Uterine sarcomas—Recent progress and future challenges
Introduction
In 2006, uterine cancer was only the thirteenth commonest cancer in the UK, and only the fourth commonest cancer in women in the UK, with an incidence of 18.1 per 100,000, accounting for 7045 cases [1]. Uterine sarcomas are especially rare, comprising only 8.4% of uterine cancers [2]. Nevertheless, there has in recent years been significant progress in the more accurate classification, staging and management of patients with uterine sarcoma. Despite the rarity of this tumour, in the last two years several review articles have been published on the current management of uterine sarcomas [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Thus, the emphasis of this article is not to repeat previous reviews, but rather to highlight recent progress, emerging evidence, and future challenges of relevance and interest to both oncologists and radiologists (Table 1).
Section snippets
Pathology
The current World Health Organisation classification of tumours of the female genital tract classifies uterine mesenchymal tumours into smooth muscle and endometrial stromal tumours [13]. Smooth muscle tumours are benign or malignant neoplasms composed of cells showing smooth muscle differentiation arising within the myometrium. They are divided into benign leiomyoma, smooth muscle tumour of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Endometrial stromal tumours arise from
Clinical presentation and diagnosis
The clinical presentation of uterine sarcomas is non-specific. The peak incidence is between 50 and 65 years of age. The classical history is often of a rapidly growing uterine mass, and additional symptoms may include pelvic or abdominal pain and vaginal bleeding. However, the diagnosis of uterine sarcomas is frequently unexpected, discovered incidentally on histopathology review following hysterectomy, often for fibroids (benign leiomyomas) [30]. Of those patients undergoing hysterectomy for
Prognostic factors and staging
Prior to treatment, newly diagnosed cancers will be staged to define tumour extent. An effective staging system will define individual stages that will accurately stratify patients into clinically meaningful groups, with distinct outcomes and prognosis, which will in turn guide management. The staging of uterine sarcomas has for many years now been unsatisfactory. Until recently the 1988 International Federation of Gynaecology and Obstetrics (FIGO) staging system for uterine corpus cancer was
Surgical management for early stage disease
Primary management for early stage operable uterine sarcomas is surgical, with total abdominal hysterectomy with or without bilateral salpingoophorectomy [68]. Surgery is the most important component of treatment, and indeed the absence of primary surgery [57], [62] or incomplete cytoreduction [30], [69] has been shown to be independent prognostic factors.
Involvement of pelvic lymph nodes in LMS is infrequent (Table 6), and is usually associated with visible enlargement of the lymph nodes
Adjuvant radiotherapy
Until recently, evidence on the role of adjuvant radiotherapy in uterine sarcomas had been limited to retrospective non-comparative case series. Papers have not clearly described outcomes for individual histological subtypes, have frequently included CS, and have not differentiated between ESS and UES. This has made assessment of the potential benefit of radiotherapy in particular sarcoma subtypes difficult to quantify. However, in the last two years, a phase III study and three population
Adjuvant chemotherapy
The pattern of relapse in uterine sarcomas, particularly in the higher grade LMS and EUS, is mostly distant metastases, often with locoregional disease [63], [83]. Hence, the use of adjuvant chemotherapy to reduce local and distant relapses and improve cure rates has been attractive. However, there are only limited data available to support the use of adjuvant chemotherapy specifically for uterine sarcoma. An early randomised study in the 1980s found that adjuvant doxorubicin compared with
Chemotherapy for metastatic disease
In soft tissue sarcoma generally, standard first line chemotherapy for metastatic disease has been unchanged for three decades and remains doxorubicin with or without ifosfamide [92], [93]. A large number of phase II studies of single chemotherapy agents have been carried out in metastatic uterine sarcomas and specifically LMS, evaluating a range of agents over the last two decades. Some of these have been active (doxorubicin, response rate (RR) 25% [94], ifosfamide RR 17.2% [105], gemcitabine
Hormone therapy – adjuvant and metastatic treatment
The incidence of hormone receptor positivity in LMS and ESS has been discussed earlier (Section 2). Given the low toxicity profile of hormonal therapies as compared with chemotherapy, their use in uterine sarcomas in both the adjuvant and advanced settings has been the subject of some considerable interest amongst both clinicians and patients.
The use of adjuvant hormonal therapy after primary surgery in ESS has been reported in a number of studies. A retrospective series of 22 patients with ESS
Novel targeted agents
The few effective chemotherapy agents, and their associated toxicities, have meant that identifying new targeted agents effective in uterine sarcomas is an important priority. Increasing numbers of targeted agents are being introduced into clinical use, and indeed one of the earliest examples that provided proof of principle in solid tumours was in sarcoma, when the receptor tyrosine kinase inhibitor imatinib mesylate was shown to be clearly effective in the previously treatment resistant
Surgery and locally ablative therapies for metastatic disease
The role of surgery and locally ablative therapies for metastatic disease in uterine sarcomas depends upon the extent of disease and the aims of treatment. Pulmonary metastatectomy has become a standard intervention with potentially curative intent in selected patients with lung metastases [147]. Recent series’ of patients who have undergone pulmonary metastatectomy for soft tissue sarcoma metastases have indicated a survival benefit for surgery, with 5 year overall survival rates of 18–38%.
