Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-Up

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Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-Up ANTICANCER RESEARCH 34: 5251-5262 (2014) Review Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-up MARCO RASTRELLI1, SAVERIA TROPEA1, UMBERTO BASSO2, ANNA ROMA2, MARCO MARUZZO2 and CARLO RICCARDO ROSSI1 1Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy; 2Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy Abstract. This review focuses on epidemiology, aetiology, Soft tissue sarcomas (STS) are a rare and heterogeneous group clinical presentation, diagnosis, management, prognosis of tumors, ubiquitous in their site of origin. A multi- and follow-up of soft tissue sarcomas (STS) involving limbs disciplinary approach (involving pathologists, radiologists, and trunk. Any patient with a suspected STS should be surgeons, radiation therapists, medical oncologists) is necessary referred to a specialized sarcoma centre and managed by a in all cases. Over the past years, many advances have been multidisciplinary group. The standard treatment is surgical made in the diagnosis and treatment of these malignancies (1- excision followed by adjuvant radiotherapy (RT). 5). In UK, clinical management guidelines have been Radiotherapy is recommended in patients with developed under the auspices of The British Sarcoma Group intermediate-or high-grade tumors, >5 cm of diameter or (BSG) and the National Institute for Health and Care <5 cm. RT may be indicated in low grade, deep and large- Excellence (NICE) has drawn up the “Improving Outcomes size STS and/or in absence of adequate margins, after Guidance for people with sarcoma (IOG)” (3, 4). In USA, The discussion within a multidisciplinary group. Neoadjuvant National Comprhensive Cancer Network (NCCN) has recently radiotherapy and chemotherapy should be taken into published the soft tissue sarcoma guidelines (1). In Europe, the consideration for patients with borderline resectable European Society of Medical Oncology (ESMO) and, in Italy, tumors. In selected cases, amputation may be the only the Italian Society of Medical Oncology (AIOM) have just curative option. Isolated limb perfusion is a pre-operative revised their guidelines (2, 5). treatment that may allow for amputation to be avoided. According to the NCCN’s Categories of Evidence and Adjuvant chemotherapy should be considered only in Consensus for STS, reported in Table I, all recommendations selected cases. Regular follow-up with clinical are category 2A unless otherwise specified in the text (1). examination, ultrasound (US) or magnetic resonance Moreover, this review is based on the BSG, NCCS and imaging (MRI) to exclude local recurrences and chest-X- ESMO guidelines together with the National Institute for ray or chest computed tomography (CT) to exclude Health (NIH) and Clinical Excellence Improving Guidance metastatic disease is recommended. For metastatic disease, for people with sarcoma (NICE-IOG) and all the most recent doxorubicin is the first-line standard therapy. Second-line scientific literature related to STS is based on searches agents include trabectedin, ifosfamide, dacarbazine and conducted in: Medline, CANCERNET PDQ, Cochrane the combination of gemcitabine-plus-docetaxel. Surgical Library Database of Systematic Reviews. resection of local recurrences or lung metastases should be evaluated in selected cases. Epidemiology STS are tumors of mesenchymal cell origin, arising from muscles, tendons, synovial membranes, fat and connective Correspondence to: Saveria Tropea, Melanoma and Sarcoma Unit, tissues. More than 50 different histological subtypes of Veneto Institute of Oncology IOV-IRCCS Padova, Italy. Tel/Fax: +39 sarcomas exist with a prevalence of fuso-cellular forms in 498212137 and +39 498218349, e-mail: [email protected] adult age (1-5). Key Words: Soft tissue sarcomas, surgery, radiotherapy, chemotherapy, Adult STS are rare (1% of all adult neoplasms) with an limb perfusion, follow-up, metastatic disease, review. estimated incidence averaging 3-5/100,000/year in Europe, 0250-7005/2014 $2.00+.40 5251 ANTICANCER RESEARCH 34: 5251-5262 (2014) and 8,700 new cases/year are estimated in the USA. The inhomogeneous and hypoechoic mass, hypervascularised, incidence rate of STS changes in relation to age with a first encapsulated or with a pseudocapsule (12, 13). CT has a more peak in paediatric age, followed by a plateau from the age specific role in calcified lesions to exclude a myositis of 20 until 60 years, after which it reaches its highest peak. ossificans and in patients in whom MRI cannot be performed Approximately, half of all STS patients with intermediate- (10-12). or high-grade tumors develop metastatic disease, which After histological diagnosis of STS, it is necessary to requires systemic