Pembrolizumab plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer

Evidence-based recommendations on pembrolizumab (Keytruda) plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer in adults.

Next-generation sequencing assisted diagnosis of cervical metastasis in EGFR-mutated lung adenocarcinoma: A case report.

EGFR mutation has been detected in more than half of non-small cell lung cancer (NSCLC) patients in Asia. Lung cancer is the main cause of malignant tumor-related death worldwide. Although distant metastases often occurs in patients with advanced NSCLC, uterine cervical metastasis is rare. Here, we report a case of EGFR-mutated lung adenocarcinoma with cervical metastasis. A 63-year-old female with known lung adenocarcinoma was found to have abnormal vaginal bleeding during osimertinib follow-up visits. Immunohistochemical (IHC) staining and next-generation sequencing (NGS) of the biopsy sample from the uterine cervical tumor confirmed metastatic dissemination from the primary lung malignancy. NGS assisted the diagnosis of uterine cervical metastasis from the primary lung. This is another major clinical application of NGS in addition to medication guidance and identification of drug resistance mechanisms.

Exploiting somatic alterations as therapeutic targets in advanced and metastatic cervical cancer.

It is estimated that 604,127 patients were diagnosed with cervical cancer worldwide in 2020. While a small percentage of patients will have metastatic disease at diagnosis, a large percentage (15-61%) later develop advanced disease. For this cohort, treatment with systemic chemotherapy remains the standard of care, with a static 5-year survival rate over the last thirty years. Data on targetable molecular alterations in cervical cancer have lagged behind other more common tumor types thus stunting the development of targeted agents. In recent years, tumor genomic testing has been increasingly incorporated into our clinical practice, opening the door for a potential new era of personalized treatment for advanced cervical cancer. The interim results from the NCI-MATCH study reported an actionability rate of 28.4% for the cervical cancer cohort, suggesting a subset of patients may harbor mutations which that are targetable. This review sets out to summarize the key targeted agents currently under exploration either alone or in combination with existing treatments for cervical cancer.

Discovery and Biological Evaluation of CD147 N-Glycan Inhibitors: A New Direction in the Treatment of Tumor Metastasis.

N-glycosylation is instrumental to the regulation of CD147 functions, including the maturation of CD147, secretion of matrix metalloproteinases (MMPs), and promotion of tumor metastasis. Glycosylated CD147 is highly expressed in various cancer types, participates in metastasis, and is associated with the poor prognosis of malignant tumors. However, to date, there has been little development of target-specific inhibitors for CD147 glycosylation. In this work, we report a strategy for discovering CD147 glycosylation inhibitors through computer-aided screening and inhibition assays. Four compounds were screened as potential CD147 glycosylation inhibitors. Of these, compound 72 was finally identified as the best candidate. Further experiments confirmed that compound 72 inhibited the production of MMPs and the metastasis of cancer cells in the Hela cell line. Results further suggest that compound 72 could promote the expression of E-cadherin by targeting CD147, thereby inhibiting tumor migration. Finally, the structures of the other potential CD147 N-glycosylation inhibitors may eventually provide guidance for future optimization.

Secondary Involvement of the Uterine Cervix by Nongynecologic Neoplasms: A Detailed Clinicopathologic Analysis.

