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Gynecological sarcomas, surgical management: primary, metastatic, and recurrent disease
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  1. Gwenael Ferron1,2,
  2. Guillaume Bataillon3,
  3. Alejandra Martinez1,4,
  4. Frederic Chibon2,5 and
  5. Thibaud Valentin2,6
  1. 1 Surgical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
  2. 2 OncoSARC (Oncogenesis of Sarcoma), INSERM UMR1037, Toulouse, France
  3. 3 Anatomopathology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
  4. 4 T2i (Anti-tumour immunity and immunotherapy), INSERM UMR1037, Toulouse, France
  5. 5 Surgical Pathology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
  6. 6 Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
  1. Correspondence to Dr Gwenael Ferron, Surgical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, Languedoc-Roussillon-Midi 31059, France; ferron.gwenael{at}iuct-oncopole.fr

Abstract

Adult-type gynecological soft tissue and visceral sarcomas are rare tumors, with an estimated incidence of 13% of all sarcomas and 4% of all gynecological malignancies. They most often develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecological organs (2%). The objective of this review is to provide an overview of the current management of gynecological sarcomas, according to international guidelines. The management of gynecological sarcomas should follow the recommendations for the management of soft tissue and visceral sarcomas. Centralizing cases in expert centers improves patient survival, both for the diagnostic phase and for multidisciplinary therapeutic management. In the case of pelvic soft tissue sarcomas, a radiological biopsy is essential before any surgical decision is taken. In the case of a myometrial tumour which may correspond to a sarcoma, if conservative surgery such as myomectomy or morcellation is planned, an ultrasound-guided biopsy with pathological analysis including comparative genomic hybridization analysis must be carried out. In all cases, en bloc surgery, without rupture, is mandatory. Many rare histological subtypes require specific surgical management.

  • sarcoma
  • pelvis
  • pathology
  • surgical oncology

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Introduction

Adult-type gynecological soft tissue and visceral sarcomas are rare tumors, with an estimated incidence of 13% of all sarcomas and 4% of all gynecological malignancies. Gynecological sarcomas most often develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecological organs (2%).1 While in general the most common histological types of adult sarcoma are liposarcomas, undifferentiated pleomorphic sarcomas and leiomyosarcomas, the most frequent sarcomas of the gynecological area are leiomyosarcoma, endometrial stromal sarcoma, adenosarcoma, and undifferentiated sarcoma.2 Note that carcinosarcomas are excluded because they are treated as epithelial tumors. About 70–80% of sarcomas are diagnosed at early stage and can be treated with curative intent.

The objective of this review is to provide an overview of the current management of gynecological sarcoma, according to international guidelines, to highlight the importance of centralizing sarcoma management in expert referral centers, both for the diagnostic phase including imaging, pre-therapeutic biopsies, surgical pathology reporting, and for multidisciplinary therapeutic management.

Histological Type According to the Organ

Gynecological mesenchymal tumors can be divided into two groups based on their anatomical localization according to the 2020 WHO classification:

  • Uterine mesenchymal tumors most commonly develop from the myometrium or the cytogenic chorion. The most prevalent are benign leiomyomas, while leiomyosarcomas represent malignant counterparts arising from the smooth muscle cells. The leiomyosarcomas exhibit genetic alterations involving genes such as TP53, PTEN, Rb, ATRX, and so on. Endometrial stromal tumors, including low-grade and high-grade variants, originate from endometrial stromal cells, display specific fusion transcripts of JAZF1, YWAHE, and BCOR. Additionally, there are rarer subtypes such as undifferentiated uterine sarcomas, adenosarcomas, and tumor of uncertain malignant potential (PEComa, UTROSCT, and TMI), each requiring distinct diagnostic approaches (Table 1) (Figures 1 and 2).3

  • Genital stromal tumors of the lower gynecological tract originate from subepithelial stromal cells within the mesenchyme, spanning from the uterine cervix to the vulva. This group of tumors presents significant heterogeneity. Although they share certain morphological and immunohistochemical characteristics, the diagnosis relies on clinico-morphological and radiological correlations, with recent considerations of specific molecular alterations (Table 2).4

Table 1

Mesenchymal tumors of the uterus

Figure 1

HES and comparative genomic hybridization (CGH) array profile of uterine leiomyosarcoma. (A) Hematoxylin and eosin (H&E) slide of leiomyosarcoma: proliferation of spindle cells with marked atypia and high mitotic count. (B) CGH profile: altered profile with notable loss of 10q (PTEN), 13q (Rb1), and 17 p (P53). HES, hematoxylin and eosin stain.

