Clinical impact of genetic alterations of CTNNB1 in patients with grade 3 endometrial endometrioid carcinoma.

To identify prognostic factors in patients with grade 3 (high-grade) endometrial endometrioid carcinoma, we evaluated the spectrum of genomic alterations and examined whether previously reported molecular subtypes of endometrial carcinoma were adapted to clinical outcome prediction. Seventy-five Japanese patients with grade 3 endometrial endometrioid carcinoma, who underwent a potentially curative resection procedure between 1997 and 2018 at the National Cancer Center Hospital, were included. We classified the patients into four risk groups of the disease based on the Proactive Molecular Risk Classifier for Endometrial Cancer. Genomic alterations in PTEN, ARID1A, TP53, and PIK3CA were detected in more than 30% of the patients. Overall survival and recurrence-free survival of patients with genomic alterations in CTNNB1 were poorer than those of patients with wild-type CTNNB1 (p = 0.006 and p = 0.004, respectively). Compared with that of alterations prevalent in Caucasians, the frequency of genomic alterations in POLE and TP53 was higher in our study than in The Cancer Genome Atlas dataset (p = 0.01 and p = 0.01, respectively). The tendency for recurrence-free survival in the POLE exonuclease domain mutation group was better than that in the TP53 mutation and mismatch repair-deficient groups (p = 0.08 and p = 0.07, respectively), consistent with the Proactive Molecular Risk Classifier for Endometrial Cancer risk classifier definition. The CTNNB1 mutation is a potential novel biomarker for the prognosis of patients with grade 3 endometrial endometrioid carcinoma, and prognosis classification using Proactive Molecular Risk Classifier for Endometrial Cancer may help screen Japanese patients with the disease.

Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients.

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.

Endometrial Endometrioid Carcinoma With Ovarian Metastasis Showing Morula-like Features in a Patient With Cowden Syndrome: A Case Report.

Cowden syndrome (CS) is a multiple hamartoma syndrome associated with the development of various tumors, including endometrial cancer. However, the histology of CS-associated endometrial cancer remains to be fully described. To our knowledge, this is the first report of a patient with CS having endometrial endometrioid carcinoma with ovarian metastasis demonstrating morula-like features. A 31-yr-old, nulliparous, Japanese woman presented with abnormal genital bleeding. Endometrial biopsy revealed endometrioid carcinoma with an extensive morular formation, partially resembling atypical polypoid adenomyoma (APAM). Moreover, she had a past history of bilateral breast cancer and a family history of juvenile breast cancer in her mother. Genetic testing revealed they shared the same pathogenic germline PTEN mutation. She underwent an abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node biopsy. Pathologic examination revealed endometrial endometrioid carcinoma with APAM-like histology. Furthermore, the solid components with morula-like morphology and immunophenotypes showed myometrial invasion and ovarian metastasis (FIGO stage IIIA/pT3aN0M0). The present case highlights the need for careful assessment of myometrial invasion and extrauterine spread for appropriate gynecologic treatment even if endometrial biopsy shows APAM-like histology. Moreover, characterization of CS-associated endometrial cancers is required.

Characteristics and prognostic significance of incidentally detected cancer cells in uterine specimens of patients with pelvic high-grade serous carcinoma.

OBJECTIVE: Cases of pelvic high-grade serous carcinoma (HGSC) with incidentally detected cancer cells (ICCs) in endometrial and/or cervicovaginal cytology have been reported. This study aimed to clarify the incidence and characteristics of pelvic HGSC with ICCs and to determine whether ICCs have a negative prognostic impact. METHODS: Patients with ovarian/tubal/peritoneal HGSC who underwent pre-treatment uterine (endometrial/cervicovaginal) cytology or biopsy between January 2007 and May 2017 were included. We reviewed the frequencies of ICCs and compared the clinicopathological features and survival outcome between the ICC-positive and ICC-negative groups. RESULTS: Of the 160 patients evaluated, 69 (43.2%) had positive ICCs in at least one uterine specimen. There were no significant differences in clinicopathological characteristics, such as age, FIGO stage, serum CA125 level, ascites, and tubal lesion, between the two groups. Moreover, ICCs had no significant survival impact on progression-free survival or overall survival. CONCLUSION: Our study showed a high rate of pelvic HGSC with ICCs in pre-treatment uterine specimens. The ICCs per se had no negative impact on survival outcomes of pelvic HGSC. Furthermore, uterine biopsy and cytology can be useful and less-invasive methods to obtain tubo-ovarian/peritoneal cancer cells before treatment.

