Endometriosis-associated ovarian cancer: a different clinical entity.

OBJECTIVE: To compare survival outcomes and patterns of recurrence between endometriosis-associated ovarian cancer patients and non-endometriosis-associated ovarian cancer patients. METHODS: This retrospective study included data of consecutive patients with endometrioid or clear cell ovarian cancer treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano between January 2010 and June 2021. Patients were assigned to one of two groups according to the absence or presence of endometriosis together with ovarian cancer at final histological examination. Survival outcomes were assessed using Kaplan-Meier and Cox hazard models. Proportions in recurrence rate and pattern of recurrence were evaluated using the Fisher exact test. RESULTS: Overall, 83 women were included in the endometriosis-associated ovarian cancer group and 144 in the non-endometriosis-associated ovarian cancer group, respectively. Patients included in the non- endometriosis-associated ovarian cancer group had a shorter disease-free survival than those in the endometriosis-associated ovarian cancer group (23.4 (range 2.0-168.9) vs 60.9 (range 4.0-287.8) months; p<0.001). Univariable and multivariable analyses showed that the association with endometriosis, previous hormonal treatment, early stage at presentation, and endometrioid histology were related to better disease-free survival in the entire study population. Similarly, patients in the non-endometriosis-associated ovarian cancer group had a shorter median (range) overall survival than those in the endometriosis-associated ovarian cancer group (54.4 (range 0.7-190.6) vs 77.6 (range 4.5-317.8) months; p<0.001). Univariable and multivariable analyses showed that younger age at diagnosis, association with endometriosis, and early stage at presentation were related to better overall survival. The recurrence rate was higher in the non-endometriosis-associated ovarian cancer group (63/144 women, 43.8%) than in the endometriosis-associated ovarian cancer group (17/83 women, 20.5%; p<0.001). CONCLUSIONS: Endometriosis-associated ovarian cancer patients had significantly longer disease-free survival and overall survival than non-endometriosis-associated ovarian cancer patients, while the recurrence rate was higher in non-endometriosis-associated ovarian cancer patients.

Clear cell carcinoma of the ovary: Clues for radiologists to perform a correct diagnosis.

Ovarian clear cell carcinoma (OCCC) is an uncommon high-grade primary epithelial ovarian cancer, covering about 10-12 % of all ovarian malignancies. It has a strong association with endometriosis. OCCC diagnosis, at advanced stages, has an aggressive biological behaviour, and the therapeutic strategies for ovarian OCCC are somehow different from other ovarian carcinomas. Therefore, early diagnosis of these tumours is of extreme importance. As some ovarian tumours subtypes have distinguishing features, it is possible to differentiate them based on their imaging characteristics, which can guide patient management and help the clinicians and pathologists in their diagnosis. A large mass on one side of the ovary that is mostly cystic, with a focal or multifocal irregular eccentric growing solid mural nodules or projections protruding into the cystic space, may suggest clear cell carcinoma of the ovary diagnosis. The solid nodules usually have an intermediate signal on T2-weighted images. The cystic component can be either single or multilocular, and the contents may contain protein or blood. CT scanning is still the preferred method for preoperative staging and postoperative restaging, and radiologists are crucial in identifying this type of tumour. We reviewed the imaging files of patients with surgically proven clear cell carcinoma at the specimens, and our findings agree with previous studies. This paper aims to perform a comprehensive revision of OCCC's radiological and clinic-pathological features and assist radiologists in recognizing OCCC and narrowing down the possibilities of differential diagnosis.

Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis.

Introduction: Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods: To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results: Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion: These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.

Surgery of abdominal wall endometriosis associated with clear-cell carcinoma: Case report and review.

