Malignant Mixed Mesodermal Tumor Research Articles

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Merger and Consolidation-Carcinosarcoma-Uterine Cervix

Carcinosarcoma of uterine cervix is an exceptionally encountered, high grade neoplasm composed of malignant epithelial and mesenchymal elements. Additionally designated as malignant mixed mesodermal tumour, homologous neoplasms of uterine cervix are denominated as carcinosarcoma.

ENDOMETRIAL CANCER IN ZARIA, NIGERIA: A TWENTY YEAR HISTOPATHOLOGICAL ANALYSIS (1991 - 2010)

Background: Cancer has become a major global public health problem. There are approximately 150,000 cases of endometrial cancer diagnosed each year, making endometrial carcinoma the fifth most common cancer in women. The predisposing factor was linked to reproductive history with duration and type of oestrogen exposure. Endometrial cancer is often diagnosed early. There has not been a comprehensive clinico-pathological study/ documentation of endometrial cancer in the study center. Materials and Method: This is a retrospective histopathological review of endometrial cancer seen over 20- year period obtained from endometrial curettage and hysterectomy specimens submitted to the Department of pathology. Histology slides were retrieved, reviewed and classified using the WHO classification of tumours of the endometrium. Analysis of the collected data was carried out using SPSS Version 15.0, and data were presented in frequency distribution tables and figures. Result: A total of 1,505 cases were diagnosed as malignant lesions of the female genital tract with the endometrial cancer represent 4.4% of the malignancies. Majority of endometrial cancer were epithelial 69.7 %, 21.7 % were grade I tumours, grade II tumours 50.0 % and grade III 28.3 % of the cases. Stromal sarcoma 19.7% of these 61.5 % were high grade stromal sarcoma, 38.5 %, low grade stromal sarcoma and Malignant Mixed Mesodermal Tumours accounted for 10.6 % cases. The age range was from 24 to 80 years. With peak age of incidence in 5th and 6th decades. Most of the endometrial cancers were diagnosed by endometrial biopsies 63.6% while the rest by total abdominal hysterectomy 36.4 %. Conclusion: Endometrial cancer represented 4.4 % of the female genital tract malignancies within the study period with possible early exposure to the aetiological factors and epithelial tumour are commoner than Malignant Mixed Mesodermal Tumours.

Clinicopathological features of malignant mixed mesodermal tumor: analysis of 50 cases

Objective: To investigate the clinicpathological, immunohistochemical and molecular genetic features of malignant mixed mesodermal tumor (MMMT) in the female reproductive system. Methods: To analyze its histopathological characteristics, we performed a retrospective review of the MMMT cases diagnosed at PLA General Hospital, Beijing, China during 2005-2019 using its surgical and pathological databases. EnVision immunohistochemical staining was used to detect the expression of ER, PR, p16, p53 and MMR proteins. Results: Fifty cases were conformed to the diagnosis, including 29 cases originated in the uterus, 16 cases in ovary, 4 cases of synchronous occurrence in uterus and ovary, 1 case in cervix. The tumor was histologically composed of two components, namely carcinoma and sarcoma ones, with clear borderline or blend mutually. The proportion of cancer component in the whole tumor ranged from 5%-90%. The proportion of carcinoma was more than 50% in 76% of the cases, and less than 50% in 24% of cases, including 2 cases with<10% of carcinoma. In the cases of primary uterine MMMT, the main carcinoma type was high grade endometrioid carcinoma (55%, 16/29). In ovarian MMMT, the main carcinoma type was serous carcinoma (12/16), while that of cervical MMMT was squamous cell carcinoma. The others were clear cell carcinoma or the undifferentiated carcinoma. There was one carcinoma type in most cases, only 7 cases had two carcinoma types. Homologous sarcomas, including stromal sarcoma, leiomyosarcoma and high-grade spindle cell sarcomas, were more commonly found in uterine MMMT (72.4%, 21/29). While heterogenic sarcomas, including chondrosarcoma, osteosarcoma and rhabdomyosarcoma, were more commonly noted in ovarian MMMT (12/16) than MMMT of other sites. There were 10 cases that consisted of two types of sarcomas. The synchronous MMMT of uterus and ovary had similar morphology and the types of carcinoma and sarcoma. The tumor cells that spread or metastasized to lymph node, omentum, intestinal wall or skin were all carcinoma cells, and were morphologically consistent with the original tumors. Immunohistochemically, ER and PR were both negative (23/25 in uterine, 8/10 in ovarian tumors). p16 was strongly positive (11/11 in uterine tumors, and 6/6 in ovarian tumors), with similar expression patterns in the carcinoma and sarcoma components. p53 showed mutant-type staining (64%, 21/33) and expressed synchronously in carcinoma and sarcoma components. p53 mutation was found in 35% cases of endometrial carcinoma and 46.7% cases of non-endometrial carcinoma. p53 mutation was also found in only 31.8% cases of heterogenic sarcomas, but in 50% of non-heterogenic sarcomas. Twenty-eight cases (28/33, 85%) presented intact mismatch repair proteins, while 5 cases (5/33, 15%) presented deficient mismatch repair proteins. Conclusions: MMMT in female reproductive system is a rare high-grade biphasic tumor with complex and diverse morphology. The immunohistochemical features are characterized by negative ER/PR and strongly positive p16, mostly mutant p53 and proficient mismatch repair proteins. The patients with a high FIGO stage have worse prognosis.

