A collaboration was established between the European Society of Gynaecological Oncology (ESGO), the European Reference Network on Rare Adult Solid Cancers (EURACAN), and the Gynecologic Cancer InterGroup (GCIG) with the aim of developing clinically relevant, evidence-based consensus guidelines on the management of patients with uterine sarcomas from diagnosis to relapse.

ESGO/EURACAN/GCIG nominated practicing clinicians from centers of expertise in the management of patients with uterine sarcomas to serve on the expert panel (25 experts). To ensure that the statements were evidence-based, data identified from a systematic search were reviewed and critically appraised. In the absence of robust scientific evidence, clinical recommendations were based on the consensus of the international development group. Prior to publication, the guidelines were reviewed by 104 independent international clinicians with expertise in uterine sarcomas.

Attention was given to imaging, pathology, and molecular analyses in addition to clinical management. Recommendations for surgery, including specific recommendations at initial diagnosis and at relapse, were developed. Indications for radiation and systemic therapies, including chemotherapy options, endocrine therapies, and targeted therapies, were addressed for the following histological subgroups of uterine sarcomas: high-grade endometrial stromal sarcomas, undifferentiated sarcomas, low-grade endometrial stromal sarcomas, uterine leiomyosarcomas, adenosarcomas, and selected very rare entities. Recommendations for follow-up and highlighted issues and unmet needs faced by long-term survivors were also discussed.

INTRODUCTION

Uterine sarcomas are rare uterine neoplasms that comprise a heterogeneous histological group of tumors, including leiomyosarcoma (LMS) (the most common subtype), followed by endometrial stromal sarcoma (ESS) (including low-grade and high-grade variants), and rarer subtypes, such as adenosarcoma, undifferentiated uterine sarcomas (UUS), and tumors of uncertain malignant potential including perivascular epithelioid cell tumors (PEComa) and neurotrophic tropomyosin-receptor kinase (NTRK)-rearranged gynecological sarcomas.1 2 They are diagnosed predominantly between the fourth and sixth decades of life and typically exhibit aggressive behavior including risk of distant metastases, even in early stages, and are associated with a poor prognosis in a significant proportion of patients with high-grade tumors. In 2014, the Gynecologic Cancer InterGroup (GCIG) published consensus reviews and recommendations for the management of a number of these rare uterine sarcomas.3–6 Advances and new evidence have emerged over the last 10 years which have affected the management of patients with uterine sarcomas. In view of this, a collaboration was established between the European Society of Gynecological Oncology (ESGO), the European Reference Network on Rare Adult Solid Cancers (EURACAN), and GCIG with the specific objective of developing clinically relevant and evidence-based contemporary guidelines to guide the multidisciplinary approach for management of patients with uterine sarcomas from initial diagnosis to relapse. Attention was given to imaging, pathology, and molecular analyses in addition to clinical management. Guidelines for surgery, including specific recommendations at first diagnosis and at relapse for all histological subtypes of uterine sarcomas, were developed. Indications for radiation and systemic therapies, including chemotherapy options, endocrine therapies, and targeted therapies, were developed for the following histological subgroups: uterine leiomyosarcoma (uLMS), high-grade endometrial stromal sarcoma (HG-ESS), UUS, low-grade endometrial stromal sarcoma (LG-ESS), adenosarcoma, and selected very rare entities. Recommendations for follow-up after treatment are provided and specific issues faced by long-term survivors, including late effects of therapy, were discussed. These guidelines are intended for use by all health professionals involved in the management of patients with uterine sarcomas across all allied disciplines. Needs for research in the topics addressed and issues that directly affect these guidelines are also presented in this article.

RESPONSIBILITIES

Our primary aim is to provide the highest level of evidence to support optimal management of patients with uterine sarcoma, but ESGO, EURACAN, and GCIG acknowledge that there will be broad variability in attitudes and practices worldwide, with significant differences in infrastructure, access to medical and surgical technology, and expertise, in addition to, medicolegal, financial, and cultural differences that impact the implementation of any guidelines. These guidelines are statements of available evidence and the consensus reached by the multidisciplinary development group based on their views and perspectives of currently accepted approaches to the management of patients with uterine sarcomas. Any clinician applying or consulting these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine optimal care and treatment for a patient. These guidelines make no representations or warranties of any kind whatsoever regarding their content, use, or application and disclaim any responsibility for their application or use in any way.

