immunohistochemical analysis, concurrent lesions, and pathology on follow-up were compiled for comparison. Weighted averages of concurrent lesions were calculated. RESULTS: Nine case reports and case series were included, published between 2000 and 2019. Of 9 studies, 6 and 5 studies reported strong, diffuse staining of p16 and increased expression of Ki-67, respectively. Stratified mucin-producing intraepithelial lesion is associated with human papillomavirus, especially type 18. The weighted average risk of concurrent high-grade squamous intraepithelial lesion was 79% (range = 33%-93%), adenocarcinoma in situ 39% (2.9%-92%), adenocarcinoma 5% (1%-25%), and squamous cell carcinoma 6% (0%-11%). Patients underwent follow-up ranging from repeat Pap to radical hysterectomy, with pathology on follow-up infrequently and irregularly reported. CONCLUSIONS: Stratified mucin-producing intraepithelial lesion is a rare lesion with a paucity of research on necessary cytology and IHC stains for diagnosis, but p16 and Ki-67 IHC stains can be performed to rule out benign lesions. The lesion is associated with high risk of concurrent high-grade squamous intraepithelial lesion, adenocarcinoma in situ, and invasive carcinoma, but studies on the risk of pursuing fertility-preserving management are needed.

Early diagnosis and treatment challenges of endodermal sinus tumors: A case report.

BACKGROUND: Ovarian endodermal sinus tumors (ESTs) are rapidly growing and highly malignant tumors that respond well to chemotherapy. They can be difficult to diagnose and delayed diagnosis can worsen prognosis. CASE: We present the case of a 20-year-old woman with an EST initially misdiagnosed as a tubo-ovarian abscess who then experienced rapid progression within weeks of initial presentation and was subsequently found to have unresectable advanced stage disease. CONCLUSION: ESTs are extremely aggressive and require prompt referral and early treatment with chemotherapy. Presenting symptoms of pain and a mass can lead to a broad range of differential diagnoses. In such patients, early consideration of tumor markers is warranted. This case report reviews the key aspects for prompt diagnosis and rapid treatment of these tumors, which significantly impacts the prognosis.

An unusual case of uterine PEComa presenting with disseminated intravascular coagulation.

Perivascular epithelioid cell neoplasms (PEComas) are mesenchymal neoplasms originating from the perivascular epithelioid cell (PEC) line. The World Health Organization (WHO) further defines PEComa as "a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells". Gynecologic PEComas account for approximately » of the PEComa cases reported in the literature and are histologically characterized by stromal hyalinization with complete or partial circumscription with hyaline background and diffuse, small vessel vascularity (Musella et al., 2015). Uterine PEComas typically present with vaginal bleeding and/or a uterine mass, are managed surgically with resection, and can be followed by adjuvant treatment if indicated based on pathologic risk factors for aggression. Adjuvant therapy is not standardized given the rarity of these tumors, and can include chemotherapy, radiation, targeted therapy (mTOR inhibitors due to common gene mutations and a hypothesized pathophysiology of this neoplasm) and/or hormones. In this case report, we describe an unusual presentation for a uterine PEComa in a woman initially complaining of worsening cutaneous bruising and petechiae, found to be in florid disseminated intravascular coagulation (DIC) without a clear etiology. Ultimately her extensive hematology evaluation only found a large uterine mass that appeared to be a 9 cm fibroid. She underwent hysterectomy following recovery from her DIC, and was diagnosed with a large uterine PEComa.

29-year-old with dyspareunia and vulvar mass: An unusual diagnosis of Bartholin's gland carcinoma.

•Bartholin's gland carcinoma, adenoid cystic subtype, can occur in younger patients.•These cancers are at high risk of local recurrence and surveillance is needed.•There remains limited evidence specific to these cancers.

Is it reasonable to administer pegfilgrastim on day 1 of a myelosuppressive chemotherapy regimen? A cost-utility analysis.