Sentinel lymph node mapping detection and recurrence rates in clinical stage I endometrial cancer

Objectives: The literature suggests that sentinel lymph node biopsy (SLNB) is an acceptable alternative to pelvic and paraaortic lymph node dissection (PPALND) in patients with clinical stage I endometrial cancers. The referenced data is largely published from high-volume specialized institutions and a complete PPALND is still performed by many surgeons at smaller, non-specialized centers. Our aim is to demonstrate that SLNB is feasible, reproducible, and sensitive without affecting cancer-specific outcomes when implemented at a non-specialized center. Methods: A retrospective review of patients with clinical stage I endometrial cancer was performed from September 2016 through February 2020. All patients had undergone either a robot-assisted or laparoscopic hysterectomy with SLNB. Endometrioid, uterine papillary serous (UPSC), malignant mixed mesodermal tumor (MMMT), and clear cell (CC) histologies were included. Indocyanine green was injected into the cervix bilaterally as per a previously described protocol. Paraaortic LND was performed at the discretion of the surgeon. In addition to SLNB, complete PPALND was performed for patients with MMMT, UPSC or CC. Sentinel lymph nodes (SLN) were evaluated using ultra-staging protocols including serial sectioning and cytokeratin staining. The medical record was queried for clinical or radiographic evidence of recurrence. Results: A total of 92 patients were included: 69 stage IA, 12 stage IB, 3 stage II and 8 stage III (2 IIIA, 2 IIIC1, 4 IIIC2). The majority of patients were endometrioid (73%), followed by UPSC (15.0%), MMMT (5.0%) and CC (4%). At least one SLN was detected in 95.4% of cases. The rate of bilateral SLN detection was 74.3% and improved over time from 2017-2019: 70% (2017), 74.4% (2018), 80% (2019). Twenty patients underwent PPALND. Non-SLN were positive in 3 patients, all with high-risk histology. There were no other patients with false-negative SLNB. There have been 3 (3%) recurrences to date; one rectal recurrence, one pelvic side wall and one paraaortic lymph node recurrence. All three patients had detected bilateral SLN which were negative at the time of their initial surgery; all three recurrences were high grade histology. Conclusions: SLNB is a sensitive and specific method for assessing lymph node involvement in patients with clinical stage I endometrial cancers. Our detection and recurrence rates are comparable to the rates reported in the literature and demonstrate that when applied at non-specialized centers this approach is safe and reproducible without affecting cancer-specific outcomes.