METHODS

The guidelines were developed using a five-step process as defined by the ESGO Guideline Comittee (see Figure 1). The strengths of the process include creation of a multidisciplinary international development group, use of scientific evidence and international expert consensus to support the guidelines, and use of an international external review process. This development process was chaired by Professor Isabelle Ray-Coquard (for ESGO), Professor Paolo G Casali (for EURACAN), and Professor Michael Friedlander (for GCIG). ESGO/EURACAN/GCIG nominated practicing clinicians with recognized expertise in the management of patients with uterine sarcomas, including demonstrated leadership in clinical care and research, national and international engagement and profiles, as well as experience in the topics addressed. The objective was to assemble a multidisciplinary development group, and it was therefore essential to include clinicians from all relevant disciplines to contribute to the validity and acceptability of the guidelines. To ensure that the statements were evidence based, the current literature was reviewed and critically appraised. A systematic, unbiased literature review of relevant studies published between April 2013 and April 2023 was carried out using the Medline database (see Online Supplemental Appendix 1). The bibliography was also supplemented by additional older relevant references (if any). The literature search was limited to publications in English. Priority was given to high-quality systematic reviews, meta-analyses, and randomized controlled trials, but studies of lower levels of evidence were also evaluated. The search strategy excluded editorials, letters, and in vitro studies. The reference list of each identified article was also reviewed for other potentially relevant articles. Based on the collected evidence and clinical expertise, the international development group drafted guidelines for all the topics. The guidelines were discussed and retained if they were supported by sufficiently high-level scientific evidence and/or when a large consensus among experts was obtained. An adapted version of the ‘Infectious Diseases Society of America-United States Public Health Service Grading System’ was used to define the level of evidence and grade of recommendation for each of the recommendations (see Figure 2).7 8 In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group.

Figure 1

Development process.

Figure 2

Levels of evidence and grades of recommendations.

ESGO/EURACAN/GCIG established a large multidisciplinary panel of practicing clinicians with expertise in the management of patients with uterine sarcomas to act as independent expert reviewers for the guidelines that were developed. These reviewers were selected according to their expertise and active involvement in clinical practice or research, while geographical balance ensured a global perspective. The international reviewers were asked to evaluate each guideline according to its relevance and feasibility in clinical practice, so that comprehensive quantitative and qualitative evaluations of the guidelines were completed. Evaluations of the external reviewers (n=104) were pooled and discussed by the international development group to finalize the guidelines development process. The list of the 104 external reviewers is available in Online Supplemental Appendix 2.

GENERAL RECOMMENDATIONS

Centralizationn of care in specialized centers and referral network is encouraged (IV, A).

Treatment planning should be multidisciplinary (within a tumor board, composed according to local guidelines) and supported by all available evidence including an understanding and appreciation of prognostic and predictive factors, potential adverse effects of treatments, and quality of life (IV, A).

Patients should be carefully counseled on the recommended management plan and potential alternatives, including risks and benefits of all options taking into full consideration their perspectives and wishes (V, A).

Treatment should be undertaken by an experienced team in the diagnosis and management of uterine sarcomas (IV, A).

Enrollment of patients with uterine sarcomas in clinical trials should be considered if available (IV, A).

International collaboration and prospective registries for this rare group of disease are encouraged (V, B).

DIAGNOSIS - PATHOLOGY

The diagnosis of uterine sarcomas can be challenging due to their rarity and numerous subtypes and often relies on integrated histological evaluation as well as immunohistochemical and molecular analyses. Given the complexity of uterine sarcomas and pathologic evaluation, the diagnosis should be confirmed by a pathologist subspecialized in gynecologic pathology and/or with experience in diagnosing uterine mesenchymal tumors, preferably at a sarcoma reference center where molecular diagnostics are available and routinely used.9–11 The diagnosis of uterine sarcomas should adhere to the guidelines outlined in the fifth edition of the WHO Classification of Female Genital Tumors and the International Collaboration on Cancer Reporting (ICCR) datasets.1 12 Adherence to ICCR guidelines by meticulous macroscopic examination and extensive tumor sampling is recommended.12 This is critical for the evaluation of differential diagnoses, such as sarcoma vs carcinosarcoma, LG-ESS vs HG-ESS, and smooth muscle tumor of uncertain malignant potential (STUMP) vs LMS. In vivo fragmentation (morcellation), which compromises specimen integrity and macroscopic evaluation of tumor size and the tumor to myometrium interface, should be avoided and acknowledged, if performed.13 14

Intra-operative evaluation is also discouraged; curettage and/or biopsies under ultrasound guidance with coaxial needles are reasonable alternatives.1 12 Immunohistochemistry is recommended for diagnosis and to support therapeutic decision-making. A list of useful antibodies is included in Table 1. In conjunction with histological evaluation and immunohistochemical studies, molecular tests are recommended to detect fusion transcripts and/or assess mutation status to refine tumor classification and/or identify therapeutic targets and can be performed on the resection or biopsy specimens, in settings where genomic analysis may be particularly informative when morphological evaluation is limited.15–17 Assays that assess gene fusions include fluorescence in situ hybridization (FISH), DNA sequencing, and RNA sequencing. While each assay has advantages and disadvantages as well as variations in turnaround time, RNA sequencing is recommended for the diagnostic evaluation of uterine sarcomas given its efficiency in the comprehensive detection of known and novel fusions and isoforms (eg, BCOR internal tandem duplication, JAZF1: BCOR or JAZF1:BCORL1 or YWHAE fusion transcript identification in HG-ESS).18 DNA sequencing may be useful in the evaluation of (1) smooth muscle tumors to assess the mutation status of genes commonly altered in LMS and (2) LG-ESS with somatic mutations (ie, TP53, RB1, ESR1, TSC2). Genomic data obtained from array-comparative genomic hybridization (array-CGH), can also aid in the evaluation of challenging smooth muscle tumors, such as STUMP.19–21 Regardless of the methods, all genomic data should be integrated in the appropriate clinicopathologic context to ensure diagnostic precision.22 Pertinent pathologic features by tumor type are described below in brief.