Abdominal wall is a rare location for endometriosis, with a reported incidence of parietal endometriosis of approximately 0.03 to 0.4%. It most often occurs in the aftermath of a caesarean section and is associated with pelvic endometriosis in only 5 to 15% of cases. Rare cases of malignant transformation have been described, mainly in the form of clear-cell tumours. We report the case of a 52-year-old patient with a history of endometriosis who presented with a retractile parietal mass at the level of her caesarean scar. Histological analysis confirmed a clear-cell adenocarcinoma (CCC). Few cases of endometriosis - associated CCC are described in the literature. A review of the literature suggests radical surgical treatment combined with adjuvant radio-chemotherapy. However, the prognosis is poor. The aim of this case report is to suggest the diagnosis of malignant transformation in the presence of a rapidly evolving parietal mass in the context of endometriosis and a history of caesarean section.

Bilateral diffuse uveal melanocytic proliferation with multifocal diffuse integumentary melanocytic proliferation paraneoplastic syndrome: A case report.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males and uro-gynaecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterised. Herein, we present a female in her 70s with diagnosis of stage IV vaginal clear-cell carcinoma and metastatic melanoma of unknown primary that developed progressive bilateral loss of visual acuity compatible with 'B-DUMP'. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP be termed 'diffuse integumentary melanocytic proliferation (DIMP)'.

Tissue factor expression and tumor-infiltrating T lymphocytes in ovarian carcinomas and their association with venous thromboembolism.

Ovarian cancer is a known risk factor of venous thromboembolism (VTE). Thrombogenic factor expression and lymphocytic infiltrate have been reported in endometriosis and ovarian cancers. We reviewed 30 cases of ovarian carcinomas (high grade serous carcinoma, 10; endometrioid carcinoma, 10; clear cell carcinoma (CCC), 10) and 16 endometriotic lesions. We immunohistochemically investigated the expressions of tissue factor (TF), podoplanin, P-selectin, and number of CD4 and CD8 positive lymphocytes in cancer tissue and endometriotic lesions, along with their relationship with VTE. The expression of TF was higher in CCC. The TF expression and the number of CD8 positive cells were higher in cancer tissues with VTE than in those without VTE. The podoplanin or P-selectin expression did not differ among histological types or between cases with and without VTE. Our results demonstrated a high TF expression and intraepithelial CD8 cells in CCC, which were associated with VTE. The results suggest that infiltrating lymphocytes may affect TF expression that, in turn, influences VTE.

Risk of second malignancy in patients with ovarian clear cell carcinoma.

OBJECTIVE: Ovarian clear cell carcinoma has unique clinical and molecular features compared with other epithelial ovarian cancer histologies. Our objective was to describe the incidence of second primary malignancy in patients with ovarian clear cell carcinoma. METHODS: Retrospective cohort study of patients with ovarian clear cell carcinoma at two tertiary academic centers in Toronto, Canada between May 1995 and June 2017. Demographic, histopathologic, treatment, and survival details were obtained from chart review and a provincial cancer registry. We excluded patients with histologies other than pure ovarian clear cell carcinoma (such as mixed clear cell histology), and those who did not have their post-operative follow-up at these institutions. RESULTS: Of 209 patients with ovarian clear cell carcinoma, 54 patients developed a second primary malignancy (25.8%), of whom six developed two second primary malignancies. Second primary malignancies included: breast (13), skin (9), gastrointestinal tract (9), other gynecologic malignancies (8), thyroid (6), lymphoma (3), head and neck (4), urologic (4), and lung (4). Eighteen second primary malignancies occurred before the index ovarian clear cell carcinoma, 35 after ovarian clear cell carcinoma, and 7 were diagnosed concurrently. Two patients with second primary malignancies were diagnosed with Lynch syndrome. Smoking and radiation therapy were associated with an increased risk of second primary malignancy on multivariable analysis (OR 3.69, 95% CI 1.54 to 9.07, p=0.004; OR 4.39, 95% CI 1.88 to 10.6, p=0.0008, respectively). However, for patients developing second primary malignancies after ovarian clear cell carcinoma, radiation therapy was not found to be a significant risk factor (p=0.17). There was no significant difference in progression-free survival (p=0.85) or overall survival (p=0.38) between those with second primary malignancy and those without. CONCLUSION: Patients with ovarian clear cell carcinoma are at increased risk of second primary malignancies, most frequently non-Lynch related. A subset of patients with ovarian clear cell carcinoma may harbor mutations rendering them susceptible to second primary malignancies. Our results may have implications for counseling and consideration for second primary malignancy screening.

