Mucinous Borderline Tumors Research Articles

Successful delivery after in vitro fertilization-embryo transfer in a woman with metachronous primary cancer of ovary and endometrium: a case report

BackgroundThe appearance of malignancies at various times in the same individual, excluding metastases of the initial primary cancer, is termed multiple primary cancers. Double primary gynecological cancers cause inevitable damage to female reproductive function, and the preservation of fertility in such patients remains a challenging issue as relatively few cases have been reported. This case report provides management options for dual primary ovarian and endometrial cancers, including the choice of ovulation induction protocols, considerations during pregnancy and parturition, with the aim of providing assistance to clinicians.Case presentationWe report a case of a 39-year-old woman with primary infertility and a medical history of right-sided ovarian mucinous borderline tumor with intraepithelial carcinoma, left-sided ovarian mucinous cystadenoma and endometrial cancer, who successfully conceived with in vitro fertilization-embryo transfer (IVF-ET) after three different ovulation induction protocols. During her pregnancy, she was complicated by central placenta praevia with placental implantation and eventually delivered a healthy female infant by caesarean section at 33 gestational weeks.ConclusionsFor patients with double primary gynecological cancers who have an intense desire for fertility, the most appropriate oncological treatment should be applied according to the patient’s individual situation, and fertility preservation should be performed promptly. Ovulation induction protocol should be individualized and deliberate, with the aim of ensuring that the patient’s hormone levels do not precipitate a recurrence of the primary disease during induction of ovulation and maximizing fertility outcomes. In addition, the risk of postpartum hemorrhage due to placental factors cannot be neglected in such patients.

Immunohistochemical expression of PRAME in 485 cases of epithelial tubo-ovarian tumors.

Preferentially expressed antigen of melanoma (PRAME) is a cancer/testis antigen selectively expressed in somatic tissues and various solid malignant tumors and is associated with poor prognostic outcome. Our research aimed to comprehensively compare its expression in a large cohort of tubo-ovarian epithelial tumors and examine its correlation with our clinico-pathologic data, as well as to assess its potential use in diagnostics and therapy.We examined 485 cases of epithelial tubo-ovarian tumors including 107 clear cell carcinomas (CCC), 52 endometroid carcinomas (EC), 103 high grade serous carcinomas (HGSC), 119 low grade serous carcinomas (LGSC)/micropapillary variant of serous borderline tumors (mSBT), and 104 cases of mucinous carcinomas (MC)/mucinous borderline tumors (MBT). The immunohistochemical analysis was performed using TMAs.The highest levels of expression were seen in EC (60%), HGSC (62%), and CCC (56%), while expression in LGSC/mSBT (4%) and MC/MBT (2%) was rare. The clinico-pathologic correlations and survival analysis showed no prognostic significance.The results of our study showed that PRAME is neither prognostic nor a suitable ancillary marker in the differential diagnosis of tubo-ovarian epithelial tumors. Nevertheless, knowledge about the PRAME expression may be important concerning its potential predictive significance, because targeting PRAME as a potential therapeutic option is currently under investigation.

Intraoperative predictors of appendiceal abnormalities in patients with mucinous ovarian neoplasms.

To evaluate intraoperative factors predicting appendiceal pathology during gynecologic oncology surgery for suspected mucinous ovarian neoplasms. We conducted a retrospective study on 225 patients with mucinous ovarian neoplasms who underwent surgery for an adnexal mass with concurrent appendectomy between 2000 and 2018. Regression analyses were used to evaluate intraoperative factors, such as frozen section of the ovarian mass and surgeon's impression of the appendix in predicting appendiceal pathology. Most patients (77.8%) had a normal appendix on final pathology. Abnormal appendix cases (n = 26) included: metastasis from high-grade adenocarcinoma of the ovary (n = 1), neuroendocrine tumor of the appendix (n = 4), and low-grade appendiceal mucinous neoplasms (n = 26; 23 associated with a mucinous ovarian adenocarcinoma, 2 with a benign mucinous ovarian cystadenoma, and 1 with a borderline mucinous ovarian tumor). Combining normal intraoperative appearance of the appendix with benign or borderline frozen section yielded a negative predictive value of 85.1%, with 14.9% of patients being misclassified, and 6.0% having a neuroendocrine tumor or low-grade appendiceal neoplasm. Benign or borderline frozen section of an ovarian mucinous neoplasm and normal appearing appendix have limited predictive value for appendiceal pathology. Appendectomy with removal of the mesoappendix should be considered in all cases of mucinous ovarian neoplasm, regardless of intraoperative findings.

