Glomus tumors of the female genital tract are rare, and to our knowledge, malignant glomus tumors (MGTs) of the female genital tract have not been previously reported. The diagnosis of MGTs is challenging, given their morphologic and immunophenotypic overlap with other common uterine mesenchymal tumors, especially in the absence of classic benign glomus tumor components. Here, we report a case involving a 34-year-old woman with uterine MGT that was positive for smooth muscle actin, h-caldesmon, cyclin D1, and synaptophysin, and negative for desmin. CARMN::NOTCH2 fusion was identified using hybrid capture-based next-generation sequencing. The presence of CARMN::NOTCH2 fusion combined with supportive immunohistochemical and morphologic features validated the diagnosis of MGT. The patient underwent 4 courses of chemotherapy with ifosfamide and pirarubicin. She had no evidence of tumor recurrence or metastasis at 20 months, as confirmed at the latest follow-up visit. The findings from this case highlight the morphologic and immunohistochemical features that are diagnostic of this rare uterine tumor. Furthermore, this report summarizes the morphologic criteria for malignancy and the key points for its differential diagnosis.

Small cell carcinoma of cervix (SCCC) was a highly aggressive tumor with dismal prognosis. Current treatment strategies manifested poor survival outcomes and novel treatment options were needed exploration. We aimed to investigate several prognostic biomarkers for SCCC and conducted a novel risk-score system to predict cancer specific survival (CSS) in early-stage SCCC. Seven cell-cycle proteins were detected by immunohistochemistry in 88 SCCCs. Univariate and multivariate analysis were performed to identify prognostic proteins and establish a predicting model. Total patients were divided into two groups by the median risk-score: the high-risk group and the low-risk group. Logistic regression and Wilcoxon test were used to investigate the association between clinical variables and the risk-score system. Seven cell cycle proteins were overexpressed in SCCC. The expression of CDC20, MAD2L1, MCM2 and BUBR1 were correlated to survival outcomes with P < 0.05. A novel risk-score system consisting of CDC20, MAD2L1 and BUBR1 was significantly an independent prognostic factor for CSS and the high-risk group possessed worse survival (P < 0.001). The c-indexes for clinical model, risk-score system and the combined model were 0.668, 0.718 and 0.727, respectively. The AUCs for these three models were 0.730, 0.775 and 0.823, respectively. Furthermore, we discovered that patients with high-risk scores were inclined to possessing older age, parametrial invasion and higher FIGO stage (IIA vs IA/IB) with P < 0.05. This risk-score system consisting of CDC20, MAD2L1 and BUBR1 presented good discrimination and predictability for SCCC. Novel biomarkers in this study might have some merits in providing guidance of novel treatment strategies for SCCC.