Early stage clear cell adenocarcinoma coexisting with tubular adenoma and adenoma with clear cell change in the colon.

Primary clear cell adenocarcinoma (CCA) of the colorectum is rare. We report a case of a 57-year-old man with early-stage CCA with conventional tubular adenoma and tubular adenoma with clear cell change in the transverse colon, diagnosed with image-enhanced endoscopy. The tumor was then treated with endoscopic submucosal dissection. The endoscopic findings characteristic of clear cell adenoma/adenocarcinoma could not be identified. Therefore, similar diagnostic tools as for conventional colorectal adenoma/cancer were considered. The pathogenesis of the clear cell change was unknown, but it might appear with the progression of the malignancy.

[Non endometroid endometrial cancer guidelines evaluation: A multicentric retrospective study]. / Évaluation de l'application des recommandations des cancers de l'endomètre de type 2 : étude rétrospective multicentrique.

INTRODUCTION: Non endometrioid endometrial cancer are infrequent and have poor prognosis. The aim of the study was to evaluate non endometrioid endometrial cancer managment by evaluating endometrial cancer guidelines application. MATERIAL AND METHODS: This multicentric retrospective study enrolled non endometrioid endometrial cancer between January 2009 to December 2019. Analyses adapted at last French guidelines applicated corresponding of year management. RESULTS: Seventy-four non endometrioid endometrial cancer analysed in 10 centers: 34 carcinosarcoma (45,9 %), 29 serous carcinoma (39,2 %), 9 clear cells carcinoma (12,2 %) and 2 undifferentiated carcinoma (2,7 %). For initial management, endometrial cancer guidelines applicated to 45,9 %. First reason of initial guidelines « non-application ¼ was lack of surgical lymph node stadification (57,1 %). For adjuvant management, endometrial cancer guidelines applicated to 38.7 %. First reason of adjuvant guidelines « non-application ¼ was lack lymph node stadification to complete staging when it previously incompletly operated (67,6 %). DISCUSSION: Non endometrioid endometrial cancer guidelines applicability is difficult. This explicated by high age and comorbidity when surgical lymph node stadification is necessary. Using new staging technic will allow target management and better select lymph node staging indication.

Gastrointestinal malignancy in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease affecting the gastrointestinal (GI) tract as well as the lungs. As survival has increased significantly over the past few decades, complications not seen previously have become apparent. There is an overall increased rate of malignancy in CF, particularly from the GI tract and in the post-transplant population. The most common sites of malignancy are the pancreatico-biliary and digestive tract, as well as an increased rate of testicular cancer. Using an illustrative case of metastatic oesophageal malignancy which initially appeared to be hepatic in origin, we have reviewed the literature surrounding malignancy in CF with a particular focus on the GI tract.

Spontaneous arterial thrombosis in a patient with advanced ovarian clear cell cancer: a case report and literature review.

Patients with ovarian cancer are often in a hypercoagulable state and have a high risk of venous thrombosis, including deep vein thrombosis and pulmonary embolism. However, arterial thrombosis is relatively rare in ovarian cancer. We report a case a 46-year-old woman with ovarian clear cell carcinoma who developed arterial and venous thrombosis in the lower extremities as the first manifestation. Her arterial thrombosis-related ischemic symptoms were not responsive to anticoagulant treatment of low-molecular-weight heparin, but improved after neoadjuvant chemotherapy and surgery. Therefore, we hypothesize that the optimal therapy for arterial thrombosis in ovarian cancer is treatment for the underlying disease (i.e., ovarian cancer). A thorough investigation is required to determine the relationships between arterial thrombosis and ovarian cancer and antithrombotic treatments for ovarian cancer related-arterial thrombosis.

