Mullerian Tumor Research Articles

Primary peritoneal carcinosarcoma arising from the secondary Müllerian system: case report and literature review

Carcinosarcomas, also known as malignant mixed Mullerian tumours (MMMT), are aggressive neoplasms that are biphasic as they contain both carcinomatous and sarcomatous elements. Most commonly arising from the endometrium, extragenital carcinosarcomas are extremely rare and most cases develop from the peritoneum. The case is reported of a 70-year-old female who presented with abdominal pain and distention. On evaluation a large abdomino-pelvic mass with ascites was noted. She underwent complete cytoreductive surgery and the histopathology reported carcinosarcoma of primary peritoneal origin, of heterologous type arising de novo from the secondary Mullerian system with no synchronous or metachronous carcinomas or endometriosis. She declined adjuvant treatment and re-presented with disseminated abdominal disease and unfortunately succumbed to the disease within four months. Carcinosarcomas of the extragenital sites have been postulated to arise from pre-existing foci of endometriosis, Mullerian duct remnants, or the secondary Mullerian system, all of which are derivatives of the coelomic epithelium. They are extremely aggressive, and there is little knowledge concerning their natural history and scant data regarding their management. (Full text available online at www.medpharm.tandfonline.com/ojgo ) South Afr J Gynaecol Oncol 2018; DOI: 10.1080/20742835.2018.1454144

Sarcomatous Component in Uterine Carcinosarcomas Correlates With Advanced Stage and Poorer Prognosis.

Uterine carcinosarcomas, also known as malignant-mixed mullerian tumors, are rare and highly aggressive tumors whose prognostic factors remain controversial. The stage at the time of presentation is the most important prognostic factor thus far, but little information exists on the prognostic impact of the sarcomatous component (SC) in these tumors. We reviewed 21 cases of uterine carcinosarcomas and estimated the volume of the SC in each case. This information was correlated with the stage of the tumor at presentation. The percentage of the SC was also used to stratify the patients into 2 cohorts (high percentage of SC and low percentage of SC), and the 2 patient cohorts were compared based on the available follow-up data to identify prognostic differences. Patients with a lower concentration of SC (<30%) typically presented with low stage of disease when compared with their counterparts. Although not statistically significant (P=0.1966), our data suggest a correlation between a lower concentration of SC with longer follow-up and longer survival rates when compared with those of patients presenting with higher volumes of the SC (≥30%). Greater volume of the SC is seen in advanced stage tumors, which could serve as an indicator of prognosis.

Une tumeur mullérienne mixte maligne rétropéritonéale de localisation et pronostic exceptionnels

Primary retroperitoneal carcinosarcoma or mixed malignant mullerian tumor (MMMT) is an extremely rare clinical entity. These aggressive tumors arise most commonly from genital tract. The retroperitoneal location is exceptional. Here we report the case of a 63-years old female diagnosed with heterologous, extra-genital, retroperitoneal carcinosarcoma, with malignant cells in the ascitic fluid and extra-ovarian metastatic implants. She was treated with complete radical surgical treatment consisting of resection of the retroperitoneal tumor, with omentectomy, hysterectomy, bilateral salpingooophorectomy and lumbo-aortic and pelvic lymphadenectomy. She received adjuvant chemotherapy with 6 cycles of Carboplatin and Paclitaxel. She is in complete clinical and radiological remission since the end of chemotherapy, for a total of 113 months. To our knowledge, this is the longest reported disease free survival of the extra-genital retroperitoneal MMMT. This case and the review of the literature illustrate the importance of surgical treatment. However, there are no evidence-based guidelines for the systemic management of these tumors.

Infrequent Immunohistochemical Expression of Napsin A in Endometrial Carcinomas.

