Diagnostic Pathology

A rare case of Alveolar Soft-Part Sarcoma in the Uterine cervix

Abstract Alveolar soft-part sarcoma (ASPS), a rare and malignant neoplasm of soft tissues, comprises less than 1% of all soft-tissue sarcomas and is characterized by distinct histopathological and molecular markers. A 27-year-old female presented with a history of postcoital vaginal bleeding and intermittent bleeding over the preceding month. Imaging studies identified abnormal echogenicity and vascular patterns in the posterior cervical lip. Initial histopathological assessment indicated a perivascular epithelioid cell tumor (PEComa) with TFE3 gene rearrangement; however, subsequent immunohistochemical and molecular analyses corroborated the diagnosis of ASPS. The patient underwent a total laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Postoperative pathology revealed that the residual tumor was confined to the inner third of the cervix, with no evidence of lymphovascular or perineural invasion. The patient did not receive adjuvant therapy and was followed for three months postoperatively, during which no recurrence or metastasis was observed. Given the extreme rarity of ASPS, its diagnosis necessitates meticulous scrutiny by pathologists to inform and guide subsequent therapeutic approaches.

Aspiration biopsy versus dilatation and curettage for endometrial hyperplasia prior to hysterectomy

Abstract Background To compare the diagnostic accuracy of aspiration biopsy and dilatation and curettage (D&C) in patients diagnosed with endometrial hyperplasia prior to hysterectomy. Methods We retrospectively reviewed medical records of 250 patients diagnosed with endometrial hyperplasia by endometrial sampling between July 2003 and March 2020. Endometrial sampling was performed by aspiration biopsy ( n  = 150) or D&C ( n  = 100), followed by hysterectomy within 6 months. Pathological findings of hysterectomy specimens of the two groups were compared to preoperative findings. Results The overall diagnostic concordance between endometrial sampling specimen including D&C and aspiration biopsy, and hysterectomy specimen was 51.0% (51/100) and 41.3% (62/150), respectively. Patients whose preoperative specimen was obtained by D&C were upgraded less significantly than those who underwent aspiration biopsy (21.0% vs 36.7%; P  = 0.008). In particular, significantly fewer patients were upgraded after D&C than after aspiration biopsy in hyperplasia without atypia (12.5% vs 29.0%; P  = 0.028). In addition, when the final pathological upgrade rate to endometrial carcinoma was evaluated between the two methods of endometrial sampling, significantly fewer cases were noted after D&C than after aspiration biopsy (15.0% vs 27.3%; P  = 0.022). Conclusions In our study, D&C more accurately reflected the final diagnosis in patients with endometrial hyperplasia than aspiration biopsy based on the histological examination of hysterectomy specimens. When considering the management strategy for women with an endometrial hyperplasia diagnosis obtained by aspiration biopsy, physicians should consider the significant rate of upgraded diseases with this method of endometrial sampling.

Ovarian mesonephric-like adenocarcinoma arising in serous borderline tumor: a case report with complex morphological and molecular analysis

Abstract Background Mesonephric-like adenocarcinoma (M-LAC) is a rare, recently described tumor occurring in the uterine corpus and ovary, which shares the same morphological and immunohistochemical features with the more common mesonephric adenocarcinoma (MAC), which mostly arises the uterine cervix. Despite the similarities between these tumors, the histogenesis of M-LAC is still disputable. Case presentation Sixty-one-year-old woman presented with an advanced tumor of the left ovary with intraabdominal spread and liver metastases. After receiving 5 cycles of neoadjuvant chemotherapy, she underwent a hysterectomy with bilateral salpingo-oophorectomy, and resection of the liver metastasis, omentum, and appendix. Histologically, the ovarian tumor consisted of two components, whose morphology and immunohistochemical results were typical of either a serous borderline tumor (immunohistochemical positivity for PAX8, WT1, ER and PR) or a mesonephric-like carcinoma (immunohistochemical positivity for PAX8, TTF1 and GATA3). Only the component of the mesonephric-like adenocarcinoma metastasized to the omentum and liver. A molecular analysis with a panel of 271 genes (size 1020 kbp) was performed separately on samples from the borderline tumor, primary ovarian mesonephric-like adenocarcinoma, and liver metastasis. The results showed the clonal origin of all samples, which shared the same KRAS (NM_004985.3:c.34G > T, p.(G12C)) and PIK3CA (NM_006218.2:c.1633G > A, p.(E545K)) somatic mutations. Moreover, in the sample from the primary mesonephric-like carcinoma and its liver metastasis a likely pathogenic somatic MYCN mutation (NM_005378.4:c.131C > T, p.(P44L) was found. In all samples, the deletion of exons 9–10 in the CHEK2 gene was present, which is in concordance with the previously performed genetic testing of the blood specimen which revealed the hereditary CHEK2 mutation in this patient. Conclusions Our result support the theory that at least some mesonephric-like ovarian adenocarcinomas are of Müllerian origin. The serous borderline tumor seems to be a precursor of mesonephric-like adenocarcinoma, which has been proven in our case by both tumors sharing the same mutations, and the presence of cumulative molecular aberrations in the mesonephric-like adenocarcinoma.

Pathological and clinical insights into DICER1 hotspot mutated Sertoli-Leydig cell tumors: a comparative analysis

Sertoli-Leydig cell tumors (SLCTs) are a rare group of sex cord-stromal tumors that account for less than 0.5% of all ovarian tumors. This study aims to compare the pathological and clinical characteristics of SLCTs with and without DICER1 hotspot mutations, highlighting the impact of these genetic variations on clinical manifestation, prognosis, and pathological morphology. A retrospective analysis was conducted on 50 SLCTs. DICER1 RNase IIIb hotspot mutations were detected by the Sanger sequence. Clinical information, such as patients' symptoms, tumor staging, prognosis, and pathological features, such as tumor differentiation and growth patterns, were collected. DICER1 mutation only appears in the intermediate/poorly differentiated SLCTs (35.7%), while none in the well-differentiated SLCTs. The patients with DICER1 mutation had a younger age of onset (17, 15-25) compared to the wild-type group (42, 27-58). Regarding pathological morphology, the mutant group showed a higher probability of having retiform components (40.0%) and cords or ribbon-like arrangement (33.3%). Besides, they exhibited mucinous edematous stroma (80.0%) and hemorrhage (80.0%) more frequently than the wild-type group. The mutant tumor had more mitotic figures. (11/10HPF), higher Ki-67 index (16.1%), and more CD20-positive cell infiltration. Patients of the mutant group were more likely to experience recurrence, and their tumors were more prone to rupture. This study demonstrates that DICER1-mutant and wildtype SLCTs have marked differences in pathological morphology and clinical manifestation. DICER1-mutatant SLCTs display worse prognosis, higher proliferative activity, and potentially more active immune microenvironments, which underscores the importance of genetic testing in diagnosing and assessing the prognosis of SLCTs.

Low grade malignant eccrine spiradenoma of the vulva: case report, review of the literature and discussion about the role of p53 and HPV

Abstract Background Malignant eccrine spiradenoma is one of the rarest sweat-gland tumors. Here, we describe a rare case of low grade malignant eccrine spiradenoma located at the vulva. Case presentation The vulvar lesion was described as a mass measured 3.5 cm and located in the dermis and subcutis with no attachment to the epidermis. The neoplasm was arranged in ragged sheets or solid nodules sometimes with focal necrosis. The tumor cells had hyperchromatism, pleomorphism, and prominent nucleoli with high mitotic index and KI-67 estimated at 70–80%. Conclusions It’s only the fifth case of malignant eccrine spiradenoma localized at the vulva. This is the first time that an HPV genotyping was made in this type of lesion with no HPV found while the p16 expression was diffuse. Moreover, it’s the first time that a p53 mutation is detected by sequencing in this location.

The role of stathmin expression in the differential diagnosis, prognosis, and potential treatment of ovarian sex cord-stromal tumors

Stathmin, a cytosolic microtubule-destabilizing phosphoprotein involved in the regulation of mitosis, is widely expressed in various malignancies and acts as an adverse prognostic factor. Our research analyzed its immunohistochemical expression on a large cohort of ovarian sex cord-stromal tumors, evaluating its potential utility in differential diagnosis, prognosis, and therapeutic application. We examined 390 cases of ovarian sex cord-stromal tumors including 281 adult granulosa cell tumors (AGCT), 5 juvenile granulosa cell tumors (JGCT), 33 Sertoli-Leydig cell tumors (SLCT), 50 fibromas/thecomas (F/T), 11 Leydig cell tumors/steroid cell tumors (LCT/SterCT), 5 sex-cord stromal tumors NOS (SCST-NOS), 3 Sertoli cell tumors (SCT), and 2 sclerosing stromal tumors (ScST). Immunohistochemical analysis was performed using TMAs. Strong expression (> 50%) was observed in all cases of AGCT, JGCT, SLCT, SCST-NOS, SCT and 1 ScST. The other case of ScST exhibited mild expression (5-10%). The negative cases included exclusively F/T and LCT/SterCT, with F/T showing 24% of negative cases and LCT/SterCT comprising 64% of negative cases. The results of our study indicate that stathmin is neither a prognostic marker nor suitable for the differential diagnosis of challenging cases of ovarian sex cord-stromal tumors. However, its predictive value may be theoretically significant, as a decrease in stathmin expression potentialy influences response to chemotherapy treatment.

Metastatic endometrial stromal sarcoma with sex cord and neuroendocrine differentiation harboring a complex gene fusion

Low-grade endometrial stromal sarcoma (LGESS) is a malignant stromal tumor characterized by an indolent clinical course, often with late recurrence or distant metastasis after a prolonged period of remission. These tumors can exhibit various lineage differentiations, making diagnosis challenging, especially in cases of remote recurrence. Most of these tumors are driven by fusions involving the JAZF1, SUZ12, and/or PHF1 genes. A case of metastatic endometrial stromal sarcoma was collected. Clinicopathologic and molecular features were documented. A senior lady with a remote history of an unknown uterine neoplasm. Imaging of the chest revealed bilateral, enlarging pulmonary nodules, which were histologically and immunohistochemically characterized as mesenchymal-like neoplastic cells with sex cord and neuroendocrine differentiation. RNA-based next-generation sequencing identified a complex JAZF1::DLG5::PHF1 fusion, confirming a diagnosis of metastatic endometrial stromal sarcoma with sex cord and neuroendocrine differentiation. This report underscores the propensity of low-grade endometrial stromal sarcoma to metastasize after a prolonged period of remission, in which the tumor exhibited sex cord and unique neuroendocrine differentiation. We also present a complex fusion in which the DLG5 gene acts as a 'filler' to maintain the in-frame configuration.

Clear cell endometrial carcinoma precursors: presentation of two cases and diagnostic issues

Abstract Background The precursors of clear cell endometrial carcinoma (CC-EC) are still undefined. Here, we deal with the diagnostic issues related to CC-EC precursors by presenting a morphological, immunophenotypical and molecular study of two representative cases and discussing the relevant literature. Case presentation Our and previous cases suggest that clear cell endometrial intraepithelial carcinoma (CC-EIC) is a real entity, which may be distinguished from metaplastic/reactive changes and from its serous counterpart. CC-EIC appears associated with atrophic polyps and may be diagnosed based on morphological and immunophenotypical features of CC-EC in the absence of invasive disease. We described a p53-mutant putative precursor characterized by high-grade nuclei in the absence of other distinctive features. Two putative low-grade precursors resembled atypical tubal metaplasia and endometrial intraepithelial neoplasia, although immunohistochemistry could not support their relationship with CC-EC. Conclusions In conclusion, pathologists should be aware of the existence of CC-EIC, since its correct diagnosis may be crucial for a correct patient management. Although several putative earlier precursors have been described, they does not show univocal features that allow their recognition in the common practice. Further studies are necessary in this field.

Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis

Abstract Background This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma. Methods Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined. Results Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p < 0.01). More patients with mesothelin expression showed myometrial invasion of more than 50% (p = 0.028) and positive lymphovascular invasion (p = 0.027). Similarly, more patients with co-expression of mesothelin and CA125 had myometrial invasion of more than 50% (p = 0.016) and positive lymphovascular invasion (p = 0.02). Patients with mesothelin expression and co-expression of mesothelin and CA125 demonstrated worse progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, mesothelin expression and co-expression were poor prognostic factors for PFS (mesothelin expression: hazard ratio [HR] = 2.14, p < 0.01; co-expression: HR = 2.19, p < 0.01) and OS (mesothelin expression: HR = 2.18, p < 0.01; co-expression: HR = 2.22, p < 0.01). Conclusions Mesothelin expression and co-expression might be associated with tumor aggressiveness and poor prognosis in patients with endometrial carcinoma. Persons with mesothelin-expressing endometrial cancers present a particularly high medical unmet need.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay

Abstract Background Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti–PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. Methods and results The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion. Conclusions In conclusion, anti–PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

Primary mucinous ovarian tumors vs. ovarian metastases from gastrointestinal tract, pancreas and biliary tree: a review of current problematics

AbstractBackgroundMaking the distinction between primary mucinous and metastatic ovarian tumors is often difficult, especially in tumors with a primary source from the gastrointestinal tract, pancreas and biliary tree. The aim of the following paper is to provide an overview of the problematics, with a focus on the possibilities of the differential diagnosis at the macroscopic, microscopic and immunohistochemical level.Main bodyThe three main aspects of mucinous ovarian tumors are described in detail, including the comparison of the available diagnostic algorithms based on the evaluation of mostly macroscopic features, characterization of the spectrum of microscopic features, and a detailed analysis of the immunophenotype comparing 20 antibodies with the assessment of their statistical significance for differential diagnosis purposes. Specific features, including Krukenberg tumor and pseudomyxoma peritonei, are also discussed.ConclusionDespite the growing knowledge of the macroscopic and microscopic features of ovarian mucinous tumors and the availability of a wide range of immunohistochemical antibodies useful in this setting, there still remains a group of tumors which cannot be precisely classified without close clinical-pathological cooperation.