Refined criteria for p53 expression in ovarian mucinous tumours are highly concordant with TP53 mutation status, but p53 expression/TP53 status lack prognostic significance

In gynecological neoplasms, immunohistochemical (IHC) expression of p53 is generally an accurate predictor of TP53 mutation status if correctly interpreted by the pathologist. However, the literature concerning cut-offs, frequency and prognostic significance of p53 staining in ovarian mucinous tumours is limited and heterogeneous. We performed an analysis of 123 primary ovarian mucinous tumours including mucinous borderline tumours (MBT), mucinous carcinomas (MC), and tumours with equivocal features between MBT and MC. We assessed p53 expression for the three recognised patterns of aberrant staining in ovarian carcinoma [overexpression ('all'), null and cytoplasmic] but using a recently suggested cut-off for aberrant overexpression in ovarian mucinous tumours (strong nuclear p53 staining in ≥12 consecutive tumour cells) and correlated the results with next generation sequencing (NGS) in all qualitatively sufficient cases (92/123). Aberrant p53 expression was present in 25/75 (33.3%) MBT, 23/33 (69.7%) MC (75% of MC with expansile invasion and 61.5% with infiltrative invasion), and 10/15 (66.7%) tumours equivocal between MBT and MC. Regarding the 92 tumours with paired IHC and mutation results, 86 showed concordant results and six cases were discordant. Three discordant MBT cases showed aberrant expression but were TP53 wild-type on sequencing. Three cases had normal p53 expression but contained a TP53 mutation. Overall, IHC predicted the TP53 mutation status with high sensitivity (94.1%) and specificity (92.7%). The accuracy of IHC was 93.5% with a positive predictive value of 94.1% and a negative predictive value of 92.7%. When comparing MC cases with wild-type TP53 versus those with TP53 mutation, there were no significant differences concerning disease-free survival, local recurrence-free survival, or metastases-free survival (p>0.05). In the MBT subgroup, there were no events for survival analyses. In conclusion, using an independent large sample set of ovarian mucinous tumours, the results of our study confirm that the suggested refined cut-off of strong nuclear p53 staining in ≥12 consecutive tumour cells reflect high accuracy, sensitivity and specificity for an underlying TP53 mutation but the TP53 mutation status has no prognostic significance in either MC or MBT.

HER2/ ERBB2 Immunohistochemical Expression and Copy Number Status in Ovarian Mucinous Tumors.