Lymphatic mapping and obesity with sentinel lymph node biopsy in endometrial cancer

<h3>Objectives:</h3> Sentinel lymph node biopsy (SLNB) has emerged as an acceptable alternative to complete pelvic and paraaortic lymph node dissection (PPALND) for patients with clinical stage I endometrial cancer. Several factors are associated with high risk of bilateral SLN detection failure. Our aim is to investigate the effect of obesity on bilateral SLN detection rates. <h3>Methods:</h3> Patients with either clinical stage I endometrial cancer or complex atypical hyperplasia were retrospectively reviewed from September 2016 through February 2020. All patients had undergone either a robot-assisted or laparoscopic hysterectomy with SLNB. Endometrioid, uterine papillary serous (UPSC), malignant mixed mesodermal tumor (MMMT), and clear cell (CC) histologies were included. Indocyanine green was injected into the cervix per our protocol. Patients with suboptimal lymph node mapping or nodes suspicious for metastasis underwent a side specific pelvic lymph node dissection (LND). In addition to SLNB, PPALND was performed for patients with UPSC, MMMT, and CC. Sentinel lymph nodes (SLN) were evaluated using ultra-staging protocols including serial sectioning and cytokeratin staining. The medical record was queried for successful bilateral or unilateral sentinel lymph node detection. Patient demographic data was then collected and analyzed with sentinel lymph node detection rate. <h3>Results:</h3> A total of 97 patients were reviewed and included: 92 had diagnosed endometrial cancer while 5 had complex atypical hyperplasia. Stage were as follows: 81 patients had stage I or II disease, and 8 patients had Stage III disease diagnosed at surgery. At least one SLN was detected 95.9% of cases, with an overall bilateral detection rate of 77.7%. In total, 53 patients classified as obese (25 Class I, 15 Class II and 13 Class III), 24 patients were overweight (BMI 25-29.9) and 20 patients had normal BMI. Unilateral and bilateral detection rates were not independently associated with obesity class. Bilateral SLN detection rates were 76% in normal BMI class and 67%, 83% and 73% for Class I, Class II and Class III obesity respectively; while at least one SLN was detected in 94% of normal BMI class and 92%, 96%, 100% and 92% in overweight weight class, Class I, II and II obesity respectively. <h3>Conclusions:</h3> Patient BMI is an important consideration for preoperative planning and success of bilateral sentinel lymph node mapping. Bilateral detection rates among obese patients are comparable to those of non-obese patients in our cohort. Despite previously reported correlation between BMI and successful bilateral mapping, our results do not demonstrate this relationship and obesity does not appear to be a contraindication to SLNB.

Malignant Mixed Mesodermal Tumour (MMMT) of the Ovary: An Unusual Primary Tumour

Ovarian carcinosarcoma (Malignant Mixed Mesodermal Tumour) is rare malignant tumour with a poor prognosis. We here present a case of ovarian carcinosarcoma in a 72-yearswoman suffering from intermittent lower abdominal pain for 5 months with previous history of Total Abdominal Hysterectomy (TAH) with Unilateral Salpingo-Oophorectomy (USO) due to leiomyoma 27 years back. Explanatory laparotomy and right salpingo-oophorectomy with complete surgical staging was done at Dhaka Community Medical College Hospital. Histopathology revealed both sarcomatous and carcinomatous component. Surprisingly the patient had no metastatic foci and consulted with a medical Oncologist, who didn’t recommend any chemotherapy and was cancer free during last one and half years follow up.&#x0D; Bangladesh J Obstet Gynaecol, 2019; Vol. 34(2): 124-126

Unexpected uterine sarcomas in 4478 patients with electric power morcellation for leiomyomas

ObjectivesOur objective is to investigate the prevalence, pathology and prognosis of uterine sarcomas in laparoscopic hysterectomy/myomectomy with electric power morcellation for presumed leiomyomas. Study DesignWe retrospectively reviewed patients with laparoscopic power morcellation (LPM) for presumed leiomyomas in a Chinese tertiary institution by chart review from September 1, 2013 to December 31, 2016. ResultsTwenty-four in 4478 patients (0.54%) with LPM for presumed leiomyomas had unexpected cancers. The patients showed the highest frequency of occult cancers (10/375, 2.6%) at 51–60 years and lowest (0/255) before 30 years. The pathology included 14 endometrial stromal sarcomas (ESS) (low-grade 12 and high-grade 2), 9 leiomyosarcomas, and 1 malignant mixed mesodermal tumor. The patients underwent abdominal re-exploration including total hysterectomy with bilateral salpingo-oophorectomy and staging surgery. Three patients were at advanced FIGO stage (IIIb-IVb) and 21 at stage I. Seven patients recurred within 1–25 (mean 6.29) months including 5 leiomyosarcomas, 1 high-grade and 1 low-grade ESS. Four recurrent patients with leiomyosarcomas and one with high-grade ESS died of disease in 1–3 months. Seventeen patients had no relapse and were alive for 6–41 (mean 24) months. ConclusionsOur study suggests that patients with LPM for presumed leiomyomas appear to have a considerable risk of unexpected cancers. Moreover, morcellation is potentially associated with adverse prognosis in patients with high-grade sarcomas. Informed consent on unexpected cancers that should be discussed before morcellation.