Clinical and molecular characteristics of constitutional mismatch repair deficiency syndrome: a case series of five children and appraisal of diagnostic guidelines

A comprehensive immunohistochemical analysis of IMP2 and IMP3 in 542 cases of ovarian tumors

Abstract Background IMP2 and IMP3 are mRNA binding proteins involved in carcinogenesis. We examined a large cohort of ovarian tumors with the aim to assess the value of IMP2 and IMP3 for differential diagnosis, and to assess their prognostic significance. Methods Immunohistochemical analyses with antibodies against IMP2 and IMP3 were performed on 554 primary ovarian tumors including 114 high grade serous carcinomas, 100 low grade serous carcinomas, 124 clear cell carcinomas, 54 endometrioid carcinomas, 34 mucinous carcinomas, 75 mucinous borderline tumors, and 41 serous borderline tumors (micropapillary variant). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher’s Exact test. Results We found IMP2 expression (in more than 5% of tumor cells) in nearly all cases of all tumor types, so the prognostic meaning could not be analyzed. The positive IMP3 expression (in more than 5% of tumor cells) was most common in mucinous carcinomas (82%) and mucinous borderline tumors (81%), followed by high grade serous (67%) and clear cell carcinomas (67%). The expression was less frequent in endometrioid carcinomas (39%), low grade serous carcinomas (23%), and micropapillary variant of serous borderline tumors (20%). Prognostic significance of IMP3 could be evaluated only in low grade serous carcinomas in the case of relapse-free survival, where negative cases showed better RFS (p = 0.033). Conclusion Concerning differential diagnosis our results imply that despite the differences in expression in the different ovarian tumor types, the practical value for diagnostic purposes is limited. Contrary to other solid tumors, we did not find prognostic significance of IMP3 in ovarian cancer, with the exception of RFS in low grade serous carcinomas. However, the high expression of IMP2 and IMP3 could be of predictive value in ovarian carcinomas since IMP proteins are potential therapeutical targets.

Extraovarian Brenner tumor in the uterus: a case report and review of literature

AbstractBackgroundExtraovarian Brenner tumors (EOBTs) are extremely rare and can be observed incidentally in both female and male patients, raising concerns regarding the origin of Brenner tumors.Case presentationA 53-year-old postmenopausal woman presented with a nodular lesion in the left side of the corpus uteri, which was found at a routine health check. Macroscopically, the lesion appeared as a solid nodule with a yellowish-gray cut surface, approximately 6 cm in greatest diameter. Microscopically, the lesion consisted of well-defined epithelial nests and spindled stromal cells. Parenchymal cells expressed CK7, GATA3, CK5/6, 34βE12, and p63. A single layer of cavity-lined cells with umbrella-like shape showed apical Uroplakin III positivity. Stromal cells were positive for SMA, ER, and PR. The final diagnosis was EOBT and the patient was followed for 2 months with no recurrence.ConclusionsWe report here the third case of EOBTs in the uterus. The combination of morphologic and immunohistochemical results supported the involvement of urothelial metaplasia in the development of EOBTs. The similarities between EOBTs and Walthard nests made Müllerian epithelium an attractive candidate as the cellular origin. Changes of tissue structure or sex hormones imbalance may lead to the translocation of Müllerian remnants to distant organs, explaining the pathogenesis of EOBTs.

A case of death of patient with ovarian fibroma combined with Meigs Syndrome and literature review

AbstractOvarian fibroma is the most common benign pure stromal tumor. It has no specific clinical manifestation, most of which are pelvic or adnexal masses. 10-15% of cases with hydrothorax or ascites, after tumor resection, hydrothorax and ascites disappear, known as Meigs Syndrome. The elevated level of CA125 in a few patients was easily misdiagnosed as ovarian malignant tumor. A case of bilateral Ovarian fibroma associated with Meigs Syndrome is reported and the literature is reviewed in order to improve the understanding of the changes and avoid misdiagnosis.

Cutaneous metastasis of carcinomatous component of ovarian carcinosarcoma: A case report and review of the literature

AbstractSkin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification.

Endocrine cell micronests in an ovarian mucinous borderline tumor: a potential diagnostic pitfall for microinvasion

AbstractThe occurrence of endocrine cell micronests in ovarian tumors is rarely reported. To our knowledge, there are only three prior cases reported to date: one occurring in an ovarian mucinous cystadenoma, one in an ovarian mucinous cystadenofibroma, and another in an ovarian mucinous carcinoma with a predominant borderline component. This is a 27-year-old woman that presented with a one-month history of abdominal pain and fullness. Imaging studies revealed a large multiloculated cystic and solid mass measuring 23 cm occupying the majority of the pelvis and abdomen concerning for a primary ovarian malignancy. The patient underwent a right salpingo-oophorectomy with appendectomy. Histologic sections from the ovary showed a multiloculated, cystic and focally solid mass lined by gastrointestinal-type mucinous epithelium with variable degrees of proliferation accounting for greater than 10% of the tumor. In addition to the mucinous epithelial component, there were several foci of bland, monotonous epithelioid cells arranged in solid nests with focal tubular/acinar formation within the fibrous septa and mucinous epithelium. Immunohistochemical studies showed that these cells were positive for cytokeratin, EMA, and synaptophysin, while negative for inhibin. The Ki-67 proliferation index was low (<1%). The presence of endocrine cell nests associated with an ovarian mucinous neoplasm is a rare phenomenon. Whether this represents preservation of endocrine cells in the context of epithelial degeneration or an independent neoplastic component is unclear. Progression related to this endocrine cell proliferation is unlikely and the recognition of this phenomenon holds more diagnostic value than prognostic significance, as it could be confused with microinvasion or sex cord stromal elements.

Comparison of clinical behavior between mucinous ovarian carcinoma with infiltrative and expansile invasion and high-grade serous ovarian carcinoma: a retrospective analysis

Abstract Background The aim of this study was to evaluate the clinicopathological factors and prognosis of mucinous carcinoma (MC) with infiltrative invasion, MC with expansile invasion, and high-grade serous carcinoma (HGSC). Methods Cases of MC and HGSC between 1984 and 2019 were identified. The clinicopathological factors and prognosis of MC with infiltrative invasion or expansile invasion and HGSC were retrospectively compared. Although our present study included cases in our previous studies, we extended observational period when analysis was performed. Accordingly, our study added increased cases and survival analysis was newly conducted. Results After pathological review, 27 cases of MC with infiltrative invasion, 25 cases of MC with expansile invasion, and 219 cases of HGSC were included. MC had a better prognosis in terms of progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than HGSC for all International Federation of Gynecology and Obstetrics (FIGO) stages; however, multivariate analysis did not show statistical differences in PFS and OS. There were no statistically significant differences in PFS and OS for all FIGO stages between MC with infiltrative invasion and HGSC. However, in cases with FIGO stages II to IV, MC with infiltrative invasion had worse PFS (p < 0.01) and OS (p < 0.01) than HGSC. In univariate analysis, MC with infiltrative invasion was a worse prognostic factor for PFS (hazard ratio [HR] 2.83, p < 0.01) and OS (HR 3.83, p < 0.01) than HGSC. Compared with HGSC, MC with expansile invasion had better PFS (p < 0.01) and OS (p < 0.01). Multivariate analysis demonstrated that MC with expansile invasion was a better prognostic factor for PFS (HR 0.17, p < 0.01) and OS (HR 0.18, p = 0.03) than HGSC. Conclusions Compared to the prognosis of HGSC, that of MC was different according to the invasive pattern and FIGO stage. Therefore, future study may be needed to consider this association.

A combination of cytokeratin 5/6, p63, p40 and MUC5AC are useful for distinguishing squamous cell carcinoma from adenocarcinoma of the cervix

Abstract Purpose Squamous cell carcinomas and adenocarcinomas are the most common types of cervical cancer. Compared to squamous cell carcinomas, adenocarcinomas are more common in younger women and have a poorer prognosis. Yet, so far, no useful biomarkers have been developed for these two types of cancer. In the following study, we examined the combination of cytokeratin 5/6, p63, p40 and MUC5AC for distinguishing squamous cell carcinoma (SCC) from adenocarcinoma of the cervix (AEC). Materials and methods A total of 101 SCC and 108 AEC were collected. Immunohistochemical analyses were conducted to determine the expression of CK5/6, p63, p40, CK7 and MUC5AC. One pathologist who was blinded to the patient’s clinical and pathological data interpreted the staining results. Results MUC5AC and CK7 were detected in 81.48 and 82.41% of AEC cases compared to 9.9 and 49.50% of SCC cases ( P  < 0.05); the specificity of MUC5AC was higher than that of CK7 in AEC (P < 0.05). The sensitivity of MUC5AC combined with p40 or p63 was similar to that of CK7, but the specificity was slightly higher than that of CK7 in AEC. Moreover, the expression of MUC5AC was correlated with the degree of tumor differentiation in adenocarcinomas ( P  = 0.036) and was not related to the prognosis of cervical adenocarcinoma and subtypes. Conclusions MUC5AC may be useful as a biomarker for differential diagnoses between squamous carcinoma and adenocarcinoma of the cervix.

Variation of PD-L1 expression in locally advanced cervical cancer following neoadjuvant chemotherapy

Abstract Background High Programmed death ligand 1 (PD-L1) expression are thought to be necessary to PD-1/PD-L1 axis blockades in many tumors. The aim of the study was to explore the variation of PD-L1 expression after neoadjuvant chemotherapy (NAC) in cervical squamous cell carcinoma (SCC) and its clinical implications. Methods A total of 142 paired SCC specimens before and after platinum-based NAC were obtained from cervical cancer patients. The expression of PD-L1 and CD3+, CD4+, CD8+ tumor infiltrating lymphocytes (TILs) was detected by immunohistochemistry and the association between TILs, chemotherapy response, clinical outcome and PD-L1 expression was evaluated. Results The fraction of patients with high PD-L1 expression was significantly increased from 32.4 to 46.5% after NAC (χ2 = 5.897, p = 0.015), while the increase of CD3+, CD4+, CD8+ TILs was not significant. High PD-L1 expression was not associated with CD3+, CD4+, CD8+ TILs before NAC, however CD8+ TILs infiltration was positively associated with high PD-L1 expression after NAC (r = 0.205, p = 0.014). The decreased PD-L1 expression was more observed in patients with clinical response to NAC (χ2 = 6.890, p = 0.009). A longer DFS was seen in patients with decreased PD-L1 expression than those with elevated or stable PD-L1 expression (p = 0.048, 95% CI: 0.091–0.987), while the difference was not significant in multivariate analysis (p = 0.113, 95% CI: 0.108–1.266). Conclusions Cisplatin based chemotherapy can increase PD-L1 expression in cervical cancer. The increased PD-L1 expression and a lymphocyte predominant microenvironment after chemotherapy provide a rational for use of PD-1/PD-L1 axis-inhibitor in the neoadjuvant setting.

Pathologic and genomic characteristics of myoepithelioma-like tumor of the vulvar region: three case reports

Myoepithelioma-like tumor of the vulvar region (MELTVR) is a rare type of soft tissue mesenchymal tumor. While MELTVR exhibits histological characteristics similar to soft tissue myoepithelial tumors, its immunohistochemical and genetic features differ significantly. To date, no comprehensive genomic analysis of this tumor has been conducted. We present the clinicopathological features, imaging characteristics, and immunophenotypes of three patients with MELTVR, along with their genomic characterization through high-throughput sequencing. Immunohistochemical analysis revealed that these tumors were negative for SMARCB1, S-100, CD34, CD31, SMA, Desmin, and Keratin. The Ki-67 proliferation index for tumor cells ranged from 10 to 35%. Genomic analyses showed copy number deletions in the SMARCB1 gene in all three patients. The tumor mutational burden was relatively low, ranging from 1.35 to 4.33. Additionally, two tumors exhibited fusion mutations involving PPP6R3::FHDC1 and MYH9::MYH6, while no fusions involving EWSR1, NR4A3, or FUS were detected. This study reports the first comprehensive genomic analysis of three patients with MELTVR, potentially identifying therapeutic targets for this rare tumor.