Primary mucinous ovarian carcinoma (MOC) is a rare ovarian epithelial cancer, which is often refractory to chemotherapy. HER2-targeting therapy is being increasingly considered in gynecologic malignancies. Although there have been limited studies examining the HER2 status of such tumors, the criteria for HER2 expression scoring have not been standardized for MOC as it has for other sites. This study aimed to survey immunohistochemical HER2 expression patterns in MOC and its precursor, mucinous borderline tumor in correlation with fluorescence in situ hybridization (FISH). Immunohistochemistry (IHC) for HER2 was performed on 12 cases of MOC and 15 mucinous borderline tumors, including 7 with intraepithelial carcinoma. HER2 expression was quantified using the gastric/gastroesophageal carcinoma protocol. Cases were considered 3+ if the tumor cells displayed strong complete or basolateral/lateral membranous staining in ≥10% of tumor cells. Cases (2+) had weak to moderate staining in ≥10% of tumor cells. Cases (1+) had faint staining in ≥10% of tumor cells. Cases considered 0 had no staining or faint staining in <10% of tumor cells. HER2 expression was also quantified with the endometrial serous carcinoma protocol, which uses a 30% tumor cell positivity cutoff. FISH for HER2 was performed on all 3+ and 2+ and a subset of 1+ cases. Of the MOC cases, 25% were 3+ and 1 mucinous borderline tumor with intraepithelial carcinoma had 3+ staining. All 3+ IHC MOC cases had >30% basolateral membranous staining. HER2 amplification was confirmed by FISH on all 3+ IHC cases and in one 2+ IHC case of MOC. Up to 25% of mucinous ovarian tumors showed HER2 IHC overexpression with an excellent correlation between IHC and FISH using the HER2 scoring protocol for either gastric/gastroesophageal carcinoma or uterine serous carcinoma.

TP53 as a Diagnostic Aid in the Distinction of Ovarian Mucinous Borderline Tumors From Mucinous Carcinoma.

Ovarian mucinous borderline tumors (MBTs) are clinically managed as benign neoplasms while the management of ovarian mucinous carcinomas (MC) is dependent on tumor stage. Despite the standardization of sampling of ovarian mucinous neoplasms, limited interobserver reproducibility between MBT and MC persists. Based on our recent finding that abnormal TP53 expression is associated with unfavorable outcome in MBT, we hypothesized that TP53 status might improve the reproducible distinction of MBT from MC. A virtual slide set of 85 consecutive ovarian mucinous neoplasms received at a single institution, with each case represented by 3 full sections, were reviewed by 3 pathologists in 2 iterations. The initial assessment was based solely on morphologic review, while the second iteration was performed with knowledge of TP53 status. The reproducibility of a trinary categorization (MBT, MBT with intraepithelial carcinoma [IEC], MC) significantly improved from a κ of 0.60 based on the initial morphologic assessment to a κ of 0.76 (t-test, P =0.0042) after consideration of TP53 immunohistochemistry (IHC) results. Six out of 85 patients died of disease, and in 2 of them, at least 1 pathologist assessed MBT with IEC and not MC even after integration of TP53 IHC. With the integration of TP53 IHC, substantial interobserver agreement for MBT and MC can be reached, particularly in cases with an uncertain degree of confluent growth. TP53 IHC can also be used to highlight and support the presence of IEC in MBT, however, discordances remained in 2 cases with adverse outcome.

Neuroendocrine Marker Expression in Primary Non-neuroendocrine Epithelial Tumors of the Ovary: A Study of 551 Cases.

Expression of neuroendocrine (NE) markers in primary ovarian non-NE epithelial tumors has rarely been evaluated. The aim of our study was to evaluate the expression of the most widely used NE markers in these neoplasms and to determine any prognostic significance of NE marker expression. The cohort consisted of 551 primary ovarian tumors, including serous borderline tumors, low-grade serous carcinomas, high-grade serous carcinomas (HGSC), clear cell carcinomas, endometroid carcinomas, mucinous borderline tumors, and mucinous carcinomas. Immunohistochemical analysis was performed using antibodies against INSM1, synaptophysin, chromogranin, and CD56 on tissue microarray. Positivity for INSM1, synaptophysin, chromogranin, and CD56 was most frequently observed in mucinous tumors (48.7%, 26.0%, 41.5%, and 100%, respectively). The positivity for these NE markers was mostly restricted to nonmucinous elements distributed throughout the tumor. The mucinous borderline tumor and mucinous carcinomas groups had similar proportions of positivity (mucinous borderline tumor: 53%, mucinous carcinomas: 39%). In the other tumor types, except for HGSC, there was only focal expression (5%-10%) or negativity for NE markers. HGSC showed high CD56 expression (in 26% of cases). Survival analysis was only performed for CD56 in HGSC as this was the only group with sufficient positive cases, and it showed no prognostic significance. Except for mucinous tumors, expression of NE markers in non-NE ovarian epithelial tumors is low. CD56 expression in HGSC occurs frequently but is without diagnostic or prognostic value.