Figure 2

HES and molecular biology of low-grade endometrial stromal sarcoma. (A) Hematoxylin and eosin (H&E) slide of low-grade endometrial stromal sarcoma: proliferation of uniform oval to spindle cells with minimal cytologic atypia, low mitotic count. (B) Rearrangement of the JAZF1 gene using break-apart fluorescence in situ hybridization. The tumor cell nuclei exhibit a separation between the 3' JAZF1 (red) and 5' JAZF1 (green) probes, indicating a rearrangement in this gene region. HES, hematoxylin and eosin stain.

Table 2

Mesenchymal tumors of the lower genital tract

Management of Gynecological Soft Tissue and Visceral Sarcomas

Management in Expert Referral Centers and Multidisciplinary Teams

Given the heterogeneity and low incidence of this malignancy, management of gynecological sarcoma must be carried out in multidisciplinary teams within reference centers.5 Because of their rarity, sarcomas are often initially misrecognized, misdiagnosed, and as a consequence not treated according to clinical practice guidelines.6 There is a large body of scientific evidence demonstrating how the initial management of the disease impacts on patients’ survival, both on the local and distant control of the disease.7 A recent study of the French sarcoma group (NETSARC) including almost 30 000 patients with soft tissue sarcomas and visceral sarcomas demonstrated the correlation between sarcoma management in a referral institution and patients’ survival.7 The complete resection rate R0 is around 50% when patients undergo surgery in a non-expert sarcoma center, and the R2 resection rate is more than twice than that of surgeons working in referral centers. Moreover, patients treated outside referral institutions have higher relapse rates, decreased survival outcome, and have an excess cost associated with their suboptimal treatment that is estimated to be approximately 60 million euros over the study period.7 Because sarcomas are often managed with multimodal treatments, a multidisciplinary approach in the case of suspected gynecological soft tissue sarcoma or visceral sarcoma is mandatory, involving specialized radiologists and nuclear medicine specialists, pathologists, surgical oncologists (or organ-based specialists), medical oncologists, and radiation oncologists. Once there is a sarcoma suspicion on imaging workup, a percutaneous biopsy must be performed for soft tissue sarcoma frequently using a transgluteal approach to avoid peritoneal spreading.6 In cases of localized tumor, transvaginal or transrectal biopsies (eg, by echoendoscopy) should be avoided to prevent contamination.

Radiological expertize is also essential to guide the pathologist with certain rare tumors such as deep angiomyomas or suspicious myometrial tumors.

Imaging

For primary pelvic sarcomas, MRI is the best imaging modality. MRI evaluation is essential to avoid morcellation, piecemeal resection, or inappropriate surgery in cases of uterine tumors with leiomyosarcoma radiological features. Pelvic MRI requires a specific protocol, including T2-weighted imaging, a T1 sequence (to search for hemorrhage), and diffusion-weighted imaging (DWI) to calculate the apparent diffusion coefficient (ADC) mapping. MRI accuracy is around 88–95% for detecting uterine leiomyosarcoma, with sensitivity of 83–100% and specificity of 88–100%. Abdominal T2 sequence up to the renal veins should be performed to evaluate para-aortic lymph node metastasis. An international consensus has recently been published defining the terms with a strong association in support of leiomyosarcoma diagnosis.8 Several algorithms have been published to help to differentiate atypical leiomyomas from uterine sarcomas on MRI but with a non-negligible false-negative rate.

CT is recommended for staging purposes, including thorax evaluation. Thorax assessment is mandatory as pulmonary metastases are the most frequent extra-abdominal location of gynecological sarcomas. More than 50% of leiomyosarcomas have pulmonary metastases at diagnosis.9 Liver and peritoneal metastasis are rare except for myxoid liposarcoma and leiomyosarcoma. Regional lymph node metastases are usually rare (fewer than 1%), but are frequently found in cases of synovialosarcoma, epithelioid sarcoma, clear-cell sarcoma, angiosarcoma, and endometrial stroma sarcoma.

