Metastatic Endometrial Stromal Sarcoma Research Articles

822TiP BFR ESS: A randomized phase II trial from the GSF/GETO French group evaluating the impact of interruption versus maintenance of aromatase inhibitors in patients with advanced or metastatic low grade endometrial stromal sarcoma after at least 3 years of therapy

Uterine sarcomas are rare tumors with an incidence of 1.7/100 000 women per year, including 20% of endometrial stromal sarcomas (ESS). Patients (pts) with low grade ESS (LGESS) have a good prognosis with 5-year overall survival rates ranging from 66 to 98%, depending on the stage of the disease. Unlike undifferentiated endometrial sarcoma (UES), which behave aggressively, LGESS are indolent. For advanced or metastatic stage, hormonal therapy (HT) is the standard of care. The use of HT for advanced or metastatic disease is recommended based on retrospective data from small series providing evidence that HT have an anti-tumor activity on LGESS.

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.

Metastatic low-grade endometrial stromal sarcoma of uterus presenting as a primary pancreatic tumor: case presentation and literature review

BackgroundMetastatic tumors to the pancreas are uncommon, accounting for approximately 2% of pancreatic malignancies. The most common primary tumors to give rise to pancreatic metastases are carcinomas.Case presentationA 50-year old female patient was investigated for a cause of abdominal discomfort. She had a 2-year history of menorrhagia and dysmenorrhea which was ascribed to a fibroid uterus. On imaging, she was found to have a large solid and cystic mass in the tail of the pancreas. Imaging also confirmed a fibroid uterus. A distal pancreatectomy and splenectomy showed a 9 cm circumscribed mass within, and grossly confined to, the parenchyma of the pancreatic tail.Microscopically, the pancreatic lesion was lobulated, and well-circumscribed, but focally infiltrative. It comprised sheets of uniform spindled to epithelioid cells with round to oval nuclei, coarse to vesicular chromatin, visible nucleoli, nuclear grooves and clear to eosinophilic cytoplasm. Prominent arterioles were identified. The stroma was collagenized in areas. Occasional hemosiderin-laden macrophages were seen, and focal cystic change was present. There was no evidence of nuclear pleomorphism, mitotic activity or necrosis, and there was no evidence of endometriosis despite multiple sections being taken. Immunohistochemistry showed that the tumor cells were positive for CD10, estrogen receptor (ER), progesterone receptor (PR), Wilms tumor-1 (WT-1) and smooth muscle actin (SMA). RNA sequencing detected a PHF1 rearrangement.The morphological, immunohistochemical and molecular features were of a low-grade endometrial stromal sarcoma (LG-ESS). Subsequent total hysterectomy and bilateral salpingo-oophorectomy 3 months later, showed uterine fibroids and a 5 cm low-grade endometrial stromal sarcoma confined to the uterus, with lymphatic invasion.ConclusionsTo the best of our knowledge, this is the first documented case of metastatic endometrial stromal sarcoma of uterus presenting as a primary pancreatic neoplasm. An unexpected extra-uterine location and unusual presentation of ESS may make the diagnosis challenging, despite classic histological features. Morphological, immunohistochemical and molecular findings must be combined to render the correct diagnosis.

Diagnostic challenge between placental transmogrification and low-grade endometrial stromal sarcoma metastases in a patient with cavitary pulmonary nodules

Cystic lung lesions have limited differential diagnosis, which includes pulmonary Langerhans cell histiocytosis (LCH), lymphangioleiomyomatosis (LAM), lymphocytic interstitial pneumonitis (LIP), tracheobronchial papillomatosis, and Birt-Hogg-Dube syndrome. However, a few rare entities such as pulmonary placental transmogrification (PPT) and metastatic endometrial stromal cell sarcoma (ESS) also can present as cystic lung lesions and pose diagnostic challenges to both radiologists and pathologists. Clinical history is the key in such situations. Since the first description in the literature of these both entities, there have been very few cases reported. We present our case in a middle-aged female who was known to have cystic lung disease but treated as LAM and had a recurrent pneumothorax. Surgical pathology ruled out LAM and other interstitial cystic lung diseases and provided a diagnosis of PPT on wedge resection. Subsequent recurrence of cystic lung nodules led to the re-examination of histopathology and immunohistochemistry, concluding a diagnosis of metastasis from remote but undiagnosed low-grade stromal cell sarcoma. We will discuss the clinical, imaging and pathologic features of both of the diagnoses in this report. Institutional review board approval was not required since it was a single patient report.