Primary peritoneal malignant mixed mesodermal (Müllerian) tumor.

Malignant mixed mesodermal tumor (MMMT) is a biphasic neoplasm (carcinosarcoma) composed of both epithelial and mesenchymal elements. Extragenital MMMT, including primary peritoneal MMMT, is an extremely rare tumor with features consistent with its origin from the secondary Müllerian system. The neoplastic elements of extragenital MMMT presumably arise directly from the mesothelium or submesothelial stroma and hence parallel the biphasic pattern of the genital (uterine or ovarian) counterpart. Here we report on the clinical, pathological, and immunohistochemical features of a case of peritoneal MMMT in a 65-year-old woman. The patient presented with abdominal fullness and pain. Gynecological examination revealed a huge pelvic abdominal mass. On histology, the tumor consisted of poorly differentiated carcinomatous and sarcomatous (rhabdomyosarcoma) components. Further immunohistochemical analysis revealed positive reactivity for both epithelial (cytokeratin and epithelial membrane antigen) and mesenchymal (vimentin, S-100, and desmin) markers. The patient refused treatment and died of the disease three months later. Based on the present case and on previous studies, primary peritoneal MMMT seems to be a rare but highly malignant neoplasm with an aggressive behavior and poor prognosis. Its exact origin, histogenesis and molecular alterations are poorly understood.

Sarcomas and malignant mixed mesodermal tumours of the uterus – Diagnosis and prognostic significance of selected morphological parameters

Sarcomas and malignant mixed mesodermal tumours of the uterus (MMMT), also called carcinosarcomas, belong to rare uterine ne- oplasms usually characterised by very aggressive clinical behaviour. Due to their low incidence, unknown etiology as well as complex molecular characteristics, until now neither prognostic factors responsible for unfavourable prognosis nor optimal treatment methods have been definitely established. This study attempts to determine prognostic significance of selected morphological parameters. Based on the analysis of primary uterine neoplasms in 43 women (including 30 sarcomas and 13 MMMT) it was shown that prognosis is dependent on the histological type of the neoplasm. The worst prognosis was observed in patients with carcinosarcomas and high- grade endometrial stromal sarcomas. Additionally, it was demonstrated that both aforementioned neoplasms occur in significantly older age groups.

Abstract MIP-075: SOMATIC MUTATIONS AND COPY-NUMBER VARIATIONS IN OVARIAN CANCERS VIA TARGETED SEQUENCING OF EXONS OF 300 CANCER-ASSOCIATED GENES, INCLUDING MULTIPLE DNA DAMAGE REPAIR GENES