Secondary involvement of the uterine cervix by nongynecologic neoplasms is rare accounting for <2% of metastases to the gynecologic tract. This study aimed to analyze the clinicopathologic features of cervical involvement by nongynecologic malignancies. A total of 47 cases were identified including 39 (83%) carcinomas, 6 lymphomas (12.8%), and 2 (4.2%) cutaneous malignant melanomas. The most common primary site of origin among carcinomas was the gastrointestinal tract (27, 69.2%), followed by breast and urothelium (5 each, 12.8%), gallbladder, and lung (1 each, 2.6%). The gynecologic tract was involved at the presentation in 16 patients (34%), including 5 (10.6%) with the cervix being the first site, 7 (14.9%) with synchronous involvement of the cervix and other gynecologic sites, and 4 (8.5%) with the involvement of other gynecologic sites before the cervical presentation. Patients with lymphoma were younger compared with those with carcinoma (43.7 vs. >50.5) (P=0.01). Mean time to identification of cervical metastases was <1 year for gallbladder carcinoma, melanomas, and gastrointestinal signet ring cell carcinomas (P=0.03). Features that varied with different types of metastatic tumor included lymphovascular space invasion, depth of stromal invasion, growth pattern (glands lacking architectural complexity, cribriforming, solid), presence of goblet cells, and signet ring cells, degree of cytologic atypia, and overall findings mimicking a benign/noninvasive process (P≤0.027). Six tumors (12.8%) were initially misdiagnosed as cervical primary. Metastatic nongynecologic tumors can mimic primary in situ or invasive neoplasms in both ectocervix and endocervix. In patients with a known prior malignancy, the clinical history with ancillary studies and a high level of suspicion are crucial to ensure accurate diagnosis.

Prediction of cervical metastasis and survival in cN0 oral cavity cancer using tumour 18F-FDG PET/CT functional parameters.

PURPOSE: Oral cavity squamous cell carcinoma (OCC) can spread to the neck without apparent lymphadenopathy. Pretreatment detection or prediction of occult metastasis might contribute to proper management of clinically node-negative (cN0) OCC. We examined the role of tumour quantitative 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) measurements for predicting OCC occult metastasis and survival. METHODS: This study included 130 cN0 OCC patients who underwent 18F-FDG PET/CT scanning and subsequent curative surgery and neck dissection. Maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured on pretreatment 18F-FDG PET/CT. Binary logistic regression was used to identify factors predicting occult cervical metastasis. Univariate and multivariate Cox proportional hazard regression were used to find factors associated with overall survival (OS). RESULTS: Pathological cervical metastasis (pN +) was found in 29 (22.3%) patients. Age, tumour differentiation, lymphovascular invasion, and T classification were significantly associated with pN + (all P < 0.05). After adjustment for these factors, MTV and TLG independently predicted pN + (P < 0.05). Invasion depth, lymphovascular invasion, T and N classifications, and overall TNM stage were significantly associated with OS. After adjustment for these factors, SUVmax and TLG independently predicted OS (all P < 0.05). Patients with TLG > 9.3 g had a 5.7-fold increased risk of overall mortality. CONCLUSIONS: Tumour 18F-FDG PET/CT parameters might predict occult metastasis and survival in cN0 OCC patients.

Value of integrated PET-IVIM MR in assessing metastases in hypermetabolic pelvic lymph nodes in cervical cancer: a multi-parameter study.

PURPOSE: To evaluate the value of integrated multi-parameter positron emission tomography-intravoxel incoherent motion magnetic resonance (PET-IVIM MR) imaging for pelvic lymph nodes with high FDG uptake in cervical cancer, and to determine the best combination of parameters. METHODS: A total of 38 patients with 59 lymph nodes with high FDG uptake were included. The imaging parameters of the lymph nodes were calculated by PET-IVIM MR, and the differences between lymph nodes diagnosed by postoperative pathology as metastasis versus non-metastasis were compared. We used the receiver operating characteristic (ROC) curve and logistic regression to construct a combination prediction model to filter low value and similar parameters, in order to search the optimal combination of PET/MR parameters for predicting pathologically confirmed metastatic lymph nodes. The correlation between diffusion parameters and metabolic parameters was analyzed by Spearman's rank correlation. RESULTS: The maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total metabolic tumor volume (MTV), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC), diffusion-related coefficient (D), and perfusion-related parameter (F) showed significant differences between the metastatic and non-metastatic groups (p < 0.05). The combination of MTV, SUVmax, and D had the strongest predictive value (area under the ROC 0.983, p < 0.05). SUVmax, SUVmean, and TLG weakly correlated with F (R = - 0.306, - 0.290, and - 0.310; p < 0.05). CONCLUSIONS: The combination of MTV, SUVmax, and D may have a better diagnostic performance than PET- or IVIM-derived parameters either in combination or individually. No strong correlation exists between diffusion parameters and metabolic parameters. KEY POINTS: • Integrated PET-IVIM MR may assist to characterize lymph node status. • The combination of MTV, SUVmax, and D may have a better diagnostic performance than PET- or IVIM-derived parameters either in combination or individually for the assessment of pelvic lymph nodes with high FDG uptake. • No strong correlation exists between diffusion parameters and metabolic parameters in pelvic lymph nodes with high FDG uptake.

