High-grade Endometrial Sarcoma Research Articles

Endometrial Sarcoma Metastasis to the Pterygopalatine Fossa: A Case Report and Review of the Literature.

Metastatic skull base malignancies infrequently occur but, when present, typically arise from breast malignancies. Pterygopalatine fossa (PPF) metastasis of any malignancy is further seldom reported, and metastasis of gynecologic malignancies to the PPF has not been previously described in the literature. We present a single case of a 42-year-old female with the first likely case of high-grade endometrial sarcoma metastatic to the PPF. The patient presented with facial pain and numbness in the V2 distribution presented for evaluation. History was significant for several months of dysmenorrhea and metrorrhagia. Computed tomography, magnetic resonance imaging, and positron emission tomography imaging revealed a PPF mass with local extension and bony metastases. Endoscopic biopsy was performed, and final pathology was most consistent with metastatic high-grade endometrial stromal sarcoma. This is the first reported case of likely metastatic endometrial sarcoma to the PPF. This case report highlights the possibility of rare distant metastasis of gynecologic malignancy to this area of the skull base.

Hormonal therapies in uterine sarcomas, aggressive angiomyxoma, and desmoid-type fibromatosis.

We review the role of hormonal therapy in the management of different conjunctive tumors. Progestin and aromatase inhibitors seem active in low-grade endometrial stromal sarcoma, but larger case-series are needed. There is no evidence to support the use of hormonal therapy as an adjuvant treatment for low-grade endometrial stromal sarcoma. We did not find relevant data on the use of hormonal therapy for other uterine sarcomas (e.g., high-grade endometrial sarcoma, undifferentiated uterine sarcoma, and adenosarcoma). Gonadotropin-releasing hormone agonist, anti-estrogens and aromatase inhibitor seem active in advanced aggressive angiomyxoma, but larger studies are warranted. The use of aromatase inhibitor in estrogen-receptor-positive uterine leiomyosarcoma requires further clinical investigation. There is no evidence supporting the use of hormonal therapy in desmoid-type fibromatosis. International collaboration efforts are warranted to better explore the role of hormonal therapies in management of estrogen-receptor-positive uterine leiomyosarcoma, low-grade endometrial stromal sarcoma, and aggressive angiomyxoma.

Vascular invasion in uterine sarcomas and its significance. A multi-institutional study

Although metastases and high-mortality are frequent in high-grade endometrial sarcomas (HGSs), these findings are less commonly seen in low-grade endometrial stromal sarcomas (LGESSs), even in cases with lymphovascular invasion (LVI). We hypothesized that the "bulging plugs" of tumor characteristic of LVI in LGESS are fundamentally different from LVI seen in HGS. We reviewed 70 uterine sarcomas: 42 HGSs (high-grade endometrial stromal sarcomas, undifferentiated uterine sarcoma, and leiomyosarcoma) and 28 LGESSs. All cases had LVI documented on the histologic slides. Immunostains for CD31, ERG, and D2-40 were performed. LGESS harbored cohesive intravascular tumor foci with direct communication from the main tumor and attached to the vessel wall. The intravascular foci included tumor cells and small arteriole-type vessels and were surrounded by a thin fibrous band. Vascular markers confirmed the LVI and highlighted positively stained endothelial cells separating intravascular tumor foci from the blood itself. In contrast, intravascular tumor foci in HGS were composed of discohesive cells clusters, lacking the features described in LGESS. Only 8 (30.8%) patients with LGESS had recurrence/metastases (6 with lung metastasis); only 1 patient died of disease. Thirty (77%) patients with HGS had recurrence/metastases, 27 (69%) patients had lung metastases, and 22 (56.4%) patients died of disease. We propose that in most LGESSs, LVI represents vascular intrusion; manipulation or trauma is potentially responsible for tumor cell detachment into the circulation increasing the chances of recurrence/metastases. Classic LVI features were identified in HGS. This important distinction may allow for better management of patients and avoid unnecessary treatment in LGESS, reducing morbidity.

