Soft tissue sarcomas (STS) are an uncommon and heterogeneous group of tumors of mesenchymal cell origin, with an estimated incidence of five cases per 100,000 per year in Europe ^[1][2][1,2]. Approximately 10–15% of all STS are retroperitoneal sarcomas (RPS). RPS usually presents at an advanced stage with nonspecific symptoms, such as increased abdominal perimeter, abdominal pain, and a change in bowel habits. Although STS comprise more than 100 histopathologic subtypes, in the retroperitoneum, the most frequent subtypes are, in order of frequency, well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), solitary fibrous tumor (SFT) and malignant peripheral nerve sheath tumor (MPNST) [3]. Each of these entities has its own distinct biological behavior in terms of risks of local (LR) or distant recurrence (DR) and overall survival (OS) [4]. Recent advances in the understanding of the biological variability of RPS have led to more personalized histology-based management that includes surgical and non-surgical treatments such as radiotherapy and chemotherapy.

RPS requires a multidisciplinary and complex therapeutic approach and should preferably be treated in specialized centers with a team of radiologists, pathologists, surgeons, and medical and radiation oncologists with expertise in the treatment of this disease. For this reason, there has been increasing interest in centralizing the management of these patients in national reference centers. In addition, international cooperation has led to the creation of collaborative groups, such as the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), to improve knowledge of this disease and advance its treatment.

2. Imaging Diagnosis

The imaging technique of choice for the diagnosis of RPS is a computed tomography (CT) scan with intravenous iodinated contrast. The administration of intravenous iodinated contrast is highly recommended because it allows the identification of areas of enhancement, not necrotic, and to obtain a biopsy with greater diagnostic accuracy ^[5][6][7][8][10,11,12,13]. It is important to determine whether the tumor arises from retroperitoneal soft tissues or from a retroperitoneal organ as the former are less frequent but typically malignant entities (e.g., a heterogeneous fatty mass arising from retroperitoneal tissue may be an LPS, whereas a renal fatty lesion suggests an angiomyolipoma) (Figure 1) ^[6][8][11,13]. Certain morphological signs allow the radiologist to deduce the origin of a retroperitoneal mass, such as the phantom organ sign, the embedded organ sign, the beak sign, and the prominent feeding artery sign ^[6][11]. A CT scan can reveal possible anatomical variants or incidental findings in the abdominal viscera. This is especially important regarding the contralateral kidney when future tumor resection implicates nephrectomy ^[7][12]. CT is also the standard method to assess tumor extension and to consider surgical planning and neoadjuvant treatment ^[5][8][10,13]. It is mandatory to include a chest CT to evaluate potential thoracic dissemination, particularly in cases of LMS (where up to 50% of patients may present pulmonary metastases at the moment of diagnosis) ^[5][7][10,12]. Magnetic resonance imaging (MRI) is a useful tool to assess the tissue composition of the tumor and to orientate its histological subtype ^[6][8][11,13], but it is reserved for patients with iodine allergies ^[7][12]. MRI is also strongly recommended in cases of pelvic-originated neoplasms to determine the anatomical relationships between the tumor, local viscera, and pelvic structures. Although 18F-FDG PET-CT (positron emission tomography with 2-deoxy-2-18F-fluoro-D-glucose integrated with CT) can be used to evaluate intermediate/high-grade soft-tissue neoplasms ^[5][10], it cannot always differentiate low-grade tumors from benign lesions ^[7][9][12,14] and therefore has no routine role in the diagnosis or assessment of tumoral extension of RP ^[7][12] except in selected doubtful cases.

• Recommendations

• A CT scan is the imaging technique of choice for the diagnosis and evaluation of resection of retroperitoneal sarcomas (IV, A).
• MRI is also recommended to evaluate pelvic tumors (IV, A).

