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Representative histology of CS case CS1 showing separately dissected carcinoma and sarcoma foci. T# , dissected foci serially numbered; T1, carcinoma component;
Source publication
Carcinosarcomas of the uterus, ovaries, and fallopian tubes are highly aggressive neoplasms with incompletely understood histogenesis. Although recent immunohistochemical, cell culture, and molecular genetic studies all favor these cancers to be monoclonal in origin, the extent of intratumoral genetic heterogeneity in these tumors with divergent hi...
Contexts in source publication
Context 1
... foci were individually microdissected from each neoplasm (Fig. 1). In case CS1 and case CS21, metastatic foci were also microdissected. A total of 172 foci were microdissected from the 17 cases. Normal control tissue was also dissected from the adjacent nonmalignant stroma, epithelium, or inflammatory infiltrates. Microdissected tissue was digested overnight at 50°C in buffer containing 0.5% NP40, ...
Context 2
... of chromosomal loss (i.e., homogeneous or heterogeneous) in the different neoplastic components of the CSs are summarized in Fig. 6. Loss of several chromosomal arms (17p, 3p, 4q, 6q, 9p, 13q, and 22q) is relatively homogeneous throughout different regions of the tumors. These homogeneous patterns of LOH suggest that these genetic changes occurred relatively early in the clonal evolution of these neoplasms. Conversely, other chromosomal losses (10q, 11p, 11q, 1p, and 1q) were commonly seen in some but not all areas of the ...
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Loss of heterozygosity (LOH) analysis on chromosome 6 was performed to define the genetic changes that occur in the development of squamous cell cervical cancer (SCC). Detailed analysis with 28 microsatellite markers revealed several loci with high frequency of deletions at the short (6p25, 6p22, 6p21.3) and long (6q14, 6q16–q21, 6q23–q24, 6q25, 6q...
Citations
... The results of recent research in genetic and molecular levels concluded that carcinosarcoma are monoclonal in origin. [8][9][10][11] The primary reason of its malignant potential is due to its carcinomatous component rather than its sarcomatous element. 11 Recently, they are reclassified as part of differentiated malignant endometrial carcinoma instead of sarcoma. ...
Background Non puerperal Uterine inversion caused by a uterine carcinosarcoma is a very rare condition. Endometrial carcinoma is the 6 th most commonly occurring cancer in women and carcinosarcoma accounts for only 4.3%. 1 However it accounts for 15% of the mortality rate caused by uterine malignancies. 2
... The malignant epithelial component is most commonly a high-grade serous carcinoma (HGSC) but can be of any of the surface epithelial types including clear cell and endometrioid carcinoma, or a carcinoma with mixed/ hybrid morphology. The literatures have demonstrated that the carcinomatous and sarcomatous components are clonally related [2][3][4][5]; thus, these tumors should be best regarded as metaplastic carcinoma for which the sarcoma is considered as a result of epithelial-mesenchymal transition [6]. ...
... Carcinosarcomas are thought to be of epithelial origin with molecular studies showing identical TP53 mutations in the carcinomatous and sarcomatous components [2,4,5]. Like its ovarian counterpart, a study of 40 cases of uterine carcinosarcoma with metastasis demonstrated that 75% (30 of 40) of metastatic tumors were purely carcinoma [18]. ...
Skin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification.
... It is commonly believed that both components of MCS share a common origin, and monoclonal genetic changes can be identified in both carcinomatous and sarcomatous components. 13 However, the observation of loss of PAX8 and WT1 in carcinomatous component of this case further indicates the genetic and differentiation heterogeneity of MCS. Large scale study is needed to further characterize the immunophenotypic presentations of concurrent carcinomatous and sarcomatous components of MCS on cytology. ...
Introduction
Limited data is present to study the cytologic findings of MCS in serous fluid samples, and clinicopathologic features that are associated with cytology yield.