CT is recommended for staging purposes, for lymph node assessment, but also for detecting calcifications in certain types of sarcomas. It is useful when considering a scan-guided biopsy.5

Fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT can be considered at the diagnostic phase, to guide the interventional radiologist in particular in cases of a necrotic tumor to target the biopsy on the most relevant area. PET/CT can also be used to search for metastasis more accessible to biopsy.5

Pre-operative Biopsy

Pre-operative biopsies, following appropriate imaging assessment, represent the cornerstone for sarcoma diagnosis including microscopy and biomolecular analysis. Frozen section at the time of the surgery is not encouraged because of the discrepancy rate, the underestimation of the tumor malignancy, and interference with adequate pathological processing.10

In suspicious gynecological mesenchymal tumors, several situations must be considered depending to the location of the tumor. Biopsies should always be carried out by a radiologist or surgeon in an expert center.5 A pathological expert validation is necessary for all cases, especially when the biopsy is performed outside of reference centers.

Cases of Pelvic Soft Tissue Tumor

The standard approach for pelvic soft tissue tumor diagnosis consists of multiple (with at least five to eight) core needle biopsies, using coaxial 14 G needles guided by CT scan or ultrasonography. Biopsies must be taken from a tissue part of the tumor and not from a necrotic area. The quantity of material taken must allow for surgical pathological analysis, including hematoxylin and eosin (H&E), immunohistochemistry, and molecular analyses, including next-generation sequencing, fluorescence in situ hybridization, or RNA sequencing, and comparative genomic hybridization, employed together to achieve a diagnosis and provide prognostic and theragnostic insights (Figures 1 and 2).4

To make the diagnosis of sarcomas, the conventional H&E staining technique is the first step to identify cellular differentiation, histological malignancy criteria, including atypia, mitotic activity, and necrosis, and to establish the histological type according to WHO 2020.

This approach is complemented by immunohistochemical panel, confirming histological types through cellular differentiation such as muscular, adipose, vascular, mesenchyma differentiation, and identifying molecular alterations, quickly and cost-effectively (p53, Rb, beta-catenin, STAT6, among others).

Additionally, molecular studies, such as next-generation sequencing for mutation detection, fluorescence in situ hybridization or RNA sequencing for the identification of fusion transcripts, and comparative genomic hybridization for evaluating copy number variations, can be performed. These analyses, sometimes essential for diagnosis, are expensive and are only available in specialized centers.

Remember that the biopsy method must be planned in consultation between the surgeon and the radiologist after multidisciplinary discussion. The biopsy tract will be removed by the definitive surgery. The biopsy entrance point can be tattooed for the same reason.5

Excisional or open surgical biopsy should be avoided because of the risk of tumor spreading, surgical contamination, and bleeding, which could lead to a change in the final surgical strategy.

Cases of Suspicious Myometrial Tumors

Uterine myometrial tumors are benign in most cases, with an estimated cumulative incidence of over 70% to 80% of women aged 50 years.11 One-third of them are conservatively treated by myomectomy and minimal invasive surgery. Both the American College of Obstetricians and Gynecologists (ACOG) and the American Association of Gynecologic Laparoscopists (AAGL) have released statements advocating for a minimal invasive approach to hysterectomy for benign indications.12 13 Compared with an abdominal approach, minimal invasive surgery decreases post-operative pain, wound complications, blood loss, hospital stay duration, and recovery time.14 Among these women, the reported prevalence of unsuspected sarcoma at surgery ranges from 1/10 000 to 1/352 depending on the inclusion criteria of different publications.8 15 MRI criteria and diagnostic algorithms do not allow discrimination with the greatest accuracy of leiomyomas, smooth-muscle tumors with uncertain malignancy potential (STUMPs), and leiomyosarcomas.

Despite advances in imaging, the risk of inappropriate surgery remains approximately 1/400, with an unacceptable loss of chance of survival in the case of myomectomy, which should be considered as a piecemeal resection.16 Re-operation does not give the same prognosis. Conversely, conservative uterine surgery for fertility purposes is offered to women of childbearing age with a leiomyoma for whom it is not acceptable to systematically perform a hysterectomy in the event of suspicion on MRI. It is therefore necessary to have histological information prior to myomectomy and avoid any oncological risk. In most cases, endometrial biopsies have a low predictive value in diagnosis of myometrial sarcoma compared with epithelial uterine malignancies17

Diagnostic management strategy was radically changed in 2023, following the publication by the Curie Institute (Paris) team of a preliminary study leading to a change in clinical practice.18 The authors demonstrated the diagnostic performance of a uterine percutaneous approach using coaxial core needle biopsy guided by ultrasonography under local anesthesia in an outpatient setting. Pathology examination included expert morphological assessment with immunohistochemistry analysis and array-comparative genomic hybridization analyses (Figure 1).