Novel Karyotypes and Cyclin D1 Immunoreactivity in Clear Cell Sarcoma of the Kidney.

Pathological diagnosis of clear cell sarcoma of the kidney (CCSK) is challenging as it resembles blastemal Wilms tumor (WT) and other pediatric sarcomas, and does not have any distinctive immunophenotype. The YWHAE-FAM22 translocation t(10;17)(q22;p13) has been reported in a subset of CCSK. This translocation also occurs in high-grade endometrial sarcoma, in which it is associated with cyclin D1 overexpression. Hence we seek to determine YWHAE-FAM22 translocation status and cyclin D1 immunoreactivity in a series of local CCSK cases. Of 8 CCSK cases from 7 patients identified, no CCSK had the YWHAE-FAM22 fusion transcript by reverse transcriptase-polymerase chain reaction. Novel karyotypes were identified for 2 cases: 1 had t(2;13)(q13;q22) and the other t(3:17)(q29;p11.2). Excluding a case with poor tissue section antigenicity, 7 of 7 CCSKs (100%) showed diffuse and strong nuclear cyclin D1 staining. Cyclin D1 immunohistochemistry was also performed on tissue microarrays of other pediatric renal tumors: blastemal areas of 18 WT cases were negative; 6 rhabdoid tumors and 1 metanephric adenoma showed patchy and weak staining; 3 mesoblastic nephromas and 18 of 29 neuroblastomas had positive staining. Cyclin D1 immunohistochemistry helps distinguish CCSK from blastemal WT and metanephric adenoma and rhabdoid tumors, but not from neuroblastomas and mesoblastic nephromas. Cyclin D1 overexpression in CCSK is not contingent on YWHAE-FAM22 translocation, and cyclin D1 inhibition may potentially be explored as a targeted therapeutic strategy in CCSK.

Gynecologic Cancer InterGroup (GCIG) consensus review for high-grade undifferentiated sarcomas of the uterus.

High-grade undifferentiated sarcomas (HGUSs) are rare uterine malignancies arising from the endometrial stroma. They are poorly differentiated sarcomas composed of cells that do not resemble proliferative-phase endometrial stroma. High-grade undifferentiated sarcomas are characterized by aggressive behavior and poor prognosis. Cyclin D1 has been reported as a diagnostic immunomarker for high-grade endometrial stromal sarcoma with an YWHAE-FAM22 rearrangement. YWHAE-FAM22 endometrial stromal sarcomas (ESS) represent a clinically aggressive subtype of ESS classified as high-grade endometrial sarcomas, and its distinction from the usual low-grade ESS with JAZF1 rearrangement and from HGUS with no identifiable molecular aberration may be important in guiding clinical management. Median age of the patients is between 55 and 60 years. The most common symptoms are vaginal bleeding, abdominal pain, and increasing abdominal girth.Disease is usually advanced with approximately 70% of the patients staged III to IV according to the International Federation of Gynecology and Obstetrics classification. Preferential metastatic locations include peritoneum, lungs, intra-abdominal lymph nodes, and bone. Median progression-free survival ranged from 7 to 10 months, and median overall survival ranged from 11 to 23 months. There is no clear prognostic factor identified for HGUS, not even stage. The standard management for HGUS consists of total hysterectomy and bilateral salpingo-oophorectomy. Systematic lymphadenectomy is not recommended. Adjuvant therapies, such as chemotherapy and radiotherapy, have to be discussed in multidisciplinary staff meetings.