Tubulovillous adenoma with high-grade dysplasia of the vulva harboring high tumor mutational burden and cancer-associated mutations: a case report

Abstract Background Vulvar cancer is a rare disease, accounting for approximately 5% of gynecological malignancies. Primary adenocarcinoma of intestinal-type of the vulva or its precancerous lesion is extremely rare, and details regarding its origin, evolution and related genetic mutations are unknown. Treatment options for this cancer have not been defined. Case presentation A 63-year-old Japanese woman came to the hospital because she was aware of a vulvar mass. There was a 1 cm mass on the dorsal side of the vulva, just outside the remains of the hymen. Biopsy revealed suspected adenocarcinoma, and wide local excision was performed. From histopathology and immunohistochemistry, the specimen was diagnosed as tubulovillous adenoma with high-grade dysplasia of the vulva. No other primary lesions were found, and the vulva was considered the primary site. A gene panel test (FoundationOneCDx assay) showed a high tumor mutational burden and mutations in TP53, KEL, RB1, RNF43, PTEN, GNAS, and PIK3CA. Conclusions The current case of tubulovillous adenoma with high-grade dysplasia of the vulva had a variety of cancer-associated mutations, despite being a precancerous lesion. In cases of intestinal-type neoplasms of the vulva, it may be helpful to check tumor mutational burden and gene mutations for treatment selection.

Long non-coding RNA DUXAP8 elevates RCN2 expression and facilitates cell malignant behaviors and angiogenesis in cervical cancer via sponging miR-1297

Abstract Background Cervical cancer (CC) endangers women’s health in the world range. Accumulating studies have revealed the crucial regulatory role of long non-coding RNAs (lncRNAs) in multiple malignancies, including CC. Our study aimed to explore the role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in cervical carcinogenesis. Methods Gene expressions in CC were assessed by RT-qPCR. Function experiments and tube formation assays were performed to evaluate the role of DUXAP8 in CC cells. Subcellular fractionation and FISH assays were conducted to determine the subcellular location of DUXAP8. Luciferase reporter, RNA pull down and RIP assays were conducted to investigate the mechanism of DUXAP8. Results DUXAP8 was notably upregulated in CC cells. Downregulation of DUXAP8 repressed cell malignant behaviors and angiogenesis in CC. Mechanically, DUXAP8 boosted the expression of reticulocalbin-2 (RCN2) through relieving the binding of miR-1297 to RCN2 3’-UTR. Moreover, miR-1297 inhibition and RCN2 overexpression could counteract the inhibitory effects of DUXAP8 knockdown on the malignant phenotypes of CC cells. Besides, enhanced RCN2 expression restored the tumor growth in vivo that was inhibited by DUXAP8 repression. Conclusions DUXAP8 promotes malignant behaviors in CC cells via regulating miR-1297/RCN2 axis. Graphical Abstract

Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm

AbstractWe previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.

Bilateral ovarian fibromas as the sole manifestation of Gorlin syndrome in a 22-year-old woman: a case report and literature review

Abstract Background Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is a rare autosomal dominantly inherited disorder that is characterized by multisystem disorder such as basal cell carcinomas, keratocystic odontogenic tumors and skeletal abnormalities. Bilateral and/or unilateral ovarian fibromas have been reported in individuals diagnosed with NBCCS. Case presentation A 22-year-old female, presented with low back pain, and was found to have bilateral giant adnexal masses on pelvic ultrasonography, which had been suspected to be malignant ovarian tumors. Positron emission tomography/computed tomography showed multiple intracranial calcification and skeletal abnormalities. The left adnexa and right ovarian tumor were resected with laparotomy, and pathology revealed bilateral ovarian fibromas with marked calcification. We recommended the patient to receive genetic testing and dermatological examination. No skin lesion was detected. Germline testing identified pathogenic heterozygous mutation in PTCH1 (Patched1). Conclusions The possibility of NBCCS needs to be considered in patients with ovarian fibromas diagnosed in an early age. Skin lesions are not necessary for the diagnosis of NBCCS. Ovarian fibromas are managed with surgical excision with an attempt at preserving ovarian function. Follow-up regime and counseling on options for future fertility should be offered to patients.

High-expressed ACAT2 predicted the poor prognosis of platinum-resistant epithelial ovarian cancer

Abstract Background Acetyl-CoA acetyltransferase 2 (ACAT2) is a lipid metabolism enzyme and rarely was researched in epithelial ovarian cancer (EOC). Methods ACAT2 expressions were confirmed in two pairs of cell lines (A2780 and A2780/DDP, OVCAR8 and OVCAR8/DDP) from Gene Expression Omnibus database by bioinformatics analysis, and in A2780 and A2780/DDP cell lines by quantitative real-time polymerase chain reaction and western blotting. Tissue samples were stained by immunohistochemistry and scored for ACAT2 expression. The relationships between ACAT2 expression and clinicopathological characteristics were analyzed by χ2 test. The prognosis of ACAT2 was analyzed by the log-rank tests and Cox regression models. Results ACAT2 was remarkably upregulated in the above drug-resistant cell lines by mRNA (all P < 0.05) and protein expression (P = 0.026) than those in sensitive ones. Patients were classified as ACAT2-high (n = 51) and ACAT2-low (n = 26) according to immunohistochemical score. ACAT2 expression had a significantly inverse correlation with FIGO stage (P = 0.030) and chemo-response (P = 0.041). A marginal statistical significance existed in ACAT2 expression and ascites volume (P = 0.092). Univariate analysis suggested that high-expressed ACAT2 was associated with decreased platinum-free interval (PFI) (8.57 vs. 14.13 months, P = 0.044), progression-free survival (PFS) (14.12 vs. 19.79 months, P = 0.039) and overall survival (OS) (36.89 vs. 52.40 months, P = 0.044). Multivariate analysis demonstrated that ACAT2 expression (hazard ratio = 2.18, 95% confidence interval: 1.15–4.11, P = 0.017) affected OS independently, rather than PFI and PFS. Conclusion The expression of ACAT2 in A2780/DDP and OVCAR8/DDP was higher than the corresponding A2780 and OVCAR8. High-expressed ACAT2 was associated with advanced FIGO stage, chemo-resistance, and decreased PFI, PFS and OS. It was an independent prognostic factor of OS in EOC.

Clinicopathological characteristics and prognosis of uterine sarcoma: a 10-year retrospective single-center study in China

Abstract Background Uterine sarcoma is a rare and heterogeneous gynecological malignancy characterized by aggressive progression and poor prognosis. The current study aimed to investigate the relationship between clinicopathological characteristics and the prognosis of uterine sarcoma in Chinese patients. Methods In this single-center retrospective study, we reviewed the medical records of 75 patients with histologically verified uterine sarcoma treated at the First Affiliated Hospital of Xi’an Jiaotong University between 2011 and 2020. Information on clinical characteristics, treatments, pathology and survival was collected. Progression-free survival (PFS) and overall survival (OS) were visualized in Kaplan-Meier curves. Prognostic factors were identified using the log-rank test for univariate analysis and Cox-proportional hazards regression models for multivariate analysis. Results The histopathological types included 36 endometrial stromal sarcomas (ESS,48%), 33 leiomyosarcomas (LMS,44%) and 6 adenosarcomas (8%). The mean age at diagnosis was 50.2 ± 10.7 years. Stage I and low-grade accounted for the majority. There were 26 recurrences and 25 deaths at the last follow-up. The mean PFS and OS were 89.41 (95% CI: 76.07-102.75) and 94.03 (95% CI: 81.67-106.38) months, respectively. Univariate analysis showed that > 50 years, post-menopause, advanced stage, ≥ 1/2 myometrial invasion, lymphovascular space invasion and high grade were associated with shorter survival (P < 0.05). Color Doppler flow imaging positive signals were associated with shorter PFS in the LMS group (P = 0.046). The ESS group had longer PFS than that of the LMS group (99.56 vs. 76.05 months, P = 0.043). The multivariate analysis showed that post-menopause and advanced stage were independent risk factors of both PFS and OS in the total cohort and LMS group. In the ESS group, diagnosis age > 50 years and high-grade were independent risk factors of PFS, while high-grade and lymphovascular space invasion were independent risk factors of OS. Conclusion In Chinese patients with uterine sarcoma, post-menopause and advanced stage were associated with a significantly poorer prognosis. The prognosis of ESS was better than that of LMS. Color Doppler flow imaging positive signals of the tumor helped to identify LMS, which needs to be further tested in a larger sample in the future.

Preoperative and intraoperative assessment of myometrial invasion in patients with FIGO stage I non-endometrioid endometrial carcinoma—a large-scale, multi-center, and retrospective study

Abstract Introduction Myometrial invasion is a prognostic factor for lymph node metastases and decreased survival in non-endometrioid endometrial carcinoma patients. Herein, we explored the mode of myometrial invasion diagnosis in FIGO stage I non-endometrioid carcinoma and evaluated the differences in diagnostic efficiency among intraoperative frozen section (IFS), intraoperative gross examination (IGE), magnetic resonance imaging (MRI), and computed tomography (CT) in clinical practice. Finally, we suggested which test should be routinely performed. Method This was a historical cohort study nationwide with 30 centers in China between January 2000 and December 2019. Clinical data, including age, histology, method of myometrial invasion evaluation (MRI, CT, IGE, and IFS), and final diagnosis of postoperative paraffin sections, were collected from 490 non-endometrioid endometrial carcinoma (serous, clear cell, undifferentiated, mixed carcinoma, and carcinosarcoma) women in FIGO stage I. Results Among the 490 patients, 89.59% presented myometrial invasion. The methods reported for myometrial invasion assessment were IFS in 23.47%, IGE in 69.59%, MRI in 37.96%, and CT in 10.20% of cases. The highest concordance was detected between IFS and postoperative paraffin sections (Kappa = 0.631, accuracy = 93.04%), followed by IGE (Kappa = 0.303, accuracy = 82.40%), MRI (Kappa = 0.131, accuracy = 69.35%), and CT (Kappa = 0.118, accuracy = 50.00%). A stable diagnostic agreement between IFS and the final results was also found through the years (2000–2012: Kappa = 0.776; 2013–2014: Kappa = 0.625; 2015–2016: Kappa = 0.545; 2017–2019: Kappa = 0.652). Conclusion In China, the assessment of myometrial invasion in non-endometrioid endometrial carcinoma is often performed via IGE, but the reliability is relatively low in contrast to IFS. In clinical practice, IFS is a reliable method that can help accurately assess myometrial invasion and intraoperative decision-making (lymph node dissection or not). Hence, it should be routinely performed in non-endometrioid endometrial carcinoma patients.

Histopathological profile of endometrium among peri and post-menopausal women with abnormal uterine bleeding and its correlation with endometrial thickness by transvaginal sonography: a retrospective study

Abstract Background Abnormal uterine bleeding (AUB) is a prevalent clinical concern, particularly in women approaching or beyond menopause. With a myriad of possible etiologies ranging from benign hyperplasia to malignant transformations, accurate diagnosis becomes crucial. This study aims to examine the histopathological patterns of the endometrium in peri- and postmenopausal women presenting with abnormal uterine bleeding and correlate these findings with endometrial thickness (ET) measured by transvaginal sonography (TVS). Methods A retrospective cohort of 307 women aged 40 and above presenting with abnormal uterine bleeding was evaluated over a year period. Clinical history and transvaginal sonography findings were meticulously recorded. Endometrial samples obtained through biopsy or curettage were studied. The correlation between endometrial thickness and histological diagnosis was statistically analyzed using Mann-Whitney U Test and Chi square test, with a focus on distinguishing functional, benign, pre-malignant, and malignant endometrial pathologies. Results Endometrial polyp is the most frequent pattern in both perimenopausal and postmenopausal women. An ET > 11 mm in peri menopausal and postmenopausal women showed a strong association with hyperplasia and malignancy. This suggests that transvaginal sonography, as a non-invasive tool, can significantly guide diagnostic and management strategies when interpreted alongside clinical and histopathological parameters. Conclusion Endometrial thickness serves as a valuable adjunct in the evaluation of abnormal uterine bleeding. However, the gold standard for a conclusive diagnosis is endometrial tissue biopsy. Integrating histopathology with imaging findings enhances diagnostic precision, allowing early identification of precancerous and cancerous lesions, especially in the postmenopausal cohort. Our study concludes that endometrial sample is recommended when ET > 11 mm in perimenopausal and ET > 5 mm in postmenopausal women, particularly when bleeding is persistent.

Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report

Abstract Background Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3’ end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR). Case presentation This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient’s mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown). Conclusions In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.

Complex papillary hyperplasia of the endometrium: an uncommon case report with cytopathological features and diagnostic implications

Complex papillary hyperplasia of the endometrium (CPHE) is a rare benign lesion with overlapping features of malignancy, posing significant diagnostic challenges. This case highlights the importance of multidisciplinary evaluation to avoid misdiagnosis and overtreatment. A 49-year-old premenopausal woman presented with irregular vaginal bleeding. Histopathological examination revealed multifocal lesions confined within and on the surface of endometrial polyps, exhibiting complex papillary structures with bland cytology. Immunohistochemistry showed strong ER/PR positivity and retained PTEN expression, while molecular analysis confirmed the absence of high-risk mutations (PTEN, PIK3CA, TP53, CTNNB1). CPHE requires integration of histopathology, immunohistochemistry, and molecular diagnostics to distinguish it from malignancies. Conservative management is justified in molecularly confirmed cases.