Table 1

Non-exhaustive list of diagnostic immunohistochemical markers217

The diagnosis of LG-ESS is based primarily on morphology and immunohistochemistry (see Table 1); detection of low-grade endometrial stromal tumor-associated fusions is helpful particularly in the setting of variant or high-grade features. The assessment of the interface between tumor and myometrium is critical in distinguishing between endometrial stromal nodule and LG-ESS, which share immunohistochemical profiles and fusion transcripts, and is not possible in limited tissue samples (ie, biopsy, curettage, myomectomy).1 23 24 Identifying high-grade transformation or dedifferentiation of LG-ESS relies on increased nuclear atypia and mitotic index and/or loss or altered expression of estrogen and progesterone receptors (ER and PR). Some histologically transformed ESS harbor ESR1 hotspot mutations that predict resistance to some endocrine therapies.25–28 Tumors with overlapping histologic and immunophenotypic features of ESS and PEComa may harbor TSC2 mutations and respond to mammalian target of rapamycin (mTOR) inhibition and endocrine therapy.26 The diagnosis of HG-ESS is based on morphology and immunohistochemistry (see Table 1). Molecular analysis is strongly encouraged in the setting of LG-ESS with unusual histologic and/or immunophenotypic features, HG-ESS, and UUS to confirm genetic alterations (ie, BCOR, BCORL1, YWHAE) diagnostic of HG-ESS.1 26 29–36 Morphology remains the cornerstone in the diagnosis of adenosarcoma. Immunohistochemistry can confirm heterologous rhabdomyosarcomatous differentiation or assignment of high grade. Adverse prognostic factors include sarcomatous overgrowth (defined by the presence pure sarcoma occupying≥25% of the tumor), high-grade histology, lymph vascular invasion, and myometrial infiltration (see Table 2).1 37–39 Molecular tests may identify potentially targetable mutations in adenosarcomas (eg, KRAS, PIK3CA etc.).40 The diagnosis of PEComa is based on morphology, and melanocytic marker expression (see Table 1).1 41–44 Two molecular subtypes of PEComa have been identified: one linked to TSC1/2 mutations and another associated with TFE3 rearrangements (for the elements of classifications, see Table 3).45 46 TSC-altered demonstrate immunohistochemical positivity for both melanocytic and myogenic markers, as well as cathepsin K44,47. TFE3-rearranged PEComas show melanocytic markers without myogenic markers. NTRK-rearranged uterine sarcomas are defined by fibrosarcoma-like morphology, absence of smooth muscle marker and hormonal receptor expression, and confirmation of a NTRK fusion. These tumors tend to occur in the uterine cervix of pre-menopausal women. Pan-Trk immunohistochemistry is a useful screening tool, but requires molecular confirmation of a NTRK fusion for diagnostic confirmation and eligibility for NTRK inhibition.15 47–52

Table 2

FIGO staging for uterine sarcomas218

Table 3

Risk stratification of gynecologic PEComas1 42 43 219

RecommendationsGeneral Diagnosis

Pathological diagnosis should be confirmed by a pathologist with expertise and experience in the diagnosis of gynecologic mesenchymal tumors, preferably at a sarcoma reference center (IV, A).

Molecular testing may be required to confirm pathological diagnosis and to identify therapeutic targets (IV, C).

According to ICCR data set, there is not a minimum recommended number of blocks (V, B).

Sampling should be based on a careful macroscopic examination and follow ICCR guidelines (V, B).

For challenging diagnoses additional/extensive sampling is necessary (eg, differential diagnosis of sarcoma from carcinosarcoma, LG-ESS from HG-ESS, STUMP from LMS) (V, B).

For low-grade tumors, biopsy can be used for diagnosis only in advanced stage disease. For stage I, biopsy is challenging to establish diagnosis (eg, differential diagnosis between endometrial stromal nodule and LG-ESS) (IV, B).

Immunohistochemistry

Immunohistochemistry is recommended to refine the diagnosis and inform therapeutic decisions, especially when molecular diagnostics are not available. However, many markers may not be specific or diagnostic alone and should be interpreted in conjunction with morphology (IV, B).