This approach presents two main limitations. The first is the risk of peritoneal spreading. This theoretical risk will in any case be less damaging than morcellation or piecemeal resection (myomectomy). In addition, the percutaneous approach has been published in gastrointestinal stromal tumors, with the same theoretical risk of peritoneal dissemination. Despite the transperitoneal approach for this type of sarcoma, there is no reported increase in the recurrence rate. The second limitation is the histological diagnostic accuracy using microscopic biopsy material. In this study, all biopsies were analyzed by an expert pathologist using microscopic and comparative genomic hybridization analyses according to Croce’s previous publications.19 The diagnostic accuracy is 100%. The sensibility, specificity, and negative predictive value were 100%, 100%, and 100%, respectively. A high genomic index was associated with malignancy. No dissemination was found at the time of the surgery. These results have modified the diagnostic management of patients planned for a myomectomy or a surgery with morcellation in France, whose omission can have dramatic consequences.

After this practice-changing publication, percutaneous biopsies with microscopic and comparative genomic hybridization analysis are included in the 2023 recommendations within the framework of the French Sarcoma Group (NETSARC+) and Malignant Rare Gynecological Tumors (TMRG) networks, in the management of patients with an indication of myomectomy or morcellation.20 If surgery with hysterectomy, a fortiori by laparotomy, is planned, the percutaneous biopsy may be omitted.

Cases of Suspicious Ovarian Tumors

Ovarian sarcomas are a very rare entity comprizing only 1% of ovarian tumors.21 Most published series of ovarian sarcomas include carcinosarcomas, which are now managed as epithelial ovarian tumors. The most common histotypes found are leiomyosarcoma, fibrosarcoma, and rhabdomyosarcoma. Differential diagnosis with ovarian metastasis from another sarcoma (Ewing sarcoma, uterine endometrioid stromal sarcoma) must be considered. Regarding surgical treatment of primary ovarian sarcomas, up to now there are no prospective studies to define management recommendations for these rare entities. The management of an ovarian tumor suggestive of sarcoma is similar to epithelial ovarian tumors, as imaging is not specific. Diagnostic surgery is most often required. Using frozen section it is difficult to distinguish sarcoma from a carcinosarcoma. For early stages, surgery including total hysterectomy and bilateral salpingo-oophorectomy is the mainstay of treatment. Tumor debulking should be considered/performed for advanced-stage disease.

Standardized Pathological Reporting

The pathological report for gynecological sarcomas should comprehensively encompass specific details, as recommended by both the College of American Pathologists and the International Collaboration on Cancer Reporting (ICCR). This report should contain the following critical information: operative procedure and specimen integrity, tumor site, maximum tumor size, histological type and grade, extent of invasion and lymphovascular invasion, margins status, TNM (Tumor, Node, Metastasis), and International Federation of Gynecology and Obstetrics (FIGO) staging.

Staging and Risk Assessment

CT is recommended for staging purposes, including thorax evaluation. Pulmonary metastases are frequent in case of sarcoma. More than 50% of leiomyosarcomas have pulmonary metastases at diagnosis. Liver and peritoneal metastasis are rare except for myxoid liposarcoma and leiomyosarcoma. Regional lymph node metastases are usually rare (fewer than 1%), but are frequently found in cases of synovialosarcoma, epithelioid sarcoma, clear-cell sarcoma, angiosarcoma, and endometrial stroma sarcoma.

FDG-PET/CT Use in Aggressive Tumors Seeking Lung or Bone Metastasis

Some promising consensus molecular classifications with prognostic relevance have been developed, but they are not used in daily practice. Developed to assess metastatic risk in soft tissue sarcomas, the Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity.22–24 CINSARC has weak prognostic power in high-risk, localized soft tissue sarcoma treated with neoadjuvant chemotherapy. CINSARC signature is being evaluated in a clinical research trial to guide the initiation of adjuvant chemotherapy in uterine leiomyosarcomas (NCT04307277).