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

BackgroundMucinous 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).MethodsTen 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.ResultsAfter 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.ConclusionsGenetic analysis revealed that Group A had higher TMB than Group B. Therefore, this result might be useful for future treatment.

Histological and Genetic Diversity in Ovarian Mucinous Carcinomas: A Pilot Study.

Tumor heterogeneity remains an ongoing challenge in the field of cancer therapy. Intratumor heterogeneity significantly complicates the diagnosis of cancer and presents challenging clinical problems due to resistance to drug therapy. This study aimed to elucidate the genetic changes histologically (mucinous cystadenoma (MCA), mucinous borderline tumor (MBT), and mucinous ovarian carcinoma (MOC)) in a portion of mucinous ovarian tumors within the same sample. Seven tumor samples obtained from different patients were used to evaluate the genetic mutations in each component. Intratumor genetic heterogeneity was observed in all patients; among them, BRAF (V600E) and p53 (T118I, P142S, T150I, and T170M) point mutations were observed in the MBT component, while KRAS (G12D and G13D) and PIK3CA (E545K) mutations were found in the MOC component. The current findings suggest that diverse genetic alterations occur in mucinous tumors, according to tumor histology. Tumor heterogeneity and genetic diversity in mucinous ovarian tumors might be the cause of treatment failure. Knowledge of intertumor heterogeneity may lead to an increased understanding of the tumor response to treatment.

Retrospective study of characteristics and hyperthermia intraperitoneal perfusion in mucinous borderline ovarian tumor and mucinous ovarian carcinoma.

Previous clinical trials regarding the therapy in epithelial ovarian tumors have involved patients with all types of ovarian tumors. Mucinous borderline tumors may progress to invasive carcinoma even after therapy and Patients with mucinous ovarian cancer (MOC) often have a worse prognosis. Our objectives were to investigate the use of hyperthermic intraperitoneal perfusion therapy (HIPE) and the clinicopathological features of mucinous borderline ovarian tumor (MBOT) and MOC. A retrospective study was conducted on 240 patients with MBOT or MOC. The clinicopathologic feature included age, preoperative serum tumor markers, surgical procedures, surgical and pathological staging, frozen pathology, treatment, and recurrence. The effect of HIPE in MBOT and MOC were examined and the occurrence of adverse events was analyzed. The median age was 34 years in 176 MBOT patients. Some 40.1% of patients had elevated CA125, 40.2% had elevated CA199, and 5.6% had elevated HE4. The accuracy rate for frozen pathology of resected specimen was 43.8%. The was no statistical difference in the recurrence rate between fertility-sparing and non-fertility-sparing surgery. Due to a short follow-up time in the HIPE group, no significant recurrence rate was found. The median age was 59 years in 64 MOC patients. Some 90.5% patients had elevated CA125, 95.3% had elevated CA199, and 75% had elevated HE4. There were 28 patients diagnosed with Federation International of Gynecology and Obstetrics (FIGO) stage I or II. For FIGO stage III and IV patients, the median progression-free survival (PFS) was 27 months in the HIPE group and the median overall survival (OS) in patients treated with HIPE was 53 months, which was significantly longer than that the other group (19 and 42 months). There was no severe fatal complication in all HIPE group. MBOT was usually diagnosed at an early stage and has a good prognosis. Hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) can improve the survival of patients with advanced MOC and is safety. Combined use of CA125, CA199, HE4 can assist in the differential diagnosis of mucinous borderline neoplasms and mucinous carcinoma. Randomized studies evaluating dense HIPEC in the management of advanced ovarian cancer should be warranted.