Rare FGFR fusion genes in cervical cancer and transcriptome-based subgrouping of patients with a poor prognosis.

BACKGROUND: Although cervical cancer is often characterized as preventable, its incidence continues to increase in low- and middle-income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed the distribution of fusion genes across cancer types and used an RNA-based classification to divide cervical cancer patients with a poor prognosis into subgroups. MATERIAL AND METHODS: RNA sequencing of 116 patients with cervical cancer was conducted. Fusion genes were extracted using StarFusion program. To identify a high-risk group for recurrence, 65 patients who received postoperative adjuvant therapy were subjected to non-negative matrix factorization to identify differentially expressed genes between recurrent and nonrecurrent groups. RESULTS: We identified three cases with FGFR3-TACC3 and one with GOPC-ROS1 fusion genes as potential targets. A search of publicly available data from cBioPortal (21,789 cases) and the Center for Cancer Genomics and Advanced Therapeutics (32,608 cases) showed that the FGFR3 fusion is present in 1.5% and 0.6% of patients with cervical cancer, respectively. The frequency of the FGFR3 fusion gene was higher in cervical cancer than in other cancers, regardless of ethnicity. Non-negative matrix factorization identified that the patients were classified into four Basis groups. Pathway enrichment analysis identified more extracellular matrix kinetics dysregulation in Basis 3 and more immune system dysregulation in Basis 4 than in the good prognosis group. CIBERSORT analysis showed that the fraction of M1 macrophages was lower in the poor prognosis group than in the good prognosis group. CONCLUSIONS: The distribution of FGFR fusion genes in patients with cervical cancer was determined by RNA-based analysis and used to classify patients into clinically relevant subgroups.

How should we appropriately classify low-risk uterine cervical cancer patients suitable for de-intensified treatment?

We suggested de-escalation would be possible for cervical cancer like human papillomavirus (HPV)-related oropharyngeal cancer. However, the classification was based on tumor shrinkage that can be obtained after half of the treatment was finished. Our other article found adverse factors which can be obtained prior to treatment, and they might classify patients earlier.

Urethral metastasis from esophageal cancer: symptoms of dysuria and cystoscopic diagnosis.

Urethral malignant tumors are rare and can lead to stenosis, causing dysuria. We report a case of urethral metastasis secondary to esophageal cancer. At the time of diagnosis, a patient with esophageal squamous cell carcinoma presented with voiding difficulties, feeble stream, terminal dribbling and incomplete voiding. The urethral tumor was diagnosed using cystoscopy, and biopsy was thereafter performed. Histopathology of the urethral tumor microscopically resembled to that of esophageal cancer. On immunohistochemistry, the urothelium markers uroplakin 2 and GATA3 were negative in the carcinomatous component; however, GATA3 was detected on the lesion's surface. This case demonstrated that esophageal cancer metastasized to the urethra. Medical oncologists should consider this diagnosis in patients with cancer presenting with dysuria.

Predictive model for the preoperative assessment and prognostic modeling of lymph node metastasis in endometrial cancer.

Lymph node metastasis (LNM) is a well-established prognostic factor in endometrial cancer (EC). We aimed to construct a model that predicts LNM and prognosis using preoperative factors such as myometrial invasion (MI), enlarged lymph nodes (LNs), histological grade determined by endometrial biopsy, and serum cancer antigen 125 (CA125) level using two independent cohorts consisting of 254 EC patients. The area under the receiver operating characteristic curve (AUC) of the constructed model was 0.80 regardless of the machine learning techniques. Enlarged LNs and higher serum CA125 levels were more significant in patients with low-grade EC (LGEC) and LNM than in patients without LNM, whereas deep MI and higher CA125 levels were more significant in patients with high-grade EC (HGEC) and LNM than in patients without LNM. The predictive performance of LNM in the HGEC group was higher than that in the LGEC group (AUC = 0.84 and 0.75, respectively). Patients in the group without postoperative pathological LNM and positive LNM prediction had significantly worse relapse-free and overall survival than patients with negative LNM prediction (log-rank test, P < 0.01). This study showed that preoperative clinicopathological factors can predict LNM with high precision and detect patients with poor prognoses. Furthermore, clinicopathological factors associated with LNM were different between HGEC and LGEC patients.