Surgical Management of Gynecological Sarcomas

En Bloc Surgery

Soft Tissue Gynecological Sarcomas

The quality of initial surgery for sarcoma is a major prognostic factor for recurrence-free survival and overall survival in all series.25 26 Optimal surgical removal of sarcoma, with en bloc macroscopic resection and histological clear margins (R0), is the mainstay of the curative treatment of localized soft tissue sarcoma.7 The minimal margin must fit in with surrounding structures, especially with the presence of resistant anatomical barriers such as muscular aponeurosis, periosteum, vascular adventis, and epineurium. This surgery must be planned based on pre-operative imaging, anticipating any procedures requiring reconstruction including vascular resection, bowel resection, urinary derivation, vaginal, or perineal reconstruction. In case of extensive surgery, neoadjuvant treatment can be considered according to the histological type, the tumor size, and site after multidisciplinary discussion.

Visceral (ie, Uterine) Sarcoma

The surgical management of pre-operative diagnosed (or suspected) uterine sarcoma should be realized in an expert center.27 Several studies have shown the relapse-free survival is higher in patients managed in a sarcoma referral center with better adherence to surgical recommendations.7

The surgical strategies for early-stage uterine sarcoma are based on complete resection of disease without tumor rupture (morcellation, fragmentation) and negative surgical margins. Standard procedure includes total extrafacial hysterectomy (type A of the Querleu and Morrow classification)28 and bilateral salpingo-oophorectomy in menopausal and peri-menopausal patients. For leiomyosarcoma, there are no data demonstrating that bilateral salpingo-oophorectomy improves prognostic outcome. Bilateral salpingo-oophorectomy is part of the standard surgical treatment for low-grade endometrial stromal sarcoma, even in pre-menopausal woman.29 30 The resection of the upper vagina or uni/bilateral parametrectomy can be associated for bulky tumors or when there is tumor extension to the uterine cervix.20 31 The preferred elective approach is median laparotomy to reduce the risk of tumor rupture. For lesions of less than 6–8 cm, laparoscopic management may be discussed, with protected extraction of the operative specimens (using large endobags). If the tumor has spread to the cervix or vagina, colpotomy must be performed to avoid visualizing the tumor and peritoneal spillage, if necessary, using surgical stapling.32 Iatrogenic rupture remains one of the independent prognostic factors for overall survival with FIGO stage and histological subtype.33

If the tumor spreads to other pelvic organs (bladder, rectum, pelvic wall), complete radical surgery must be performed in the absence of metastases.

Role of Lymph Node Dissection

Regional lymph nodes metastasis are rare in most subtypes of gynecological sarcomas ranging from 1% to 5.8%.34 Low-grade and high-grade endometrial stroma sarcoma present a high rate of lymph node positivity, namely 10.3% and 19.8%, respectively.35 Lymph node metastasis is also common in proximal-type epithelioid sarcoma, clear cell sarcoma, rhabdomyosarcoma, synovialosarcoma, and angiosarcoma, in which lymph node involvement is reported in 10–40% of cases.36–38 Lymph node involvement constitutes an adverse prognosis factor. Indeed, patients with lymph node metastasis have a similar survival outcome to patients with metastatic disease.39

In early-stage disease, systematic lymphadenectomy is not recommended and does not improve the prognosis,34 40–42 except for patients with high-grade endometrial stroma sarcoma who may benefit from lymphadenectomy.33 43

Lymph node resection seems to be beneficial as a complete resection, only when pre-operative imaging and intra-operative findings suggest the presence of lymph node metastasis.42 In the case of sarcoma with a high risk of lymph node invasion, specific staging including PET/CT or whole-body MRI should be considered.

The role of sentinel lymph node dissection is uncertain and should be only discussed in some rare cases with specific histological subtypes, such as epithelioid sarcomas, clear cell sarcomas, or alveolar soft part sarcomas.44–46

Ovarian Preservation in Pre-menopausal Women

Bilateral salpingo-oophorectomy should be performed in all post-menopausal patients. For leiomyosarcoma or high-grade sarcoma, ovarian conservation can be considered in early-stage disease, as the survival benefit of bilateral oophorectomy is not established.41 46

In low-grade endometrial stroma sarcoma or adenosarcoma, ovarian preservation can be considered in selected young patients with stage I tumor, depending on tumor hormonal receptor status. Extensive counseling is advised.47–52