Many studies described napsin A as a specific diagnostic marker that aids in differentiating lung adenocarcinomas from other respiratory tumors. This study describes the expression phenotype of napsin A in endometrial neoplasms, it investigates the relationship between this expression profile and the clinicopathologic parameters, and assess its utilization as an independent predictive marker. A total of 76 cases of previously diagnosed endometrial carcinoma (including 53 endometrioid adenocarcinomas, 6 endometrioid adenocarcinomas with squamous differentiation, 9 serous adenocarcinomas, 6 clear cell adenocarcinomas, and 2 malignant mixed mullerian tumors) and 30 tissue samples of noncancerous endometrium (including 16 proliferative endometriums, 10 secretory endometriums and 4 endometrial polyps) were retrieved from the archives of Pathology Department at King Abdulaziz University, Jeddah, Saudi Arabia. For napsin A detection, tissue microarrays and immunostaining were used. A total number of 12 (15.78%) cases were positive for napsin A immunostaining. Brown granular cytoplasmic expression of napsin A was detected in 9.4% of endometrioid adenocarcinomas, 16.7% of endometrioid adenocarcinomas with squamous differentiation, 22.2% of papillary serous endometrial carcinomas, and 66.7% of clear cell carcinomas. Three (10%) control cases showed similar granular cytoplasmic expression. Positive napsin A immunostaining was more frequent in clear cell carcinoma, and there is a significant association between positive napsin A immunostaining and clear cell carcinoma (P-value=0.007). Significant associations have been found also between napsin A expression and older ages (above 60 y) and higher stage (IVB), the P-values of which were 0.035 and 0.043, respectively, but not with the tumor recurrence or survival rate. Although napsin A is infrequently expressed in endometrial carcinomas, positive results of napsin A immunostaining in endometrial neoplasms might support the diagnosis of clear cell carcinoma when the pathologic differential diagnosis includes other histologic subtypes.

Use of Hormone Replacement Therapy After Risk Reducing Salpingo-oophorectomy and Risk of Malignancy in High Risk Genetic Mutation Carriers: A Pilot Study

Objectives: To assess the effect of hormone replacement therapy (HRT) on the incidence of subsequent malignancies in patients with genetic mutations predisposing to Mullerian cancers who have undergone risk reducing salpingo-oophorectomy (RRSO).

Multiple pulmonary metastases with halo-sign from malignant mixed Müllerian tumors.

The lungs are one of the most common organs to which cancer metastasizes, but are a location not common for uterine sarcoma. A malignant mixed Müllerian tumor (MMMT) of the uterus is an extremely rare and aggressive sarcoma, characterized by a mixture of epithelial and mesenchymal components. There are few reports regarding the pulmonary metastasis from MMMTs. The present study presents the case of a 58-year-old woman with hemoptysis and post-menopausal vaginal bleeding. The woman was initially diagnosed with invasive aspergillosis based on a chest computed tomography (CT) scan showing multiple pulmonary nodular opacities surrounded by a ground-glass attenuation halo (halo-sign). Diagnostic curettage and a percutaneous CT-guided lung biopsy were conducted for the pathological diagnosis. Finally, the diagnosis was confirmed as MMMT with lung metastasis based on the histopathological examination of cervical canals, uterus and lung specimens, which showed a mixture of carcinomatous and sarcomatous elements, and morphology exhibiting hyperchromatic nuclei and necrosis. Immunohistochemical staining was positive for vimentin, focally positive for p16, and negative for napsin, cytokeratin 7 (CK7), CK20, carcinoembryonic antigen, carbohydrate antigen 125, homeobox protein CDX2 and villin in the lung specimens. This case highlights that pulmonary metastatic tumor from uterine sarcoma can present as halo-sign, which is commonly observed in pulmonary aspergillosis. Therefore, it needs to be considered in the differential diagnosis of such lesions, and pathological confirmation is required.

The evolving role of cytopathology in the era of neoadjuvant chemotherapy for the accurate pathologic diagnosis of epithelial ovarian cancer.

The evolving role of cytopathology in the era of neoadjuvant chemotherapy for the accurate pathologic diagnosis of epithelial ovarian cancer.

Correction: Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors.