Extrapelvic Metastases in Endometrial Stromal Sarcomas: A Clinicopathological Review With Immunohistochemical and Molecular Characterization.

Endometrial stromal sarcoma is a rare uterine tumor associated with favorable outcomes despite its ability to recur and metastasize to distant sites. Most recurrences are local, being limited to the abdomen/pelvis, but distant metastases can occur. Metastatic endometrial stromal sarcoma can occur many months to years after the original diagnosis or may present prior to the primary, potentially creating a diagnostic challenge. We report a bi-institutional review of 10 cases of endometrial stromal sarcoma with extrapelvic metastases without a prior history of endometriosis. The histologic, immunophenotypic, and molecular characteristics of these tumors are analyzed in the context of a relevant literature review.

Low-grade Endometrial Stromal Sarcoma with Unusual Metastasis to the Skull

Background Endometrial stromal sarcomas (ESSs) are the second most common uterine sarcomas. Although ESSs are often indolent, they have metastatic potential. To the best of our knowledge, there are only three reports of brain metastasis, and the present report is the first to describe a late skull metastasis of an ESS. Case Report We describe the case of a 51-year-old woman who presented abnormal vaginal bleeding 14 years ago; she was diagnosed with an uterine mass and submitted to a hysterectomy. One year ago she presented ESS lung metastasis followed by a left parietal calvarial metastasis. The optimal treatment for metastatic ESS is controversial, but the use of progesterone and aromatase inhibitors is advisable.

Cytologic Features of Metastatic Endometrial Stromal Sarcoma and Undifferentiated Endometrial Sarcoma

Cytologic Features of Metastatic Endometrial Stromal Sarcoma and Undifferentiated Endometrial Sarcoma

Hormonal treatments in metastatic endometrial stromal sarcomas: the 10-year experience of the sarcoma unit of Royal Marsden Hospital.

BackgroundHormonal manipulation is sometimes recommended in the treatment of metastatic endometrial stromal sarcoma, but there are few data assessing the efficacy of endocrine therapies in this subtype of uterine sarcomas.MethodsWe performed a retrospective electronic medical record review of patients with metastatic ESS treated with a hormonal agent at Royal Marsden Hospital between 1999 and 2011. We assessed progression-free survival (PFS), objective response and toxicity profile among patients with measurable disease.ResultsThirteen patients with metastatic ESS were treated with hormonal therapies. Hormone receptor status (estrogen and progesterone receptors) was assessed in 9 out of 13 patients and in all of them it was moderately to strongly positive. Aromatase inhibitors (AIs) were prescribed as first endocrine line in 11/13 patients and progestins in the remainder, while in 2nd line treatment AIs were prescribed in 7/10 patients, followed by progestins and GnRH analogues. Median PFS for 1stline was 4.0 years (95% CI: 2.4 – 5.5 years) with 5-year progression-free rate of 30.8% (95% CI: 5.7 – 55.9%), both of which reflect the indolent natural history of ESS. Best objective response was partial response (PR) in 6/13 patients (46.2%; 95% CI: 19.2 – 74.9) and clinical benefit rate (defined as complete response + PR + stable disease ≥6 months) was 92.4% (95% CI: 64.0 – 99.8%; 12/13 patients). Median PFS for 2nd line was 3.0 years (95% CI: 2.0 – 4.1 years) with 2-year progression-free rate of 88.9% (95% CI: 68.3 – 100.0).ConclusionsIn this cohort of metastatic ESS patients, 1st line endocrine treatment achieved objective response in 46.2% of them and clinical benefit in 92.4%. Tamoxifen and hormone replacement therapy should not be prescribed in patients with ESS due to their detrimental effects. Until more solid data are available, a reasonable recommendation would be that 1st line treatment with an endocrine treatment, preferably with an AI. Moreover, in view of the positive outcomes of our patients that received 2nd/3rdline endocrine treatments, all available hormonal options should be used in sequence in the management of ESS.

Endometrial stromal sarcomas: immunoprofile with emphasis on HMB45 reactivity.