Specific Situations

Deep Angiomyxoma

Deep angiomyxoma formerly called aggressive angiomyxoma is a rare, infiltrative, hormone-dependent, benign-mesenchymal tumor that occurs in the deep soft tissues of the perineal regions. The clinical presentation is unusual, with a slow-growing, large, painless mass that is frequently difficult to palpate, and discrepancies in tumor size on imaging. Deep angiomyxoma typically presents on MRI as a mass compressing the surrounding tissues and viscera without infiltration. MRI aspect on T2-weighted images is a laminated pattern with intense homogeneous contrast enhancement53 (Figure 3). Diagnosis can be obtained by transperineal biopsy. The recent WHO classification qualified deep angiomyxoma as an intermediate risk sarcoma with slow growth. Conservative resection limited to macroscopically invaded organs associates with a low rate of recurrence.54 Planned conservative en bloc complete removal of the tumor without margins is required. This tumor is often considered to have a high risk of recurrence, mainly because the tumor insinuates itself through the muscular fibers of the perineum and surgical resection is incomplete. Complete resection must be confirmed by post-operative MRI. The rate of recurrence is low in cases of complete resection performed by an expert sarcoma team.54 Wait-and-see strategies and hormonotherapy can be discussed, especially during pregnancy or in case of local relapse.55

Figure 3

Deep angiomyxoma typically presents on MRI as a mass compressing the surrounding tissues and viscera without infiltration. MRI aspect on T2-weighted images is a laminated pattern with intense homogeneous contrast enhancement.

Solitary Fibrous Tumors

Solitary fibrous tumors are uncommon mesenchymal tumors and are particularly rare in the female pelvis. Several cases have been described associated with a paraneoplastic syndrome consisting of a life-threatening hypoglycemia (Doege–Potter syndrome). Overall prognosis is good and local recurrence is rare when complete resection is performed and in well-differentiated tumors. The Demicco multivariate risk stratification system serves as an assessment tool for predicting the likelihood of an adverse clinical outcome, specifically the risk of metastasis. This system takes into account four variables: patient age, tumor size, mitotic rate, and the presence or absence of necrosis.56

Sporadic Desmoid Tumors

Sporadic desmoid tumors (or desmoid-type fibromatosis) are locally aggressive, benign, mesenchymal tumors with no potential for metastasis. They are characterized by infiltrative growth and can affect organs and adjacent structures, leading to vascular, urinary, enteric, and/or neural manifestations. Earlier diagnosis is difficult because of their rarity and non-specific clinical and imaging features. On MRI, desmoid tumors are usually hypo- or iso-intense to muscle on T1-weighted images and hyperintense on T2-weighted images with a moderate enhancement. Radiological biopsies are the cornerstone of management to avoid primary devastating surgery. Considering that the majority of sporadic cases carry point mutations in CTNNB1, mutation analysis may offer utility when morphological characteristics are atypical and fail to provide a definitive diagnosis, and when B-catenin immunohistochemistry yields interpretable results.

Some 30% of patients present spontaneous regression.57 An initial non-surgical approach with wait-and-see strategy was initially described in abdominal wall fibromatosis and for extra-abdominal wall tumor.58 In this study, 95% of patients affected by extra-abdominal wall fibromatosis were safely managed conservatively.

Surveillance monitoring should be performed frequently, at the first month after diagnosis and then every 3 months. Medical therapy at progression consists of hormonal therapy, anti-COX2, and imatinib. Cryoablation has been described in different studies with promising results.59 Surgery can be indicated in selected cases of continuous progression. When surgery requires a mutilating procedure and/or is incomplete, radiotherapy is an effective option.60

Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans is a rare soft tissue tumor that involves the dermis and subcutaneous fat of the vulva or perineum, but rarely involves the fascia or the muscle.

It presents as an asymptomatic skin-colored to red-brown indurated plaque. Diagnosis is made by skin biopsy without excision. All dermatofibrosarcoma protuberans present a recurrent translocation t(17;22)(q22;q13). Fibrosarcomatous transformation can occur with an associated metastatic risk.