Pulmonary metastases of a borderline ovarian tumor with multiple cystic formations: a case report

BackgroundMetastatic lung tumors rarely present with cystic formations. This is the first report of multiple cystic formations in pulmonary metastases from mucinous borderline ovarian tumors written in English.Case presentationA 41-year-old woman underwent left adnexectomy + partial omentectomy + para-aortic lymphadenectomy for a left ovarian tumor 4 years ago. The pathological finding was mucinous borderline ovarian tumor with a microinvasion. A chest computed tomography performed 3 years after surgery revealed multiple cystic lesions in both lungs. After 1-year follow-up, the cysts increased in size and wall thickness. Subsequently, she was referred to our department with multiple cystic lesions in both lungs. No laboratory findings indicated infectious diseases or autoimmune disorders that could cause cystic lesions in both lungs. Positron emission tomography showed slight accumulation in the cyst wall. Partial resection of the left lower lobe was performed to confirm the pathological diagnosis. The diagnosis was consistent with pulmonary metastases from a previous mucinous borderline ovarian tumor.ConclusionsThis is a rare case of lung metastases from a mucinous borderline ovarian tumor presenting with multiple lesions with cystic formation. Pulmonary cystic formations in patients with a borderline ovarian tumor should be considered as possible pulmonary metastases.

Survival rate, recurrence rate, and complications of routine appendectomy for patients with borderline and malignant mucinous ovarian tumor: A systematic review and meta-analysis

OBJECTIVE: The objective of the study is to determine the survival rate, recurrence rate, and complication rate among patients diagnosed with borderline and malignant mucinous ovarian tumor (MOT) who underwent complete surgical staging with appendectomy. METHODOLOGY: Eligibility criteria – A search of published literature was conducted in the electronic databases of MEDLINE (PubMed), Cochrane, and Google Scholar through 2000–2022, using a search strategy based on the PIO framework. Information of sources – The citations were identified with the use of a combination of the following text words: “mucinous ovarian tumors,” “MOT,” “appendectomy,” and “pseudomyxoma peritonei.” All retrospective studies with histopathologic diagnosis of borderline or malignant MOTs with patients who underwent appendectomy during primary surgery, including encompassing data on survival rate, recurrence rate, and/or incidence of complications (postoperative infections, appendectomy site leakage, hemorrhage, abscess, peritonitis, bowel perforation, and intestinal obstruction) that matched the terms set by the researchers were retrieved. Risk of bias – For the methodological quality of the individual clinical trials, the Jadad scale was used, which is based on the three following subscales: randomization (2, 1, or 0), blinding (2, 1, or 0), and dropouts/withdrawals (1 or 0). Guidelines for Cochrane collaboration were used to assess the risk bias. Synthesis of results – Review Manager version 5.3 (RevMan 5.4.1) was used by the researcher to perform the systematic review and meta-analysis of included studies. RESULTS: There were eight retrospective studies included in this study. The random interval for survival rate is 64.9%–99.7% with a P &lt; 0.1. The prediction interval for recurrence rate is 0%–100% with 95% confidence interval. The odds of complications occurring are &lt;0.69–2.99 times with 95% confidence interval, with mean effect size is 0.083, and with a 95% confidence interval is 0.027–0.23. CONCLUSION: The mean prevalence of abnormal histology of the appendix in patients diagnosed with borderline and malignant MOTs and underwent appendectomy during primary surgery is 3%–13%. There is no statistically significant difference in survival rate of patients who were diagnosed with borderline and malignant MOTs with or without appendectomy during primary surgery. The prediction interval for recurrence rate is 0%–100% with 95% confidence interval. There is no significant difference between the rate of complications in patients who underwent appendectomy and those without.

L1-CAM in Mucinous Ovarian Carcinomas and Borderline Tumors: Impact on Tumor Recurrence and Potential Role in Tumor Progression.