The metalloproteinase SAS1B [ovastacin, ASTL, astacin-like] was immunolocalized on the oolemma of ovulated human oocytes and in normal ovaries within the pool of growing oocytes where SAS1B protein was restricted to follicular stages spanning the primary-secondary follicle transition through ovulation. Gene-specific PCR and immunohistochemical studies revealed ASTL messages and SAS1B protein in both endometrioid [74%] and malignant mixed Mullerian tumors (MMMT) [87%] of the uterus. A MMMT-derived cell line, SNU539, expressed cell surface SAS1B that, after binding polyclonal antibodies, internalized into EEA1/LAMP1-positive early and late endosomes. Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement. A saporin-immunotoxin directed to SAS1B induced growth arrest and cell death. The oocyte restricted expression pattern of SAS1B among adult organs, cell-surface accessibility, internalization into the endocytic pathway, and tumor cell growth arrest induced by antibody-toxin conjugates suggest therapeutic approaches that would selectively target tumors while limiting adverse drug effects in healthy cells. The SAS1B metalloproteinase is proposed as a prototype cancer-oocyte tumor surface neoantigen for development of targeted immunotherapeutics with limited on-target/off tumor effects predicted to be restricted to the population of growing oocytes.

Magnetic Resonance Imaging in Mixed Mullerian Tumour: Report of Two Cases.

Malignant Mixed Mullerian Tumours (MMMTs) or carcinosarcomas of uterus are rare aggressive tumours of mesenchymal origin. It is associated with high incidence of lymphatic, pulmonary and peritoneal metastasis. We hereby present two cases of mixed mullerian tumour. Case-1 was a 60-year-old post menopausal woman who had come with complaint of metrorrhagia and a protruding mass in the vagina. Case-2 was of a 54-year-old post-menopausal woman who came with complaints of heavy vaginal bleeding, pelvic pain since two months. For the assessment of these tumours Magnetic Resonance Imaging (MRI) is preferred imaging modality due to excellent tissue contrast to detect the myometrial invasion, local extent and staging. Preoperative differentiation of mullerian tumour with endometrial carcinoma is important as both have different treatment.

Malignant mixed mullerian tumor of ovary-scrape cytology: Findings with review of literature.

Malignant mixed mullerian tumor of ovary-scrape cytology: Findings with review of literature.

Uterine adenofibroma: An unsual cause of nonpuerperal uterine inversion in postmenopausal female

Uterine adenofibroma is an extremely rare benign mixed mullerian tumor, most often presenting as vaginal mass with pain and abnormal uterine bleeding in postmenopausal females. Nonpuerperal uterine inversion is also an uncommon entity. We present a rare case of nonpuerperal uterine inversion due to a uterine adenofibroma. A 56-year-old postmenopausal female presented to us with bleeding and discharge per vaginum. Examination showed a polyp. Due to associated comorbidities, polypectomy was chosen as management modality failing which laparotomy was done, and the uterus was found to be inverted through the cervix, hysterectomy was done. Histopathological evaluation showed uterine adenofibroma. This is the first case of inversion reported due to uterine adenofibroma.

New features in the 2014 WHO classification of uterine neoplasms

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides apapillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an "all or null pattern" assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.

Carcinoma Fallopian Tube with Sarcomatous Component in the Metastatic Omental Deposit: A Rare Event

Background Carcinosarcoma (malignant mixed mullerian tumour) is a rare malignancy of the female genital tract and rarer to arise from the fallopian tube. Approximately 60 cases are reported in world literature so far. Carcinosarcoma with the sarcoma component only in the metastatic deposit is highly uncommon.

Abstract 131: Allelic imbalance analysis of uterine carcinosarcoma: An inquiry into the dual nature of the neoplasm