The morphological characteristics and arrangements of cells in the liquid-based cytology preparation of patients with endometrial lesions

The accurate cytological diagnosis of endometrial carcinomas by minimally invasive method has a broad application. There are several articles described the morphological characteristics but not arrangements of endometrial lesion cells on LBC slides. A retrospective study was conducted using 175 endometrial samples obtained by direct negative pressure suction with disposable endometrial sampler. All lesions were diagnosed both cytologically and histologically, and the diagnostic results were compared and analyzed. The cytological diagnoses of polyps, simple or complex hyperplasia, and atypical hyperplasia were highly consistent with the histological diagnosis. The cytological features of polyps and normal endometrium, as well as simple and complex hyperplasia, are the same. Among 82 cases of histologically confirmed adenocarcinoma, the cytological diagnosis were adenocarcinoma cells (46 cases, 56.10%), suspected for adenocarcinoma cells (22 cases, 26.83%), and false negative (14 cases,17.07%). Retrospective reviewing the slide suggest diagnostic parameters such as significantly enlarged nuclei, multistage papillary arrangements, large and numerous nucleoli, and large vacuoles containing neutrophils in the cytoplasm are reliable diagnostic criteria for endometrial carcinoma cells; on the other hand, ignorance of lobulated arrangements and escaped arrangements are the main reasons for missed diagnosis. The cytological diagnosis of endometrial lesions not only depends on the morphological characteristics of cells, but also need careful observations of the cellular arrangements.

Prognostic factors and survival outcomes of immunohistochemically detection based-molecular subtypes of endometrial cancer–analysis of 576 clinical cases

The study aimed to identify distinct molecular subtypes of endometrial cancer (EC) by immunohistochemistry and to analyze their pathological characteristics, independent prognostic factors, and patient survival outcomes for potential clinical applications. 576 patients with preoperative EC confined to the uterus were divided into three subgroups based on the immunohistochemical detection method: MMR-deficiency (MMRd), P53 wild type (P53wt) and P53 abnormal (P53abn). These subgroups were retrospectively analyzed, and their pathological characteristics, prognostic factors and survival outcomes were compared. We identified 401 (69.6%), 123 (21.4%), and 52 (9%) cases of P53wt, MMRd, and P53abn subgroups, respectively. A significant difference was observed in the median age of onset, tumor stage, high-grade tumor differentiation, non-endometrioid carcinoma, myometrial invasion, lymphovascular invasion, the incidence of lymph node metastasis postoperative, and expression of ER and PR receptors among the three groups. Pathological type, lymphovascular invasion, ER and PR expression were identified as independent prognostic factors for disease-free survival (DFS). Additionally, pathological type, lymphovascular invasion, myometrial invasion, and PR expression were recognized as independent prognostic factors for overall survival (OS) in the study cohort. However, the survival outcome for P53abn was the worst, with lymphovascular invasion identified as an independent prognostic factor for DFS. Lymph node status, FIGO stage, and ER expression were identified as independent prognostic factors for OS. The study concludes that immunohistochemical detection-based subtyping of EC holds clinical practicality and can be employed to explore both pathological and clinical prognoses for EC patients.

Pathological characteristics and immune microenvironment of SMARCA4-deficient undifferentiated uterine sarcoma

Abstract SMARCA4- deficient undifferentiated uterine sarcoma (SDUS) is a highly invasive single-gene malignant tumor caused by mutations in the SMARCA4 gene. SDUS has a poor prognosis, with no established treatment strategy at present. Further, there is a lack of relevant research on the role of the immune microenvironment in SDUS worldwide. Here, we report a case of SDUS that was diagnosed and analysed using morphological, immunohistochemical, and molecular detection techniques, along with the analysis of the immune microenvironment. By immunohistochemistry, the tumor cells showed retained INI-1 expression, focal CD10 expression, and loss of BRG1, CK-pan, synaptophysin, desmin, and ER expression. Further, some of the immune cells expressing CD3 and CD8 had infiltrated into the SDUS, but no PD-L1 expression was detected. The multiple immunofluorescent staining results showed that a proportion of the immune cells and SDUS cells expressed CD8/CD68/PD-1/PD-L1. Therefore, our report will help in the diagnostic awareness of SDUS.

A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report

Abstract Background Defect in proofreading exonuclease activity of polymerases epsilon and delta (Pols ε and δ) leads to mutagenesis and genomic instability and has been described in several cancer types. Somatic POLE exonuclease domain mutations (EDMs) have been reported in 7–12% endometrial cancers (ECs) and defined a subgroup of endometrial cancers with ultrahigh somatic mutation frequencies, high tumor infiltrated lymphocytes and favorable outcomes. Case presentation Herein, we presented a novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer. A novel POLE EDM (p.T278K) was found by a 11-gene NGS panel. The MSS status detected by the MSI test was inconsistent with the dMMR status by IHC. The loss of MSH6 expression in the tumor could be interpreted by the two nonsense mutations (p.E1234* and p.E1322*) of the MSH6 gene which may lead to truncated proteins. The T278K mutation was pathogenic identified by a 602-gene NGS panel with 27.3% of C > A substitution, 0.6% of indels, 0.6% of C > G substitution and a high TMB of 203.8 mut/Mb. Conclusions We report an endometrial cancer patient harbored a novel somatic POLE T278K mutation. This mutation was a novel pathogenic POLE EDM should be considered as “ POLE (ultramutated)” in clinical practice for the molecular classification of EC.

Breast metastasis in high-grade endometrial stromal sarcoma (HG-ESS) with BCOR rearrangement: a case report of a novel metastatic site

Abstract Background The ZC3H7B-BCOR fusion gene has recently been described in tumours with kinship to so-called high grade endometrial stromal sarcoma (HG-ESS). This subset of tumour behaves similarly to YWHAE-NUTM2A/B HG-ESS, however, they are both morphologically and immunophenotypically distinct neoplasms. The identified rearrangements in the BCOR gene have been accepted as both the driver and requisite feature in creating a novel sub-entity within the category of HG-ESS. Preliminary investigations into BCOR HG-ESS have shown similar outcomes to YWHAE-NUTM2A/B HG-ESS, with patients typically presenting with high stage disease. Clinical recurrences and metastases to lymph nodes, sacrum/bone, pelvis/peritoneum, lung, bowel and skin have been identified. In this report, we describe a case of BCOR HG-ESS, that is deeply myoinvasive and widely metastatic. Metastatic deposits include a mass in the breast discovered on self-examination; a metastatic site that has yet to be reported in the literature. Case presentation A 59-year-old female underwent biopsy for post-menopausal bleeding, yielding a diagnosis of “low-grade spindle cell neoplasm with myxoid stroma and endometrial glands”, favouring endometrial stromal sarcoma (ESS). She was then referred for total hysterectomy and bilateral salpingo-oophorectomy. The resected uterine neoplasm was both intracavitary and deeply myoinvasive with morphology consistent with that of the biopsy specimen. Characteristic immunohistochemistry (IHC) was noted, and fluorescence in situ hybridization confirmed BCOR rearrangement, supporting a diagnosis of BCOR HG-ESS. A few months postoperatively, the patient underwent needle core biopsy of the breast which revealed metastatic HG-ESS. Conclusions This case highlights some of the diagnostic challenges posed by uterine mesenchymal neoplasms, and exemplifies the emerging histomorphologic, immunohistochemical, molecular and clinicopathologic features of the recently described HG-ESS with ZC3H7B-BCOR fusion. It adds to the body of evidence supporting the inclusion of BCOR HG-ESS as a sub-entity of HG-ESS within the endometrial stromal and related tumours subcategory of uterine mesenchymal tumors, as well as the poor prognosis and high metastatic potential of this tumor.

p16 is superior to Stathmin-1 and HSP27 in identifying cervical dysplasia

Abstract Background The aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas. Methods Fifty cases including benign cervical tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ of the endocervix, invasive endocervical adenocarcinoma, and endometrial adenocarcinoma were selected. Stathmin-1 and HSP27 immunohistochemistry (IHC) were performed for each case and the results were compared to the previously available p16 IHC stains. Results p16 stained positively in 100% of HSIL, endocervical adenocarcinoma in situ, and invasive endocervical cases. Stathmin-1 stained positively in 43% of HSIL and 90% of endocervical adenocarcinoma in situ and all invasive endocervical cases. Stathmin-1 and p16 were negative in all benign cervical samples. Stathmin-1, HSP27, and p16 stained 100% of LSIL cases. HSP27 stained indiscriminately, including 100% of benign cervical tissue. 87% of the endometrial adenocarcinomas stained positively for p16, Stathmin-1, and HSP27. Conclusion p16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix.

Our experience diagnosing 225 patients with cervical glandular lesions: current technologies, lessons learned, and areas for improvement

Abstract Objective To explore the relative sensitivity of different methods for detecting cervical glandular lesions. Methods A total of 225 patients with cervical glandular lesions diagnosed from January 2018 to February 2023 were retrieved from the pathology database of Guangdong Maternal and Child Health Hospital, and their clinicopathological features were reviewed. Results Four human papillomavirus (HPV) genotypes: HPV18, 16, 45, and 52, dominated all glandular lesions, and accounting for 74.10% of HPV-positive tumors. Furthermore, 36.89% of abnormal squamous cells were diagnosed as abnormal based on cytological examinations leading to the detection of cervical glandular lesions; only 16.89% were diagnosed based on the initial detection of abnormal glandular cytology. The most common abnormal cervical screening result was ASC-US on cytology (14.22%), followed by HSIL (11.56%). Only few number of patients were diagnosed with or suspected of having cervical adenopathy via a Pap test (18.22%). Nearly one-third of cervical glandular lesions cases were not detected on the Pap test; but were diagnosed upon cervical biopsy or based on the histological examination of ECC, LEEP, or CKC specimens. The LEEP or CKC biopsy specimens had negative margins in 49 cases (40.83%), while the margins were positive in the other 71 cases (59.17%). Five cases (10.20%) with negative margins still had residual lesions following total hysterectomy, and 19 (26.76%) with positive margins had no residual lesions after total hysterectomy. Conclusion The ability to detect cervical glandular lesions varies for routine HPV genotyping, Pap test, or biopsy/ECC, with different sensitivities and advantages and disadvantages for each method.

Application value of TPAS staining technique for cervical exfoliated cells in cervical cancer screening

Abstract Background Recent studies have shown that tumor cell membranes exhibit lower polarity than normal cell membranes, a characteristic that can be harnessed for cancer diagnosis. TPAS (viscosity-responsive plasma membrane probe), a recently developed staining method using cell membrane polarity probes, may selectively visualize cervical cancer cells by targeting membrane polarity differences, offering a potential new approach for cervical cancer screening.To investigate the diagnostic value of TPAS staining combined with liquid-based thin-layer cytological testing (TCT) and human papillomavirus (HPV) testing in detecting cervical cancer. Methods A total of 100 patients with suspected cervical precancerous lesions from the People’s Hospital of Shaanxi Province between May 2024 and May 2025 were studied. All patients underwent TPAS testing, HPV testing and TCT. Biopsy results were the gold standard for evaluating positivity rates and diagnostic values of the tests, both individually and in combination. Results Among the 100 participants, the positive rates of the tests were as follows: TPAS detection rate was 86.7%, HPV detection rate was 80%, TCT rate 66.7%, and TCT + HPV rate was 35.00%. The combined TPAS + HPV testing showed higher accuracy (72.00%) and sensitivity(70.6%) than TCT + HPV (58.0%)and (54.1%), and the differences were statistically significant ((χ2 = 14.00, P  = 0.0002). Conclusion TPAS combined with HPV testing has high specificity, sensitivity and accuracy, making it a promising approach for cervical cancer diagnosis.

Bilateral, multicystic fumarate hydratase-deficient renal cell carcinoma in patient with hereditary leiomyomatosis & renal cell carcinoma syndrome: A case report and review of the literature

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an autosomal dominant tumor predisposition syndrome with germline fumarate hydratase (FH) pathogenic variants. We describe the unusual clinical presentation, morphologic, and immunohistochemical features of bilateral renal cell carcinoma (RCC) occurring in polycystic kidneys in a 15-year-old male with HLRCC. The patient was diagnosed with bilateral polycystic kidneys at 1-year old. At 8-years old he was diagnosed with cutaneous leiomyomas, prompting germline testing which revealed heterozygous variant (c.1301G > A) in the FH gene. Serial imaging identified interval enlargement of several bilateral renal lesions with solid components. Biopsy of a right solid lesion revealed an oncocytic neoplasm. He underwent left total nephrectomy and right partial nephrectomy, revealing numerous bilateral solid and cystic lesions, some with papillary excrescences. Histologic evaluation revealed large cells with eosinophilic to clear cytoplasm and large nuclei with occasional nuclear pseudoinclusions arranged in variable architectural patterns including papillary, tubular, tubulocystic, microcystic and solid. Large cysts were lined by varying thickness of neoplastic cells. By immunohistochemistry, lesional cells were positive for 2-succinocysteine (2SC), TFE3, PAX8 and AMACR, showed retained SDHB, variable FH, and were negative for Cathepsin K, CK20, and CK7. An RNA fusion panel (including TFE3) was negative. Multiple microscopic renal leiomyomas were also present. Multicystic kidney disease has been previously reported in HLRCC but is not currently included in the WHO classification. Bilateral involvement may mimic polycystic kidney disease and cysts may represent precursor lesions. TFE3-positivity raises the possibility of translocation RCC and is a diagnostic pitfall.