Mucinous ovarian carcinoma (MOC) is a rare histotype of primary ovarian carcinoma. Frequent pathogenic molecular alterations include mutations in KRAS , TP53 , and overexpression of human epidermal growth factor receptor 2, but without having prognostic relevance. As L1-CAM (cell adhesion molecule) has previously shown prognostic relevance in other epithelial tumors of the female genital tract, we analyzed whether L1-CAM expression affected MOC prognosis. In addition, we investigated L1-CAM expression in mucinous borderline tumors (MBOTs) with and without adjacent MOC to identify its potential role in the pathogenesis of MOC. We examined a well-characterized collective of 39 MOCs by immunohistochemistry and compared their expression with clinicopathologic data. L1-CAM positivity was defined as any (even single-cell) positivity. Furthermore, we compared the L1-CAM expression in 20 MBOT regions adjacent to a MOC with that of 15 pure MBOTs. L1-CAM expression in MOC was significantly associated with recurrence, independent of tumor stage. Overall, 7/20 positive cases recurred versus 0/19 L1-CAM-negative cases ( P =0.032), showing a significant difference in time to progression. Furthermore, the presence of at least 1 defined molecular alteration (L1-CAM, aberrant p53, or human epidermal growth factor receptor 2) was found more frequently in the MBOT regions adjacent to a MOC (14/20) than in pure MBOTs (3/15) ( P =0.024). Expression of the tumor marker L1-CAM is frequent (51%) in MOC and is associated with tumor recurrence. The lack of L1-CAM may serve to characterize cases with a low risk of recurrence. Furthermore, the presence of specific molecular alterations in MBOTs is associated with adjacent carcinomas and may define potential pathways in tumor progression.

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

BackgroundIMP2 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.MethodsImmunohistochemical 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.ResultsWe 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).ConclusionConcerning 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.

Primary squamous cell carcinoma of the ovary accompanied by transition of a mucinous borderline ovarian tumor

This report describes a woman with a rare primary squamous cell carcinoma of the ovary accompanied by transition of a mucinous borderline ovarian tumor. A woman in her late 40s was referred for abdominal discomfort, which worsened during defecation. Pelvic magnetic resonance imaging showed a multiloculated cystic lesion in the left adnexa measuring approximately 7.5 × 9.5 × 7.0 cm. An intraoperatively obtained frozen biopsy sample of the mass in the left ovary was positive for malignancy, resulting in a surgical staging operation. The tumor was composed of squamous cell carcinoma and mucinous borderline tumor. There was no evidence of capsular invasion or invasion of other internal organs, including pelvic and para-aortic lymph nodes (0/41). Immunohistochemistry showed that the tumor was diffusely positive for cytokeratin 7, cytokeratin 20, Ki-67, and P40 but negative for P16. After a debulking operation, the patient has been monitored regularly without adjuvant therapy owing to final surgical staging of the tumor as stage IA.

Claudin18.2 as a potential therapeutic target for primary ovarian mucinous carcinomas and metastatic ovarian mucinous carcinomas from upper gastrointestinal primary tumours