Abstract Uterine carcinosarcoma (UCS), also known as Malignant Mixed Mullerian Tumor, is a neoplasm of the female genital tract that shows histological features of both carcinoma and sarcoma. Some studies have indicated that UCS arises from sarcomatous differentiation of high-grade carcinoma while others have confirmed a bi-clonal nature of the tumor. Given these differences, further investigation in the origin of this tumor with newer approaches and technologies is warranted. In this study we determined the allelic imbalance (AI) profiles of the two components of UCS and compared the AI events that were shared by, or differed between, them. Samples were obtained from 10 patients diagnosed with UCS and were preserved in formalin fixed paraffin embedded (FFPE) blocks. The two components (carcinoma &amp; sarcoma) were identified and micro-dissected, and whole-genome DNA micro-arrays were applied to the isolated DNA. We then applied a sensitive computational method that combines haplotype information with SNP array data to identify somatic segmental copy number variations and copy-neutral loss of heterozygosity (cnLOH). After we obtained the AI events we filtered small events (&amp;lt;2 MB) to rule out germline duplications. We then obtained events that are common to both components by using a criterion of 80% reciprocal overlap. All such events were classified as a gain, loss or cnLOH. We found that, on an average, 80% of the events found in the carcinoma component are common with the sarcoma component. Conversely, only 64% of events seen in the sarcoma component are found in the carcinoma. This may be in part due to the fact that the sarcoma component usually showed greater number of events and most of these events were larger than the corresponding carcinoma component. Also the sarcoma component showed an increased degree of allelic imbalance than the counterpart. We then looked into particular regions of known tumor suppressor and oncogenes and identified loss in the TP53 gene region (60% of tumors), gains in PIK3CA and PTEN gene regions (40% of tumors), among other events. Our analysis showed that the sarcomatous component shared major portions of the AI profile with the carcinomatous component, but also showed additional events and a greater degree of AI. One explanation for this observation can be that the sarcomatous component retains the AI profile of the carcinomatous component and also gathers additional imbalance. This suggests directionality to the development of UCS: that it arises by sarcomatous differentiation of already existing carcinoma of the uterus. We are pursuing additional assessments of point mutations and expression profiles to complement our existing analyses. Citation Format: Aditya S. Deshpande, Zachary Weber, Raed Sulaiman, Natasha Flier, Cheryl Ageton, Mary Fagerness, Joseph Sulaiman, Gareth E. Davies, David Starks, Luis Rojas-Espaillat, Paul A. Scheet, Erik Ehli. Allelic imbalance analysis of uterine carcinosarcoma: An inquiry into the dual nature of the neoplasm. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 131.

Adenosarcoma Mulleri Associated with Tamoxifen use after Breast Cancer Therapy: A Case Report

Abstract The term ‘mixed Mullerian tumour’ applies to uterine tumours composed of epithelial and mesenchymal elements of Mullerian origin. These neoplasms are classified into adenomyomas, adenofi bromas, adenosarcomas, and carcinosarcomas (malignant Mullerian mixed tumours) based on whether the epithelial and stromal elements are benign or malignant. Adenosarcomas are low-grade neoplasms classified halfway along the spectrum of mixed Mullerian tumours, with adenofi bromas at one end and carcinosarcomas (malignant Mullerian mixed tumours) at the other. Adenosarcoma is a mixed Mullerian tumour composed of benignappearing but neoplastic glandular elements and a sarcomatous stroma, which is usually low grade. Histologically, there are heterologous mesenchymal elements (usually rhabdomyosarcoma, but also cartilage, fat, and other elements) in 20-25% of cases. We have observed that some women with these tumours have received tamoxifen treatment for breast cancer or have a history of radiation therapy. We herein report the case of a 46-year-old patient who was hospitalized at OGC CC Kragujevac because of excessive bleeding from the uterus. The patient had undergone right mastectomy three years earlier for breast cancer. After surgery, she had received Nolvadex (tamoxifen) treatment. Exploratory curettage was performed, and then, a classic abdominal hysterectomy with bilateral adnexectomy was completed. The histopathological findings indicated adenosarcoma Mulleri; therefore, the patient received postoperative radiation therapy according to our current protocol.

Epidemiology and survival trends of epithelial ovarian cancer (EOC) subtypes in SEER database: Time to focus on minor histologies.

1561Background: Management of EOC is largely based on the more common serous (SC) and endometroid (EnC) subtypes, but differences in clinical characteristics of less common histologies such as clear cell (CC), mucinous (MC) and malignant mixed mullerian tumor (MMMT) are increasingly clear. Yet, treatment strategies remain uniform. Methods: We obtained data on incident EOC cases from the Surveillance, Epidemiology and End Results (SEER 13) database between 1993-2007, and compared their disease characteristics. Survival analysis was performed using Kaplan-Meier and flexible parametric models. Results: Of 25358 incident EOC cases, 15405 (60.8%) had SC, 2748 (10.8%) EnC, 4264 (16.8%) MC, 1913 (7.5%) CC and 1028 (4.1%) MMMT. Age adjusted incidence rate per 100K (standard US 2000 population) was highest in SC (5.3), followed by EnC (1.5), MC (1.0), CC (0.7) and MMMT (0.4). The proportion of CC, MC and MMMT was more common in Asians (15.1%), American Indians (15.4%) and Blacks (5.4%) respectively (p<0.001). Mean...