A non-exhaustive list of diagnostic immunohistochemical markers includes (IV, B):

Smooth muscle tumors: desmin, h-caldesmon, smooth muscle actin

Fumarate hydratase (FH) deficient smooth muscle tumors: FH and 2SC

LMS: ATRX, RB, PTEN, p53, DAXX, MTAP, MDM2

Endometrial stromal tumors: CD10, IFITM1, Cyclin D1, BCOR

PEComa: HMB45, Melan A, TFE3

NTRK-rearranged sarcomas: Pan-TRK, CD34, S100

p53 useful in distinguishing between complex genomic sarcomas (aberrant expression in LMS, UUS) and simple genomic sarcoma (wild-type expression fusion driven sarcomas such as LG-ESS, HG-ESS, NTRK-rearranged sarcoma)

ER, PR, ALK, ROS-1, Pan-TRK

Ancillary techniques

Molecular tests are recommended to confirm fusion and/or mutation status for diagnosis and/or therapeutic decision making. Suspected therapeutic targets (eg, NTRK, ALK, ROS fusions) require molecular confirmation. Assays may include FISH, RNA and/or DNA sequencing for fusion confirmation and DNA sequencing for mutation confirmation (IV, B).

HG-ESS

The diagnosis of HG-ESS is based on morphology (atypia, mitotic count and necrosis, frequent lymphovascular invasion) and immunohistochemistry (frequent Cyclin D1 and/or BCOR overexpression and/or altered ER/PR expression). This can be associated with a low-grade component (IV, C).

Molecular analysis is indicated and encouraged to detect BCOR, YWHAE, or BCORL1 alterations (IV, B).

UUS

Especially in UUS with uniform histology, immunohistochemistry and molecular studies (RNA sequencing) are indicated to exclude other tumor types (IV, B).

LG-ESS

An endometrial stromal tumor with permeative (tongue-like) infiltration of the myometrium (>3 finger-like projections measuring>3 mm from tumor periphery) and/or lympho-vascular invasion is diagnostic of LG-ESS. Detection of LG-ESS associated fusions may be helpful (IV, C).

Adenosarcoma

The diagnosis is based on morphology (IV, B).

The following aggressive prognostic factors should be taken into account (IV, B):

Sarcomatous overgrowth

High-grade component

Lympho-vascular invasion

Myometrial infiltration

PEComa

The diagnosis is made based on a combination of morphology (perivascular epithelioid cells) and melanocytic markers (HMB45, Melan A) (IV, B).

Principles of Pre-/Post-Operative Imaging

The pre-operative work-up for suspicious uterine smooth muscle tumors is presented in Figure 3. Based on the literature, the suspicious imaging findings for uterine sarcoma which should be looked for on ultrasound are in general solid masses with inhomogeneous echogenicity (the ‘cooked appearance’) with irregular tumor borders, and sometimes irregular cystic areas. Rarely seen is fan shaped shadowing or calcifications. Most are moderately or very well vascularized.53–55 The ultrasound protocol is described in Box 1. If suspicious characteristics are seen on ultrasound, a pelvic MRI is suggested. Alternatively, second-opinion ultrasound could be performed at a dedicated gynecological cancer facility by an expert in ultrasound imaging (level III, European Federation of Societies for Ultrasound in Medicine and Biology).56

Figure 3

Pre-operative work-up in uterine smooth muscle tumors. *Immediate hysterectomy is not accepted by patient (fertility desire, etc). CT CAP, CT scan of chest, abdomen, and pelvis. Dashed line indicates possible additional steps.

Box 1 Ultrasound protocol for uterine mass characterization.EXAMINATION OF THE UTERINE MASS

High-resolution gray-scale and color Doppler transvaginal scan is preferred generally, allowing for detailed assessment of the endometrium and myometrium. Transabdominal scan may be necessary for imaging beyond the small pelvis.

Examination by transvaginal approach commences with a dynamic two-dimensional scan of the uterus in two perpendicular planes.

Three-dimensional ultrasonography enables the offline examination and manipulation of ultrasound images. In difficult cases this may facilitate access to a second opinion from an expert examiner. Coronal sections of the uterus provide information on the external uterine contour and cavity shape.

Myometrial pathology should be described using standardized MUSA (Morphological Uterus Sonographic Assessment) terms.

On MRI, the following eight features should be looked for to determine the likelihood of a sarcoma57 58: on T2 weighted imaging (WI) heterogeneity and hyperintensity of solid enhancing component; on T1WI (pre-contrast): intra-tumoral hemorrhage; on T1WI (post-contrast): heterogeneous enhancement, enhancing finger-like projections, ill-defined borders with the myometrium, central necrosis; on diffusion -weighted imaging (DWI) restricted diffusion (apparent diffusion coefficient value <0.9). Having more than four features raises suspicion. The MRI protocol is described in Table 4.

Table 4

MRI protocol for uterine mass characterization for 1.5T and 3.0T58

For indeterminate masses, positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) can be considered as a second-line of imaging evaluation. While the mean standardized uptake value of uterine sarcomas has in general been shown to be higher than that of uterine leiomyomas, false positives can occur with cellular or very vascular leiomyomas.59

Only in cases with suspicious imaging features but where immediate hysterectomy is not an option, should pre-operative ultrasound guided transuterine cavity (in-organ) or percutaneous (for less accessible mass) core needle biopsy (≥14–16G) of the most suspicious lesion be performed, with expert pathologic review using microscopic and genomic analysis.21 60–63

RecommendationsGeneral Recommendations

In cases with atypical uterine fibroid findings on baseline pelvic ultrasound scans, the patient should be referred to MRI or specialized ultrasound (V, B).