Methods
We studied 30 MCS patients diagnosed on surgical resection samples, and reviewed their cytomorphology and immunophenotypes on concurrent serous fluid cytology samples. Clinicopathologic features were also compared between cases with positive or negative cytology.
Results
Fourteen out of 30 patients showed positive cytology, including 12 patients with only carcinomatous components and 2 with sarcomatous cells. Cytomorphology of MCS was mostly consistent with adenocarcinoma, with psammoma bodies occasionally present. The 2 cases with sarcomatous cells showed spindle cells without signs of heterologous differentiation. PAX8 was positive in 10/11 cases, and WT1 was positive in 8/11 cases including the case with negative PAX8. In one case, PAX8 and WT1 were only positive in the sarcomatous but not in carcinomatous cells. MOC31 showed consistent positivity in carcinomatous cells, which appeared to be more sensitive than B72.3 (positive in 72.7%). In addition, sarcomatous cells showed CD10 positivity in one case. Clinically, patients who developed body cavity effusions or with higher stage diseases were more likely to have positive cytology.
Conclusion
Cytologic diagnosis of MCS in the serous fluid is challenging due to the rare presence of sarcomatous component. Staining both PAX8 and WT1 is recommended to confirm their Mullerian origin, although both markers may be positive only in sarcomatous cells. Cytology yield of MCS is highly associated with the disease stage.
... The transformation of carcinoma to sarcoma in these tumors resulted in sarcomatoid carcinomas, which were then termed carcinosarcomas when they demonstrated well-defined differentiation to sarcomatous tissues. The sarcoma and carcinoma components of these tumors both shared the same genetic alteration and were monoclonal, which has been demonstrated in patterns of clonality, genomic analysis, and loss of heterozygosity [18]. ...
Carcinosarcomas are biphasic tumors comprising carcinoma and sarcoma components that occur in many tissues but are rarely found in the orbit. A 70-year-old male presented to the ophthalmic clinic with progressive proptosis, having decreased vision in the left eye for 8 months. On examination, severe exophthalmos and lagophthalmos with limited extraocular movement were noted. Orbital computed tomography scans revealed a large, well-defined, heterogeneously enhanced mass in the left retrobulbar orbital cavity. The tumor was completely resected, and the pathological examination revealed a carcinosarcoma. The prognosis was excellent without local recurrence at 48 months postoperatively. Thus, when considering treatment for effective management of such tumors, tumor resection followed by radiotherapy or chemotherapy is highly recommended.
... High level HRD has been sensitive to inhibitors of a PARP [9,10]. IP regimen as well as paclitaxel and carboplatin, and bevacizumab have been used for ovarian CSs, but the results remained controversial [12,19]. The IP regimen and PARP inhibitor(s) have been effective in the present case. ...
... Uterine carcinosarcoma (UCS), an uncommon and highly aggressive tumor [1], is characterized by biphasic histology, with both carcinomatous and sarcomatous components. Tumorigenesis of UCS has been explained by the conversion theory based on immunohistochemical and molecular studies [2,3] UCS is a challenging tumor to treat; 61% of patients Hiroshi Yoshida and Tadaaki Nishikawa contributed equally to this work. display the disease confined to the uterine corpus but were found to have occult metastasis during comprehensive staging [4]. ...