BackgroundThe vast majority of ovarian mucinous carcinomas are metastatic tumours derived from nonovarian primary cancers, typically gastrointestinal neoplasms. Therapy targeting claudin18.2 might be used in gastric, gastroesophageal junction and pancreatic cancers with high expression of claudin18.2. In this study, we aimed to profile the expression of claudin18.2 in primary ovarian mucinous carcinoma (POMC) and metastatic gastrointestinal mucinous carcinoma (MGMC).MethodsImmunohistochemistry was used to detect claudin 18.2 expression in whole tissue sections of ovarian mucinous carcinomas, including 32 POMCs and 44 MGMCs, 23 of which were derived from upper gastrointestinal primary tumours and 21 of which were derived from lower gastrointestinal primary tumours. Immunohistochemical studies for claudin18.2, SATB2, PAX8, CK7 and CK20 were performed in all 76 cases.ResultsAmong 76 primary and metastatic mucinous carcinomas, claudin18.2 was expressed in 56.6% (43/76) of cases. MGMCs from the upper gastrointestinal tract, including 22 derived from primary stomach tumours and one derived from a pancreas tumour, were positive for claudin 18.2 in 69.5% (16/23) of cases. MGMCs from the lower gastrointestinal tract, including 10 derived from primary appendiceal cancer and 11 derived from colorectal cancers, showed no claudin18.2 expression (0/21). The expression rate of claudin18.2 in primary ovarian mucinous neoplasms, including 22 primary ovarian mucinous carcinomas and 10 primary ovarian borderline mucinous tumours, was 84.4% (27/32). The common immunophenotypic characteristics of POMCs, upper gastrointestinal tract-derived MGMCs, and lower gastrointestinal tract-derived MGMCs were claudin18.2 + /PAX8 + /SATB2- (17/32), claudin18.2 + /PAX8-/SATB2- (16/23) and claudin18.2-/PAX8-/SATB2 + (19/21), respectively.ConclusionClaudin18.2 is highly expressed in POMCs and MGMCs derived from upper gastrointestinal tract primary tumours; therefore, claudin18.2-targeted therapy might serve as a potential therapeutic strategy for POMCs and MGMCs from the upper gastrointestinal tract.

The value of ultrasonography combined with carbohydrate antigen 125 and 19-9 detection in the diagnosis of borderline ovarian tumors and prediction of recurrence.

This study aimed to investigate the clinical value of ultrasonography combined with tumor markers in the diagnosis and prediction of recurrence of borderline ovarian tumors (BOTs) and analyze the value of the combination of two different auxiliary examinations in the diagnosis and prediction of recurrence of BOTs. Here, 221 patients with BOTs confirmed by postoperative pathology were enrolled. Their clinical data, including the ultrasonography features, tumor markers, and clinicopathological data, were retrospectively analyzed. The statistical data of the 221 cases with BOTs were as follows: 94 (42.5%) with left-sided lesions, 102 (46.2%) with right-sided lesions, and 25 (11.3%) with bilateral lesions. Moreover, 93 cases (42.1%) had a borderline serous tumor, 110 (49.8%) had a borderline mucinous tumor, 12 (5.4%) had a borderline serous mucinous tumor, 2 (0.9%) had a borderline endometrioid tumor, 1 (0.5%) had a borderline Brenner tumor, and 2 (0.9%) had a clear cell BOT. There were 104 cases (47.1%) with a tumor diameter of ≤10 cm and 117 cases (52.9%) with a tumor diameter of >10 cm as suggested by ultrasonography. There were 89 cases (40.3%) with septation, 44 (19.9%) with papilla, and 97 (43.9%) with blood flow as demonstrated by ultrasonography. Carbohydrate antigen 125 (CA 125) was elevated in 132 cases (59.7%), and CA 19-9 was elevated in 52 cases (23.5%). In general, BOTs are difficult to diagnose preoperatively and have a certain recurrence rate. Ultrasonography combined with CA 125 and CA 19-9 is significant for the preoperative diagnosis and selection of surgical modality for BOTs and could be used as a guideline to achieve good preoperative preparation and avoid secondary surgery.

Primary Mucinous Tumors of the Ovary: An Interobserver Reproducibility and Detailed Molecular Study Reveals Significant Overlap Between Diagnostic Categories

Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms, and their diagnosis may be challenging. We analyzed 124 primary ovarian mucinous tumors originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and the potential for diagnostic support by molecular profiling using a next-generation sequencing targeted panel of 727 DNA and 147 RNA genes. Fourteen experienced pathologists independently assigned a diagnosis from preset options, based on a review of a single digitized slide from each tumor. After excluding 1 outlier participant, there was a moderate agreement in diagnosing the 124 cases when divided into 3 categories (κ = 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT as a combined category and MC was found in only 36.3% of the cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic. After a reclassification of the tumors into near-consensus diagnostic categories on the basis of the initial participant results, a comparison of molecular findings between the MBT and MC groups did not show major and unequivocal differences between MBTs and MCs or between MCs with expansile vs infiltrative pattern of invasion. In contrast, HER2 overexpression or amplification was found only in 5.3% of MBTs and in 35.3% of all MCs and in 45% of MCs with expansile invasion. Overall, HER2 alterations, including mutations, were found in 42.2% of MCs. KRAS mutations were found in 65.5% and PIK3CA mutations in 6% of MCs. In summary, although the diagnostic criteria are well-described, diagnostic agreement among our large group of experienced gynecologic pathologists was only moderate. Diagnostic categories showed a molecular overlap. Nonetheless, molecular profiling may prove to be therapeutically beneficial in advanced-stage, recurrent, or metastatic MCs.

Molecular Status of BRAF Mutation in Epithelial Ovarian Cancer: An Analysis of 57 Cases in the Northeast of Iran.

Epithelial ovarian cancer (EOC) is the most prevalent type of ovarian cancer. Previous studies have elucidated different pathways for the progression of this malignancy. The mutation in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene, a member of the MAPK/ERK signaling pathway, plays a role in the development of EOC. The current study aimed to determine the frequency of the BRAF V600E mutation in ovarian serous and mucinous tumors, including borderline and carcinoma subtypes. A total of 57 formalin-fixed paraffin-embedded samples, including serous borderline tumors (SBTs), low-grade serous carcinomas (LGSCs), high-grade serous carcinomas (HGSCs), mucinous borderline tumors (MBTs), and mucinous carcinomas, and 57 normal ovarian tissues were collected. The BRAF V600E mutation was analyzed using polymerase chain reaction (PCR) and sequencing. While 40% of the SBT harbor BRAF mutation, we found no BRAF mutation in the invasive serous carcinoma (P=0.017). Also, there was only 1 BRAF mutation in MBT and no mutation in mucinous carcinomas. In addition, we found no mutation in the control group. The BRAF mutation is most frequent in borderline tumors but not in invasive serous carcinomas. It seems that 2 different pathways exist for the development of ovarian epithelial neoplasms: one for borderline tumors and the other for high-grade invasive carcinomas. Our study supports this hypothesis. The BRAF mutation is rare in mucinous neoplasms.

Role of magnetic resonance imaging in the differentiation of mucinous ovarian carcinoma and mucinous borderline ovarian tumors.

This study was carried out to investigate the differentiation of mucinous borderline ovarian tumor from mucinous ovarian carcinoma using magnetic resonance imaging. We evaluated 77 women patients who underwent abdominal magnetic resonance imaging due to pelvic mass. magnetic resonance imaging was reviewed by an experienced radiologist. A total of 70 women patients were included in the study. The magnetic resonance imaging features were retrospectively evaluated and compared between the two pathologies. There was no difference between the two groups in terms of maximum tumor size. Age at diagnosis was 56.29±11.92 in the mucinous ovarian carcinoma group and 44.74±13.60 in the mucinous borderline ovarian tumor group (p<0.05). A significant difference was found between the two groups, and it was observed that mucinous borderline ovarian tumors appeared in the younger age group compared to mucinous ovarian carcinomas. Presence of ascites, peritoneal dissemination, lymphadenopathy, and mural nodules was found significantly more frequently in mucinous ovarian carcinomas than in mucinous borderline ovarian tumors. Honeycomb appearance was found more frequently in mucinous borderline ovarian tumor patients than in mucinous ovarian carcinoma patients. magnetic resonance imaging findings of these two pathologies overlapped considerably. Compared with mucinous borderline ovarian tumors, mucinous ovarian carcinomas frequently had mural nodules larger than 5 mm, larger tumor size, peritoneal dissemination, and abnormal ascites.