The majority of inflammatory myofibroblastic tumors (IMTs) in the gynecologic tract occur in the uterine corpus and harbor anaplastic lymphoma kinase ( ALK ) rearrangement. Herein, we report 1 uterine IMT case with a novel fusion involving ALK and 1 uterine IMT case with ROS1 rearrangement. The ages of the patients were 56 and 57 yr, respectively. The tumor size was 10.0 and 8.0 cm, respectively. Both patients had stage IB disease. Histologically, the 2 IMT cases had classic morphologic features and predominantly comprised bland spindle cells with hypercellular (fascicular/storiform) and hypocellular (myxoid rich) areas admixed with variably prominent lymphoplasmacytic infiltration. Immunohistochemically, the ALK -rearranged case was positive for ALK , and the ROS1 -rearranged case was positive for ROS1 . Both cases were diffusely positive for desmin. The tumor cells were variably positive for estrogen receptor (1/2 cases, 50.0%) and progesterone receptor (1/2 cases, 50.0%). Targeted RNA sequencing revealed one case each with either a novel CASC15-ALK or TFG-ROS 1 fusion. We identified a novel ALK fusion partner CASC15 in IMT and described the first uterine IMT with a TFG-ROS1 fusion. This study improves our understanding of molecular events in IMT.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm that mainly harbors NCOA1-3 rearrangements with partner genes ESR1 or GREB1. Here, we explored 23 UTROSCTs by targeted RNA sequencing. The association between molecular diversity and clinicopathologic features was investigated. The mean age of our cohort was 43 years (23-65 y). Only 15 patients (65%) were originally diagnosed with UTROSCTs. Mitotic figures ranged from 1 to 7/10 high power fields, of primary tumors and increased from 1 to 9/10 high power fields in recurrent tumors. Five types of gene fusions were identified in these patients, including GREB1::NCOA2 (n=7), GREB1::NCOA1 (n=5), ESR1::NCOA2 (n=3), ESR1::NCOA3 (n=7), and GTF2A1::NCOA2 (n=1). To our knowledge, our group included the largest cohort of tumors with GREB1::NCOA2 fusions. Recurrences were most common in patients with GREB1::NCOA2 fusion (57%), followed by 40% (GREB1::NCOA1), 33% (ESR1::NCOA2), and 14% (ESR1::NCOA3). The recurrent patient who harbored an ESR1::NCOA2 fusion was characterized by extensive rhabdoid features. Both of the recurrent patients who harbored GREB1::NCOA1 and ESR1::NCOA3 had the largest tumor sizes in their own gene alteration groups, and another recurrent GREB1::NCOA1 patient had extrauterine involvement. The GREB1-rearranged patients were of older age, larger tumor size, and higher stage than non-GREB1-rearranged patients (P=0.004, 0.028, and 0.016, respectively). In addition, the GREB1-rearranged tumors presented more commonly as intramural masses rather than non-GREB1-rearranged tumors presenting as polypoid/submucosal masses (P=0.021). Microscopically, nested and whorled patterns were frequently seen in GREB1-rearranged patients (P=0.006). Of note, estrogen receptor expression was weaker than progesterone receptor in all 12 GREB1-rearranged tumors, whereas the similar staining intensity of estrogen receptor and progesterone receptor was observed in all 11 non-GREB1-rearranged tumors (P<0.0001). This study demonstrated that UTROSCTs were present at a younger age in the Chinese population. The genetic heterogeneity of UTROSCTs was correlated with variable recurrence rate. Tumors with GREB1::NCOA2 fusions are more likely to recur compared with those with other genetic alterations.

本文报道1例47岁女性阴道壁赘生物。镜下阴道黏膜鳞状上皮下纤维间质中腺体结节状增生，腺体呈圆形、不规则或分支状。腺上皮呈黏液柱状，无异型，细胞核扁平或矮立方状，位于细胞基底部。免疫组织化学结果：PAX8、MUC6、CA19-9、细胞角蛋白（CK）7、癌胚抗原阳性；雌激素受体、孕激素受体、CK20、p16、嗜铬粒素A和CDX2-88阴性；p53野生型表达。患者赘生物摘除术后6个月，随访预后良好。阴道胃型腺病罕见，需要和胃型腺癌鉴别。

Undifferentiated carcinoma of the gastrointestinal tract has variable rhabdoid features. Expression of switch/sucrose nonfermenting (SWI/SNF) complex subunits is reportedly lost in a portion of cases; however, the prognostic significance of this loss remains unknown. Herein, 30 undifferentiated carcinoma cases were assessed for the expression of 4 SWI/SNF complex subunits (SMARCB1, SMARCA2, SMARCA4, and ARID1A). Tumor origin sites comprised stomach (40.0%), large intestine (20.0%), small intestine (16.7%), lower esophagus and stomach fundus (13.3%), ileocecal junction (3.3%), rectum (3.3%), and pancreas (3.3%). The tumors were composed of epithelioid neoplastic cells arranged in diffuse solid or discohesive sheets, nests, cords, poor cohesive pseudoglandular, and trabecular patterns. Rhabdoid tumor cells were identified in 66.7% (20/30) of cases. In total, 29/30 (96.7%) showed complete loss of at least 1 SWI/SNF subunit: SMARCA4(-)/SMARCA2(-) (11), isolated SMARCA4(-) (2), SMARCA4(-)/SMARCA2 unknown (6), isolated SMARCA2(-) (7), SMARCA2(-)/ARID1A(-) (1), and isolated ARID1A(-) (2). Negative or decreased expression (<= 10% positive) of pan-cytokeratin was observed in 58.6% (17/29) of cases. In addition, 66.7% (20/30) of patients were late-stage (III or IV), and 65.2% (15/23) of stage IIB to IV patients succumbed to the disease at a mean clinical follow-up of 12.7 months. Specifically, patients with loss of SMARCA4 expression had the worst overall survival (P=0.028) and disease-free survival (P=0.006) rates, compared with those with SMARCA4 expression. The loss or decreased expression of epithelial markers is thus common in SWI/SNF complex-deficient undifferentiated carcinoma of the gastrointestinal tract, and loss of SMARCA4 correlates with poor prognosis.