Uterine carcinosarcoma (UCS) is an uncommon and highly aggressive tumor. There is no HER2 testing protocol for UCS despite the development of HER2 antibody conjugates. We aimed to elucidate histopathological HER2 expression details in UCS, to compare HER2 scores between ASCO/CAP criteria for gastric and breast cancer, and to propose requirements for HER2 testing for UCS. Eighty-nine specimens from 84 patients with metastatic/recurrent UCS were prospectively collected from May 2018 to July 2020. We performed HER2 immunohistochemistry (IHC) for 89 specimens and FISH for 44 specimens. HER2 expression details and HER2 score were evaluated according to the latest ASCO/CAP criteria for gastric (2016) and breast cancer (2018). HER2 IHC scores according to the gastric cancer criteria were 0 in 31 cases (35%), 1+ in 26 (29%), 2+ in 22 (25%), and 3+ in 10 cases (11%) of the 89 specimens. A lateral/basolateral membranous staining pattern was observed in 28/32 (88%) specimens with HER2 scores of 2+/3+. HER2 intratumoral heterogeneity was identified in 28/32 (88%) of the specimens with HER2 scores of 2+/3+. The overall concordance rate of HER2 score was 70% between the gastric and breast criteria. FISH revealed HER2 gene amplification in 10/44 (23%) specimens containing only lateral/basolateral membranous staining pattern. Based on the histopathological features of HER2 expression in UCS, a scoring system that accepts lateral/basolateral staining patterns should be applied. Furthermore, we proposed specific requirements for UCS testing, including specimen selection, scoring system, and calculating the proportion of HER2-positive cells.
... TP53, as well as the presence of MSI or loss of heterozygosity (LOH) are shared between both of them (Abeln et al., 1997;Fujii et al., 2000;Gallardo et al., 2002;Kounelis et al., 1998;Wada et al., 1997;Thompson et al., 1996). Moreover, similar karyotype abnormalities and c-MYC amplifications have been also described in vitro in carcinomatous and sarcomatoid subclones of UCS cells (Emoto et al., 1997). ...
Uterine carcinosarcoma (UCS), also known as malignant mixed Müllerian tumor, is a rare gynecological malignancy characterized by poor prognosis. This “biphasic” neoplasm presents an admixture of epithelial and mesenchymal/sarcomatoid tumor cells which partially share their molecular signature and exhibit a typical epithelial-to-mesenchymal transition gene expression profile. Due to the rarity of this cancer, at present there is a scarcity of specific treatment guidelines. Surgical resection remains the best curative option for localized disease, whereas the addition of peri-operative radiotherapy, chemotherapy and chemoradiation has been shown to further improve disease outcomes. In the metastatic setting, palliative chemotherapy is currently the treatment of choice, although no consensus exists about the best regimen to be delivered. Besides standard treatment options for the advanced disease, mechanistic insights into UCS pathogenesis and identification of its histopathological and molecular features boosted the development of novel, and potentially more effective, therapeutic agents, that will be here discussed.
... At present the last one postulating the sarcoma derives from carcinoma has been favored [17] [18]. Recent immunohistochemical and molecular findings support this hypothesis, which the OCS represent metaplastic carcinoma [19] [20]. Clonality studies pattern, genomic analysis and loss of heterozygosity studies have shown that carcinomatous and sarcomatous components of OCS share common genetic alterations and are monoclonal [19]. ...
... Recent immunohistochemical and molecular findings support this hypothesis, which the OCS represent metaplastic carcinoma [19] [20]. Clonality studies pattern, genomic analysis and loss of heterozygosity studies have shown that carcinomatous and sarcomatous components of OCS share common genetic alterations and are monoclonal [19]. In addition, carcinomatous component showed positive reaction for CK7 and negative for CK20, suggesting a Müllerian origin [21]. ...
... In this case, BRCA1/2 mutations could not be found, suggesting that OCS cells were not sensitive to PARP inhibitors. As the first line chemotherapy for OCS, IP regimen as well as TC and bevacizumab have been used, but the results remained controversial [10] [19]. In the present case, even though four courses of TC and bevacizumab were treated as the first line chemotherapy, serum CA125 increased. ...
