NTRK and other recently described kinase fusion positive uterine sarcomas: A review of a group of rare neoplasms.

The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.

Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.

OBJECTIVE: Endometrial stromal sarcoma (ESS) is a rare uterine malignancy. The current treatment approaches yield unsatisfactory results, and potential therapeutic targets need exploration. METHODS: We reviewed the electronic medical records of 74 patients with low-grade ESS who had been evaluated at the University of Texas MD Anderson Cancer Center between 1995 and 2006. Using immunohistochemistry, we tested the expression of targets in paraffin-embedded tissue samples taken from 13 of the patients. RESULTS: Forty-seven patients (64%) had a recurrence, and 16 (22%) had died of their disease at last follow-up. The 10-year progression-free survival (PFS) rate was 43% (median PFS duration, 108months), and the overall survival (OS) rate was 85% (median OS, 288months). Patients who received hormonal therapy had an overall response rate of 27%; another 53% had stable disease, with a median time to progression of 24months. No complete response or partial response was observed among patients who received radiotherapy or chemotherapy. In the paraffin-embedded specimens we tested, c-abl was expressed universally. Expression of PDGF-α, PDGF-ß, VEGF, and c-Kit was detected in 33%, 36%, 54%, and 8%, of specimens, respectively. EGFR and HER-2 were not detectable in any specimens. CONCLUSIONS: Our study suggests that ESS is a hormone-dependent malignancy, with hormonal therapy having activity in recurrent disease. Targeted therapy, specifically targeting c-abl may be a potential treatment for this disease.

Estrogen sulfotransferase expression in endometrial stromal sarcomas: an immunohistochemical study.

Levels and activity of the enzyme estrogen sulfotransferase (EST) have been reported to play an important role in the regulation of in situ estrogen levels in human breast, prostate, and endometrial cancer. To better understand growth progression in endometrial stromal sarcomas (ESS), estrogen-dependent tumors, we analyzed the expression of EST in a series of 29 ESS. Archival formalin-fixed, paraffin-embedded material was analyzed immunohistochemically with a monoclonal antibody to EST using the peroxidase-antiperoxidase method. A score was calculated based on the percentage of positive tumor cells and staining intensity. EST staining was identified in 5 of 29 (18%) ESS and was scored as weakly positive, while 24 of 29 (82%) ESS were negative for EST. We demonstrate that a subset of ESS express EST, which may allow them to inactivate intratumoral estrogens. ESS without EST expression may have increased levels of biologically active estrogen, which explains the tumor progression of this entity and these patients may be at increased risk for recurrences and metastases.

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells.

Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class I HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G1-S transition and influencing expression of p21WAF1 and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21WAF1 was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS.

Aromatase expression in low-grade endometrial stromal sarcomas: an immunohistochemical study.

Aromatase expression has been described in stromal cells of endometriosis, adenomyosis and endometrial cancer. We analyzed aromatase expression in a series of 23 low-grade endometrial stromal sarcomas. Archival formalin-fixed and paraffin-embedded material was analyzed with immunohistochemistry. Aromatase expression was evaluated with a monoclonal and a polyclonal antibody using the peroxidase-antiperoxidase method. A score was calculated based on the percentage of positive tumor cells and the staining intensity. Aromatase was seen in 19 (83%) of 23 tumors with monoclonal antibody and 20 (87%) of 23 tumors with polyclonal antibody. Aromatase expression using the monoclonal antibody was scored as high in five (22%), moderate in nine (39%) and low in five (22%) tumors. Four (17%) low-grade endometrial stromal sarcomas did not stain for aromatase. Aromatase expression with the polyclonal antibody was scored as high in seven (31%), moderate in four (17%) and low in nine (39%) tumors. Three (13%) low-grade endometrial stromal sarcomas did not stain for aromatase. Little or no aromatase expression tended to correlate with stage I disease, while higher scores were more frequently associated with advanced disease. Our results demonstrate that most low-grade endometrial stromal sarcomas express aromatase. The staining pattern, however, is heterogeneous. The high percentage of aromatase positivity in low-grade endometrial stromal sarcomas may have implications in the management of these tumors and offer new treatment modalities such as hormonal therapy with aromatase inhibitors.

Expression of metalloproteinases endometrial stromal sarcoma: immunohistochemical study using image analysis.

AIM: To investigate the expression of matrix metalloproteinases (MMP), a group of proteolytic enzymes with a central role in extracellular matrix invasion and degradation, in stromal sarcomas. METHODS: 11 endometrial stromal sarcomas (four low grade tumours, seven high grade) were stained for MMP-2, MMP-3, and MMP-9 using immunohistochemical stains. The surgical material consisted of nine hysterectomy specimens and two pelvic recurrences. Three hysterectomy specimens, removed for leiomyomas, were studied as controls. Staining area was evaluated using image analysis. RESULTS: Age at the time of diagnosis ranged from 21 to 67 years. Four of the 11 patients (three with high grade tumours and one with a low grade tumour) died of the disease, six remained free of disease, and one was lost to follow up. Staining for MMP-2, MMP-3, and MMP-9 was more diffuse in high grade tumours than in low grade tumours and controls. Staining for MMP-3 and MMP-9 was more pronounced in high grade than in low grade tumours (p = 0.04; p = 0.05). Staining for MMP-9 was significantly greater in all stromal sarcomas than in controls (p < 0.001 for high grade tumours v controls; p < 0.01 for low grade tumours v controls). Diffuse staining for MMP-2, exceeding 90% of the tumour area, was observed in three of seven high grade tumours but in no low grade tumours. There was no apparent correlation between staining for any of the three enzymes and survival. CONCLUSIONS: Both low and high grade endometrial stromal tumours express matrix metalloproteinases. MMP-3 and MMP-9 are expressed more diffusely in high grade than in low grade tumours. In the individual case, diffuse staining for MMP-2 appears to best characterise the high grade tumours. Thus staining for MMP-2 may aid in differentiating high grade from low grade tumours, and MMP-9 in differentiating normal endometrial stroma from low and high grade endometrial stromal sarcomas. MMP expression does not appear to predict disease outcome in endometrial stromal sarcoma.

Pulmonary metastatic lesion of endolymphatic stromal myosis expresses metastasis-related genes but not invasion-related matrix type metalloproteinase.

A case of endolymphatic stromal myosis (ELSM) with multiple metastasis to lungs was studied. A single biopsy specimen from the lung was analyzed for c-erbB-2, CD44E, and autocrine motility factor receptors (AMFR) mRNA expression, all putatively associated with metastasis. Estrogen and progestin receptors (ER, PR) expression were studied by reverse transcription polymerase chain reactions. Expression of an invasion-related gene, membrane type matrix metalloproteinase (MT-MMP) was also studied. The metastatic lesion showed positive expression of c-erbB-2, CD44E, AMFR, PR and ER expression, whereas no expression of MT-MMP was detected. These results correspond with the present clinical history that is early and multiple lung metastasis but essentially benign in nature and with excellent response to gestagen treatment.