Conclusions
Uterine sarcomas are a rare group of tumours, and it is this rarity that makes their management challenging. There is a lack of data, and in particular a lack of randomised controlled trials, to guide management of these patients, which leaves a reliance on information derived from small retrospective case series. Recently this has been overcome to some degree by utilising large population based databases, which have provided important insights into treatments. In addition, useful information
Acknowledgement
This work has been supported by UCLH/UCL Comprehensive Biomedical Research Centre.
References (167)
- et al.
Clinical management of uterine sarcomas
Lancet Oncol
(2009) - et al.
Uterine sarcomas: a review
Gynecol Oncol
(2010) - et al.
The management of patients with uterine sarcoma: a debated clinical challenge
Crit Rev Oncol Hematol
(2008) The management of uterine sarcomas
Clin Oncol (R Coll Radiol)
(2008)- et al.
Smooth muscle, endometrial stromal, and mixed Mullerian tumors of the uterus
Mod Pathol
(2000) - et al.
Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles
Gynecol Oncol
(2009) - et al.
Genetic aberrations in soft tissue leiomyosarcoma
Cancer Lett
(2009) - et al.
Leiomyosarcoma in a premenopausal patient after uterine artery embolization
Am J Obstet Gynecol
(2004) - et al.
Does pelvic magnetic resonance imaging differentiate among the histologic subtypes of uterine leiomyomata?
Fertil Steril
(1998) - et al.
Positron emission tomography using 2-[(18)F] fluoro-2-deoxy-d-glucose in the diagnosis of uterine leiomyosarcoma: a case report
Clin Imaging
(2001)
Positron emission tomography with (18)F-fluorodeoxyglucose of uterine sarcoma: a comparison with magnetic resonance imaging and power Doppler imaging
Gynecol Oncol
Predictive value of FIGO and AJCC staging systems in patients with uterine leiomyosarcoma
Eur J Cancer
Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy
Gynecol Oncol
Prognostic parameters in endometrial stromal sarcoma: a clinicopathologic study in 31 patients
Gynecol Oncol
Endometrial stromal sarcoma: analysis of treatment failures and survival
Gynecol Oncol
Endometrial stromal sarcoma of the uterus: analysis of 25 patients
Eur J Obstet Gynecol Reprod Biol
Endometrial stromal sarcoma of the uterus. A clinical and histopathological study. The Radiumhemmet series 1936–1981
Eur J Obstet Gynecol Reprod Biol
The prognostic significance of surgery, tumor size, malignancy grade, menopausal status, and DNA ploidy in endometrial stromal sarcoma
Gynecol Oncol
FIGO staging for uterine sarcomas
Int J Gynaecol Obstet
Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus
Gynecol Oncol
Treatment of endometrial stromal tumors
Gynecol Oncol
Low-grade endometrial stromal sarcoma: hormonal aspects
Gynecol Oncol
Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group study (protocol 55874)
Eur J Cancer
Adjuvant radiotherapy for stage I endometrial cancer: systematic review and meta-analysis
Ann Oncol
Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999
Gynecol Oncol
The role of adjuvant radiation in uterine sarcomas
Int J Radiat Oncol Biol Phys
A multi-institutional review of outcomes of endometrial stromal sarcoma
Gynecol Oncol
Radiation therapy in the treatment of endometrial stromal sarcoma
Int J Radiat Oncol Biol Phys
Uterine leiomyosarcoma: analysis of treatment failures and survival
Gynecol Oncol
Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial
Gynecol Oncol
Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study
Gynecol Oncol
Adjuvant gemcitabine plus docetaxel for completely resected stages I–IV high grade uterine leiomyosarcoma: results of a prospective study
Gynecol Oncol
Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) study
Gynecol Oncol
Phase II trial of etoposide in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study
Gynecol Oncol
Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths
Am J Obstet Gynecol
Uterine sarcoma 2008
Curr Oncol Rep
Update on treatment of uterine sarcoma
Curr Opin Obstet Gynecol
Optimal management of uterine leiomyosarcoma
Expert Rev Anticancer Ther
Gynaecological sarcomas
Curr Opin Oncol
Treatment of early uterine sarcomas: disentangling adjuvant modalities
World J Surg Oncol
Management of advanced stage uterine sarcomas: a bone of contention
Eur J Gynaecol Oncol
Tumours of the breast and female genital organs
Uterine carcinosarcoma is derived from a single stem cell: an in vitro study
Int J Cancer
Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors
Cancer Res
Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas?
J Clin Pathol
Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors
Cancer
Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases
Am J Surg Pathol
Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma
Cancer
Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma
Cancer
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