treatment with a 5-year overall survival proceed with additional exams. (OS) of not more than 55% (1-5). Patients with STS should be staged with high resolution chest CT to identify possible lung metastases and, depending Aetiology on histological type and grade, a CT abdomen-pelvis, as well as an US of regional lymph nodes may also be indicated. The vast majority of STS are not associated with an Positron emission tomography- CT (PET- CT) may be useful identifiable aetiology. Many risk factors are known, such as to clarify eventual doubts (17). exposure to ionizing radiation or chemical agents (e.g. pesticides) but it is difficult to demonstrate a clear causal Biopsy. The standard approach to diagnosis of a suspicious relationship (1-5). mass consists of multiple core needle biopsies (FNAB), Moreover, recent studies have demonstrated genetic preferably US guided and using >14-16 G needles (1-5). associations with STS, such as the 10% lifetime risk of An incisional biopsy may be useful if FNAB results malignant peripheral nerve sheath tumor (MPNST) in inadequate or if abundant material is necessary to make a individuals with familial neurofibromatosis by mutation in the histological diagnosis. Excisional biopsy may be performed NF1 gene or an increased risk of sarcomas in families with for <5 cm superficial lesion, but it is not recommended. The polyposis and Li-Fraumeni syndrome (related to mutation in biopsy should be planned in such a way that the biopsy the p-53 tumor suppressor gene) or a genetic alteration of pathway and the scar can be removed by definitive surgery to regulatory gene RB-1 (familial Retinoblastoma) (6-9). reduce the risk of seeding (18). Fine needle aspiration cytology (FNAC) is not Clinical Presentation recommended as a primary diagnostic modality, but it may be useful in confirming disease recurrence or metastases. STS may involve any anatomical area; 60% of cases develop in the limbs, 10% in the trunk and 15% in the Histology. Histological diagnosis should be performed retroperitoneum. These tumors generally occur as according to the World Health Organization (WHO) considerable size solid masses and they may cause pain, classification (1-5). soreness or other dysfunctions only when they increase in Malignancy grade should be provided in all cases. In size, pressing against nearby nerves and muscles (1-5). Europe, the Federation Nationale des Centres de Lutte Any soft tissue lump should be considered malignant, until Contre le Cancer (FNCLCC) grading system is generally proven otherwise, and patients should be referred to a used. It distinguishes three malignancy grades based on diagnostic centre if their lump shows any of the following differentiation, necrosis and mitotic rate (Table II) (19-20). clinical features: Because of tumor heterogeneity, an FNAB may not provide -increasing in size (the best indicator); accurate information about grade. In addition, certain -size >5 cm; translocation-driven sarcomas have a relatively uniform cellular -deep to deep fascia; morphology and can be misleadingly scored as intermediate- -painful. rather than high-grade. Some sarcomas are not considered The risk of malignancy is greater when more of these clinical gradable (as alveolar soft tissue sarcoma, epithelioid sarcoma, features are present (1-5). clear cell sarcoma), while for other istotypes, grading has no prognostic value (as malignant tumor of the peripheral nerve Investigation sheath) (20-21). For cases characterized by a chromosomal translocation or for doubtful diagnoses or when the clinical Imaging. The preferred and elective method of investigation pathological presentation is unusual, pathological diagnosis in patients with STS is contrast-enhanced magnetic resonance should be complemented with molecular pathology (fluorescent imaging (MRI), but also computed tomography (CT) or in situ hybridisation -FISH- or reverse transcription polymerase ultrasound (US) with the use of contrast agents may be chain reaction -RT-PCR-) (19-21). appropriate imaging modalities (1-5, 10-13). MRI defines as A pathological expert second opinion is strongly malignant a mass with an inhomogeneous signal intensity in recommended in all cases when the original diagnosis is T2-weighted images (10, 14-16). US shows sarcoma as a large made outside a reference centre. 5252 research. obtained fromthepatienttoenablelateranalysesand later stage.Informedconsentfortumorbankingshouldbe molecular pathologyassessmentcouldbeperformedata recommended bothforfutureresearchandbecausenew (21-22). significance prognostic percentage ofresidualvitalcellshasnospecific the report shouldincludehistologicalassessment.However, the pathologicalassessmentofmargins. risk oflocalrecurrenceispresent)(21-23). andaminimal compartments,isremoved including
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