Prevalence and characteristics of immune checkpoint inhibitor-related myocardial damage: A prospective observational study.

An increasing number of patients with cancer are being treated with immune checkpoint inhibitors. Consequently, the incidence of immune checkpoint inhibitor-related myocarditis has been increasing. Nonetheless, the diagnostic criteria for the immune checkpoint inhibitor-related myocarditis have not been sufficiently established. Therefore, the real-world incidence or prevalence of immune checkpoint inhibitor-related myocardial damage remains unknown. This was a single-center cohort study that included 100 patients admitted for immune checkpoint inhibitor therapy for any type of cancer. The patients underwent monthly measurement of cardiac troponin I and N-terminal pro-brain natriuretic peptide levels with electrocardiography. Additionally, echocardiography was performed every 3 months. Our protocol was continued until 6 months after the initiation of immune checkpoint inhibitors. We defined immune checkpoint inhibitor-related myocardial damage as an increase in cardiac troponin I levels by >0.026 ng/mL and/or a decrease in the left ventricular ejection fraction by >10% to <53% on echocardiography. The mean patient age was 64 years; 71% were men. The most commonly used immune checkpoint inhibitor was nivolumab (47%), followed by pembrolizumab (29%). Overall, 5% of patients received combination therapy. Among 100 patients, 10 (10%) were diagnosed with immune checkpoint inhibitor-related myocardial damage. Among them, five patients underwent endomyocardial biopsy. Of these patients, four were histopathologically observed to have lymphocyte infiltration in their myocardium. In conclusion, serial cardiac troponin I measurement during immune checkpoint inhibitor treatment could help detect early-phase myocardial damage. The prevalence of myocardial damage was much higher than previously expected.

TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer.

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets (P = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy.

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3-153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.

Chemotherapy-associated foam cell aggregates as a prognostic factor in patients with pelvic high-grade serous carcinoma receiving neo-adjuvant chemotherapy.

High-grade serous carcinoma (HGSC) tends to recur after treatment; therefore, the Chemotherapy Response Score (CRS) has been proposed as a histopathological prognostic scoring system for measuring the response to neo-adjuvant chemotherapy and the risk of recurrence. This study aimed to evaluate the CRS in only those with an R0 debulking status and to investigate new prognostic factors for progression-free survival (PFS). We reviewed the CRS of HGSC patients with R0 using surgical specimens of the omental sections. Patients were categorized according to foam cell change (FCC), defined as foam cells occupying more than half of the area of the chemotherapy-associated scar. In total, 100 HGSC patients were evaluated. PFS was significantly different according to the CRS. For CRSs of 1/2 and 3, the median PFS were 18 and 27 months, respectively (HR, 1.84; 95% CI 1.01-3.33, p = 0.045). Moreover, the FCC group showed significantly longer PFS than did the non-FCC group (20 vs 59 months; HR 2.43; 95% CI 1.15-5.14; p = 0.020). The present study validated the CRS of those in the R0 cohort. Furthermore, an increase in foam cells in the regression scar reflects the chemotherapy response and the FCC may be a useful novel prognostic factor for patients undergoing R0 resection. This finding must be further validated independently.

Endometrial cancer arising after complete remission of uterine malignant lymphoma: A case report and mutation analysis.