The interpretation should be performed by subspecialist radiologists evaluating specific MRI features (V, A).

Specialized ultrasound examination should preferably be performed in a specialized cancer center by an experienced sonographer fully dedicated to the imaging of gynecological cancers (V, A).

Tailoring Surgery in Patients with Symptoms, High-risk Factors, Fertility Needs, Suspicion on Ultrasound or Pelvic MRI

Pre-operative pelvic MRI (preferably), or transvaginal/transabdominal ultrasound performed only by an expert sonographer at a highly specialized site to assess the mass and to determine if features associated with a higher likelihood of sarcoma are present, is recommended (IV, B).

In patients with suspicious imaging features in whom hysterectomy is not immediately feasible, pre-operative image-guided biopsy is an option in a specialized cancer center by an experienced sonographer or interventional radiologist, while also making the patient aware that false negatives may exist with this pathway (IV, B).

Pre-operative ultrasound guided transuterine cavity (in-organ) core-needle biopsy (≥14–16G) of the most suspicious lesion should be performed with expert pathologic review using microscopic and molecular analysis as needed (IV, B).

Percutaneous biopsy using coaxial needle (for less accessible masses) may be an option but should be used with caution in a specialized center (IV, C).

Patients Incompletely Resected with Malignant Uterine Smooth Muscle Tumors and Patients with Incidental Findings of Malignant Uterine Smooth Muscle Tumors after Hysterectomy

Chest/abdomen/pelvis contrast-enhanced CT scan or abdominal/pelvic MRI plus chest CT scan are recommended for evaluation of locoregional tumor extension and distant metastases (IV, B).

18F-FDG PET/CT in the specific case of indeterminate lesions can be considered (IV, B).

PRINCIPLES OF SURGERY

Minimally invasive techniques may cause rupture of the uterus with the possible dissemination of the sarcoma within the abdominal cavity. This could happen even during a simple hysterectomy in 0.27% of cases.64 In addition, laparoscopic or robotic surgery is associated with the use of morcellation of the specimen, which might lead to a higher risk of recurrence and reduced survival if a uterine sarcoma is diagnosed.65 Only in cases when integrity of the uterus can be assured, should minimally invasive techniques be considered.66 There are no consistent data available on the impact of hysteroscopic surgery on the prognosis of uterine sarcomas (ESS mainly).67 As intraperitoneal fragmentation or morcellation worsens the prognosis, such procedures should be discouraged.68–70 Morcellation is reported with varying frequency in the available literature. According to an analysis of the German prospective sarcoma registry, morcellation was performed in 11.4% of patients with sarcoma who underwent hysterectomy.71 As shown in different studies morcellation of occult sarcoma is associated with a worse prognosis and higher mortality.72–74 There are no high-quality data regarding electromechanical morcellation containment systems in gynecology.14 The largest study to evaluate this was a multicenter prospective study of 76 patients who underwent contained electromechanical morcellation for hysterectomy or myomectomy.75 Spillage of tissue or dye was assessed by gross visualization and was found in 9.2% of cases, although containment bags were intact.

No imaging method has been able to rule out sarcoma pre-operatively with certainty and no pre-operative scoring system is applicable to routine clinical practice to date.76 If risk factors are identified, morcellation should be strictly avoided. The following are considered risk factors for occult sarcoma of the uterus: peri- or post-menopausal age, fast growing or new myoma, recent onset of symptoms such as abdominal pain or vaginal bleeding, and tamoxifen exposure.77 Anemia and an increase of serum lactate dehydrogenase levels may provide additional information, but sensitivity is very low.78 In the event of morcellation of occult sarcoma, further investigations are recommended, including clinical assessment, a whole-body CT scan followed by surgery (eg, resection of cervical remnants) based on the standard approach for uterine sarcoma surgery, although this has not as yet been shown to have an effect on overall survival. In situations where there is evidence of macroscopic residual disease following morcellation, neoadjuvant chemotherapy should be discussed and considered in high-risk cases with high-grade sarcomas.

Early Stage (FIGO I and II)

Surgery is the mainstay of management for early-stage uterine sarcoma. Pre-operative imaging and biopsy may help diagnose early-stage uterine sarcomas. In uterine sarcomas confined to the uterus, complete removal of the uterus (total hysterectomy) is the gold standard.5 79 Bilateral salpingo-oophorectomy is usually performed in post-menopausal women, whereas it may be individualized in pre-menopausal women. Patients with LG-ESS or estrogen receptor positive uterine sarcomas had an increased recurrence rate when the ovaries were left in situ, but with no impact on overall survival.53 80–83 Therefore, the benefits of ovarian preservation in young patients should be carefully weighed against the higher risk of disease recurrence. Pelvic and/or para-aortic lymph node metastases are unfavorable prognostic factors, but are uncommon in uterine sarcomas confined to the uterus.84 85 Furthermore, there is no evidence that systematic pelvic and para-aortic lymphadenectomy improves survival outcomes.5 79 86 Therefore, systematic pelvic and para-aortic lymphadenectomy is not recommended for patients with uterine sarcoma confined to the uterus.5 79 87 88 However, lymph nodes that are suspicious for metastasis should be removed at surgery. Lymphadenectomy has little prognostic or therapeutic benefit in patients with uterine sarcoma.89–91