Ovarian carcinosarcoma composed of high-grade carcinoma and sarcoma is an extremely rare neoplasm and typically occurs in postmenopausal women aged over 60 years. A 73-year-old female, gravida three para three, presented to our hospital with right lower abdominal pain. Right pelvic solid tumor with ascites was detected on pelvic ultrasound examination. She underwent hysterectomy, bilateral salpingo-oophorectomy and partial omentectomy, but the tumor had invaded to the right ureter, and some fragile tumor could not be taken (sub-optimal surgery). On the imprint and ascitic cytology specimens
during operation, atypical cells suggestive of adenocarcinoma and spindle atypical cells with immunocytochemically vimentin positive were found. The resected tumor was histopathologically carcinosarcoma consisted of serous adenocarcinoma, chondrosarcoma and fibrosarcoma. Immunohistochemical analysis revealed that adenocarcinoma cells were positive for AE1/AE3 and fibrosarcoma cells stained with vimentin. The final diagnosis was the right ovarian carcinosarcoma (stage pT3CNxMx). Microsatellite instability was stable and BRCA1/2 mutations could not be found in the carcinosarcoma cells. The patient was given four cycles of chemotherapy with paclitaxel, carboplatin and bevacizumab regimen, and thereafter she was treated with the ifosfamide and cisplatin because of slight elevation of serum CA125.
... At present the last one postulating the sarcoma derives from carcinoma has been favored [17] [18]. Recent immunohistochemical and molecular findings support this hypothesis, which the OCS represent metaplastic carcinoma [19] [20]. Clonality studies pattern, genomic analysis and loss of heterozygosity studies have shown that carcinomatous and sarcomatous components of OCS share common genetic alterations and are monoclonal [19]. ...
... Recent immunohistochemical and molecular findings support this hypothesis, which the OCS represent metaplastic carcinoma [19] [20]. Clonality studies pattern, genomic analysis and loss of heterozygosity studies have shown that carcinomatous and sarcomatous components of OCS share common genetic alterations and are monoclonal [19]. In addition, carcinomatous component showed positive reaction for CK7 and negative for CK20, suggesting a Müllerian origin [21]. ...
... In this case, BRCA1/2 mutations could not be found, suggesting that OCS cells were not sensitive to PARP inhibitors. As the first line chemotherapy for OCS, IP regimen as well as TC and bevacizumab have been used, but the results remained controversial [10] [19]. In the present case, even though four courses of TC and bevacizumab were treated as the first line chemotherapy, serum CA125 increased. ...
Ovarian carcinosarcoma composed of high-grade carcinoma and sarcoma is an extremely rare neoplasm and typically occurs in postmenopausal women aged over 60 years. A 73-year-old female, gravida three para three, presented to our hospital with right lower abdominal pain. Right pelvic solid tumor with ascites was detected on pelvic ultrasound examination. She underwent hysterectomy, bilateral salpingo-oophorectomy and partial omentectomy, but the tumor had invaded to the right ureter, and some fragile tumor could not be taken (sub-optimal surgery). On the imprint and ascitic cytology specimens during operation, atypical cells suggestive of adenocarcinoma and spindle atypical cells with immunocytochemically vimentin positive were found. The resected tumor was histopathologically carcinosarcoma consisted of ser-ous adenocarcinoma, chondrosarcoma and fibrosarcoma. Immunohisto-chemical analysis revealed that adenocarcinoma cells were positive for AE1/AE3 and fibrosarcoma cells stained with vimentin. The final diagnosis was the right ovarian carcinosarcoma (stage pT3CNxMx). Microsatellite instability was stable and BRCA1/2 mutations could not be found in the carci-nosarcoma cells. The patient was given four cycles of chemotherapy with pac-litaxel, carboplatin and bevacizumab regimen, and thereafter she was treated with the ifosfamide and cisplatin because of slight elevation of serum CA125.
... Unfortunately, 80% of patients with advanced/recurrent disease succumb within two years [4][5][6]. UCS is characterized by biphasic tumors composed of epithelial and mesenchymal elements and demonstrated to be of monoclonal origin [2,[7][8][9][10], hence epithelial to mesenchymal transition (EMT) is considered a critical cellular process responsible for poor prognosis and therapy resistance [11,12]. ...
Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGFβ signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.