3. Biopsy

In patients with a suspected RPS, histological sampling should be conducted before any treatment is undertaken, except in exceptional cases where biopsy is high risk and a clear radiological diagnosis is available, e.g., well-differentiated liposarcoma (WDLPS) ^[10][11][15,16]. A percutaneous image-guided core needle biopsy is usually preferred to a surgical biopsy. The biopsy target and the needle trajectory should be determined following a thorough review of all the patient’s radiological studies and ideally after discussion by an MDT. Most retroperitoneal tumors can be percutaneously biopsied without entering the peritoneal space. When a retroperitoneal mass is heterogeneous in the radiological examinations, the biopsy should be directed to the most “dedifferentiated” solid areas ^[12][17]. Multiple (3–4) biopsies using a 14–16 G trucut needle are recommended. A coaxial biopsy system may be used to obtain multiple tumor samples with a single percutaneous access. Percutaneous biopsy of deep retroperitoneal tumors is usually performed under CT image guidance, but large or superficial tumors can be safely biopsied using ultrasound guidance. If the standard safety requirements for radiological interventional procedures are fulfilled, the rate of early complications of percutaneous needle core biopsy in RPS is low, and the risk of tumor seeding also seems to be low (0.5–2%) ^[13][14][18,19]. In metastatic retroperitoneal sarcomas, a biopsy of the metastatic sites could be considered, as it would allow people to confirm the histological diagnosis and the advanced stage in a single procedure.

• Recommendations

• Before any treatment for a suspected RPS, a core needle biopsy should be performed (IV, A).
• It should be directed to the most “dedifferentiated” solid areas (IV, A).
• In RPS with metastases, a biopsy of the metastatic sites could be considered to reach a histological diagnosis if they are more easily accessible (V, B).

4. Pathological Diagnosis of Soft Tissue Sarcomas—Indication of Molecular Studies

The pathology report of a trucut biopsy should include the histological type, or if this is not possible, at least establish the morphologic category (spindle cell, myxoid, pleomorphic, round cell, etc.), the histologic grade and the results of the complementary studies performed (immunohistochemistry (IHC) and/or molecular biology). From the resection specimen, the pathologist must provide the following information:

• A macroscopic description: measurements of the surgical specimen, type of surgical specimen, and identification of the tissues and organs included.
• Description of the tumor: size, appearance, location, presence of necrosis, and invasion of neighboring structures.
• Resection margins: the distance of the tumor to the margins should be measured and those that are less than 2 cm should be specified. It should be indicated whether the margin is formed by fascia, visceral, adventitial, or periosteal tissue.
• Presence and description of satellite nodules.
• Lymph nodes: although lymph node involvement is rare in STS (except for rhabdomyosarcoma (RMS), angiosarcoma, or epithelioid sarcoma), the status of any lymph nodes present should be included.
• Any additional techniques performed should be reported: IHC, reverse transcriptase-polymerase chain reaction (RT-PCR), next generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), fluorescence in situ hybridization (FISH), and their results.

The most common subtypes in this location are LPS and LMS ^[15][20]. Other less common subtypes occurring in the retroperitoneum are SFT, MPNST, undifferentiated pleomorphic sarcoma (UPS), intimal sarcoma (IS), synovial sarcoma (SS), perivascular epithelioid cell tumor (PEComa), and undifferentiated small round cell sarcoma. Retroperitoneal LPS is subclassified into four histologic types: WDLPS, DDLPS, pleomorphic (PL), and myxoid LPS (MXLPS). The latter two entities are extremely rare, and it is not unusual that even large series have no cases. Because DD-LPS can present a varied histomorphology (spindle cell, pleomorphic, myxoid, small round cell, or epithelioid), the use of IHC techniques (antibodies against MDM2, CDK4, and p16), at least in doubtful cases, is highly recommended and helpful in the RPS diagnosis. Appropriate IHC techniques, including neural and myoid markers, should be performed to rule out these possibilities (Table 1).