Advanced Stage (FIGO III and IV)

The standard treatment of stage III uterine sarcoma of all histological subtypes is complete surgical resection of all macroscopic tumor similar to the approach used in ovarian cancer surgery, given one of the most important prognostic factors is the volume of residual tumor following initial surgery.92 93 This could include total hysterectomy, bilateral salpingo-oophorectomy, debulking of peritoneal lesions (peritonectomy), removal of bulky/suspicious nodes, organ or partial organ resection including partial small or large bowel resection, or splenectomy.82 Guckenberger et al recently proposed a novel dynamic model of oligometastatic disease to aid decisions regarding radical local treatment for patients with oligometastases. The model is based on a number of binary disease characteristics including de novo oligometastatic disease; synchronous oligometastatic disease; metachronous oligorecurrence or induced oligometastatic disease following systemic therapy for polymetastatic disease. Surgery should be discussed and considered in patients with oligometastatic uterine sarcomas. Alternative local treatments can be considered if not resectable, with acceptable morbidity.94 95 Stereotactic ablative radiotherapy could be an option as well as other ablative techniques.96 Patients with extra-uterine disease have a higher rate of lymph node metastases than those with disease confined to the uterus.97 98 Lymphadenectomy should be undertaken only if the lymph nodes are grossly enlarged intra-operatively.85 A systematic review on the use of intraperitoneal hyperthermic chemotherapy did not demonstrate efficacy and yielded a mortality rate of 4%.99 In patients with LG-ESS where complete tumor resection is not expected, endocrine treatment may be an effective option prior to surgery.100 Reassessment of response performed after 3 months to identify good responders who could potentially benefit from surgical resection is an option.82

Recurrent Disease

There is no established relapse-free interval threshold to support decisions about further surgery, but all cases should be evaluated by a multidisciplinary team. About half of patients with recurrent uterine sarcoma present with abdominal/pelvic disease alone and half with lung metastases only, with a median interval of 18 months to recurrence after complete removal of the primary tumor. In abdominal recurrences, it is important to have all the details of the previous surgery available, particularly the operation record and pathology report with a description of the resected specimen, which might provide information about contributing factors to recurrent disease. Histological subtype is crucial, and, when in doubt, reference pathologists must be involved. The German prospective sarcoma registry data show that LMS contributes to 60% to 70% of patients with recurrent disease.71 In LG-ESS, cytoreduction can potentially improve outcomes when combined with endocrine treatment.101–103 Relapsed adenosarcoma without sarcomatous overgrowth, LG-ESS, and estrogen receptor positive tumors could be treated with endocrine therapy alone, or surgery followed by endocrine therapy, similar to the approach in recurrent LG-ESS.

A local recurrence after incomplete resection is located typically in the region of the lateral pelvic uterine vessels. Given the challenge in obtaining clear margins, for some histological subtypes chemotherapy and/or radiation therapy can be offered prior to surgical resection.104 In cases of disseminated recurrence, the tumor type is most commonly a high-grade sarcoma. Surgery usually cannot control abdominal spread without effective systemic treatment. Depending on the systemic therapy regimen used, 2–4 cycles should be administered prior to considering surgery in carefully selected cases who have a good response to treatment. Surgery should be considered if complete resection can be achieved. Debulking should be as radical as possible, although post-operative quality of life must be taken into account. Post-operative systemic therapy should be discussed depending on the result of surgery and the histological subtype. The extent of surgical resection is a highly significant predictor of survival. Patients with no gross residual disease have better survival than those whose disease was not amenable to complete resection.105 In the scenario of abdominal or distant recurrence after prior complete surgery, the time interval to recurrence as well as the number and location of metastases are critical for making decisions about further surgery. If the Guckenberger et al criteria for oligometastatic disease are fulfilled, surgery is indicated as an initial approach.94 Resection of lung or liver metastases can potentially be performed with low morbidity in the relapsed disease setting.104 106

Special SituationsInitial Surgery with Residual Disease

In the setting of an incidental diagnosis of uterine sarcoma after total hysterectomy or supracervical (subtotal) hysterectomy, expert pathologic review and imaging studies are warranted. Pelvic MRI is beneficial to evaluate local tumor extension.107 If the tumor was initially morcellated or the cervix was left, re-exploration of the abdominopelvic cavity with resection of residual disease and/or the cervix should be considered.108 For incidental diagnosis of uterine sarcoma after myomectomy, expert pathologic review and imaging studies are also warranted. If the tumor is confined to the uterus, a total hysterectomy is recommended. If extra-uterine disease is suspected and surgically resectable, resection of metastatic disease is recommended along with a total hysterectomy.108 If bilateral salpingo-oophorectomy was not conducted initially, it should be considered in post-menopausal women.