Uterine malignant lymphoma is rare and its association with secondary cancer has not been fully described. Here, we report a rare case of endometrial cancer arising after 1 year of complete remission of uterine diffuse large B-cell lymphoma (DLBCL). An 88-year-old woman was referred to us for abnormal genital bleeding and was diagnosed with uterine DLBCL. She underwent chemotherapy comprising rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone followed by radiation therapy; subsequently, she achieved complete remission. One year later, she noticed genital bleeding recurrence, and endometrial biopsy revealed endometrial adenocarcinoma. Total hysterectomy and bilateral salpingo-oophorectomy were performed. Her pathological diagnosis was endometrial endometrioid carcinoma, grade 1 (pT1aN0). Adenocarcinoma was observed over foamy macrophages aggregates, indicating remission of DLBCL. Targeted sequencing of both DLBCL and endometrial cancer revealed 24 gene mutations including the truncation-type mutations of ARID1A and PTEN occurring only in endometrial cancer. These multiple somatic gene mutations accumulating within 1 year imply endometrial carcinogenesis induced by DNA damages caused by treatment for DLBCL. Although the epidemiological risk of secondary malignancies after uterine lymphoma remains unclear, the present case serves as a warning for secondary cancer and highlights the importance of early detection and treatment.

Prognostic impact of intraoperative peritoneal cytology in interval debulking surgery for pelvic high-grade serous carcinoma.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine whether peritoneal washing cytology (PWC) during interval debulking surgery (IDS) could predict the prognosis of patients with pelvic high-grade serous carcinoma (HGSC) achieving R0 status. METHODS: Between January 2007 and May 2018, 110 patients with ovarian/tubal/primary peritoneal HGSC received platinum-based neo-adjuvant chemotherapy, followed by IDS at National Cancer Center Hospital, Japan. All the patients achieved R0 debulking status, defined as no macroscopic residual tumor in the peritoneal cavity at the completion of IDS. PWC was performed before debulking during IDS. The survival outcomes were compared between the PWC-positive and PWC-negative groups. RESULTS: The median progression free survival (PFS) for the entire cohort was 17 months (range, 5-133 months). The median PFS for the PWC-positive group was significantly shorter than that of the PWC-negative group (16 vs 19 months, HR 2.04, 95% CI 1.22-3.41, P-value < 0.01). Increased risk of progression was observed on both univariate and multivariate analyses, including age and FIGO stage (HR 2.28; 95% CI 1.35-3.84, P < 0.01). CONCLUSIONS: The positive PWC during IDS was found to predict earlier disease recurrence in patients with pelvic HGSC achieving R0 status. As performing PWC during IDS becomes standard practice, prospective validation should be conducted in the future.

Incidental lymphangioleiomyomatosis in the lymph nodes of gynecologic surgical specimens.

OBJECTIVES: Incidentally discovered lymphangioleiomyomatosis (LAM) in sampled lymph nodes are infrequent but intractable issues for gynecologists. The aims of this study were to elucidate the prevalence of incidental nodal LAM in a consecutive cohort of gynecologic surgical specimens from Japanese patients, to document clinicopathological features of nodal LAM cases, and to investigate the association between the subsequent development of pulmonary LAM and tuberous sclerosis complex (TSC). STUDY DESIGN: We retrospectively reviewed 1732 consecutive Japanese patients who underwent gynecologic surgery with lymph node sampling in the National Cancer Center Hospital between January 2004 and April 2017. The pathological diagnosis of LAM was performed by pathologists. Clinicopathological data were obtained from patients' electronic medical records. RESULTS: We found that 0.46% (8/1732) of gynecologic surgical specimens with lymph node sampling showed incidental nodal LAM. The size of the lesions was less than 10 mm, and external iliac and obturator nodes were frequently affected. Although there has been no report of a case of incidental nodal LAM developing pulmonary LAM, we identified the first case of a 36-year-old woman who developed pulmonary LAM 7 years after the diagnosis of incidental nodal LAM. None of the 8 patients had a personal or family history of TSC. CONCLUSIONS: Our case brings attention to the risk of developing subsequent pulmonary LAM. To date, insufficient long-term follow-up data of young patients have hindered us from drawing a definite conclusion that patients with incidental nodal LAM are not at risk for subsequent pulmonary LAM. Future studies should collect and share long-term follow-up data to elucidate the true risk of developing pulmonary LAM in women with incidental nodal LAM.