The Efficacy And Safety Of Apatinib Treatment For Patients With Metastatic Or Recurrent Cervical Cancer: A Retrospective Study.

BACKGROUND: This study was performed to assess the efficacy and safety of apatinib in patients with metastatic or recurrent cervical cancer. METHODS: Twenty-six patients with metastatic or recurrent cervical cancer and treated with apatinib until progressive disease or unacceptable toxicity were included in this multicenter, retrospective, observational study from January 2016 to April 2018. The primary end point was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity. Toxicities were assessed according to Common Terminology Criteria for Adverse Events. RESULTS: A total of 26 metastatic or recurrent cervical cancer patients were enrolled in this study. No complete response (CR) occurred, 4 patients (15.4%) showed partial response (PR), 11 patients (42.3%) had stable disease (SD), and 11 patients (42.3%) had progressive disease (PD), with DCR of 57.7% and ORR of 15.4%. Median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI]: 0-6.3 months) and overall survival (OS) was 7.0 months (95% CI: 5.1-8.9 months) respectively. The most common adverse effects were hand-foot syndrome (50.0%), secondary hypertension (26.9%) and fatigue (26.9%). Three patients discontinued treatment due to grade 3 toxicities (one case for hand-foot syndrome, two cases for diarrhea) and 6 patients required dose reduction because of adverse effects. CONCLUSION: Apatinib seems active in heavily-pretreated metastatic or recurrent cervical cancer. The adverse effects were moderate but manageable.

Primary endocervical gastric-type adenocarcinoma: a clinicopathologic and immunohistochemical analysis of 23 cases.

BACKGROUND: Endocervical gastric-type adenocarcinoma (GAS) is a rare non-human papillomavirus-associated adenocarcinoma (NHPVA) with morphologic and immunohistochemical features of gastric differentiation. This study aimed to evaluate cytologic and clinicopathological features, differential diagnosis of endocervical GAS. METHODS: A total of 23 patients diagnosed with endocervical GAS/minimal deviation adenocarcinoma (MDA) at Peking University People's Hospital between 2009 and 2018 were included. Clinical characteristics, cytologic/histopathologic findings, and immunohistochemical results were collected and analyzed. RESULTS: The average age of patients was 51 years old (range from 28 to 73). Cytologically, tall columnar epithelial cells with pale, foamy or vacuolated cytoplasm were mostly common, followed by well-defined cytoplasmic borders. Fourteen endocervical GAS cases demonstrated mild cytologic atypia, and 9 cases showed moderate to marked cytologic atypia. Ovarian and fallopian tube involvement were identified in 5 and 6 cases, respectively. Immunohistochemically, tumor cells were diffusely positive for CK7, MUC6 and CA-IX, but focally positive for CK20 and CDX2. P16 was negative or patchy positive in most cases and p53 mutation was identified in 12 cases (12/21, 57.1%). CONCLUSIONS: Endocervical GAS shows different morphologic and immunological features from endocervical usual type adenocarcinoma, but it may be difficult to be differentiated from metastatic mucinous adenocarcinoma to cervix due to similar morphology and overlapping immunohistochemical profile. Therefore, awareness of the morphologic features and immunohistochemical profile of GAS will allow pathologists to recognize and accurately diagnose this rare and aggressive entity.

Metastatic Carcinoma of Endometrium from Primary Ovarian Serous Carcinoma Mimicking a Primary Uterine Tumour.