Ovarian Preservation

Large population-based studies in pre-menopausal patients show that retention of ovaries during primary surgery is not associated with inferior overall survival.53 68 83 109 110 This is particularly important in young women, owing to the impact of surgical castration on quality of life. Furthermore, there is an option for ovarian preservation in selected patients since gametes are available for surrogacy. In the absence of any survival benefit, there is no indication to perform bilateral salpingo-oophorectomy in cases of pre-menopausal uterine sarcoma, unless the ovaries are involved.111 This applies to all subtypes of uterine sarcoma.

In recurrent adenosarcoma without sarcomatous overgrowth and LG-ESS in pre-menopausal women with ovaries in situ, bilateral oophorectomy or ovarian suppression with gonadotropin-releasing hormone (GnRH) analogs should be considered to decrease the estrogen levels.

Uterine Preservation

Preservation of the uterus in the majority of young women is not recommended, since most uterine sarcomas invade into the corpus uteri and there is a high chance of recurrent disease, even in early-stage sarcomas. There is some evidence to support the potential for fertility preservation and subsequent pregnancy in carefully selected patients.112–115 However, there are a number of concerns associated with conservative surgery and leaving the uterus in situ. First, there is an increased risk of local recurrence due to presence of residual sarcoma, which can result in a fatal outcome. Second, sarcoma cells might spread to the peritoneal cavity during hysteroscopic resection and reduce survival. Finally, surgically induced myometrial damage might complicate future pregnancies. In a recent systematic review of the literature, a fatality rate of 57% (4/7) was reported for LMS managed conservatively.112 Although the recurrence rate for LG-ESS was 54% (34/63), the fatality rate was only 2% (1/63). Figures were best for adenosarcoma where in 19 cases, there were no recurrences in patients managed conservatively.112 The duration of follow-up was variable but generally less than 5 years. In cases where LG-ESS can be completely removed (ie, confined to a polyp), uterine conservation may be considered in highly motivated and adequately informed patients, or in patients with low-grade adenosarcoma without sarcomatous overgrowth.112 Given the low numbers, further safety assessment is warranted. The fatality rate for high-grade uterine sarcomas is too high and fertility preservation should not be considered. Thus, tumor biology, resection margins, and wish of the patient are crucial factors that need to be taken into consideration when a fertility-sparing option is discussed. Hysterectomy can be considered after the completion of pregnancy and delivery.82

RecommendationsGeneral Recommendations

An open approach should be the preferred route of surgery in most cases (IV, B).

Only in cases when integrity of the uterus can be assured, minimally invasive techniques may be considered (IV, C).

Morcellation should always be avoided in cases with pre-operative suspicion of uterine sarcoma—for example, rapid growing mass or suspicious appearances on MRI (II, A). Patients undergoing morcellation for an apparently benign condition must be counseled on the low risk of unsuspected sarcoma even in an apparently benign lesion (V, A).

Early Stage (FIGO I and II)

Complete removal of the intact uterus is the gold standard of surgical management (III, A).

Bilateral salpingo-oophorectomy is the standard of care in post-menopausal women (III, A).

In pre-menopausal women with stage I disease, ovarian preservation with bilateral salpingectomy could be considered in selected cases regardless of the histological subtype to avoid the need for post-menopausal endocrine therapy (IV, C).

Routine systematic lymphadenectomy should not be performed (III, D).

Suspicious nodes or peritoneal lesions should be removed as well (IV, B).

Advanced Stage (FIGO III and IV)

For stage III, complete surgical removal of disease is the gold standard, including total hysterectomy and bilateral salpingo-oophorectomy and resection of any other suspicious lesions including peritoneal disease and/or bulky/suspicious nodes (IV, A).

For stage IV, the option for primary resection depends on the number and location(s) of metastases as well as the biology and histological subtype. Surgery should be considered in primary oligometastatic disease together with complete surgical resection of primary tumor if it is deemed feasible with acceptable morbidity (IV, A).

Lymphadenectomy should be undertaken only if the lymph nodes are grossly enlarged intra-operatively or suspicious for metastases on pre-operative diagnostic work-up (IV, B). There is no indication for routine systematic lymph node dissection (IV, D).

In cases of initially unresectable uterine sarcoma, primary systemic treatment is an option followed by re-evaluation for surgery depending on response (IV, B).

Recurrent Disease

All cases should be evaluated by a multidisciplinary team to determine if surgery is a reasonable and feasible option for all types of uterine sarcomas, with the primary goal of complete resection (V, A).

Selection of the best candidates for surgery should be based on the following criteria (V, B):

Tumor biology and histology;

Localization of relapse, number of lesions, and tumor burden;

Recurrence-free interval (although there is no validated cut-off point);

Performance status;

Severity of co-morbidities;

Patient perspectives;

Potential complications;

Prior treatment.