YWHAE rearrangement identified by FISH and RT-PCR in endometrial stromal sarcomas: genetic and pathological correlations

Endometrial stromal sarcomas represent the second most common mesenchymal uterine tumor. The 2003 WHO classification distinguishes low-grade and undifferentiated endometrial stromal sarcomas with different prognoses. Endometrial stromal sarcomas are a genetically heterogeneous group of sarcomas harboring different cytogenetic anomalies. Recently, a fusion between the YWHAE and FAM22A/B genes subsequent to a t(10;17) (q22;p13) has been described in endometrial sarcomas with high-grade histology. We examined YWHAE rearrangements by FISH break-apart and RT-PCR in a series of 27 undifferentiated uterine stromal sarcoma without JAZF1 rearrangements. Immunohistochemistry (IHC) was carried out with a panel of antibodies (estrogen (ER) and progesterone (PR) receptors, CD10, Cyclin D1, β-catenin, p53, and Ki-67). We identified a subgroup of endometrial sarcomas with high-grade histology and uniform morphology harboring YWHAE rearrangements. FISH break-apart was interpretable in 20 cases (74%). Twelve cases (60%) showed <10% of tumor cells with a YWHAE rearrangement, 4 cases (20%) showed between 10 and ≤20%, and 4 (20%) >20%. RT-PCR was tested on 24/27 cases (88%) and 19 cases were interpretable (79%). Five cases (26%) showed a specific fusion transcript YWHAE–FAM22A/B sequence. The best concordance rate between FISH and RT-PCR (94%) was obtained with the threshold of 20% of cells with a YWHAE rearrangement. The YWHAE-rearranged cases showed high-grade morphology with uniform appearance, spindle or round epithelioid cells, low ER and PR, CD10 expression, and a high and diffuse positivity for Cyclin D1, p53, and nuclear β-catenin negativity. Cyclin D1 was the most sensitive marker for high-grade endometrial sarcomas with YWHAE rearrangement. All undifferentiated uterine sarcomas with pleomorphic appearances did not harbor any YWHAE rearrangements, except for one case. Overall, for endometrial sarcoma cases with high-grade morphology we recommend to test for YWHAE rearrangements by FISH break-apart, a cost- and time-efficient method, and to complete the investigation by RT-PCR in borderline cases.

The high-grade endometrial sarcoma: a rare entity

With an estimated incidence of one to two per one million women, the endometrial stromal sarcoma (ESS) is a rare disease. It is subclassified into a high-grade and a prognostically better low-grade type. Evidence-based data for a standardized therapy is lacking. A 32-year-old obese nulligravida presented with persistent vaginal bleeding after the operation of an acute adnextorsion at another hospital. The repeat gynecological ultrasound examination showed a 5.3x5.3x3.6 cm vascularized, partially inhomogeneous mass in the uterus. A fractioned curettage yielded a differential diagnosis of malignant muellerian mixed tumor or a non-differentiated endometrial sarcoma. For completion of the operative treatment, laparotomy with hysterectomy, adnexectomy, and pelvine lymphonodectomy were performed. The final histological report described a 7 cm non-differentiated endometrial sarcoma with infiltration of the left ovary and 25 tumor-free lymph nodes. Standard therapy for resectable sarcoma is abdominal hysterectomy and bilateral adnexectomy. So far, there is little data from studies reporting radio- or chemotherapy treatment of small patient numbers in an adjuvant setting. The ESS is a very rare disease of the uterus. Due to missing clinical data, it remains a multidisciplinary therapeutic challenge requiring individual decisions. To receive more information on this rare disease, treatment should be performed according to international protocols.