A 44-year female was admitted to the hospital, complaining of vaginal bleeding. Ultrasound imaging revealed two masses in the pelvic cavity, measuring 6.6 x 3.4 x 1.8 cm and 8.2 x 4.7 x 3.7 cm in size. After surgical debulking of the tumours, the patient underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic disease dissection, appendicectomy, omentectomy, and pelvic lymph node dissection. Histological and immunochemical examinations confirmed the diagnosis of serous carcinomas in both ovaries involving the right tubal fimbria, the omentum, pelvic nodules, and the endometrium. Ovarian serous carcinoma spreading to the endometrium is a rare phenomenon and may mimick a primary uterine serous cercinoma. Although difficult, it is important to distinguish concomitant independent primary tumours from metastases because the most appropriate management strategy and prognosis differs in both.

Touch Imprint Cytology: Can It Serve as an Alternative to Frozen Section in Intraoperative Assessment of Cervical Metastasis in Oral Squamous Cell Carcinoma?

PURPOSE: The purpose was to assess the diagnostic accuracy of touch imprint cytology (TIC) compared with frozen section (FS) analysis as an intraoperative diagnostic tool to assess nodal metastasis in oral squamous cell carcinoma. MATERIALS AND METHODS: We intraoperatively assessed 38 patients undergoing neck dissection for oral squamous cell carcinoma, wherein a total of 248 nodes were sectioned and subjected to TIC and, subsequently, FS analysis and were finally submitted to the gold-standard histopathologic examination. The sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) of TIC and FS analysis for the detection of metastasis in the cervical nodes were determined with the corresponding 95% confidence intervals. RESULTS: TIC had a sensitivity of 62.86%, specificity of 96.24%, PPV of 73.33%, NPV of 94.04%, and accuracy of 91.53% compared with histopathologic results. The sensitivity of FS analysis was 60%, specificity was 98.12%, PPV was 84%, NPV was 93.72%, and accuracy was 92.74% compared with histopathologic examination. These results of TIC were comparable to those of FS analysis. CONCLUSIONS: TIC is a straightforward, quick, and reliable technique. It has a definitive role in being used as an adjunct to FS analysis to increase intraoperative diagnostic accuracy. It can serve as a useful technique in centers that do not have FS availability.

Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression.

We had previously reported that in addition to p53 inactivation, overexpression of the DNA sensor protein-absent in melanoma 2 (AIM2)-contributes to tumorigenesis of oral squamous cell carcinoma (OSCC). Given that AIM2 is highly expressed in the OSCC tumors from patients with metastasis, we investigated whether AIM2 expression contributes to the progression of OSCC metastasis. In in vitro assays using OSCC cell lines, the high migration and invasion capacity of OSCC cells were dependent on the increased expression of AIM2, resulting in enhanced epithelial-mesenchymal transition (EMT), with EMT-related gene expression. Moreover, the in vivo short-term metastasis assay using orthotopic implantation into immunodeficient mice demonstrated that OSCC cells with high levels of AIM2 expression exhibited enhanced tumor growth in the tongue, resulting in decreased survival of the mice. Further, the cells overexpressing AIM2 dominantly invaded into the tumor lymphatic vessels, unlike OSCC cells with low AIM2 expression. Thus, the high expression of AIM2 in OSCC enhances progression of tumor growth.

Diagnostic Performance of Transvaginal Ultrasound for Detecting Cervical Invasion In Women With Endometrial Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVES: To evaluate the role of transvaginal ultrasound (TVUS) for diagnosing cervical invasion in the preoperative assessment of endometrial carcinoma. METHODS: A search for studies evaluating the role of TVUS for assessing cervical invasion in endometrial carcinoma from January 1990 to December 2016 was performed in the PubMed/MEDLINE, Web of Science, www.ClinicalTrials.gov, and www.who.int/trialsearchdatabases. The quality of the studies was evaluated by the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: We identified 211 citations. Ultimately, 17 studies comprising 1751 women were included. The mean prevalence of cervical invasion was 16.3%. The risk of bias was high in 7 studies for the domains "patient selection" and "index test," whereas it was considered low for the "reference test" domain. Overall, the pooled estimated sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of TVUS for detecting cervical invasion were 63% (95% confidence interval [CI], 51%-74%), 91% (95% CI, 87%-94%), 10.2 (95% CI, 5.7-18.3), and 0.38 (95% CI, 0.28-0.53), respectively. Heterogeneity was high for both sensitivity and specificity. CONCLUSIONS: Transvaginal ultrasound has acceptable diagnostic performance for detecting cervical invasion in women with endometrial carcinoma.