Mixed Serous and Clear Cell Adenocarcinoma of the Ovary Presenting with Symptomatic Hypercalcemia: A Case Report and Clinical Considerations.

INTRODUCTION: Hypercalcemia is a common phenomenon in patients with cancer but is more common among certain cancer types. Hypercalcemia in ovarian cancer is the common presenting sign in small cell carcinoma of the ovary, hypercalcemic type; however, there are no known documented cases of hypercalcemia as the presenting sign for mixed serous and clear cell adenocarcinoma. This case report describes symptomatic hypercalcemia as the presenting sign of mixed serous and clear cell carcinoma of the ovary. CASE PRESENTATION: A 60-year-old woman with a medical history of hypertension and hyperlipidemia presented to the outpatient clinic with weakness, nausea, emesis, constipation, and an unintended 9-kg (20-lb) weight loss. Her calcium level was elevated at 15.7 mg/dL (reference range = 8.5-10.3 mg/dL). She was treated for hypercalcemia and subsequently admitted to the hospital 4 times because of recurrence of symptoms. On outpatient workup, she was noted to have an abnormal positron emission tomography scan showing intense activity in the uterus consistent with malignancy. An exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node staging was performed, and pathologic findings demonstrated high-grade ovarian carcinoma with serous and clear cell features. DISCUSSION: Hypercalcemia is a rare but possible primary presenting symptom of ovarian cancer. In these patients, serum calcium measurements could possibly serve as a tumor marker for disease.

Endometriosis-associated ovarian cancer is not a distinct clinical entity among young patients: A 12-year cohort study.

OBJECTIVES: To investigate the clinicopathological features and prognostic value of endometriosis in young patients with ovarian endometrioid carcinoma (OEC) and ovarian clear cell carcinoma (OCCC). METHODS: The medical files and clinical follow-up data of patients aged 40 years or younger with OEC or OCCC between January 2006 and December 2017 who had undergone complete surgical staging followed by systemic chemotherapy were retrospectively reviewed. RESULTS: A total of 94 women were included in this study. Univariate analysis revealed that the progression-free survival (PFS) and overall survival (OS) rates of patients with endometriosis-associated ovarian carcinoma (EAOC) did not improve compared with those of patients without EAOC (5-year PFS: 80.0% vs. 75.9% and 5-year OS: 85.0% vs. 86.0%, respectively). Multivariate analyses confirmed that FIGO stage (II-IV), cytology-positive ascites or peritoneal washes and residual disease > 1 cm were independent predictors of PFS and that residual disease > 1 cm was the only predictor of OS. CONCLUSIONS: Endometriosis is not independently associated with the prognosis of OEC and OCCC among young patients. The intrinsic relationship between endometriosis and ovarian cancer warrants further investigation.

[Nephrogenic clear cell carcinoma of nasal cavity：a case report].

SummaryRenal clear cell carcinoma（RCCC） is the most common type of renal cell carcinoma, but metastasis to the nasal cavity is extremely rare. A case of RCCC to the nasal cavity and paranasal sinuses was reported. The early clinical manifestations of this case were intermittent epistaxis and subsequent massive epistaxis. Imaging examination revealed that there were masses in the nasal cavity and paranasal sinus, accompanied by bleeding and destruction of the skull base. Renal CT examination showed a tumor in the right kidney, and considered the patient suffering from renal cell carcinoma. The patient underwent a nasal side incision to remove the tumor, the patient's pathological return; nasal nephrogenic clear-cell carcinoma.

Pathology of Endometrioid and Clear Cell Carcinoma of the Ovary.

This review is an appraisal of the current state of knowledge of 2 enigmatic histotypes of ovarian carcinoma: endometrioid and clear cell carcinoma. Both show an association endometriosis and the hereditary nonpolyposis colorectal cancer (Lynch) syndrome, and both typically present at an early stage. Pathologic and immunohistochemical features that distinguish these tumors from high-grade serous carcinomas, each other, and other potential mimics are discussed, as are staging, grading, and molecular pathogenesis.

The effect of concurrent endometriosis on the prognosis of women with ovarian clear cell or endometrioid carcinoma.