Imatinib Mesylate (Gleevec)-Targeted Kinases Are Expressed in Uterine Sarcomas

The purpose of this study was to determine whether 3 tyrosine kinases known to be inhibited by imatinib mesylate are expressed in a variety of uterine sarcomas. The authors assessed c-kit, abl, and platelet-derived growth factor receptor-beta (PDGFR-beta) expression in 8 endometrial stromal sarcomas (ESSs), 5 leiomyosarcomas (LMSs), 4 high-grade endometrial sarcomas (HGESs), and 21 malignant mixed mullerian tumors (MMMTs). Tissue sections were stained with commercially available antibodies for c-kit, abl, and PDGFR-beta. Staining intensity was described as 0 (no staining), +1 (weak), +2 (moderate), and +3 (strong). Positive staining was defined as moderate to strong if found in more than 10% of tumor cells. Expression of c-kit ranged from 0% in LMSs to 25% in HGESs. Protein expression of abl was more significant, ranging from 25% in LMSs and ESSs to 43% in MMMTs. Only 1 LMS sample stained focally for abl (+1). Abl expression was observed in only the carcinomatous elements of the MMMTs, with diffuse staining in the cytoplasm and nucleus. In most, the staining intensity was +2. All tumors stained positive for PDGFR-beta. MMMT samples showed PDGFR-beta expression in both the carcinomatous and sarcomatous portions. In all samples, staining for PDGFR-beta was concentrated at the cell membrane and diffusely in the cytoplasm. These results indicate that many uterine sarcomas express 1 or more of the kinases targeted by imatinib mesylate and that further investigation of imatinib as a therapy for uterine sarcomas is warranted.

Expression of androgen receptors in benign and malignant endometrial stromal neoplasms.

Several studies have shown that endometrial stromal neoplasms express estrogen and progesterone receptors (ER, PR). To our knowledge, the presence or absence of androgen receptors (AR) in these rare uterine neoplasms has not been investigated. Tumors ( n=20)-3 endometrial stromal nodules, 14 low-grade endometrial stromal sarcomas (ESS, low grade), and 3 high-grade endometrial sarcomas (undifferentiated endometrial sarcoma, UES)-were studied. Immunohistochemical analyses for ER, PR, and AR were performed on formalin-fixed, paraffin-embedded archival material. Positive immunoreactions for ER and PR were observed in 14 (70%) and 17 (85%) cases, respectively. Furthermore, 9 cases (45%) were positive for AR. Among 17 ESS and UES cases, 7 (41%) revealed positivity for AR. Two of three benign stromal nodules were also positive for AR. Moreover, one of the three high-grade sarcomas (undifferentiated endometrial sarcoma) was negative for both ER and PR, but showed positive reaction for AR. In summary, ARs are expressed in 45% of endometrial stromal neoplasms. In addition to determination of ER and PR, the results of immunohistochemical examination of AR in these rare uterine tumors may have some impact on the postoperative management of the patients.

Expression of CD10 in Malignant Müllerian Mixed Tumors and Adenosarcomas: An Immunohistochemical Study

CD10 has been demonstrated to be positive in endometrial stromal sarcoma (ESS) and thus is useful in establishing the diagnosis, but its expression in malignant müllerian mixed tumor (MMMT) and müllerian adenosarcoma remains to be clarified. In this study, 12 cases of MMMT (9 uterine, 2 tubal, and 1 metastatic), 6 cases of müllerian adenosarcoma (three corporeal, two cervical, and one tubal), and 7 cases of primary uterine sarcomas had their tissues examined immunohistochemically for expression of CD10, desmin, myoglobin, α-smooth muscle actin (SMA), and cytokeratin. Of the primary uterine sarcomas, two were primary rhabdomyosarcomas (one cervical and one corporeal), two were ESSs, two were high-grade leiomyosarcomas, and one was a high-grade endometrial sarcoma. Sarcomatous components in all cases of MMMT and müllerian adenosarcoma, as well as all uterine sarcomas, were positive for CD10, showing moderate to marked staining intensity with varying distribution except in one MMMT, which showed weak and very focal staining. In four MMMTs, three adenosarcomas, and one rhabdomyosarcoma, myoglobin- and/or desmin-positive rhabdomyoblastic cells were positive for CD10. The immunoreactivity for CD10 showed the same distribution for α-SMA and myoglobin in three and two MMMTs, respectively. In five cases of MMMT, carcinomatous components were focally positive for CD10, and in two cases small populations of round or short spindle cells in sarcomatous components were positive for CD10, α-SMA, and cytokeratin (CAM5.2). These results indicate that CD10 expression is not restricted to ESS but can be positive in MMMT and müllerian adenosarcoma as well as in a variety of uterine tumors including high-grade leiomyosarcoma and rhabdomyosarcoma. CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.