The fumarate hydratase (FH) gene germline mutations cause hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), predisposing carriers to uterine and cutaneous leiomyomas and renal cell carcinoma. In this study, we aim to investigate morphology and the correlation between FH mutation in FH-deficient (FH-d) uterine smooth muscle tumors (uSMTs). We conducted immunohistochemical staining in 161 cases of uSMTs to detect FH deficiency. We identified 52 cases (52/161, 32%) of FH-d, including 34 leiomyomas with bizarre nuclei, 10 uSMTs of uncertain malignant potential (STUMPs), 4 cellular leiomyomas, 3 usual type leiomyomas, and 1 leiomyosarcoma. Patients with FH-d were aged 24-67 years (median, 40 years). The most common FH-d morphological features included staghorn-shaped blood vessels (87%), bizarre nuclei (81%), alveolar pattern edema (65%), macronucleoli surrounded by a halo (65%), cytoplasmic eosinophilic globules (56%), and chain-like distribution of smooth muscle cells (52%). A targeted next-generation sequence was performed in 11 of 52 FH-d tumors. Five cases (5/11, 45%) were found with FH germline mutations, including 4 leiomyomas with bizarre nuclei and 1 STUMP. The median age of patients with germline FH mutation was 30 years. The germline mutations included 3 pathogenic, 1 likely pathogenic, and 1 rare uncertain clinical significance variants. Our results revealed that FH-d uSMTs usually exhibit the distinct morphology features and high frequency of FH germline mutations. The combination of predictive morphology evaluation, FH immunotype, and molecular testing is helpful for the screening of HLRCC in uSMTs. (C) 2022 Elsevier Inc. All rights reserved.

Ewing sarcoma (ES) is a highly malignant tumor that rarely occurs in the uterine cervix. Herein, we report 8 cases with ES arising primarily in the uterine cervix by focusing on clinicopathologic and molecular cytogenetic features and differential diagnoses. Eight cases of cervical ES were diagnosed between February, 2012, and September, 2018. The age of patients ranged from 13 to 47 years. Abnormal vaginal bleeding and lower abdominal pain were the most common symptoms. Histologically, the tumor was composed of uniform, round, and oval cells with a narrow rim of eosinophilic cytoplasm. Fibrous septa were observed between tumor cell nests. The tumors showed brisk mitotic activity and areas of coagulative necrosis. According to immunohistochemical studies, 50% (4/8) of the cases were positive for cytokeratin (AE1/AE3), and 87.5% (7/8) were positive for synaptophysin, which resulted in a diagnostic confusion with small cell carcinoma, primarily when dealing with small cervical biopsies. Molecular testing demonstrated the rearrangement of the EWSR1 gene in all of the 8 cases, which confirmed the diagnosis of ES. Although rare, ES should be considered as indicators of cervical small round cell neoplasms. Molecular analysis may greatly contribute to the final diagnosis of ES occurring in this unusual location.

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.