Abstract INTRODUCTION: Recent studies demonstrated frequent alterations in DNA damage repair (DDR) genes in ovarian cancer, from well-established variants in BRCA1/2 to rarely altered genes in various DDR pathways that may be clinically relevant. Here we summarize somatic alterations in DDR related genes identified by targeted sequencing of several hundred ovarian cancers. EXPERIMENTAL PROCEDURES: Targeted next-generation sequencing was performed on formalin-fixed tumor tissues from &amp;gt;500 patients with ovarian cancer enrolled in an IRB-approved protocol at Dana-Farber Cancer Institute (DFCI). The current dataset includes 269 patients whose tumors underwent gynecologic pathology review. Targeted sequencing via hybrid capture was performed for exons of 300 cancer-associated genes. Sequence data was analyzed at Brigham and Women's Hospital to identify single-nucleotide variants (SNVs) and insertions/deletions (indels). Putative copy number variants (CNVs) were computationally inferred from sequencing coverage in a subset of patients (n=219). Germline analysis was not performed in this study, but SNVs were filtered against variant databases. Corresponding clinical data is undergoing analysis. RESULTS: In the 269-patient cohort, 67% of samples were primary tumors, 25% metastatic recurrences, and 3% local recurrences. Histologies included high-grade serous (34%), endometrioid (12%), clear cell (9%), malignant mixed mesodermal tumor (MMMT, carcinosarcoma) (9%), low-grade serous (7%), granulosa cell (7%), mucinous (3%), and borderline variants (6%). We focused upon alterations in DDR related genes in the targeted panel. Of the 269 patients, ~9% harbored BRCA1 variants and ~13% harbored BRCA2 variants; frameshift and nonsense mutations were frequent. Copy losses in BRCA1 or BRCA2 were predicted in up to 1/3 of patients, some of whom also carried SNVs/indels in the same gene. BRCA1/2 alterations were more frequent in high-grade serous cancers, but were also observed in other histologic subtypes. SNVs/indels in ATM were common, present in ~9% of patients. Another ~10% of patients had a variant in one of the Fanconi Anemia (FA) genes (FANCA,B,C,D2,E,F,G,I) or BRIP1. Alterations in MMR genes (MLH1, MSH2, MSH6, PMS2) were present in ~12%. SNVs in genes encoding DDR associated helicases BLM or WRN were observed in ~8%. PRKDC, encoding the DNA-PK catalytic subunit involved in non-homologous end joining, was altered in up to 7%. The SNVs in these DDR genes were observed in all histologic subtypes at varying frequencies. CNVs in DDR related genes were common, including predicted amplifications of CCNE1 and 2-copy deletions in several FA genes. Several limitations of this dataset may result in overestimates of the frequency of clinically significant alterations, e.g. some SNVs may represent benign variants (specific mutations are undergoing more detailed analysis to eliminate these); some patients harbor multiple mutations; and CNVs are predicted but need to be confirmed by orthogonal methods. CONCLUSIONS: Targeted sequencing data from a large cohort of ovarian cancer patients collectively support previous work indicating a significant frequency of alterations in DDR related genes in ovarian cancer, across multiple histologic subtypes. Further analysis of specific mutations and clinical correlations with DDR gene alterations are ongoing. Identifying alterations in DDR genes in ovarian cancer patients is feasible and may have clinical relevance, particularly regarding DNA repair targeted agents and chemotherapeutics. Citation Format: Elizabeth Stover, Brooke Howitt, Levi Garraway, Ursula Matulonis. SOMATIC MUTATIONS AND COPY-NUMBER VARIATIONS IN OVARIAN CANCERS VIA TARGETED SEQUENCING OF EXONS OF 300 CANCER-ASSOCIATED GENES, INCLUDING MULTIPLE DNA DAMAGE REPAIR GENES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-075.

Factores de riesgo para carcinoma de endometrio de alto grado

Endometrial carcinoma (EC) has traditionally been divided into 2groups: type I, considered to have a good prognosis and to be oestrogen-dependent and type II, with a poorer prognosis and oestrogen-independent. The aim of the study is to analyse the risk factors associated with high-grade EC. Material and MethodsRetrospective multicentre cohort study in 3Spanish reference hospitals: Hospital Universitario Miguel Servet in Zaragoza, Hospital Clínico San Carlos in Madrid and Hospital Virgen del Rocío in Seville. We studied the presence of risk factors associated with high grade EC: G3 endometrioid (G3EC), serous carcinoma (SC), clear cell carcinoma (CCC) and malignant mixed mesodermal tumours (MMMT). Differences between subtypes were analysed depending on whether the EC was type I or II. A total of 373 cases of high-grade EC were included, of which 135 were G3EC or type I and 238 were type II (96 SC, 64 CCC and 78 MMMT). ResultsDiabetes, obesity, nulliparity and use of hormonal replacement therapy showed no significant difference between subtypes. MMMT was less frequently associated with hypertension and conversely it showed greater association with the use of tamoxifen. ConclusionsRisk factors associated with high-grade EC are similar in type I and II.