Uterine leiomyoma-like inflammatory myofibroblastic tumour with a rare ALK::SYN3 fusion: a clinicopathologic and molecular analysis

Uterine inflammatory myofibroblastic tumour (IMT) is a relatively rare mesenchymal tumour of the uterus, with recurrence and metastasis rates of 25% and 2%, respectively. As IMT frequently harbours ALK gene rearrangements, some patients may benefit from treatment with tyrosine kinase inhibitors, making accurate identification of this tumour essential. Here, we report the case of a 38-year-old female patient with a tumour clinically resembling uterine leiomyoma. Microscopically, the spindled tumour cells were arranged in orderly intersecting fascicles, accompanied by a sparse infiltrate of inflammatory cells and a notable absence of myxoid matrix. Immunohistochemistry and molecular testing revealed an ALK::SYN3 fusion, suggesting the diagnosis of a uterine leiomyoma-like inflammatory myofibroblastic tumour (UL-like IMT). UL-like IMT is exceedingly rare and can easily be misdiagnosed as smooth-muscle tumours based solely on clinical manifestations and morphology. Therefore, it is recommended that the diagnosis be based on a combination of histopathological features, immunohistochemical markers, and genetic testing results to ensure a comprehensive and accurate assessment.

Clinical pathological and molecular features of 100 patients with gastric-type cervical adenocarcinoma

To investigate the clinicopathological and molecular features, diagnosis, and differential diagnosis of gastric-type cervical adenocarcinoma (GAS). A retrospective analysis was conducted on 100 patients diagnosed with GAS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, from January 2017 to January 2025. Clinicopathological data, histological characteristics, and immunohistochemical expression patterns were analyzed. Targeted next-generation sequencing (NGS) was performed on 11 cases. The cohort comprised 100 GAS patients (median age 50 years). Common clinical manifestations included abnormal uterine bleeding and vaginal discharge, with a significant proportion presenting at advanced FIGO stages (II-IV). Histological features were characteristic, and immunohistochemistry, including markers like MUC6, p16, PAX8, and PAX2, was crucial for diagnosis and differential diagnosis. Molecular analysis of 11 cases revealed a distinct high-frequency somatic mutation profile, including TP53 (72.7%), KRAS (45.5%), SMAD4 (45.5%), CDKN2A (36.4%), PIK3CA (27.3%) and STK11 (18.2%). This profile showed molecular homology with pancreaticobiliary adenocarcinoma and was characterized by microsatellite stable (MSS) and low tumor mutational burden (TMB). Regarding molecular markers and prognosis, aberrant p53 expression was frequent (50%, 37/74) but showed no significant association with clinicopathological factors or survival outcomes (p > 0.05). In contrast, PD-L1 expression (CPS ≥ 1) was significantly associated with higher FIGO stage (p = 0.021) and shorter progression-free survival (PFS) (p = 0.046). GAS is a highly malignant, HPV-independent cervical adenocarcinoma characterized by atypical clinical symptoms and complex histology. This study, representing a large cohort from Northern China, provides comprehensive insights into its clinicopathological and molecular landscape. We characterized its unique molecular profile and, importantly, identified PD-L1 (CPS ≥ 1) as a potential prognostic marker associated with shorter PFS. These findings contribute to improving diagnosis, understanding biological behavior, and identifying potential therapeutic targets for this aggressive subtype.

Two cases of mixed large cell neuroendocrine carcinoma and adenocarcinoma of the cervix: case report and review of the literature

Mixed adenoneuroendocrine carcinoma (MANEC) of the cervix is a rare malignant tumor with high malignancy and poor prognosis, of which large-cell neuroendocrine carcinoma and HPV-independent adenocarcinoma are particularly rare, which have been reported limitedly in the literature. Here, we present 2 cases of MANEC of the cervix and discuss important considerations for diagnosing cervical poorly differentiated carcinoma. we reported two cases of mixed large cell neuroendocrine carcinoma and adenocarcinoma of the cervix, one HPV-independent and one HPV-associated, both with vaginal bleeding. Magnetic resonance imaging showed a mass-like shadow in the cervix, with varying degrees of invasion into the vagina or the lower part of the uterine body. Histologically, the tumors showed two components: solid and glandular areas, with solid areas containing nests of tumor cells and focal necrosis. In the glandular area, one showed gastric-type glandular changes, while the other showed usual-type glands. The solid area expressed CgA (1/2), Syn (2/2), and the glandular area expressed p16 (1/2), Muc-6 (1/2), MSH2 (1/2). We made a diagnosis of mixed adenoneuroendocrine carcinoma (MANEC) of the cervix and performed a literature review to better supplement epidemiological data and assist in developing standardized treatment methods.

Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma

Abstract Background Ovarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). ARID1A mutation is an important pathogenetic mechanism in OCCC that leads to loss of ARID1A expression in approximately half of OCCCs. However, the correlation of MMR status and ARID1A deficiency is unclear. The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency. Methods A cohort of 176 primary OCCC patients was enrolled and review included histological characteristics (nuclear atypia, necrosis, mitosis, stromal hyalinization, and background precursors) and host inflammatory response (tumor-infiltrating lymphocytes, peritumoral lymphocytes, intratumoral stromal inflammation and plasma cell infiltration). Immunohistochemical staining of MLH1, PMS2, MSH2, MSH6 and ARID1A was performed using tissue microarrays. Results dMMR was detected in 10/176 tumors (6 %), followed by MSH2/MSH6 (6/176), MLH1/PMS2 (3/176), and MSH6 (1/176). The average age of patients with dMMR was younger than that of patients with intact MMR (46 y vs. 53 y). Tumors with diffuse intratumoral stromal inflammation remained significantly associated after multivariate analysis. ARID1A expression was absent in 8 patients with dMMR (8/10), which is a significantly higher frequency than that observed in patients with intact MMR (80 % vs. 43.2 %). Conclusions Our study indicates that diffuse intratumoral stromal inflammation of OCCCs is associated with dMMR, with loss of MSH2/MSH6 expression being most frequent. dMMR is strongly associated with the loss of ARID1A expression in OCCC.

A rare case of FH-deficient renal cell carcinoma with signet ring cells features

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a clinically aggressive tumor with high rates of progression and mortality. A wide range of morphological variations has been observed in FH-deficient RCC, initially described as type 2 papillary RCC or unclassified RCC. Here, we report a case of FH-deficient RCC with rare signet ring cells features. The patient was diagnosed with FH-deficient renal cell carcinoma and suspected to have hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. After 4 months, pulmonary metastasis occurred in the patient. We herein describe the first case of FH-deficient renal tumor with signet ring cells features, which expands the morphological spectrum of this tumor. More importantly, this variant can be a diagnostic pitfall, we emphasize that pathologists should consider not only the diagnosis of metastatic signet ring cell carcinoma and ALK rearrangement renal cell carcinoma but also FH-deficient renal cell carcinoma.

Immunohistochemistry staining of Eag1 and p16/Ki-67 can help improve the management of patients with cervical intraepithelial Neoplasia after cold knife conversion

Abstract Background Immunohistochemistry (IHC) is widely used in the management of patients with cervical intraepithelial neoplasia (CIN) but still has many limitations in clinical practice. We analyzed the correlation of new biomarkers with the severity of CIN and follow-up outcomes in patients after conization to improve the management of patients with CIN. Methods IHC staining of Eag1 and p16/Ki-67 was performed on cervical tissue sections from 234 patients with suspected CIN2/3. After a series of follow-ups, including human papillomavirus (HPV) test and thinprep cytologic test (TCT) for 1–2 years, the outcomes were collected. IHC scores of biomarkers and follow-up results were used to analyze the correlation and assess the diagnostic efficiency of biomarkers. Results The IHC staining intensity of Eag1 and p16/Ki-67 was significantly different from that of the CIN1-3 groups (p < 0.05). Eag1 expression scores were significantly different in the distribution between the two follow-up groups (p < 0.001). ROC curves based on the correlations between the follow-up outcomes and the Eag1 scores and IS of p16/ki-67 showed that Eag1 had a greater AUC (0.767 vs. 0.666). Logistic regression analysis of the combination of biomarkers revealed a greater AUC value than any single biomarker. Conclusions Eag1 expression was significantly correlated with CIN grade and follow-up outcomes after conization. IHC staining of combinations of biomarkers of Eag1, p16 and Ki-67 may help us to improve the ability to identify risk groups with abnormal follow-up outcomes after treatment for CIN.

A rare adult case of primary uterine rhabdomyosarcoma with mixed pattern: a clinicopathological & immunohistochemical study with literature review

Abstract Background Rhabdomyosarcomas are aggressive tumors that comprise a group of morphologically similar but biologically diverse lesions. Owing to its rarity, Mixed pattern RMS (ARMS and ERMS) constitutes a diagnostic and therapeutic dilemma. Case Herein is presented a very rare case of mixed alveolar & embryonal rhabdomyosarcoma in the uterus of a 68-year-old woman. The wall of the uterine corpus & cervix was replaced by multiple whitish–yellow, firm nodules, measuring up to 12 cm. Microscopically, the tumor was predominantly composed of round to polygonal cells arranged in nests with alveolar pattern intermingled with hypo- & hypercellular areas of more primitive cells with scattered multinucleated giant cells seen as well. Extensive sampling failed to show epithelial elements. Immunohistochemical staining showed positive staining for vimentin, desmin, myogenin, CD56 & WT-1. However, no staining was detected for CK, LCA, CD10, ER, SMA, CD99, S100, Cyclin-D1 & Olig-2. Metastatic deposits were found in the peritoneum. The patient received postoperative chemotherapy and radiotherapy but died of systemic metastases 3 months after surgery. Conclusion The rarity of this histological tumor entity and its aggressive behavior and poor prognosis grab attention to improving recognition and treatment modalities in adults.

Cytological diagnosis of patients with embryonal rhabdomyosarcoma of the cervix: case report and literature review

AbstractCervical embryonal rhabdomyosarcoma(ERMS) is a rare malignancy. To date, no cases of ERMS diagnosed by cervical cytology have been reported. In this study, we report a case of cervical ERMS identified by a liquid-based cytology test and cell blocks in a 46-year-old postmenopausal woman. We describe the cytological features of ERMS, with the aim of helping cytopathologists recognize this rare cervical tumor.

“Colon”ised by the unexpected: a case of extrauterine epithelioid trophoblastic tumour

Abstract Introduction Extrauterine epithelioid trophoblastic tumour is an exceedingly rare and aggressive form of gestational trophoblastic disease that arises outside the uterus and is characterised by the proliferation of intermediate trophoblastic cells. Unlike more common forms of gestational trophoblastic diseases, such as hydatidiform moles and choriocarcinoma, this entity presents unique diagnostic and therapeutic challenges due to its atypical location and clinical features. Thus far, no documented cases of this entity have been reported in the colon. Case presentation We report the case of a 42-year-old woman who presented with complaints of lower abdominal pain and a palpable mass in the left iliac fossa, initially suspected to be an ectopic pregnancy. On radiological evaluation, a provisional diagnosis of gastrointestinal stromal tumour was made, following which the patient underwent a left colectomy with resection and anastomosis, and the excised specimen on comprehensive histopathological and immunohistochemical analysis was diagnosed as a case of extrauterine epithelioid trophoblastic tumour. However, the patient’s condition deteriorated, and she succumbed to the disease one month after the diagnosis. Conclusion The rarity of extrauterine trophoblastic tumours contributes to limited clinical experience and treatment protocols, resulting in poor prognoses. This case report highlights the importance of histopathological examination for a confirmatory diagnosis, ensuring timely identification and improving patient outcomes.

Genetic analysis for mucinous ovarian carcinoma with infiltrative and expansile invasion and mucinous borderline tumor: a retrospective analysis

Abstract Background Mucinous carcinoma (MC) is a histological subtype of ovarian cancer that has a worse prognosis at advanced stages than the most prevalent histological subtype, high-grade serous carcinomas. Invasive patterns have been recognized as prognostic factors for MCs. MCs with infiltrative invasion were more aggressive than those with expansile invasion. MC with an expansile pattern exhibited behavior similar to mucinous borderline tumors (MBT). However, genomic analysis of invasive patterns is insufficient. This study aimed to compare genetic information between groups with MC and infiltrative invasion (Group A) and those with MC with expansile invasion or MBT (Group B). Methods Ten cases each of MC with infiltrative invasion, MC with expansile invasion, and MBT between 2005 and 2020 were identified. Deoxyribonucleic acid (DNA) extraction from formalin-fixed paraffin-embedded tissues was performed, and cases with DNA fragmentation or the possibility of DNA fragmentation were excluded. Mutant base candidates and tumor mutation burden (TMB) values (mutations/megabase) were calculated. Results After assessing the quality of purified DNA, seven cases of MC with infiltrative invasion, five cases of MC with expansile invasion, and three cases of MBT were included. More patients in group A experienced recurrence or progression (p < 0.01) and died of disease (p = 0.03). Moreover, the TMB value was statistically higher in group A than in group B (p = 0.049). There were no statistical differences in the incidence of the mutations of KRAS, TP53, and CREBBP. KRAS, TP53, and CREBBP mutations were discovered in 8/15 (53.3%), 6/15 (40.0%), and 5/15 (33.3%) cases, respectively. Conclusions Genetic analysis revealed that Group A had higher TMB than Group B. Therefore, this result might be useful for future treatment.