Recommendation for Immunohistochemistry in Adipocytic Tumors or Tumor with Fatty Areas in Retroperitoneum
MDM2/CDK4	To distinguish between benign and malignant adipocytic tumors or to subclassify LPS
HMB-45/STAT-6	Angiomyolipoma or SFT
MYOGENIN	Allows recognition of rhabdomioblastic differentiation in DD-LPS
Immunohistochemistry techniques to consider in retroperitoneal fusocellular tumors
MDM2/CDK4	LPS (DD-LPS or WD-LPS), IS, MPNST
SMA/Desmin/H-Caldesmon	LMS or IS
CD34/STAT6	SFT
S100/SOX10/H3K27me3	MPNST/neural tumor
CKIT/DOG-1	GIST
SS18-SSX/TLE-1/EMA	SS
HMB-45/MELAN-A	PEComa or metastatic melanoma
MYOGENIN	RMS or rhabdomyoblastic differentiation in other STS

Detection of MDM2 amplification by FISH is currently the gold standard for the diagnosis of WD/DDLPS. It is particularly useful in the following situations: (1) to confirm the diagnosis of WDLPS in an adipocytic tumor with minimal cytologic atypia; (2) to establish the diagnosis of DDLPS in a relatively non-descript spindle cell or pleomorphic retroperitoneal sarcoma, and (3) to classify a pleomorphic or myxoid adipocytic sarcoma such as DDLPS with homologous lipoblastic differentiation that could be mistaken for pleomorphic or myxoid liposarcoma (Figure 2). The diagnosis of primary retroperitoneal MXLPS should be made with caution because such cases represent either metastatic disease or stromal changes in WDLPS/DDLPS. In absence of MDM2 amplification, the demonstration of FUS translocation is useful for the diagnosis. Smooth muscle tumors usually have a spindle-shaped morphology. They are positive for myoid differentiation and need to be positive for at least two markers, including smooth muscle actin (SMA), desmin, H-Caldesmon, calponin, and smooth muscle myosin heavy chain. This histomorphology of LMS bears a certain semblance to other entities such as myoid differentiation in DD-LPS, gastrointestinal stromal tumor (GIST), PEComa, and IS. Consequently, a judicious panel of immunohistochemical markers is necessary to ensure correct classification, including SMA, desmin, H-Caldesmon, MDM2, CDK4, HMB45, CD117, and DOG-1. IHC of MPNSTs may be diagnostically useful in some cases. Half of the cases retain S100 or SOX10 expression. However, this may be only patchy or focal in spindle cell morphology. Loss of H3K27me3 expression occurs in approximately 50% of cases. Nevertheless, this usually occurs in high-grade neoplasms. RMS is even less frequent in the retroperitoneum. Therefore, if a primary RMS is diagnosed in this location the possibility of a MPNST (Triton Tumor) or a DD-LPS with heterologous elements should be considered. SS may be monophasic, biphasic, or poorly differentiated. In the immunohistochemical study, EMA expression is more frequent than cytokeratin expression, and focal expression of S100 may be detected (40% of SSs). The vast majority of SS are positive for CD99 and for the transcriptional corepressor TLE-1 (transducin-like enhancer of Split 1) with strong nuclear expression. Classically, the diagnosis of synovial sarcoma is confirmed by demonstrating the SS18 gene translocation by FISH. Antibodies specific to the SS18-SSX fusion (E9X9V, designed for the breakpoint) and SSX (E5A2C, designed for the C-terminus of SSX), which typically exhibit nuclear staining, are good surrogate markers of the characteristic SS translocation (sensitivity (95%) and specificity (100%)). In SFT, STAT-6 detection by IHC is the most useful diagnostic marker, with nuclear expression identified in more than 95% of cases. It is important to remember that benign soft tissue tumors with a retroperitoneal location should also be considered, such as angiomyolipoma, lipoma, hibernoma, leiomyoma, schwannomas, and neurofibromas. For the evaluation of the pathologic response in those RPS that have received neoadjuvant treatment, it is advisable to follow the recommendations of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). By establishing uniform criteria and methodologies, these guidelines provide a framework for pathologists and clinicians to consistently assess treatment response in soft tissue sarcomas, facilitating effective communication and comparisons of outcomes between different treatment centers and research studies ^[17][22].

• Recommendations

• Detection of MDM2 amplification by FISH is currently the gold standard for the diagnosis of WD/DDLPS (I, A).
• Molecular testing has no diagnostic role in leiomyosarcoma, SFT, or MPNST (I, A).