OBJECTIVES: To evaluate features of ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC) by presence of endometriosis among women with endometriosis-associated ovarian cancer (EAOC). METHODS: A retrospective review of the medical records of 578 women diagnosed and treated for ovarian cancer at a university hospital in Korea between July 2004 and December 2016. Clinical and prognostic features of ovarian CCC and EC were compared between women with endometriosis and those without. RESULTS: Ovarian CCC and EC were diagnosed at an earlier FIGO stage for women with endometriosis than for those without (P=0.033). The 5-year disease-free survival (DFS) and overall survival (OS) were 77.6% vs 65.0% (P=0.038) and 80.3% vs 70.9% (P=0.048), respectively. In univariate analysis, advanced stage, higher grade, bilateral tumors, lymph node metastasis, residual tumor greater than 1 cm, and non-concurrent endometriosis were related to shorter DFS and OS; however, residual tumor greater than 1 cm was the only independent predictor in multivariate analysis (DFS: hazard ratio (HR), 9.83; 95% confidence interval (CI), 4.84-19.93; OS: HR, 5.07; 95% CI, 2.33-11.03). No factors affected survival after stratification by stage. CONCLUSION: No association was found between the presence of endometriosis and the prognosis of ovarian CCC or EC.

Alternating Amaurosis Fugax in Trousseau Syndrome: A Case Report.

Amaurosis fugax (AmF) is defined as transient monocular visual loss secondary to retinal ischemia. In most patients presenting with AmF, the attack of visual loss occurs in the same eye. A 64-year-old woman experienced transient visual loss in her right eye. Three days after that, an attack happened on the left side. In total, she had 5 episodes of AmF in 2 months. AmF occurred on both sides at different times, and so may be referred to as "Alternating AmF". Diffusion-weighted magnetic resonance imaging showed high-intensity lesions in various parts of brain, and laboratory examination revealed elevated D-dimer and ovarian tumor marker. We suspected Trousseau syndrome and found a giant ovary tumor. After removal of the tumor, no recurrence was observed. When a patient with alternating AmF is encountered, screening for malignancy is essential.

Endometriosis-Associated Ovarian Cancer: Population Characteristics and Prognosis.

OBJECTIVE: The aim of this study was to analyze and compare the clinicopathologic features and prognosis of clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (EOC) associated or not with endometriosis. METHODS: This was a reconstituted cohort study from a single-institution Brazilian cancer center approved under review board no. 68150617.7.0000.5404 with 50 patients with CCOC and EOC diagnosed between 1995 and 2016, followed up until 2017. Clinicopathologic characteristics and survival outcomes were analyzed. RESULT(S): There were 23 women (46%) with CCOC and 27 with EOC (54%); 80% of those women had histologic confirmation of endometriosis; 42% were nulliparous, and 42% were premenopausal; and cancer antigen 125 was elevated in both International Federation of Gynecology and Obstetrics stages I-II disease (mean, 614.7 Ui/mL; range, 3-6030 Ui/mL) or International Federation of Gynecology and Obstetrics stages III-IV disease (mean, 2361.2 Ui/mL; range, 8-12771 Ui/mL). Women with EOC were 7 years younger than those with CCOC. When associated with endometriosis, CCOCs were more likely diagnosed at earlier stages. Endometrioid ovarian carcinoma and CCOC at initial stage and EOC at advanced stage share similar good prognosis. Univariate analysis showed that CCOC not associated with endometriosis has worse overall survival (OS). However, multivariate analysis showed that only abnormally elevated levels of cancer antigen 125 and advanced stage at diagnosis were significantly associated with reduced progression-free survival. Tumor stage remains the only prognostic factor for OS. CONCLUSIONS: The presence of coexisting endometriosis did not change the prognosis of EOC but was associated with better OS in patients with CCOC. Patients with CCOC and EOC at initial stages and EOC at advanced stages have a good prognosis; however, CCOC at advanced stages had a sooner recurrence and shorter OS.