Synchronous thyroid cancer and malignant struma ovarii: concordant mutations and microRNA profile, discordant loss of heterozygosity loci

Abstract Background Struma ovarii is an unusual ovarian teratoma containing predominantly thyroid tissue. Less than 10% of cases undergo malignant transformation in the thyroid tissue and are considered malignant struma ovarii (MSO). MSO have been reported with concurrent thyroid lesions, but molecular data is lacking. Case presentation A 42-year-old female developed MSO and synchronous multifocal subcentimeter papillary thyroid carcinoma (PTC). The patient underwent a salpingo-oophrectomy, thyroidectomy, and low-dose radioactive iodine ablation. Both the thyroid subcentimeter PTC and MSO were positive for BRAF V600E mutation, and microRNA expression profiles were similar across all tumor deposits. However, only the malignant component demonstrated extensive loss of heterozygosity (LOH) involving multiple tumor suppressor gene (TSG) chromosomal loci. Conclusions We present the first reported case of MSO with synchronous multifocal subcentimeter PTC in the thyroid containing concordant BRAF V600E mutations and resulting with discordant LOH findings. This data suggests that loss of expression in tumor suppressor gene(s) may be an important contributor to phenotypic expression of malignancy.

A comprehensive immunohistochemical analysis of 26 markers in 250 cases of serous ovarian tumors

Abstract Background We examined a large cohort of serous tubo-ovarian tumors with 26 immunohistochemical markers, with the aim to assess their value for differential diagnosis and prognosis. Methods Immunohistochemical analyses with 26 immunomarkers were performed on 250 primary tubo-ovarian tumors including 114 high grade serous carcinomas (HGSC), 97 low grade serous carcinomas (LGSC), and 39 serous borderline tumors (micropapillary variant, mSBT). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher’s Exact test. Results We found significantly different expression of p53, p16, ER, PR, PTEN, PAX2, Mammaglobin, RB1, Cyclin E1, stathmin, LMP2, L1CAM, CD44, and Ki67 in HGSCs compared to LGSCs. No significant differences were found between LGSC and mSBT. None of the other included markers (PAX8, ARID1A, HNF1B, Napsin A, CDX2, SATB2, MUC4, BRG1, AMACR, TTF1, BCOR, NTRK) showed any differences between the investigated serous tumors. Regarding the prognosis, only PR and stathmin showed a statistically significant prognostic meaning in LGSCs, with better overall survival (OS) and recurrence-free survival (RFS) in cases positive for PR, and worse outcome (RFS) for stathmin. None of the study markers showed prognostic significance in HGSCs. Conclusion We provided an extensive immunohistochemical analysis of serous ovarian/tubo-ovarian tumors. Although we found some differences in the expression of some markers in HGSCs compared to LGSCs, only p53, p16, and Ki67 seem to be useful in real diagnostic practice. We also suggested the best discriminative cut-off for Ki67 (10% of positive tumor cells) for distinguishing HGSC from LGSC. We found prognostic significance of PR and stathmin in LGSCs. Moreover, the high expression of stathmin could also be of predictive value in ovarian carcinomas as target-specific anti-stathmin effectors are potential therapeutic targets.

Correlation analysis of risk factors for cervical lymphatic metastasis in papillary thyroid carcinoma

Abstract Objective This study aims to identify and analyze the risk factors associated with Cervical Lymph Node Metastasis (CNM) in Papillary Thyroid Carcinoma (PTC) patients. Methods We conducted a retrospective study involving the clinicopathological data of 2384 PTC patients admitted to our hospital between January 2016 and December 2020. All relevant data were statistically processed and analyzed. Results The related risk factors for Central Lymph Node Metastasis (CLNM) were gender (male), age (≤ 30 years old), tumor lesion size (> 0.855 cm), and multifocal tumor foci. The ROC curve revealed that the critical value for predicting CLNM based on tumor lesion size was 0.855 (sensitivity = 57.9%, specificity = 69%, AUC = 0.269, and P < 0.05). Lateral Lymph Node Metastasis (LLNM) was positively correlated with tumor diameter. Specifically, the LLNM rate increased with the tumor diameter. LLNM occurrence was significantly higher in zones II, III, and IV than in zones I and V. Although the BRAF gene mutation detection assay has certain clinical benefits in diagnosing PTC and LLNM, no statistically significant difference was found in its relationship with central and lateral neck lymph node metastases (P = 0.741). Conclusion Our findings revealed that CLNM is associated with gender (male), age (≤ 30 years old), tumor lesion size (> 0.855 cm), and multiple tumor lesions in PTC patients. Central Lymph Node Dissection (CLND) is recommended for patients with these risk factors. On the other hand, preoperative ultrasound examination, fine-needle pathological examination, and genetic testing should be used to determine whether Lateral Cervical Lymph Node Dissection (LLND) is needed.

Ovarian mucinous tumors with mural nodules: immunohistochemical and molecular analysis of 3 cases

Abstract Background Primary ovarian mucinous tumors with mural nodules are very rare. The histogenesis of the mural nodules remains unclear. Methods We investigated the clincopathological and molecular features in 3 cases with mural nodules. Results Patient 1 was diagnosed as mucinous carcinoma with mural nodules of anaplastic carcinoma that was composed of CK+ and CK7+ spindled cells and polygonal cells with marked pleomorphism. Aberrant p53 staining was found in the mural nodules rather than in the mucinous components. A concordant KRAS mutation (c.35G > A p.G12A) was identified in both mucinous tumors and mural nodules. She died of disease at 44 months. The mural nodule in patient 2 was interpreted as a sarcoma, no other specified. The uniform short spindle cells were separated by abundant myxoid matrix. They were CD10 + , CCND1-, SMA-, and negative for break-apart BCOR, PHF1, and JAZF1 FISH assay. The adenocarcinomatous component harbored LOH at D18S51 and FGA loci while the sarcomatous component had LOH at D19S433. She had lung metastasis at 18 months and was alive without evidence of disease for 40 months. Patient 3 harbored multiple mural nodules that were composed of vimentin+, focal CK+, atypical spindle cells. A diagnosis of sarcoma-like mural nodules was rendered. She was alive with no evidence of disease for 13 months. No hotspot mutant AKT1, KRAS, HRAS, and PI3KCA alleles were found in patients 2 and 3. Conclusions Mural nodules with anaplastic carcinoma or with true sarcomas may represent the dedifferentiation form of mucinous tumors or collision tumors, respectively. The worrisome histology in sarcoma-like mural nodules necessitates meticulous treatment for these patients.

Heterochronic pelvic high-grade myxoinflammatory fibroblastic sarcoma and uterine endometroid carcinoma harboring common gene mutations: a rare case report with genomic analysis

This report presents a rare case involving an extreme epithelial-to-mesenchymal transition, in which a specific type of sarcoma developed heterochronically as a recurrence of endometrioid carcinoma. A female in her 50's presented with abnormal genital bleeding, and an endometrial biopsy revealed endometrioid carcinoma. Following the diagnosis of stage IA endometrioid carcinoma according to the 2008 classification system of the International Federation of Gynecology and Obstetrics, a robot-assisted simple hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node navigation surgery were performed. Six months postoperatively, a tumor mass developed in the pelvis. A transrectal needle biopsy revealed spindle cell proliferation, and pelvic tumor resection was conducted for diagnostic therapy. The patient received no adjuvant chemotherapy or radiotherapy after the second surgery and remained free of tumor recurrence for 8 months. The resected yellowish solid tumor mass, measuring 16 × 12 × 9 cm, exhibited hemorrhage, necrosis, and cystic degeneration and was composed of fascicular proliferation of spindle tumor cells showing nuclear pleomorphism and frequent mitotic figures within a myxoid and inflammatory stroma. No epithelial component or organoid patterns were observed. Immunohistochemically, the tumor cells were positive for factor XIIIa, CD10, and cyclin D1, but negative for keratins (AE1/AE3 and CAM5.2) and other specific markers, supporting a diagnosis of high-grade myxoinflammatory fibroblastic sarcoma (MIFS). Genomic analysis revealed identical mutations in PTEN, PIK3R1, CDKN2 A, and TP53 in both the primary uterine endometrioid carcinoma and heterochronic pelvic MIFS. An integrative approach involving histology, immunohistochemistry, and genomic analysis is critical for elucidating the pathogenesis of rare pelvic and uterine tumors.

High-grade uterine endometrial stromal sarcoma harboring GLI1 and MDM2/CDK4 co-amplifications

GLI1 gene alterations including fusions and amplifications compromise a subset of malignant mesenchymal tumors exhibiting characteristic monomorphic nested morphology and frequent S100 positivity, which mimic glomus tumors or well differentiated neuroendocrine tumors. We report four high-grade uterine endometrial stromal sarcomas (ESS) harboring GLI1 and MDM2/CDK4 co-amplifications with a median age of 51.5 years (range 43 ~ 72 years). Histologically, tumors showed a heterogenous morphology, including ovoid to spindle cells, showing nested/nodular arrangement (4/4). Myxoid background was observed at least partially in 4 tumors with prominent capillary networks. Mitoses index was 2 to 20/10 HPF (median 9.5/10 HPF). Immunochemically, tumors showed diffuse staining of CD10 (3/4) with frequently positive CyclinD1(2/4 tested) and mostly negative S100 protein (3/4). Next-generationsequencing (NGS) studies revealed GLI1 and MDM2/CDK4 co-amplification in all cases (4/4) and GLI1 fusion in 1 case (1/4), which were validated by fluorescence in situ hybridization (FISH) analysis. BCOR fusions were firstly identified with GLI1 and MDM2/CDK4 co-amplification in 2 cases (2/4). Copy number (CN) segmentation data showed GLI1 co-amplified cases present generally a single peak at the 12q13.3-15 locus. Follow-up (range:3 to 112 months; median 37.5 months) showed recurrence and/or metastasis in all cases (4/4), in which 1 patient developed lungs and liver metastasis. Relapse-free survival (RFS) analysis showed similar median RFS between GLI1 co-amplified HGESS and GLI1 non-amplified HGESS groups, which were shorter than LGESS group. Unusual clinicopathologic features of these HGESS with GLI1 and MDM2/CDK4 co-amplification mimicked other neoplasms, which caused significant diagnostic challenge and pitfalls. However, identification of GLI1 alterations in these tumors is beneficial for diagnosis and potential use of targeted GLI1 inhibitors.

Successful neoadjuvant chemotherapy plus sintilimab for locally advanced cervical cancer: case series and review of the literature

Abstract Background The locally advanced cervical cancer (LACC) of FIGO stage IB3-IIA2 is characterized by large local mass, poor prognosis and survival rate. Tumor response to neoadjuvant chemotherapy for LACC, utilized as a surrogate endpoint, is urgently needed to improve. Given that the antitumor immune response can be suppressed by programed death-1 axis, the treatment paradigm of neoadjuvant chemotherapy combined with immunotherapy has been explored as one of the prognostic treatments in a variety of solid carcinoma. So far, the application of sintilimab, a domestic immune checkpoint inhibitor, combined with neoadjuvant chemotherapy is still limited in LACC, especially in large lesions. Case description We present three postmenopausal women diagnosed with FIGO stage IB3-IIA2 cervical squamous cell carcinoma with lesions larger than 5 cm. Demographic, clinical, histopathological, laboratory and imaging data were record. At the completion of the neoadjuvant therapy with paclitaxel plus carboplatin combined with sintilimab, all patients underwent hysterectomy. After neoadjuvant treatment, a pathologic complete response in case 1 and partial responses in case 2 and case 3 were achieved, and neither patient showed any relapse during the follow-up period of 16 to 22 months. Conclusions This report provide evidence to support the combination of sintilimab with neoadjuvant chemotherapy in cervical cancer, which has yet to be validated in prospective studies. More clinical data are needed to verify the effectiveness of the combined regimens. This literature review also collected studies involving potential predictors of response to NACT and immunotherapy, which would be helpful in stratifying patients for future trials.