Mullerian mixed tumor of the uterus with metastasis to the scalp

Mullerian mixed tumor of the uterus with metastasis to the scalp

Clusterin immunoexpression is associated with early stage endometrial carcinomas

Clusterin has anti-apoptotic, regeneration and migration stimulating effects on tumor cells. This study investigates the relation between clusterin expression and the clinicopathological parameters in endometrial carcinomas. Seventy one cases of previously diagnosed endometrial carcinoma (including 59 endometrioid adenocarcinoma, 9 serous adenocarcinoma, 1 clear cell adenocarcinoma, and 2 malignant mixed Mullerian tumor) and 30 tissue samples of non-cancerous endometrium (including 16 proliferative endometrium, 10 secretory endometrium and 4 endometrial polyps) were employed for clusterin detection using tissue microarrays and immunostaining. A total number of 23 (32.4%) cases were positive for clusterin immunostaining. Brown granular cytoplasmic expression of clusterin was detected in 33.9% of endometrioid adenocarcinomas, 22.2% papillary serous endometrial carcinomas. Three (10%) control cases showed granular cytoplasmic expression. Positive clusterin immunostaining was found more frequent in well differentiated and stage I endometrial carcinomas, showing significant statistical association (p-value=0.036 and p-value=0.002 respectively). Significant difference in clusterin expression was observed between tumor cases and control group (P-Value=0.019), i.e., endometrial carcinoma cases are more than four times likely to show positive clusterin immunostaining (odds ratio 4.313 with 95% confidence interval 1.184–15.701). This study did not find relation between clusterin expression and disease recurrence, survival or any of the other clinicopathological parameters in endometrial tumors. The results of our study confirms the diagnostic values of clusterin in supporting the diagnosis of endometrioid carcinoma. When clusterin is expressed in endometrial tumors, it is associated with lower stage. The correlation of clusterin with tumor stage suggests involvement of this molecule in endometrial tumor progression.

Serous carcinomatous component championed by heparin-binding EGF-like growth factor (HB-EGF) predisposing to metastasis and recurrence in stage I uterine malignant mixed mullerian tumor

The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-α5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-α5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-α5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-α5 and does not seem to require overexpression of EGFR. Further study is required.

GHRH Receptor Expression in Malignant Mixed Müllerian Tumors: A Potentially Targetable Biopredictor.

Malignant mixed Müllerian tumors (MMMTs) are aggressive malignant neoplasms with a high recurrence rate and poor prognosis. Despite advances in adjuvant therapies in recent years, the prognosis of these tumors has not improved. Growth hormone-releasing hormone (GHRH) is produced by a variety of malignant tumors and acts as a growth factor in an autocrine/paracrine manner. Its function requires the presence of its receptors to exert its effects on neoplastic cells. In this study, we evaluated the expression of GHRH receptors (GHRH-R) in a group of MMMTs. Thirty-one examples of MMMTs from endometrium, ovary, uterine tube, and pelvic peritoneum were retrieved from the files of Department of Pathology at the University of Miami, Jackson Memorial Hospital. Immunohistochemistry for GHRH-R was performed on paraffin sections and the staining results were evaluated separately in both epithelial and mesenchymal components of each tumor. The presence of pituitary type growth hormone-releasing hormone receptor mRNA and that of its biologically active splice variant were also evaluated by RT-PCR in 6 of the tumors. Positive immunohistochemical reaction for GHRH-R was detected in 30 tumors (96%). The epithelial and sarcomatous components were positive in 30 (96%), whereas one endometrial tumor was negative in both components. The mRNA for GHRH-R and its splice variant was found in all 6 tested tumors. This study shows that GHRH-R is expressed by the majority of MMMTs in both epithelial and mesenchymal components. This finding could potentially serve as a basis for therapeutic approaches using synthetic peptide antagonists of GHRH-R that have shown significant efficacy with minimal side effects in experimental models.