Background and purpose: Primary female genital system lymphoma (PFGSL) is a rare malignant tumor of female genital system. Its incidence rate is extremely low, and most reports are case reports. This paper aimed to analyze clinical features, diagnosis, treatment and prognosis of PFGSL. Methods: A retrospective analysis of clinical data of 57 PFGSL patients, treated in Fudan University Shanghai Cancer Center from Jan. 2008 to Dec. 2019 was conducted. All the patients met the PFGSL diagnostic criteria. Patients were divided into two groups: single treatment group (33cases) and comprehensive treatment group (24 cases). The median follow-up time was 37.5 months (2.0-85.0 months). Forty out of 57 patients’ local lesions were located in cervix (70%), 13 in ovary (22.8%), 3 in uterus (5.3%) and 1 in vagina (1.8%). According to the International Prognostic Index (IPI) score, 36 patients were low-risk (63.2%) and 21 patients were middle-risk (36.8%). As to lymphoma stage, 36 cases were in stage ⅠE (63.2%), 19 cases were in stage ⅡE (33.83%), and 2 cases were in stage ⅢE (3.5%). Out of 57 patients, the pathologic type of 42 patients were diffuse large B-cell lymphoma (73.7%). Results: Fourteen cases had recurrence, in which twelve were from single treatment group and two from the comprehensive treatment group. The recurrence rate was 24.6% (14/57). Four cases recurred in central nervous system, 1 in eyeball, 4 had loco-regional recurrence and 5 had systemic metastases. The 3-year and 5-year overall survival (OS) rates of 57 patients were 82% and 78%, respectively. The 3-year and 5-year disease-free survival (DFS) rates of 43 patients were 77% and 71%, respectively. The recurrence rate of single treatment group was 36.4% (12/33). In single treatment group, the 3-year and 5-year OS rates were 72% and 64% respectively; the 3-year and 5-year DFS rates were 67% and 57% respectively. In the comprehensive treatment group, the 3- and 5-year OS rate was 95%, and the 3- and 5-year DFS rate was 91%. Multivariate analysis showed that the OS and DFS rates were all significantly correlated with treatment (P<0.05). Conclusion: PFGSL has very low incidence rate and nonspecific clinical manifestations. It is easily misdiagnosed. Gynecological doctors should improve the understanding of this disease and work with chemoradiotherapy doctors to treat this disease.

Chemoresistance is one of the major reasons leading to ovarian cancer high mortality and poor survival. Studies have shown that the alteration of cellular autophagy is associated with cancer cell chemoresistance. Here, we investigated whether the ovarian cancer chemoresistance is associated with the autophagy induced by the inhibitor of DNA binding 1 (ID1). By using gene overexpression or silencing, luciferase assay and human specimens, we show that ID1 induces high autophagy and confers cancer cell chemoresistance. The mechanistic study demonstrates that ID1 first activates the NF-κB signaling through facilitating the nuclear translocation of NF-κB p65, which strengthens the expression and secretion of IL-6 from cancer cells to subsequently activate the signal transducer and activator of transcription 3 (STAT3) through the protein phosphorylation at Y705. We further identified that STAT3 functions to promote the transcription of the activating transcription factor 6 (ATF6), which induces endoplasmic reticulum stress to promote cellular autophagy, granting cancer cell resistance to both cisplatin and paclitaxel treatment. Moreover, we found a significant correlation between the expression of ID1 and ATF6 in 1104 high grade serous ovarian cancer tissues, and that patients with the high expression of ID1 or ATF6 were resistant to platinum treatment and had the poor overall survival and progression-free survival. Thus, we have uncovered a mechanism in which ID1 confers cancer cell chemoresistance largely through the STAT3/ATF6-induced autophagy. The involved molecules, including ID1, STAT3, and ATF6, may have a potential to be targeted in combination with chemotherapeutic agents to improve ovarian cancer survival.