Myoepithelioma-like tumor of the vulvar region: a case report in China and review of the literature

AbstractBackgroundMyoepithelioma-like tumor of the vulvar region (MELTVR) is a recently described mesenchymal neoplasm which typically arising in vulvar regions of adult women.Case presentationHere we report a case of a 65-year-old woman who presented with a 6-year history of subcutaneous mass in the vulvar region. The mass had recently increased in size continuously. Histologically, the tumor cells had an epithelioid to spindled shape. Epithelioid tumor cells proliferated singly or in a loosely cohesive manner with myxoid areas, while spindled tumor cells grew in diffuse sheets or storiform arrangements mainly in nonmyxoid areas. Immunohistochemically, the tumor cells were positive for vimentin, epithelial membrane antigen, calponin, and were partially mild to moderate positive for estrogen receptor, but completely negative for S100 protein, glial fibrillary acidic protein, CD34, desmin, SMA and cytokeratin. INI1/SMARCB1 expression was deficient.EWSR1andFUSgenes were intact tested by fluorescence in situ hybridization analysis. Based on these findings, we diagnose this case as MELTVR. The patient remained relapse-free after the lesion was widely excised during 8 months follow-up.ConclusionsThis disease should be included in the differential diagnostic list of vulvar tumors with epithelioid to spindled morphology. Recognition of its histopathological features and immunohistochemical reactivity will help to understand the tumor better.

Primary immature teratoma in the liver with growing teratoma syndrome and gliomatosis peritonei: a rare case report

Abstract Background Primary liver immature teratoma is extremely rare and only 4 cases have been reported, let alone with growing teratoma syndrome (GTS) and/or gliomatosis peritonei (GP). Case presentation Here, we report a case of a 44-year-old female presenting with progressive abdominal distension and elevated serum alpha fetal protein (AFP) level. CT/MRI scans revealed a large cystic-solid mass in the right lobe of the liver, accompanied with implant or metastasis in the abdominal cavity. Pathologic examination at biopsy suggested immature teratoma. After 4 cycles of chemotherapy, an MRI showed a slight increase in tumor size. Therefore, surgical resection of the right lobe of the liver was performed. The final histological diagnosis was a mature teratoma (tumor size 28 cm × 14 cm × 13 cm), with no residual immature component, and the diagnosis of GTS was considered. The patient continued to receive 2 courses of postoperative chemotherapy. An abdominal CT scan revealed innumerable miliary nodules in bilateral adnexal areas 2 months after surgery. Histologically, large numbers of mature glia were observed, supporting the diagnosis of GP. Conclusions We report for the first time a case of primary liver immature teratoma with GTS and GP in an adult. Longer follow-up is needed to assess definitive efficacy.

Accuracy of HPV E6/E7 mRNA examination using in situ hybridization in diagnosing cervical intraepithelial lesions

Abstract Background The consistency of pathologists in the diagnosis of cervical intraepithelial neoplasia (CINs) is not ideal, especially between low- and high-grade squamous intraepithelial lesions (LSIL and HSIL). This study was aimed to explore efficient strategies for the grading of CINs. Methods The medical records of patients with high risk human papillomavirus (HR-HPV) infections who had underwent cervical biopsy or conization from April 2018 to April 2019 in Beijing Chao-Yang Hospital were collected and examined. The HR-HPV E6/E7 mRNA in the tissues of patients with CINs was detected using RNAscope chromogenic in situ hybridization (RISH). Immunohistochemistry (IHC) was performed to evaluate the expression of p16INK4a (P16) and Ki67. Results HR-HPV E6/E7 mRNA signals were detected in 3/27 (11.1 %) of CIN 1, and in 32/33 (97.0 %) of CIN 2/3. Most of the staining patterns (27/32, 84.4 %) had a full-thickness epithelial layer staining with weak-to-strong nuclear and cytoplasmic dot-like signals in CIN 2/3, and there were also few special staining patterns that were significantly different from the others. A number of indicators were compared between LSIL and HSIL. There were statistically significant differences in E6/E7 mRNA, p16, Ki67 and cytology between the two groups ( P  < 0.05). According to the logistic regression analysis, merely E6/E7 mRNA positivity was significantly associated with CIN2/3 (OR: 52.53, 95 % CI, P  < 0.05). In the detection of CIN 2/3, the sensitivity and specificity of HPV E6/E7 mRNA alone was not significantly inferior to that of its different combinations with Ki67, p16 and cytology (all, P  > 0.05). Conclusions RISH is efficient in grading of CINs. The HPV E6/E7 mRNA expression might reflect the phase HPV infections, and its positive pattern might predict the development direction of CINs, providing the possibility to realize more accurate treatments for patients.

STAT3 exerts pro-tumor and anti-autophagy roles in cervical cancer

Abstract Background STAT3 plays an important role in cervical cancer. LC3B, the most potential molecular biomarker of autophagy that may promote or inhibit cancer progression, can be downregulated by STAT3. However the role of STAT3 in the autophagy of cervical cancer remains unclear. Purpose This study aimed to evaluate the relationship between STAT3 and LC3B in protein level, and verify whether STAT3 promotes proliferation, migration and plate colony formation by inhibiting autophagy of cervical cancer cells through bcl2-beclin1 axis. Results STAT3 was overexpressed in cervical cancer tissues, and negatively correlated with the expression level of LC3B. STAT3 knockout or knockdown significantly increased the autophagy level and decreased proliferation, migration, plate colony formation and subcutaneous tumorigenesis of cervical cancer cells in vitro and in vivo. STAT3 is known to mediate autophagy through Bcl2-Beclin1 complex. Bcl2 was positively whereas Beclin1 negatively correlated with STAT3 expression, indicating that Bcl2-Beclin1 complex involved in this transition. Conclusion STAT3 may upregulate the autophagy level of cervical cancer cells through the Bcl2-Beclin1 axis. This indicates that STAT3 may be an important prognostic and therapeutic target for cervical cancer.

Molecular subtyping of endometrial cancer via a simplified one-step NGS classifier, ARID1A and ZFHX4 mutations help further subclassify CNL/MSI-H patients

Abstract Background Molecular subtyping has changed the prognostic stratification and therapeutic guidance for patients with endometrial cancer (EC). However, simultaneous application of sanger sequencing and immunohistochemistry under ProMisE criteria may be time- and tissue-consuming. This study attempted to measure subtype-specific biomarkers by one-step next-generation sequencing (NGS) resulting in a shorter turnaround time and less requirement of tissue samples. Methods FFPE samples from 233 EC patients were retrospectively collected. Overall survival (OS) information was available for 131 patients with a median follow-up of 66 months. Genomic DNA was extracted and subjected to a one-step NGS panel including TP53, POLE and MSI measurement. Further comprehensive genomic analyses were performed on DNA from MSI-H and copy number low (CNL) subtypes. Results The molecular typing ratio of the 233 patients was 8.15% for POLE subtype, 18.88% for MSI-H subtype, 11.59% for copy number high (CNH) subtype and 61.37% for CNL subtype. The 10-year OS and disease-specific survival (DSS) rate was 100% in POLE subtype, while only 33.51% and 39.69% in CNH subtype. In patients with CNL and CNL/MSI-H subtypes, ARID1A and ZFHX4 mutations were significantly associated with worse prognosis respectively. Conclusion This simplified one-step NGS panel can effectively subgroup EC patients into four prognostically different subtypes. New biomarkers are able to potentially refine the classification of patients with CNL/MSI-H subtypes into groups with distinct clinical outcomes.

SOX17/PAX8 dual immunohistochemical expression in the diagnosis of Müllerian carcinomas

Abstract Background Metastatic Müllerian carcinomas, including endometrial and ovarian adenocarcinomas, are challenging to diagnose due to factors like similar malignancies, insufficient clinical history, multiorgan dissemination, and small tumor specimens. Immunohistochemistry (IHC) stains are commonly used to identify these cancers. PAX8 is a widely used IHC marker with varying sensitivity levels for different types of gynecologic carcinomas. SOX17, a transcription factor involved in embryonic differentiation and development, has high specificity for ovarian and endometrial carcinomas but is weakly expressed in other epithelial neoplasms. Methods . 56 endometrial carcinomas cases,56 ovarian cancer case and 56 cases of non-gynecological cancer, were subjected to immunohistochemical (IHC) analysis of SOX17 and PAX8. Results In endometrial carcinomas, PAX8-high/SOX17-high co-expression strongly favored endometrioid histology (90% vs. 68.8%, p  = 0.04), while ovarian high-grade serous carcinomas commonly expressed PAX8 (78.9% high) with heterogeneous SOX17 expression (47.4% high). Notably, double-negative PAX8/SOX17 status completely excluded Müllerian origin in metastases from colorectal, breast, and pulmonary primary tumors (100% specificity), though renal (all PAX8+) and thyroid neoplasms (63.6% PAX8+) required additional markers for distinction. Statistical analyses confirmed subtype-specific trends ( p  < 0.05 for all applicable comparisons) with loss of SOX17 associated with aggressive histotypes (25% negative in serous versus 10% in endometrioid). Conclusions Müllerian carcinomas can be distinguished from non-gynecological metastases using PAX8 and SOX17 immunohistochemistry, with PAX8-high/SOX17-high patterns strongly indicating endometrioid differentiation and double-negative results excluding gynecologic origin with consistency in colorectal, breast, and pulmonary carcinomas. Renal and thyroid carcinomas are the diagnostic traps on the basis of PAX8 expression and require additional markers for final classification in metastatic workups.

Mutational analysis and protein expression of PI3K/AKT pathway in four mucinous cystadenocarcinoma of the breast

Cytological diagnosis of dysgerminoma associated with pregnancy via peritoneal effusion analysis: a case report

Dysgerminoma, a uncommon malignant neoplasm originating from primitive ovarian germ cells, is exceptionally rare during pregnancy. While several studies have documented dysgerminoma diagnosis via peritoneal effusion cytology, no cases identified during pregnancy have been reported to date. This study presents the first reported case of dysgerminoma diagnosed through peritoneal effusion cytology in a pregnant patient. A 27-year-old pregnant woman presented to our hospital with an early intrauterine pregnancy and a right adnexal mass detected on B-ultrasound at a local hospital. Cytological evaluation of the peritoneal effusion revealed a polymorphic cell population dominated by discrete large tumor cells mixed with reactive lymphocytes and histiocytes. These tumor cells exhibited moderate to abundant eosinophilic or vacuolated cytoplasm with well-defined borders. Most had round or oval nuclei with high nuclear-to-cytoplasmic (N/C) ratios, granular chromatin with uneven distribution, and distinct nucleoli visible in some cells. While a subset of large cells showed irregular nuclear contours and angular appearances. Immunocytochemistry (ICC) results of cell block (CB) showed positive staining for SALL4, CD117, OCT3/4, PLAP, and D2-40, but negative staining for LCA, CD30, EMA, CK-P, CR, and SF-1. The final diagnosis of dysgerminoma was made by integrating peritoneal effusion cytology, cell block analysis, and ICC results. The patient underwent right adnexectomy and subsequently delivered a healthy female infant at 36 + 4 weeks of gestation. Four-year postoperative follow-up showed no evidence of disease recurrence. This report describes the cytopathological features of dysgerminoma in peritoneal effusion, specifically the presence of discrete large tumor cells with hyperchromatic nuclei and prominent nucleoli. Cytopathologists should maintain a high index of suspicion for this entity, particularly in young patients, and adopt a comprehensive diagnostic approach including cytomorphological assessment, CB examination, and immunocytochemical analysis to make an accurate diagnosis.

Complex immunohistochemical and molecular study on 5 cases of ovarian juvenile granulosa cell tumors reveals a consistent alteration in the PI3K/AKT/mTOR signaling pathway

Juvenile granulosa cell tumor (JGCT) of the ovary is a rare tumor with distinct clinicopathological and hormonal features primarily affecting young women and children. We conducted a complex clinicopathological, immunohistochemical, and molecular analysis of five cases of JGCT. The immunohistochemical examination was performed with 32 markers, including markers that have not been previously investigated. Moreover, DNA next-generation sequencing (NGS) and PTEN methylation analysis was performed. We found the expression of calretinin, inhibin A, SF1, FOXL2, CD99, CKAE1/3, ER, PR, AR in all cases. WT1 was expressed in one case. Conversely, the expression of p16, OCT3/4, SALL4, GATA3, Napsin A, SATB2, MUC4, TTF1, and CAIX was completely negative. All tumors showed the wild-type pattern of p53 expression. Regarding predictive markers, all tumors were HER2 negative and did not express PD-L1. Mismatch repair proteins (MMR) showed no loss or restriction of expression, similarly to ARID1A, DPC4, BRG1, and INI1. The molecular analysis revealed AKT1 internal tandem duplication in two tumors. Two other cases exhibited mutations in TERT and EP400 and both developed recurrence. All AKT1-wild type tumors exhibited immunohistochemical loss of PTEN expression. However, no mutations, deletions (as assessed by CNV analysis), or promoter hypermethylation in the PTEN gene were detected. The results of our study further support the hypothesis that the pathogenesis of JGCT may be driven by activation of the PIK3/AKT/mTOR pathway. These findings could potentially have future therapeutic implications, as treatment strategies targeting the PTEN/mTOR pathways are currently under investigation.