BACKGROUND: There is recent evidence supporting the safety and efficacy of same-day dosing of pegfilgrastim in patients undergoing chemotherapy. OBJECTIVE: To determine the cost-effectiveness of pegfilgrastim on day 1 (D1) versus day 2 (D2) for primary prevention of neutropenia in women receiving chemotherapy. MATERIALS AND METHODS: A cost-utility model was designed comparing standard D2 versus D1 administration of pegfilgrastim to ovarian cancer patients receiving chemotherapy with an intermediate risk (10-15%) of febrile neutropenia (FN). Rates of FN despite prophylaxis were modeled as 10% for D1 and 5% for D2. Societal costs associated with D2 injection ($175.71) were incorporated. Quality of life (QOL) was modeled from published data; we assumed a small decrement in QOL on treatment days. Sensitivity analyses were performed. RESULTS: D1 administration was less costly ($17,195 versus $17,681) and resulted in higher QOL (0.2298 quality adjusted life years (QALYs) versus 0.2288 QALYs) than D2. Results were sensitive to the risk of FN. D1 remained dominant or cost-effective (ICER less than $50,000/QALY) compared to D2 if the FN rate with D1 was assumed less than 14.5% (baseline estimate 10%). If the FN rate with D1 was assumed greater than or equal to 15%, D1 was not cost-effective compared to D2, with an ICER greater than $100,000/QALY. Findings are insensitive to variations in the modeled cost of treating FN, the additional cost of D2 injection, and the reduced QOL associated with treatment visits. CONCLUSION: Administration of D1 pegfilgrastim is cost-effective in women with ovarian cancer who are treated with intermediate risk chemotherapy.

Posterior reversible encephalopathy syndrome (PRES) associated with ovarian cancer and voltage-gated potassium channel antibodies: A case report.

•We report a case of PRES in conjunction with high grade serous ovarian carcinoma•There is a documented association between chemotherapy agents and PRES•Paraneoplastic panel was positive for voltage-gated potassium channel antibodies•Paraneoplastic workup may be justified in cases with high suspicion of PRES.

Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis.

OBJECTIVE: POLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed. METHODS: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models. RESULTS: POLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09-1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03-1.42). CONCLUSIONS: POLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

Survival outcomes of obese patients in type II endometrial cancer: Defining the prognostic impact of increasing BMI.

OBJECTIVE: To investigate the role of obesity as a risk factor for type II endometrial cancer (EC), as well as the prognostic significance of increasing body mass index (BMI) on survival. METHODS: A single institution retrospective analysis of 154 type II EC cases from 1987 to 2010 was conducted. Patients were categorized into cohorts by BMI (normal (<25), overweight (25-29.9), obese class I (30-34.9), and obese class II-III (≥35)). Descriptive, regression and ANOVA analyses were performed. Kaplan-Meier curves were compared with log rank tests. RESULTS: The BMI distribution was 22.8% normal BMI; 24% overweight; 17.5% class I; and 35.7% class II-III. The median follow up was 41 months. The median progression-free survival (PFS) was 45.4, 36.0, 35.3 and 42.0 months and overall survival (OS) was 54.7, 44.7, 44.8 and 49.7 months, among the respective groups. There was no association between BMI and PFS (p=0.71), OS (p=0.72), or time to recurrence (p=0.71). There were no differences among the increasing BMI groups compared to normal weight women for the risk of death. CONCLUSIONS: Our analysis did not reveal any differences in outcomes by BMI group. Our data reveals that obesity is highly prevalent in type II ECs, though obesity has not historically been described as a risk factor. While BMI as a single variable may not be prognostic for survival outcomes, the role of obesity as a risk factor for type II EC should be further investigated, given the increasing prevalence of obesity in type II ECs.

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.

PURPOSE: The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. PATIENTS AND METHODS: ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. RESULTS: Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. CONCLUSION: Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Evaluation of the Hematologic Safety of Same Day Versus Standard Administration (24- to 72-Hour Delay) of Pegfilgrastim in Gynecology Oncology Patients Undergoing Cytotoxic Chemotherapy.

OBJECTIVE: We assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies. METHODS: A retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia. RESULTS: Four hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87-3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9-1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6-1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group. CONCLUSIONS: The incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.