In particular, bilateral salpingo-oophorectomy should be considered in pre-menopausal patient subgroups with low-grade uterine sarcoma (including LG-ESS and adenosarcoma without sarcomatous overgrowth) when the ovaries are in situ, to decrease endocrine stimulation (IV, B).

In indolent uterine sarcomas (ie, LG-ESS, low-grade adenosarcoma without sarcomatous overgrowth, and selected low grade LMS), surgical resection might be a reasonable option in cases with second or third recurrences (IV, C).

Re-laparotomy for recurrence in high-grade uterine sarcoma and adenosarcoma with sarcomatous overgrowth might be a valid option if disseminated disease is not present (IV, C).

Special Situations

In cases of unexpected diagnosis of sarcoma after myomectomy, a hysterectomy should be performed. If extra-uterine disease or residual disease is suspected and surgically resectable, complete resection is recommended along with the total hysterectomy (IV, B).

Resection of a uterine sarcoma with preservation of the uterus is a non-standard approach and could only be considered in referral centers for highly-selected cases of LG-ESS and low-grade adenosarcoma without sarcomatous overgrowth with informed consent (V, C).

Ovarian preservation should be considered in stage I sarcomas where hormonal and gametes preservation is desired (IV, B).

UTERINE LEIOMYOSARCOMA

uLMS are the main subgroup of uterine sarcomas. According to data from European cancer registries, their incidence is in the range of 0.5/100 000 /year, although this may be an underestimation due to difficulties in pathologic diagnosis on a population basis. Nonetheless, they fall within the category of rare cancers.116 Their peak incidence is in the sixth decade. The main differential diagnosis is leiomyomas, which are very common.

In localized, stage I disease, total hysterectomy is the standard treatment. Post-operative radiation therapy is not indicated, based on the results of a negative randomized clinical trial.117 Likewise, adjuvant chemotherapy is not standard due to the lack of evidence to indicate a survival benefit.118 However, it is felt by many that this issue has not been resolved and remains an open question due to limitations with earlier trials. The available randomized evidence includes obsolete regimens in relatively small numbers of patients or is inconclusive.119–121 Uncontrolled and observational retrospective evidence suggested that there might be benefit, but cannot support a firm recommendation as results are conflicting.122–125 There is indirect evidence from two randomized trials of neoadjuvant or adjuvant chemotherapy in non-uterine soft tissue sarcomas, including LMS.126 127 Thus, the inclusion of patients in new clinical trials is recommended. Some institutions do offer adjuvant chemotherapy to selected patients after discussing the uncertainty of available evidence and share the decision-making with individual patients.

In patients with locally advanced, stage II–III, disease, chemotherapy is commonly recommended following surgery, particularly in patients with more advanced disease (although an alternative option is delaying chemotherapy until progression, given that the aim of treatment is palliation, not cure). When surgery is not feasible, or considered unreasonable given the extent of disease, chemotherapy is an option, incorporating the most active regimens such as doxorubicin+trabectedin. This combination, which was more effective than doxorubicin alone in a randomized trial, or doxorubicin+dacarbazine, which combines two active drugs in LMS.128–130 Depending on the symptoms and presentation, primary pelvic radiation therapy may also be an option. Pelvic radiation may be used as an adjuvant to surgery when the cervix and/or parametria are involved, given the high risk of pelvic relapse.

In pelvic/abdominal relapses, pre-operative or post-operative chemotherapy may be considered, following the same principles as for stage II–III disease.

If distant metastases are present, chemotherapy is the standard treatment, but surgery, or ablative procedures, can be used in selected patients based on the presence of more favorable prognostic factors. When prognostic factors are unfavorable, but the disease is considered resectable, chemotherapy may be used either pre- or post-operatively. The prognostic factors to consider include the site and the number of metastases and the disease-free interval as well as symptoms and performance status.131 The role of surgery for metastases, particularly lung metastases, is supported by its extensive use in sarcomas and a large body of uncontrolled evidence.132–134

With respect to the regimens used in first-line systemic therapy of uLMS, there is randomized evidence that a multiagent chemotherapy regimen with doxorubicin and trabectedin improves progression-free and overall survival.129 130 Other active multiagent combinations are doxorubicin+dacarbazine and gemcitabine+docetaxel.128 135 Alternative options include single-agent doxorubicin, or single-agent gemcitabine, or liposomal doxorubicin, factoring in their lower toxicity in a palliative setting.136–138 The choice of treatment is based on multiple factors, including age, symptoms, co-morbidities, site of metastases, site of progression, and patient preferences.

With respect to second-line systemic therapy in uLMS, the same regimens as used in the first-line setting can be considered, taking into account a number of factors, including response to first-line therapy, duration of response, adverse effects of treatment, as well as the cumulative dose of anthracyclines. The most commonly used single-agent therapies include trabectedin, gemcitabine, pazopanib, dacarbazine, although multiagent chemotherapy regimens including gemcitabine+dacarbazine or gemcitabine+docetaxel are also options. All these treatments are supported by prospective phase III or phase II trials with demonstration of improvement in progression-f