We describe the morphologic and immunohistochemical features of 17 endometrial stromal neoplasms, 16 sarcomas, and one stromal nodule. We reviewed 35 cases interpreted as endometrial stromal neoplasms, but 17 high-grade endometrial stromal sarcomas (ESS) and one case of mixed endometrial sarcoma and leiomyosarcoma were excluded from the study. Data from the Surveillance Epidemiology and End Results program on low- and high-grade ESS for 1973 through 2003 were obtained. One uterine primary ESS had collections of clear cells (20%), while a metastatic ESS contained predominantly clear cells (90%). CD10 (88.2%) and smooth muscle actin (70.5%) were the most common positive immunohistochemical markers. The latter marker was located in the cytoplasm in 47% of the ESS and in the nucleus in 23.5%, a previously unreported feature. HMB45 was detected in 23.5% of the ESS, which contrasts with the 2% reported by other authors. The presence of clear cells and HMB45 reactivity does not justify the term perivascular epithelioid cell tumors for these neoplasms. Two of 17 patients with ESS died of metastatic disease. However, among 274 cases of ESS (all stages included) collected by the Surveillance Epidemiology and End Results Program of the National Cancer Institute during a 30-year period, the 10-year survival rate was 94%.

Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma.

Background. Endometrial stromal sarcomas (ESS) are a subtype of gynaecological sarcomas characterized by the overexpression of hormone receptors. Hormone treatment is widely used in ESS but primary or acquired resistance is common. The mammalian target of rapamycin (mTOR) pathway has been suggested to play a key role in the mechanisms of hormone resistance. Recent studies in breast and prostate cancer demonstrate that this resistance can be reversed with the addition of an mTOR inhibitor. This phenomenon has never been reported in ESS. Methods. We report the outcome of one patient with pretreated, progressing low grade metastatic ESS treated with medroxyprogesterone acetate in combination with the mTOR inhibitor sirolimus. Results. Partial response was achieved following the addition of sirolimus to the hormone treatment. Response has been maintained for more than 2 years with minimal toxicity and treatment is ongoing. Conclusion. This case suggests that the resistance to the hormone manipulation in ESS can be reversed by the addition of an mTOR pathway inhibitor. This observation is highly encouraging and deserves further investigation.

18F‐Fluorodeoxyglucose uptake and clinicopathological features of recurrent or metastatic endometrial stromal sarcoma

Maximum standardized uptake value on (18) F-fluorodeoxyglucose positron emission tomography was evaluated as a predictive surrogate marker in developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma. Clinical information was obtained from records of patients with recurrent or metastatic endometrial stromal sarcoma who underwent surgery or biopsy following (18)F-fluorodeoxyglucose positron emission tomography. Pathological features - including estrogen receptor, progesterone receptor and Ki-67 expression - were immunohistochemically evaluated. We classified lesions as 'positron emission tomography positive' if the maximum standardized uptake value was 3.0 or higher. Clinicopathological features were compared between patients with positive and negative positron emission tomography findings by using the χ(2)-test. Among eight recurrent and one metastatic endometrial stromal sarcoma patients, four (44%) had positron emission tomography-positive findings. Two positron emission tomography-positive patients were estrogen receptor negative and the five positron emission tomography-negative patients were estrogen receptor positive (P = 0.073). The Ki-67 index was 10% or higher in the four positron emission tomography-positive patients, but less than 5% in the five positron emission tomography-negative patients (P = 0.003). Three patients with positron emission tomography-positive tumors received more aggressive treatment (e.g. cytotoxic chemotherapy and additional surgery) than did those with positron emission tomography-negative tumors. One patient who died of disease had positron emission tomography-positive tumors, was negative for estrogen and progesterone receptors, and had a 20% Ki-67 index. (18)F-Fluorodeoxyglucose uptake was associated with tumor biology of recurrent or metastatic endometrial stromal sarcoma. (18)F-fluorodeoxyglucose-positron emission tomography was useful for developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma.

Pulmonary metastatic nodules of uterine low‐grade endometrial stromal sarcoma: histopathological and immunohistochemical analysis of 10 cases

To identify histopathological and immunohistochemical findings that aid diagnosis of metastatic endometrial stromal sarcoma (ESS) in small biopsy specimens of the lung. We reviewed the histology of 46 lung nodules from 10 cases of pulmonary metastatic ESS. Biopsy sections were analysed by immunohistochemistry to highlight blood and lymphatic vasculature, and for expression of CD10 and oestrogen receptor (ER). Various histological changes were identified that could mislead in making a diagnosis on small biopsy samples: haemangiopericytomatous blood vessels (39%), absence of characteristic spiral arteriole-like vasculature (26%), intratumoral cysts formed by dilatation of airways (22%) or intratumoral myxoid change (11%), prominent interstitial collagen deposits (48%), foam cell infiltration (4%) and smooth muscle differentiation (2%). Peribronchial/peribronchiolar distribution of tumour cells with juxtaepithelial growth was a frequent feature, observed in 59% of nodules. In two very small nodules the lesion was barely recognizable histologically; tumour cells were detected only by expression of ER and CD10. Combined staining for ER and CD10 can be helpful in avoiding an erroneous diagnosis. As lymphatics are not normally present in the juxtaepithelial bronchial/bronchiolar wall, juxtaepithelial tumour growth beneath the bronchial epithelium in early metastatic lesions indicates a haematogenous metastastic route through the bronchial artery.

