Elsevier

The Lancet Oncology

Volume 10, Issue 12, December 2009, Pages 1188-1198
The Lancet Oncology

Review
Clinical management of uterine sarcomas

https://doi.org/10.1016/S1470-2045(09)70226-8Get rights and content

Summary

Malignant pure mesenchymal uterine tumours encompass endometrial stromal sarcoma (ESS), uterine leiomyosarcoma, and undifferentiated sarcomas. This Review discusses pathology, preoperative diagnosis, and standard treatment of uterine leiomyosarcoma and low-grade ESS (distinct from undifferentiated uterine sarcomas), with an emphasis on targeted treatment. We show that several features on ultrasonography and MRI can raise suspicion of a uterine sarcoma; however, there are no pathognomonic features on any imaging technique. For both ESS and uterine leiomyosarcoma, hysterectomy with bilateral salpingo-oophorectomy, but without lymphadenectomy, is the standard surgical treatment for early stage disease. The clinical benefit of chemotherapy is limited, which underscores the importance of targeted therapy. ESS and uterine leiomyosarcoma are driven by different pathways, resulting in a different clinical behaviour. ESS typically is a hormone-sensitive tumour with indolent growth. Uterine leiomyosarcoma is notorious for its aggressive growth and poor outcome. Individualisation of treatment is mandatory, because randomised trials are almost non-existent. The progesterone and oestrogen receptors are clinically important targets for most primarily advanced or recurrent ESS and a subset of recurrent uterine leiomyosarcomas. Potential future targets and targeted treatments that are under investigation are presented for both entities.

Introduction

Mesenchymal tumours other than uterine fibroids are uncommon because sarcomas of the uterus constitute only 3% of uterine malignancies.1 Uterine sarcomas encompass leiomyosarcoma (figure 1), carcinosarcoma, and endometrial stromal sarcoma (ESS) according to traditional classification systems. Tumour biology of carcinosarcomas points toward an epithelial origin, as shown by in-vitro data, immunohistochemical studies, and molecular comparison between the epithelial and mesenchymal component.2 The focus in this Review will be on the most common pure mesenchymal tumours: uterine leiomyosarcoma and ESS. ESS was formerly classified as low-grade ESS. Tumours previously termed high-grade ESS are currently called poorly differentiated or undifferentiated uterine sarcoma. Although there is no universal staging system for uterine sarcomas, the International Federation of Gynecology and Obstetrics (FIGO) surgical staging system for endometrial cancer is used.

No imaging modality can offer a reliable preoperative diagnosis. CT is unable to differentiate between different types of uterine pathology. However, ultrasonography and MRI are able to offer a much more detailed analysis of pathology.3 Thus, uterine sarcomas are uncommon and the preoperative diagnosis is problematic. Preoperative referrals are rare. Many women have surgery for presumed benign conditions (eg, uterine leiomyoma) and snap frozen tissues are not preserved. As a result, the collection of satisfactory tumour samples and the undertaking of prospective trials are challenging. Only a few series are reported and results from studies with level 1 evidence are non-existent.

The purpose of this Review is to provide information on the pathology, preoperative diagnosis, and standard treatment of uterine leiomyosarcoma and ESS. Knowledge of tumour biology forms the basis for delineating targeted treatment modalities that are currently used, under investigation, or avoidable.

Section snippets

Histopathology

Most uterine leiomyosarcomas are sufficiently differentiated, at least focally, to allow recognition of their smooth-muscle nature. They are obviously malignant on microscopic examination. The diagnostic strategy should include a search for the mitotic index, presence of atypia, and coagulative tumour-cell necrosis.4 Uterine leiomyosarcomas need to be distinguished from mitotically active or atypical leiomyomas and uterine smooth-muscle neoplasms with low malignant potential. Coagulative

Histopathology

Endometrial stromal neoplasms are exclusively composed of cells resembling the endometrial stroma in its proliferative phase. The stromal nodule is the benign variant; it has well circumscribed borders and is rare.57, 58 ESS represents the entity with infiltrating borders and behaves like a low-grade sarcoma, with the potential for recurrence and metastasis.59 Microscopic findings that unequivocally correspond to ESS include a uniform population of endometrial stromal-type cells invading the

Undifferentiated sarcoma

Undifferentiated uterine sarcoma is a poorly defined group. These tumours do not show evidence of gene-specific fusions, suggesting that they arise by a different pathogenetic mechanism compared with ESS. Immunohistochemical data are also sparse, including only a few cases per article published. On the basis of these data, it seems that undifferentiated sarcomas are positive for PDGFR-α,34 androgen receptor,38 and WT1.51 Of note, one of four samples were positive for ERBB2.39

Gastrointestinal stromal tumours

Gastrointestinal

Conclusion

Uterine sarcomas are uncommon and preoperative diagnosis is frequently unknown. As a result, centralisation, large series, and randomised trials are problematic. Hysterectomy is the cornerstone of treatment for early stage uterine leiomyosarcoma and ESS. There is no proven benefit from any adjuvant treatment (ie, radiotherapy, chemotherapy, or hormonal targeted) for both entities. Hormone receptors are the most important targets for primarily advanced or recurrent ESS, as for a subset of

Search strategy and selection criteria

Information for this Review was obtained by a Search of Medline and references from relevant articles using the search terms: “sarcoma”, “endometrial stromal”, “leiomyosarcoma”, “uterine”, “ultrasonography”, “hormonal”, “magnetic resonance imaging”, “computed tomography”, “neoplasm”, “genetics”, “imaging”, “surgery”, “chemotherapy”, “molecular signature”, and “targeted therapy”. The search strategy was not limited by date and no language restrictions were applied.