背景与目的:原发女性生殖系统非霍奇金淋巴瘤(primary female genital system lymphoma,PFGSL)是女性生殖系统少见的恶性肿瘤,其发病率低,临床报道较少.探讨PFGSL的临床特征、诊治及预后.方法:回顾分析2008年1月—2019年12月期间于复旦大学附属肿瘤医院就诊的57例PFGSL患者的临床病理学资料.57例患者均符合PFGSL诊断标准,其中单一治疗组33例,综合治疗组24例.中位随访时间37.5个月(2.0～85.0个月).病灶位于宫颈的40例(70.2％)、卵巢13例(22.8％)、子宫3例(5.3％)、阴道1例(1.8％).按国际预后指数(International Prognostic Index,IPI)评分,低危组36例(63.2％),中危组21例(36.8％).按淋巴瘤分期标准,ⅠE期36例(63.2％),ⅡE期19例(33.3％),ⅢE期2例(3.5％).病理学类型为弥漫大B细胞淋巴瘤的患者有42例(73.7％).结果:57例患者中,复发14例,复发率为24.6％(14/57),其中12例位于单一治疗组,2例位于综合治疗组.其中复发位于中枢神经系统者4例,眼1例;局部复发者4例,全身多处转移者5例.57例患者的3年总生存(overall survival,OS)率为82％,5年OS率为78％;3年无病生存(disease-free survival,DFS)率为77％,5年DFS率为71％.单一治疗组复发率为36.4％(12/33),3年OS率为72％,5年O率为64％;3年DFS率为67％,5年DFS率为57％.综合治疗组复发率仅为8.3％(2/24),3、5年OS率为95％;3、5年DFS率为为91％.多因素分析显示,患者的OS率及DFS率均与治疗方式明显相关(P<0.05).结论:原发女性生殖系统淋巴瘤发病率低,临床表现无特异性,极易造成误诊,妇科医师应提高对此病的认识,并参考放化疗科医师意见进行诊治.

Background and purpose: Cervical cancer is the most common gynecological malignancy, and human papillomavirus (HPV) is closely related to cervical cancer/precancerous lesions. Correlation between expressions of HPV16 E7 and FoxM1 was found in cervical tissue biopsy RNA samples and cervical cancer cell lines. This study aimed to discover the potential immunohistochemical markers for cervical squamous cell carcinoma (SCC) and its precursor. We conducted correlation analysis for high-risk HPV (hrHPV) infection versus nuclear protein expressions of transcriptional factor FoxM1 and its downstream target Cdc25B using uterine cervical tissues. Methods: Histological samples obtained from cervical biopsy, conization or hysterectomy were collected from pathology archives of Fudan University Shanghai Cancer Center from 2007 to 2009. Nuclear expressions of FoxM1 and Cdc25B were evaluated by immunohistochemistry and compared with P16 and Ki-67 immunostaining, as well as HPV DNA tests for 23 genotypes. Results: A total of 140 cases were recruited, including normal (n=22), cervical intraepithelial neoplasia (CIN)1 (n=28), CIN2/3 (n=50) and SCC (n=40) specimens. The positive rates of hrHPV, FoxM1, Cdc25B, P16 and Ki-67 in CIN2+ were 100.00% (90/90), 100.00% (90/90), 94.44% (85/90), 85.56% (77/90) and 97.78% (88/90) respectively, and all rates increased with the severity of the disease (Jonckheere-Terpstra test, P<0.0001). FoxM1 and Cdc25B expressions correlated with hrHPV infection, P16 and Ki-67 (Spearman’s correlation test, P<0.0001). The area under the curve (AUC) values of FoxM1 and Cdc25B for diagnosing CIN2+ were 0.850 and 0.822, respectively. Conclusion: The correlation between hrHPV infection and FoxM1 or Cdc25B protein expression in cervical squamous epithelium was confirmed. Nuclear FoxM1 and Cdc25B proteins may be potential biomarkers for CIN2+.

BACKGROUND: Most teratomas are benign and can be removed by surgery, but the gene mutations in teratomas are seldom reported. CASE: A 35-year-old woman was diagnosed with a fallopian tube teratoma mixed with multiple uterine leiomyomas. The right salpingectomy was performed; bipolar electric coagulation was taken from the right oviduct umbrella end to the uterus angle to remove the right fallopian tube. The specimen was removed, and grease-like liquid and hair were observed after the sac wall was cut. A number of blue-purple endometriosis lesions were observed at the rear body of the uterus and Douglas nests. Frozen sections were made from the right fallopian tube with benign cyst teratoma. Histopathological examination showed mature cartilage tissues, well-differentiated squamous epithelia and sebaceous glands, and fibrous adipose tissues. Although fallopian tube tissues appeared benign, an allelic mutation of p53 was found at the nucleotide 469, which resulted in amino acid mutation from valine to phenylalanine. The patient recovered without reproductive obstacles and was pregnant after 8 months. The potential genetic alteration and possible mechanism of teratomas are discussed. CONCLUSION: This is the first reported teratoma case carrying a p53 mutation in a woman who later became pregnant and delivered a healthy infant after successful surgery.