Uterine sarcomas.

Uterine sarcomas.

Molecular alterations of PIK3CA in uterine carcinosarcoma, clear cell, and serous tumors.

Type II endometrial carcinomas-uterine carcinosarcomas or uterine malignant mesodermal mixed tumors (UMMMTs), clear cell carcinomas (UCCs), and uterine serous carcinomas (USCs)-are aggressive malignancies that present with advanced disease and have high mortality rates. PIK3CA mutations are commonly found in endometrial cancers. The objective of the study was to characterize molecular alterations in the PIK3CA gene in these tumors. A total of 84 cases (20 UMMMTs, 18 UCCs, and 46 USCs) were selected from the surgical pathology files of Weill Cornell Medical College and Johns Hopkins Hospital. The diagnoses were confirmed by gynecologic pathologists (L.H.E. and A.Y.). DNA was extracted from paraffin-embedded tissue. Polymerase chain reaction was performed for mutational analysis. All the studies were performed in accordance with approved Institutional Review Board protocols. Mutations in the PIK3CA gene were identified in 3 (15%) of 20 UMMMT, 3 (16.7%) of 18 UCC, and 10 (21.7%) of 46 USC cases. We report novel mutations in PIK3CA in uterine carcinosarcoma. A significant percentage of UMMMTs, UCCs, and USCs have mutations in PIK3CA. Further investigation is needed to develop targeted therapies for these aggressive uterine cancers.

PAX8 expression in uterine malignant mesodermal mixed tumor (carcinosarcoma).

PAX8 has emerged as a useful immunohistochemical marker for epithelial neoplasms of gynecologic origin. Expression of PAX8 in uterine malignant mesodermal mixed tumors (MMMT, carcinosarcoma) has not been characterized in detail. The goal of this study is to evaluate PAX8 expression in uterine MMMTs, with particular attention to its distribution in specific tumor components. Thirty-seven cases were studied. PAX8 expression was assessed by immunohistochemistry and scored separately in the epithelial and mesenchymal components of the tumors. The extent of staining was scored based on the estimated percentage of positive tumor cells as 1+: 1% to 25%; 2+: 26% to 50%; 3+: 51% to 75%; 4+: 76% to 100%. The epithelial component expressed PAX8 in all but 1 tumor, with 92% of tumors displaying 3+ and 4+ extent of staining. The mesenchymal component lacked PAX8 expression in 27 cases (73%) with variable expression in the remaining 10 cases. In addition, 12 tumors contained undifferentiated areas that were not readily classifiable as carcinoma or sarcoma based on morphologic features. Of these, 8 (67%) were negative for PAX8, whereas 4 (33%) demonstrated variable extent of expression. Thus, PAX8 is expressed in the carcinomatous components of nearly all uterine MMMTs (97%), with expression in sarcomatous and undifferentiated components being less common and less extensive. The uniform, extensive expression in the carcinomatous components makes PAX8 a useful marker for diagnosis of carcinomatous metastases of uterine MMMT at extrauterine sites. Its infrequent expression in the sarcomatous and undifferentiated components limits its utility in identifying sarcoma-predominant metastases as gynecologic in origin.

Review literature on uterine carcinosarcoma.

Carcinosarcoma of the uterus is a rare gynaecological neoplasm, which is also known as malignant mixed mesodermal tumor. Traditionally this tumour has been regarded as a subtype of uterine sarcoma, and its origin remains controversial. The exact nature and prognosis was not clear in the past. It is believed that uterine carcinosarcoma have a Mullerian duct origin and have a capacity to differentiate into various mesenchymal and epithelial components. Regarding the histogensis, various theories have been given; of which 'conversion theory' was broadly accepted. Carcinosarcoma are mostly of monoclonal origin with the carcinomatous component being the driving force. This type of tumor is broadly divided into two groups, homologous and heterologous, depending on the characteristics of the stroma or mesenchymal components of endometrial tissue. It is more frequent in black women and postmenopausal women. Radiation is a possible etiological factor but the exact etiology is not known yet. However, tamoxifen may induce carcinogenesis in some patients. Its clinical feature is very similar to endometrial carcinoma i.e. postmenopausal vaginal bleeding, have a very aggressive behavior and a poor prognosis. This pelvic malignancy is treated by multimodality therapy including surgery, chemotherapy and radiotherapy. Here we are reviewing old concepts about the disease and modern understandings of the origin, classification, pathogenesis and recent advances in the treatment of the uterine carcinosarcoma.