Metastatic endometrial stromal sarcoma of the lung: importance of immunohistochemical staining, clinical history and imaging studies

Proper evaluation of lung nodules is a difficult issue for clinical management of patients. Discriminating metastatic endometrial stromal sarcoma (ESS) from other primary spindle cell neoplasms of the lung using histological analysis can be challenging. This is particularly true when an adequate clinical history is lacking, because ESS metastasis can be delayed by a couple of decades. To emphasize the importance of the correlation of pathological findings with clinical history and imaging studies, we investigated 11 cases of ESS (seven low grade and four high grade) metastatic to the lung. All cases presented with one to multiple unilateral or bilateral lung nodules that were detected by chest computed tomography. Primary ESS was diagnosed from hysterectomy specimens except for one by endometrial biopsy, 0.5 to 23 years prior to metastasis. Immunohistochemical studies showed that all ESS cases were moderately to strongly positive for Bcl-2 and CD10 with > 50% of tumor cells stained, except for one high grade ESS that was negative for CD10. Eight (72.7%) and seven (63.6) of the 11 cases showed positive estrogen and progesterone receptors, respectively, with a majority of positive cases showing diffuse and moderate to strong staining. Strong but patchy staining for CD34 was detected in one (9.1%) case with smooth muscle differentiation. CK7 and TTF-1 were negative in all cases. Two (18.2%) cases exhibited patchy and strong positivity for caldesmon. Two (18.2%) low grade ESS cases showed moderate to strong AE1/AE3 positivity in > 50% of tumor cells, one of which also showed moderate CK19 and Cam 5.2 staining in >30% of tumor cells. One should be cautious when assessing spindle cell neoplasms of the lung in women with a history of hysterectomy. Correlation of clinical history and imaging studies with histological and immunohistochemical findings is essential to diagnosis of metastatic ESS to the lung.

Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Cystic fibrohistiocytic tumor of the lung presenting as a solitary lesion

Cystic fibrohistiocytic tumor of the lung is a rare neoplasm. In many cases it represents a metastasis from a benign or low-grade fibrohistiocytic tumor of the skin, but occasionally it may be primary. Radiologically it usually occurs as a cystic change of multiple pulmonary nodules, and pneumothorax is the most frequent presenting symptom. We present here a 16-year-old man with recurrent right pneumothorax. The patient had no history of cutaneous fibrohistiocytic lesions. He underwent videothoracoscopic right apical segmentectomy, right lower lobe nodulectomy, and pleuroabrasion. Microscopy of the apical segmentectomy showed a cystic fibrohistiocytic tumor, whereas the nodule of the lower lobe was an intraparenchymal lymph node. The patient is alive with no tumor recurrence. The differential diagnosis includes Langerhans cell histiocytosis, lymphangioleiomyomatosis, pleuropulmonary blastoma, and metastatic endometrial stromal sarcoma. This disease usually occurs with multiple pulmonary cysts and cavitation. This case is the first reported presenting as a single lesion.

A case of uterine tumour resembling ovarian sex cord tumour responding to second‐line, single agent anastrazole

Uterine tumour resembling ovarian sex cord tumour (UTROSCT) are a histological variant of endometrial stromal sarcomas (ESS). There is no established medical management of metastatic UTROSCT or ESS, although there is evidence supporting the use of hormonal therapy. Given the success of aromatase inhibitors in breast cancer, their potential role in ESS and UTROSCT is of current interest. We report the first case of response to second-line, single agent anastrazole in a patient with metastatic UTROSCT.