Mucinous adenocarcinoma, gastric type of the uterine cervix: clinical features and HER2 amplification.

Mucinous adenocarcinoma, gastric type (GAS) is difficult to diagnose and shows poor prognosis. Trastuzumab, an anti-human epidermal growth factor type 2 (HER2) monoclonal antibody, is effective in HER2-positive stomach cancer. The objectives of this study were to identify the clinicopathological characteristics of GAS and to evaluate HER2 expression in GAS. We retrospectively reviewed 322 cervical cancer cases diagnosed at the Kyoto University Hospital from 2010 to 2016. The incidence, clinical factors including age, stage, and lymph node status, tumor markers, immunoreactive expression of MUC6, HIK1083, and HER2, and HER2 amplification were evaluated. Of the 322 cases of cervical cancer, 13 cases of the adenocarcinoma cases were diagnosed as GAS. Watery discharge, lower abdominal pain, CA19-9 elevation, and lymph node metastasis were frequently observed in GAS (p = 0.0226, p = 0.0400, p = 0.0346, and p = 0.0274, respectively). Immunohistochemistry showed positive MUC6 status in all 13 cases and positive HIK1083 status in 8 cases. The HER2 expression status was equivocal in six cases by immunohistochemistry and HER2 amplification was identified in one case. GAS exhibits frequent lymph node metastasis and clinical symptoms such as watery discharge and lower abdominal pain, high levels of CA19-9. In addition, some parts of GAS exhibit HER2 amplification.

Lobular carcinoma of the breast with metastasis to the uterine cervix.

Metastases may occur in early-stage or locally-advanced tumors in diverse locations. Nevertheless, the uterine cervix is an uncommon site for metastasis, since the majority of tumors in this organ is primary carcinomas or result from the direct extension of primary pelvic tumors. The objective of the current study was to report a clinical case considered rare in the literature, as well as discuss its implications and peculiarities. This case report describes a 57-year-old patient with lobular carcinoma metastatic to the uterine cervix, >3 years after the termination of the left breast cancer treatment. A literature analysis confirmed that most cases presented with vaginal bleeding or abdominal discomfort, but many were asymptomatic. Common characteristics between the cases were the patient's age, the time period between primary tumor diagnosis and the emergence of metastatic lesions, treatment, medication, and signs/symptoms. Although rare, metastasis should be considered in women with a history of breast cancer, particularly when the complaint is abnormal vaginal bleeding.

Metastatic Breast Cancer to the Cervix Presenting with Abnormal Vaginal Bleeding During Chemotherapy: A Case Report and Literature Review.

The most common sites of invasive breast cancer metastasis are the lungs, liver, bones and brain. Less frequent sites include the gastrointestinal tract, pancreas, spleen, thyroid, adrenals, kidneys, heart and female genital tract. The uterus is reported as a rare site for metastasis, and even more so for an isolated metastasis. Other sites of extra-genital sources for uterine metastases include the colon, stomach, pancreas, gallbladder, lung, cutaneous melanoma, urinary bladder and thyroid. The rarity of breast cancer metastasis to the uterine cervix could be explained by the fact that the cervix has a small blood supply and an afferent lymph drainage system alone. It is rare to diagnose a cervical metastasis prior to eliciting the primary breast disease. Invasive lobular carcinoma metastasises to the female reproductive system more frequently than invasive ductal carcinoma. This paper presents a case of breast cancer metastasis to the cervix.