Preinvasive Lesions in Gynaecology – Ovary

In comparison to malignant tumors of vulva, vagina, cervix and uterine corpus, clear morphologic and molecular genetic features of precursor lesions of ovarian carcinoma have not been defined yet. We can see an effort to describe preinvasive lesions to allow dia-gnostics and treatment prior to development of invasive ovarian cancer. This tendency is magnified by the fact that ovarian carcinomas have the highest mortality from all gynecological malignancies. Currently, reports confirming different morphology, pathogenesis and molecular alterations in heterogeneous group of ovarian carcinomas have been described. There is a tendency to divide epithelial malignant tumors into two groups. Low grade ovarian serous carcinoma, low grade endometrioid, clear cell, mucinous ovarian cancers and Brenner tumors of ovary are categorized as type I ovarian tumors. Highgrade serous carcinoma, undifferentiated carcinomas and malignant mixed mesodermal tumors of the ovary (MMMTs) belong to type II tumors. A potential precursor lesion of highgrade serous ovarian cancer has been defined - serous tubal intraepithelial carcinoma.

Abstract IA4: A dualistic model of ovarian carcinogenesis

Abstract Recent morphologic, immunohistochemical and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer (EOC) based on a dualistic model of carcinogenesis that divides EOC into two broad categories designated type I and type II. Type I tumors are comprised of low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary) and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN PIK3CA, ARID1A, and PPPR1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 and are relatively stable genetically. Type II tumors are comprised of high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promotor methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and as endometriosis is thought to develop from retrograde menstruation these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tubo-peritoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways, and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility. Citation Format: Robert J. Kurman. A dualistic model of ovarian carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA4.

Molecular alterations of PIK3CA in uterine malignant mesodermal mixed tumors and clear cell carcinomas

Objective: Uterine clear cell carcinoma (UCC) and uterine malignant mesodermal mixed tumor (UMMMT), also known as uterine carcinosarcoma, are rare but clinically aggressive histologic variants of endometrial carcinoma. The molecular alterations in the oncogenic P13K-alpha pathway have not been studied in detail in these subtypes. In prior studies, 80% of PIK3CA mutations were found in exons 9 and 20 and the remaining 20% were found in exons 1-7. Our objective was to analyze UCC and UMMMT cases for mutations in PIK3CA in exons 1-9 and 20.

Clinical and Ultrasound Features of Type I and Type II Epithelial Ovarian Cancer

The objective of this study was to assess whether there are differences on ultrasound features between epithelial ovarian cancer (EOC) type I and type II. This was a retrospective study comprising 244 women (mean age, 55.2 years old) with histologically proven EOC treated at our institution over a 12-year period. Clinical (patient age and symptoms and tumor stage), ultrasound (tumor volume, tumor appearance on gray-scale ultrasound, and color score), and histopathologic records were reviewed. Tumors were classified as EOC type I or type II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell, mucinous, and transitional cell carcinomas, whereas type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors, and undifferentiated carcinomas. Categorical variables were compared using χ(2) test. Continuous variables were compared using 1-way analysis of variance with Bonferroni post hoc test or Mann-Whitney U or Kruskal-Wallis test, depending on data distribution. Sixty-seven women (27.5%) had type I EOC, and 177 (72.3%) had type II EOC. We observed that women with type I EOC were younger, presented asymptomatic at diagnosis more frequently, and had lower CA-125 levels and lower tumor stage than women with type II EOC. Type II EOCs were more frequently identified as a solid mass and were smaller lesions than type I EOC. Some differences exist between type I and type II EOC in clinical and ultrasound manifestations. Although the clinical significance of these findings is still to be determined, this information could provide some clues to clinicians faced with the diagnosis of ovarian cancer.