Hormonal treatment of metastatic endometrial stromal sarcoma

e16576 Background: Endometrial stromal sarcomas (ESS) traditionally have been classified as low grade or high grade based on mitotic activity and histologic appearance. High-grade tumors are currently referred to as undifferentiated uterine sarcomas and are not included in this series. ESS are known to have high expression of estrogen and progesterone receptors. This is a retrospective study of patients with metastatic ESS treated with hormonal therapy. Methods: Following approval by the institutional review board all patients diagnosed with ESS from 1987–2007 were identified. Clinical and demographic information were abstracted from the charts and all histologic materials were re-reviewed. Estrogen and progesterone receptor testing was performed utilizing mouse monoclonal antibodies and the Cell Analysis Systems 200 Image analyzer. Survival was calculated using the Kaplan-Meier method and comparisons utilized the log rank test. Results: Thirteen patients with ESS were identified during this period. Seven had disease confined to the uterus. Six had extrauterine disease; 5 patients presented with metastases and 1 patient presented with a pelvic recurrence 20 years following a hysterectomy. All underwent surgical resection except for 1 patient that declined surgery. All 6 patients with metastases had tumors that tested positive for estrogen and progesterone receptors; all were treated with megestrol acetate initially for a period of 1–4 years. Two patients were then changed to maintenance with medroxyprogesterone acetate. Three patients with persistent disease were changed to aromatase inhibitors; 1 to letrozole and 2 to anastrazole. One of these patients has had a complete response and 2 have had stable disease. One patient has been lost to follow-up. Follow-up for the 6 patients was 2–22 years; no known patients died of their disease. Actuarial 2- and 5-year survivals were 80% and 65%, respectively. There was no significant difference in survival between patients with metastases and without metastases. Conclusions: ESS tumors are relatively uncommon and there is an absence of studies to guide treatment of patients with metastases. This experience indicates that these tumors respond well to hormonal manipulation. Treatment with progestins or aromatase inhibitors may result in remission or stable disease. No significant financial relationships to disclose.

Uterine sarcomatous extension: Abdominal pain and fatigue were symptoms of a deadly development

A 44-year-old woman presented to the emergency department with chief complaints of abdominal pain and fatigue. She had a history of metastatic endometrial stromal sarcoma and a chronic right lower-extremity deep vein thrombosis. On admission, computed tomography of the chest, abdomen, and pelvis was ordered. Imaging demonstrated a large pelvic uterine tumor with tumoral thrombus that distended the entire inferior vena cava and the right internal iliac and common iliac veins; peritoneal carcinomatosis and ascites were evident as well (Figure 1).

Current treatment options in uterine endometrial stromal sarcoma: report of a case and review of the literature

Uterine sarcomas are a rare form of uterine cancer. They occur in women from 40 to 60 years and are generally characterized by poor prognosis, a high rate of local recurrence, and distant metastases. Endometrial stromal sarcoma (ESS) accounts for 0.2% of all gynecological malignancies. Forms of possible treatment include surgery, radiotherapy, chemotherapy, and endocrine treatment. Randomized trials analyzing these treatment options are limited due to the rarity of this disease; therefore, a standard therapy could not be established thus far. To present an overview of the current treatment options of ESS, a search of Medline, Embase, and the Cochrane Library was performed and the results concluded. We report the case of a 32-year-old woman who presented with FIGO stage II ESS. Initial treatment with tamoxifen and local perfusion with cisplatin resulted in disease progression and were discontinued. A novel, therapeutic approach using two cycles of combination chemotherapy with doxorubicin and ifosfamide followed by surgery was applied. Five years after surgery, the patient is still in complete remission. Thus, we conclude that although there is no data from randomized trials available, chemotherapy in advanced or metastatic ESS can provide an opportunity for surgical treatment and can lead to long-term remission.

Expression of platelet‐derived growth factor receptor in low‐grade endometrial stromal sarcomas in the absence of activating mutations

To investigate platelet-derived growth factor receptor (PDGFR)alpha and PDGFRbeta expression and a mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) genes in endometrial stromal sarcomas (ESS). Gastrointestinal stromal tumours (GISTs), which have somatic mutations of the transmembrane tyrosine kinase receptor, respond to tyrosine kinase inhibitors, which act through an inhibitory effect on class 3 receptor tyrosine kinase members such as PDGFRalpha, PDGFRbeta and c-kit. The immunohistochemical expression of PDGFRalpha and PDGFRbeta was investigated in 37 archival c-kit- ESS. Staining was scored as negative (0-10% positive tumour cells) and positive (weakly positive 11-50% positive cells; strongly positive > 50% positive cells). PDGFRalpha was expressed in 24/37 ESS [65%; strongly by 19/37 (51.5%) and weakly by 5/37 ESS (13.5%)]. ESS tumour cells were negative for PDGFRbeta, but endothelial cells stained positive. A mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) genes on frozen metastatic ESS from three patients detected no mutations leading to amino acid changes in the mature protein. Patients with PDGFRalpha+ ESS may benefit from treatment with tyrosine kinase inhibitors by blocking autocrine and paracrine stimulation loops, blocking neovascularization and enhancing the effects of chemotherapy.