The tumor characteristically spreads through neoplastic tentacles. Wide local excision was traditionally performed with 2–4 cm margins with a high risk of recurrence. Surgical removal is now based on Mohs micrographic surgery61 for improved oncological safety thanks to immunohistochemical analysis of the peritumoral cup, and on-demand enlargement with smaller surgical defects.62

Uterine Adenosarcoma

Uterine adenosarcoma is a rare malignant disease, representing fewer than 5% of uterine sarcomas, defined as a biphasic tumor composed of both a benign epithelial component and a malignant sarcoma component.63 The most important histopronostic factors are the existence of a sarcomatous overgrowth defined by a sarcomatous contingent occupying more than 25% of the volume of the tumor and the presence of a heterologous and/or a high-grade component.50 Most women with uterine adenosarcoma present with early-stage tumors and have a favorable outcome after surgical removal.64 The role of adjuvant treatment including hormonotherapy and chemotherapy is not clearly established.65 In the advanced inoperable or metastatic setting, hormonotherapy is an option for low-grade adenosarcomas with estrogen receptor and progesterone receptor overexpression. For high-grade tumors, the standard chemotherapies are doxorubicin-based combinations, although an integrated approach of surgery and medical treatment should also be considered in this setting.50

Role of Systemic Treatment in Localized Disease

High-grade Sarcoma (Leiomyosarcoma, Undifferentiated Sarcoma, High-grade Endometrial Stroma Sarcoma)

Despite the fact that 75% of uterine sarcoma are diagnosed at early stage (limited to the uterus, stage I FIGO) their prognosis is poor, with up to 70% of patients having metastatic relapse after appropriate surgery.47 This has led to investigation of the role of adjuvant chemotherapy, with a small number of single-arm phase II studies and two randomized phase III studies.

In high-grade uterine sarcoma after appropriated surgery, the French Sarcoma Group Study SARCGYN randomized adjuvant chemotherapy (four cycles of doxorubicin, cisplatin, and ifosfamide) followed by pelvic radiotherapy, to radiotherapy alone.66 This study planned to include 256 patients with early FIGO stages (I or II), but was prematurely stopped due to slow recruitment at 81 patients. Note that 19 patients were included with carcinosarcoma, which limits interpretation of the study. Nevertheless, the results show a significant increase of 3 years’ disease-free survival (55% vs 41%, p=0048) with chemotherapy, with a non-significant trend of overall survival improvement. We also have to note the high rate of grade 3–4 toxicity (in particular hematological, in 76% of patients) following chemotherapy, meaning that this option should be reserved for young and fit patients.

In the specific subgroup of patients with leiomyosarcoma, based on the results of small phase II studies67 suggesting promising survival results with adjuvant chemotherapy based on the combination of gemcitabine and docetaxel, the American GOG-277 study randomized adjuvant chemotherapy with eight cycles of chemotherapy (gemcitabine and docetaxel four cycles, followed by doxorubicin four cycles) after surgery for FIGO stage I uterine leiomyosarcoma.68 Once again, this study was closed prematurely because of slow recruitment (38 patients/216 planned), with no interpretable results.

Because of the small number of studies and their results, adjuvant chemotherapy is not considered as a standard treatment in uterine high-grade sarcoma according to European Society for Medical Oncology (ESMO) guidelines,5 though it may be discussed as an option in selected patients in expert centers.

Low-grade Endometrial Stromal Sarcoma

Most cases of low-grade endometrial stroma sarcoma (60%) are also diagnosed at early stage (limited to the uterus, stage I FIGO). Despite the lower aggressivity of these low-grade malignancies, relapse may occur in up to 45% of cases after local treatment, in particular following inappropriate surgery (incomplete resection or morcellation)

In cases of low-grade endometrial stroma sarcoma being associated with high estrogen and progesterone receptors expression, adjuvant hormonal therapy using aromatase inhibitors and gonadotropin-releasing hormone (GnRH) analogs may be discussed in expert centers for pre-menopausal patients.69

Management of Uterine Sarcomas in Cases of Tumor Effraction or Morcellation

Traditionally for soft tissue sarcoma management, re-excision at reference centers must be considered in cases of unplanned surgery (“whoops” surgery) with R2 resection. In cases of unsuspected uterine sarcoma morcellation/effraction, risks of recurrence are mainly in the pelvis and occurrence of a peritoneal sarcomatosis. Morcellation, tumor effraction, and myomectomy are associated with decreased early survival of women with occult leiomyosarcomas, with a three to four times greater risk of recurrence at 3 years compared with en bloc surgery.70

In cases of complete surgery (hysterectomy), surveillance or adjuvant chemotherapy are recommended.