References (90)

  • J Yang et al.

    Genetic aberrations in soft tissue leiomyosarcoma

    Cancer Lett

    (2009)
  • YL Cho et al.

    Array comparative genomic hybridization analysis of uterine leiomyosarcoma

    Gynecol Oncol

    (2005)
  • TO Nielsen et al.

    Molecular characterisation of soft tissue tumours: a gene expression study

    Lancet

    (2002)
  • SF Adams et al.

    PDGFR-alpha as a potential therapeutic target in uterine sarcomas

    Gynecol Oncol

    (2007)
  • J Lasota et al.

    Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas

    Am J Pathol

    (1999)
  • RS Rushing et al.

    Uterine sarcomas express KIT protein but lack mutation(s) in exon 11 or 17 of c-KIT

    Gynecol Oncol

    (2003)
  • MC Chu et al.

    Low-grade endometrial stromal sarcoma: hormonal aspects

    Gynecol Oncol

    (2003)
  • F Amant et al.

    ERBB-2 gene overexpression and amplification in uterine sarcomas

    Gynecol Oncol

    (2004)
  • L Salmena et al.

    Tenets of PTEN tumor suppression

    Cell

    (2008)
  • J Cuzick et al.

    Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement

    Lancet Oncol

    (2009)
  • S Nakatsuka et al.

    Immunohistochemical detection of WT1 protein in a variety of cancer cells

    Mod Pathol

    (2006)
  • A Coosemans et al.

    Upregulation of Wilms' tumour gene 1 (WT1) in uterine sarcomas

    Eur J Cancer

    (2007)
  • F Amant et al.

    2-methoxyestradiol strongly inhibits human uterine sarcomatous cell growth

    Gynecol Oncol

    (2003)
  • F Amant et al.

    The diagnostic problem of endometrial stromal sarcoma: report on six cases

    Gynecol Oncol

    (2003)
  • B Cacciatore et al.

    Ultrasound findings in uterine mixed müllerian sarcomas and endometrial stromal sarcomas

    Gynecol Oncol

    (1989)
  • J Riopel et al.

    Lymph node metastases in low-grade endometrial stromal sarcoma

    Gynecol Oncol

    (2005)
  • A Gadducci et al.

    Endometrial stromal sarcoma: analysis of treatment failures and survival

    Gynecol Oncol

    (1996)
  • Y Yokoyama et al.

    Asymptomatic intracardiac metastasis from a low-grade endometrial stromal sarcoma with successful surgical resection

    Gynecol Oncol

    (2004)
  • F Amant et al.

    Transition of endometrial stromal sarcoma into high-grade sarcoma

    Gynecol Oncol

    (2006)
  • K Leunen et al.

    Endometrial stromal sarcoma presenting as postpartum haemorrhage: report of a case with a sole t(10;17)(q22;p13) translocation

    Gynecol Oncol

    (2003)
  • G Sutton et al.

    Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group

    Obstet Gynecol

    (1996)
  • R Foster et al.

    Reclassification of a tubal leiomyosarcoma as an eGIST by molecular evaluation of c-KIT

    Gynecol Oncol

    (2006)
  • CBM Wingen et al.

    Uterine gastrointestinal stromal tumors (GIST)

    Gynecol Oncol

    (2005)
  • P Clement et al.

    Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature

    Hum Pathol

    (1990)
  • F Amant et al.

    Immunohistochemical determination of estrogen and progesterone receptor positivity in uterine adenosarcoma

    Gynecol Oncol

    (2004)
  • C Zaloudek et al.

    Mesenchymal tumors of the uterus

  • S Bell et al.

    Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases

    Am J Surg Pathol

    (1994)
  • I Szabó et al.

    Uterine sarcoma: diagnosis with multiparameter analysis

    Ultrasound Obstet Gynecol

    (1997)
  • A Sahdev et al.

    MR imaging of uterine sarcomas

    AJR Am J Roentgenol

    (2001)
  • F Amant et al.

    Leiomyomata and sarcoma

  • A Kido et al.

    Diffusely enlarged uterus: evaluation with MR imaging

    Radiographics

    (2003)
  • S Chander et al.

    Positron emission tomographic—computed tomographic imaging of a uterine sarcoma

    Clin Nucl Med

    (2002)
  • F Major et al.

    Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study

    Cancer

    (1993)
  • DS Kapp et al.

    Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas: emphasis on impact of lymphadenectomy and oophorectomy

    Cancer

    (2008)
  • G Omura et al.

    A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a gynaecologic oncology group study

    J Clin Oncol

    (1985)
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