The Use of Transvaginal Ultrasound in Type II Endometrial Cancer.

OBJECTIVE: To determine the use of the transvaginal ultrasound (TVUS) in postmenopausal women with type II endometrial cancer. METHODS/MATERIALS: A retrospective review was conducted for 173 women with pathology proven type II endometrial cancer at a single institution. Those who underwent preoperative TVUS were included, and the following data were obtained: endometrial stripe (EMS) measurement, uterine and/or adnexal findings, and uterine size/volume. Clinicopathologic factors were abstracted. Descriptive and regression analyses were performed. RESULTS: Fifty-eight women comprised the cohort, and the median age was 66.5 years (50-85 years). The most commonly reported symptom was postmenopausal bleeding in 53 patients (91.4%). The EMS was reported as thin (≤ 5 mm) or indistinct in 16 patients (27.5%). Approximately 60% of patients had 1 or more ultrasound abnormalities: intracavitary mass (31%), intracavitary fluid (12.1%), myometrial lesion (31.03%), and adnexal mass (12.1%). Poorly differentiated endometrioid cancer (53.45%) represented the predominant histology. Of the 16 (27.5%) women with a thin/indistinct EMS, 5 women (8.6%) did not have any abnormal ultrasound findings whatsoever. CONCLUSIONS: Women with type II endometrial cancer had a thin/indistinct EMS on TVUS in approximately 25% of cases. Lack of any ultrasound abnormality, including a thickened EMS, was noted in approximately 10% of patients. The use of TVUS, which has been of value in type I cancer, is limited in type II endometrial cancer. Therefore, endometrial sampling should be included in the evaluation of all women with postmenopausal bleeding, regardless of EMS thickness.

Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing.

BACKGROUND: DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC. METHODS: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided. RESULTS: Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 (MLH1) methylation (P<.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127). CONCLUSIONS: The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing.

Does intra-operative radiation at the time of pelvic exenteration improve survival for patients with recurrent, previously irradiated cervical, vaginal, or vulvar cancer?

OBJECTIVE: To determine whether intra-operative radiation therapy (IORT) at the time of pelvic exenteration (PE) or laterally extended endopelvic resection (LEER) improves progression-free survival (PFS) in patients with recurrent, previously irradiated gynecologic cancers. METHODS: We conducted a single institution retrospective review of patients who had undergone a complete PE for locally recurrent gynecologic cancer. Demographic and clinicopathologic data were collected. RESULTS: 32 patients were identified (2000-2012); 21 (66%) cervical cancer, 8 (25%) vaginal, and 3 (9%) vulvar cancer. All patients were previously irradiated. Twenty-one (66%) received IORT. Mean age was 51. Eight patients had a LEER, all with IORT. Median PFS and OS, respectively, for those with PE alone was 33 and 41 vs. 10 and 10 months for PE+IORT compared to 9 and 17 months for LEER+IORT (P=.04). Increasing tumor size negatively impacted PFS (hazard ratio 1.3; 95%CI 1.12-1.52). Margin status was not associated with survival. No patients undergoing LEER+IORT recurred only locally whereas 62% recurred with a distant component (+/- local). Patients with PE alone had mainly local (36%) and few (9%) distant recurrences compared to 31% local and 38% distant (+/- local) recurrences for those with PE+IORT. CONCLUSIONS: We failed to demonstrate that IORT changes survival and recurrence outcomes. However, patients with clinical indications for IORT at the time of PE have worse prognosis compared to those who do not require IORT. If the need for IORT is anticipated, the surgeon may consider performing a LEER to decrease local recurrence if cure is the goal or consider palliative treatment options.

Options for repair of rectus abdominis myocutaneous perineal/vaginal flap prolapse: A case series.

•The VRAM flap is commonly used for perineal and vaginal reconstruction at the time of pelvic exenteration.•Prolapse of the VRAM flap may be under reported.•We have shown successful repair of VRAM flap prolapse via an obliterative technique and sacral suspension.