Benign Metastasizing Leiomyoma: New insights into a rare disease with an obscure etiopathogenesis

Abstract Background Benign metastasizing leiomyoma (BML) is a rare disease with an unknown etiopathogenesis that mostly affects middle-aged women with uterine leiomyoma. Many metastatic nodules outside the uterus characterize the condition. The metastases are smooth muscle lesions without malignancy. Morphologically and immunohistochemically, they resemble uterine leiomyomas, indicating a shared clonal origin. The lungs are the most prevalent site for incidental metastasis detection. BML has a relatively slow progression and good prognosis, and historically, there has been a lack of established guidelines for its treatment. Case presentation Herein, we report a case of BML in a patient with multiple metastases. Through extensive histological and immunohistochemical analyses, this complex case enabled not only the definitive diagnosis of BML, but also shed light on its complex etiopathogenesis. Conclusion This study presents novel histology evidence suggesting a potential causal relationship between metaplasia and the development of BML.

Cervical lymphoepithelioma-like carcinoma with deficient mismatch repair and loss of SMARCA4/BRG1: a case report and five related cases

Abstract Background We encountered a cervical lymphoepithelial carcinoma (LEC) possessing a predominantly solid architecture with deficient mismatch repair (dMMR) and loss of expression of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex subunit. This is the first case report of LEC with dMMR and loss of SWI/SNF complex subunit. Case presentation A 34-year-old woman presented at our hospital with menstrual irregularities and abnormal vaginal bleeding. Magnetic resonance imaging revealed an exophytic mass in the posterior uterine cervix. Biopsy specimens confirmed squamous cell carcinoma with a 2018 International Federation of Gynecology and Obstetrics (FIGO) uterine cervical cancer stage of IB2. In a subsequent conization specimen, the tumor appeared exophytic. Microscopically, the tumor cells formed a predominant solid architecture. Abundant lymphocytic infiltration was observed. The pathological diagnosis indicated human papillomavirus (HPV)-associated squamous cell carcinoma with LEC pattern and pT1b2. Immunohistochemically, high programmed death-ligand 1 (PD-L1) expression, dMMR, and loss of the switch/sucrose non-fermentable family-related, matrix-associated, actin-dependent regulator of chromatin subfamily member 4 (SMARCA4)/BRG1, an SWI/SNF complex subunit, were observed. The patient underwent a radical hysterectomy and is alive without disease one year and five months later. Our analysis of five additional LEC cases revealed a consistent association with high-risk HPV and elevated PD-L1 expression. In addition to the present case, another patient exhibited dMMR. The SWI/SNF complex was retained except in the present case. The prognosis was favorable in all cases. Conclusions This unique case of LEC with dMMR suggests a distinct clinical entity with potential immunotherapy implications. Analysis of the other five LEC cases revealed that LEC was immune hot, and immune checkpoint inhibitors may be effective. The two dMMR cases showed loss of MLH1 and PMS2 expressions, and prominently high tumor PD-L1 expression. In those cases, dMMR might have contributed to the morphological characteristics of LEC.

A case of Pseudomyxoma Peritonei of an unexpected origin

Abstract Background Pseudomyxoma peritonei (PMP) is a complex and partially understood disease defined by mucin deposits in the peritoneal cavity, mostly of appendiceal origin caused by the rupture of a mucocele often containing Low or High grade Appendiceal Mucinous Neoplasm (LAMN/HAMN). Other origins include primitive ovarian mucinous cystadenoma or cystadenocarcinoma almost always with an associated teratoma, but to our knowledge no case of ovarian teratomatous appendiceal-like mucocele with LAMN has been reported as a cause of PMP. Case presentation A 25-year old female with infertility was diagnosed with an isolated left ovarian tumor in a context of PMP. Histological examination revealed an ovarian teratoma containing an appendiceal-like structure with mucocele and LAMN, without any associated lesion of the appendix on full histological analysis. Molecular characterization of the ovarian lesion showed co- KRAS and GNAS mutations, as described in PMP of appendiceal origin, while only KRAS mutations are reported in primitive ovarian mucinous tumor. Conclusions Detection of co- KRAS and GNAS mutations in our case of ovarian teratomatous appendiceal-like mucocele with LAMN shows that when PMP derives from a mucinous ovarian lesion (with histological proof of none-appendiceal involvement), it is probably of a digestive teratomatous origin, emphasizing the need to actively search for tetatomatous signs in a context of ovarian PMP.

Squamous cell carcinoma with sarcomatoid differentiation or carcinosarcoma of the uterine cervix associated with HPV33 infection: report of a rare case

Abstract Background Squamous cell carcinoma is the most common malignant tumor of the uterine cervix with a well-documented link to infection with human papillomaviruses (HPV). According to a recent classification, there are several morphological variants of cervical squamous carcinoma, without reference to sarcomatoid squamous cell carcinoma, which is well described in other organs. Case presentation In this paper, we describe an extremely rare case of a 77-year-old woman with primary malignant cervical tumor displaying biphasic histomorphology with an epithelioid and sarcomatoid part; the latter was immunohistochemistry positive for cytokeratin and vimentin. The association with a high-grade squamous intraepithelial lesion and molecular proof of HPV33 infection in the tumor tissue supported our diagnosis of carcinoma with partial sarcomatoid differentiation. Conclusion We report a rare case of a primary cervical epithelial tumor with a partial sarcomatoid phenotype, an unequivocal HPV infection, and an associated precancerous lesion in the cervical mucosa. This is the first description of an HPV33 infection underlying a biphasic epithelioid-sarcomatous tumor of the uterine cervix. The terminology overlap between sarcomatoid carcinoma and carcinosarcoma is also discussed.

SMARCB1 (INI-1) deficient vulvar neoplasms: report of 4 cases with review of literature

SMARCB1 (INI-1) deficient vulvar neoplasms are rare tumors with scarce available literature. These tumors can be comprised of proximal type epithelioid sarcoma (ES), myoepithelial carcinoma (MEC), myoepithelioma-like tumor of the vulvar region (MELTVR), and myxoepithelioid tumor with chordoid features (METC). A subset of vulvar yolk sac tumors (VYSTs) also exhibit INI-1 deficiency. Unlike other vulvar germ cell tumors, some researchers speculate these to be of non-germ cell origin. Herein, we report a spectrum of INI-1 deficient vulvar tumors comprising VYST (1 case), ES (1 case) and MELTVR (2 cases) which showed variable histomorphological features and concomitant lack of INI-1 expression on immunohistochemistry. The clinical course ranges from indolent to aggressive and all tumors warrant close clinical follow up. Management includes surgical excision with or without adjuvant therapy. Recognition of these unique neoplasms can aid in refining the classification scheme for such uncommon vulvar tumors.

Expression and clinical significance of CLDN7 and its immune-related cells in breast cancer

Abstract Background CLDN is a core component of tight junctions (TJs). Abnormal expressions of CLDNs are commonly detected in various types of tumors. CLDNs are of interest as a potential therapeutic target. CLDNs are closely associated with most cancers of epithelial origin, especially when CLDN7 promotes cancer cell metastasis, such as in gastric, cervical, and ovarian cancers.Its expression and prognosis in breast cancer (BC) remain unknown.The purpose of this study was to investigate the expression pattern of CLDN7 and related immune factors in BC and shed light on a better therapeutic avenue for BC patients. Method The cBioPortal, GEPIA, and TCGA databases were used to comprehensively assess the expression of CLDN7 in BC. The Kaplan-Meier Plotter (KMP) database was applied to examine the relationship among the CLDN7 overexpression (OE), prognosis, and overall survival (OS) of BC patients. Immunohistochemical staining was performed on 92 BC tissue samples and 20 benign breast tumors to verify the expression level of CLDN-7 protein and its correlation with clinicopathological features and prognosis. TIMER2.0 was used to analyze the correlation between the CLDN7 OE and immune gene activation using BC-related transcriptomic data. Enrichment analyses of CLDN7-related immune pathways were conducted using online databases. The risk of expression of CLDN7-related immune genes was assessed and differentially expressed (DE) genes were included in the construction of the risk prognosis nomogram. Results Both database analysis and clinical sample validation results showed that CLDN7 was significantly overexpressed (OE) in BC, and the OE was correlated with poor DFS in BC patients (p < 0.05). TIMER2.0 analysis indicated that CLDN7 OE was negatively associated with the activation of B-cells, CD4+ T-cells, and CD8+ T-cells but positively with the M0 macrophages. Pathway enrichment analysis suggested that CLDN7-related immune factors were mostly involved in the NF-κB and T-cell receptor (TCR) signaling pathways. Univariate Cox regression was used to analyze the correlation between 52 CLDN7 related genes and OS, and 22 genes that are related to prognosis were identified. Prognostic genes were included in the prognostic nomogram of BC with a C-index of 0.76 to predict the 3-year and 5-year OS probabilities of BC individuals. Conclusions These findings provide evidence for the role of CLDN7-linked tumor immunity, suggesting that CLDN7 might be a potential immunotherapeutic target for BC, and its association with immune markers could shed light on the better prognosis of BC.

A retrospective study on incidence, diagnosis, and clinical outcome of gastric-type endocervical adenocarcinoma in a single institution

Abstract Background Gastric-type endocervical adenocarcinoma is rare but the most common subtype of cervical adenocarcinoma not associated with human papillomavirus. It is more aggressive with a shorter five-year survival rate compared to human papillomavirus-associated usual type endocervical adenocarcinoma. The objectives of our study were to determine the incidence and clinical-pathological characteristics of Gastric-type endocervical adenocarcinoma in a single institution. Methods Twenty four cases of invasive cervical adenocarcinoma were identified between January 2000 and December 2015, from the Saskatoon Health Region pathology database using International Endocervical Adenocarcinoma Criteria and Classification to retrospectively classify endocervical adenocarcinoma. Immunohistochemistry was performed with antibodies for Gastric mucin-6 (MUC-6), p16 INK4a , cyclin-dependent kinase inhibitor 2A (p16), p53 protein (p53), estrogen and progesterone receptors. Clinical and pathological data was retrieved from pathology reports and charts. Statistical analysis was performed using Mann-Whitney U test and Chi-Square test. Results Using the International Endocervical Adenocarcinoma Criteria and Classification criteria, 19 cases (79.2%) were classified as human papillomavirus-associated usual type endocervical adenocarcinoma, and five cases (20.8%) as Gastric-type endocervical adenocarcinoma. In our study 40% of Gastric-type endocervical adenocarcinoma cases presented at stage III compared to none of the usual type endocervical carcinoma cases. All the Gastric-type endocervical adenocarcinoma cases were positive for MUC-6, and negative for p16. 60% Gastric-type endocervical adenocarcinoma cases demonstrated mutant type p53 staining. In contrast, 84.2% of human papillomavirus-associated usual type endocervical adenocarcinoma cases showed block like nuclear and cytoplasmic positivity with p16 antibodies. The Gastric-type endocervical adenocarcinoma group had significantly shorter median survival time than human papillomavirus-associated usual type endocervical adenocarcinoma group, Gastric-type endocervical adenocarcinoma is 22 months compared to human papillomavirus-associated usual type endocervical adenocarcinoma at 118 months ( p  = 0.043). Conclusions In this study, Gastric-type endocervical adenocarcinoma accounted for 20.8% of all cervical adenocarcinoma with higher stage at presentation and shorter overall survival. Criteria proposed by International Endocervical Adenocarcinoma Criteria and Classification (IECC) are simple and reproducible in differentiating between, HPV- associated (HPVA) and non HPV associated (NHPVA) endocervical adenocarcinoma. Although none of the IHC assays is specific for GAS, but p16, MUC-6, ER, PR and p53 may further aid in confirming GAS and to differentiate it from benign and malignant mimics.

A risk model based on 10 ferroptosis regulators and markers established by LASSO-regularized linear Cox regression has a good prognostic value for ovarian cancer patients

AbstractOvarian cancer is the deadliest gynecologic cancer due to its high rate of recurrence and limited early diagnosis. For certain patients, particularly those with recurring disorders, standard treatment alone is insufficient in the majority of cases. Ferroptosis, an iron- and ROS (reactive oxygen species)-reliant cell death, plays a vital role in the occurrence of ovarian cancer. Herein, subjects from TCGA-OV were calculated for immune scores using the ESTIMATE algorithm and assigned into high- (N = 185) or low-immune (N = 193) score groups; 259 ferroptosis regulators and markers were analyzed for expression, and 64 were significantly differentially expressed between two groups. These 64 differentially expressed genes were applied for LASSO-regularized linear Cox regression for establishing ferroptosis regulators and a markers-based risk model, and a 10-gene signature was established. The ROC curve indicated that the risk score-based curve showed satisfactory predictive efficiency. Univariate and multivariate Cox risk regression analyses showed that age and risk score were risk factors for ovarian cancer patients’ overall survival; patients in the high-risk score group obtained lower immune scores. The Nomogram analysis indicated that the model has a good prognostic performance. GO functional enrichment annotation confirmed again the involvement of these 10 genes in ferroptosis and immune activities. TIMER online analysis showed that risk factors and immune cells were significantly correlated. In conclusion, the risk model based on 10 ferroptosis regulators and markers has a good prognostic value for ovarian cancer patients.

Genetic profiling of patients with adenoid cystic carcinoma of the Bartholin’s glands reveals potential new routes for targeted therapies: a case report

Abstract Background Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin’s glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine. Case presentation We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors. Conclusions A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.