In the event of incomplete surgery (myomectomy, subtotal hysterectomy) and in the absence of any sign of progression on post-operative imaging, the completion of surgery is indicated.

In cases of early pelvic progression or peritoneal sarcomatosis, a multidisciplinary discussion is needed to decide on neoadjuvant treatment, which will depend on the tumor histotype and the presence of hormone receptors. Once a partial or complete radiological response to neoadjuvant treatment has been obtained, surgical treatment remains indicated when complete resection can be performed.20 Complete surgical resection in cases of recurrent metastatic lesions of uterine leiomyosarcoma is associated with a better prognosis compared with chemotherapy alone and/or radiotherapy.71 72

Management of Recurrent/Oligometastatic Disease

Patients presenting after a long progression-free interval with an isolated site of recurrence amenable to complete resection are the best candidates for attempted surgical resection.72 In every case of recurrence or metastasis it is important to check whether surgery with the aim of complete macroscopic resection is possible. The addition of local therapies to systemic treatment, in selected patients, improves the management of symptoms and disease control.

Some 25% of patients with leiomyosarcoma tumors will develop pulmonary metastases, the most common site of distant metastases being the lungs (73% of cases).73 Significant long-term survival can be attained with metastasectomy associated or not with peri-operative chemotherapy in patients with metastatic sarcoma including leiomyosarcoma.73 74 Among this carefully selected group of patients undergoing resection of pulmonary metastases (or local measures) from uterine sarcomas, long-term survival was achieved by a substantial proportion of patients. Alternatively, stereotactic body radiation therapy, radiofrequency ablation, and thermal ablation are mainly adopted for lung or liver metastasis.

In cases of oligo-metastatic disease, focal treatment of metastases should be considered. The choice of strategy must take account of metastases size, number of metastases, disease-free interval, response to possible neoadjuvant treatment, and histological subtype.

Peritoneal sarcomatosis after uterine sarcoma is rare, and is observed in advanced disease or after tumor effraction. As described for peritoneal carcinomatosis, cytoreductive surgery has been developed, with appropriate surgical removal of all sarcomatous lesions. Complete surgery remains the cornerstone of treatment of patients with sarcomatosis, with significantly extended survival. The best results are observed for low-grade sarcomatosis, especially for well-differentiated liposarcoma. Administration of intraperitoneal chemotherapy or hyperthermic intraperitoneal chemotherapy after complete cytoreductive surgery for peritoneal sarcomatosis was evaluated in one randomized study75 and several heterogenous case series publications, without increasing survival outcomes.

Role of Germline Testing

Soft tissue (including gynecological sarcoma) and bone sarcoma may arise in the context of germline TP53 mutation (Li–Fraumeni syndrome). As a consequence, germline testing must be considered according to Chompret criteria.76

Briefly, testing should be carried out:

  • In patients developing soft tissue sarcoma <46 years of age, with at least one first- or second-degree relative with a previous history of TP53-associated tumor (breast cancer, soft tissue sarcoma, bone sarcoma, central nervous system tumor, adrenocortical carcinoma) <56 years of age.

  • In patients developing soft tissue sarcoma (especially in radiotherapy fields) with a personal previous history of another TP53 core tumour <46 years of age.

Conclusions

The management of gynecological sarcomas should follow the recommendations for the management of soft tissue and visceral sarcomas. Centralizing cases in expert centers improves patient survival, both for the diagnostic phase and for multidisciplinary therapeutic management. In the case of pelvic soft tissue sarcomas, a radiological biopsy is essential before any surgical decision is taken. In the case of a myometrial tumor which may correspond to a sarcoma, if conservative surgery such as myomectomy or morcellation is planned, an ultrasound-guided biopsy with pathological analysis including comparative genomic hybridization analysis must be carried out. In all cases, en bloc surgery, without rupture, is mandatory. Many rare histological subtypes require specific surgical management.

The indication of neoadjuvant or adjuvant treatment should be proposed in selected patients by an expert tumor board.

Surgery for recurrence or metastatic disease (including peritoneal sarcomatosis) can be indicated for patients presenting after a long progression-free interval with an isolated site of recurrence amenable to complete resection.

Ethics statements

Patient consent for publication

Ethics approval

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References

Footnotes

  • Twitter @Alejandra

  • Contributors Conceptualization: GF, TV. Writing original draft: GF, TV, GB. Writing, reviewing, and editing: all the authors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.