Soft tissue sarcomas

Overview

• Epidemiology (US 2025): ~13,500 STS cases/yr; ~5,200 deaths. STS ~80% and bone sarcoma ~20% of sarcomas; GIST is the most common sarcoma overall.
• Classification: WHO classifies by line of differentiation and defining molecular features (liposarcoma, synovial, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, angiosarcoma); if origin is uncertain, by architectural pattern (ASPS, epithelioid sarcoma, clear cell sarcoma).
• Adult most common: GIST, UPS, liposarcoma, leiomyosarcoma. Pediatric: small round blue cell sarcomas (Ewing and related, CIC-DUX4) and rhabdomyosarcoma.
• Common sites: lower extremity and pelvis ~50%, trunk ~20%, upper extremity ~10%, head/neck ~10%, retroperitoneum ~10%. Epithelioid sarcoma favors forearm/finger; desmoplastic small round cell tumor favors abdomen/pelvis in AYA males.
• Most common met site: lung (~80% of mets); ~10% have mets at diagnosis. Risk rises with grade and depth of invasion.

Histologic markers

• Desmin: myogenic differentiation (rhabdomyosarcoma, to a lesser degree leiomyosarcoma).
• S100: neural sheath and melanocytes (clear cell sarcoma); PEComa is HMB45/Melan-A/SMA positive and usually S100-negative.
• Cytokeratin: synovial or epithelioid sarcoma (fibrosarcomas do not express it).
• Factor VIII-related antigen: endothelial (vascular) origin.

Grading and staging

• Two grading systems: NCI three-tier and French FNCLCC (differentiation, mitotic activity, necrosis; the system recommended by AJCC); for AJCC staging, grade 1 is low and grades 2 and 3 are high.
• Grading is not applicable to MPNST (mostly high grade), angiosarcoma, ASPS, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, epithelioid sarcoma.
• ~2.5% present with node involvement; ↑ risk with rhabdomyosarcoma, synovial, epithelioid, clear cell, angiosarcoma. N1M0 is stage IIIB in retroperitoneal STS and stage IV in trunk/extremity STS; AJCC8 assigns no prognostic stage groups for head/neck or visceral STS.
• T stage (retroperitoneal and trunk/extremity STS): T1 ≤5 cm, T2 5 to 10 cm, T3 10 to 15 cm, T4 >15 cm. T stage (head/neck STS): T1 ≤2 cm, T2 2 to 4 cm, T3 >4 cm, T4 local invasion.

• AJCC is not preferred for RP STS (does not account for histology and site); a prognostic nomogram to estimate postoperative survival is recommended.

Imaging and diagnosis

• MRI is superior to CT for extremity, trunk, and head/neck STS, and should be done before biopsy (postprocedural edema interferes with MRI interpretation).
• CT is preferred for RP and visceral sarcomas, and is more sensitive than PET for subcentimeter lung nodules that may appear inactive on PET. CT chest for staging in tumors >5 cm, deep, intermediate or high grade.
• PET: mainly useful for high-grade STS; helps distinguish neurofibroma from MPNST and well-differentiated from dedifferentiated retroperitoneal liposarcoma. SUV >6 and <40% FDG decrease after neoadjuvant chemo associate with poor outcome (small study).
• Site-directed staging: CT abdomen for epithelioid, angiosarcoma, myxoid/round cell liposarcoma (↑ extrapulmonary mets); CNS imaging for cardiac angiosarcoma and ASPS (↑ CNS mets); MRI spine for myxoid/round cell liposarcoma (↑ bone mets).
• Core needle biopsy at a sarcoma center (avoid open). NGS especially for translocation-driven types or NTRK suspicion.

Localized STS: surgery and radiation

• Wide local excision with negative margins (R0) is the cornerstone; limb-sparing surgery plus RT is preferred over amputation (RCTs with >10 yr follow-up: ↑ local recurrence with limb-sparing but same DFS and much less handicap).
• Local control with wide resection with or without RT has ~90% success; however 40 to 50% develop distant mets, especially large (>5 cm), deep, high-grade tumors. 5-yr OS for metastatic disease ~15% (higher in selected pts after complete metastasectomy).
• RT ↓ local recurrence (no OS benefit alone). Pre-op (50 Gy) vs post-op (60 to 66 Gy): pre-op ↑ wound complications but ↓ late fibrosis (NCIC SR2); post-op has lower wound issues but higher long-term morbidity. Indications: intermediate/high-grade, ≥5 cm, deep, close margins.

Adjuvant and neoadjuvant chemotherapy

• Systemic chemo is nearly mandatory for rhabdomyosarcoma and Ewing sarcoma; extraskeletal osteosarcoma is an older-adult tumor managed primarily by resection, with chemo/RT individualized (uncertain benefit) but remains controversial for resected adult-type extremity STS (liposarcoma, leiomyosarcoma, synovial).
• SMAC 1997 meta-analysis (14 RCTs, 1,568 pts): doxorubicin-based chemo improved absolute RFS 6 to 10% at 10 yr; longer local RFS (HR 0.73), distant RFS (HR 0.70), overall RFS (HR 0.75); trend toward better OS not significant (HR 0.89).
• 2008 meta-analysis (18 RCTs, 1,953 pts): doxorubicin alone gave no significant mortality reduction, but doxorubicin plus ifosfamide showed an OS benefit (OR for death 0.56; ~11% absolute mortality reduction (death ~41% to ~30%)); however it excluded the largest negative EORTC trials.
• EORTC (351 pts): adjuvant doxorubicin/ifosfamide/lenograstim vs observation showed no OS difference overall (HR 0.94) or in limb STS (HR 0.84); trend toward benefit in extremity, large, grade III tumors. On revisiting, pts with predicted OS <60% by nomogram had significant DFS and OS benefit. A pooled analysis of 2 EORTC trials (819 pts) of doxorubicin-based adjuvant chemotherapy (CYVADIC in 62771, doxorubicin-ifosfamide in 62931) showed no OS benefit.
• NCCN and ESMO endorse adjuvant chemo case-by-case for high-risk pts, weighing performance status, age, site, size, and histology (myxoid/round cell liposarcoma and synovial are relatively chemosensitive). Adjuvant regimen: 6 cycles of AIM (doxorubicin ~75 mg/m2 per cycle, ifosfamide 9 to 10 g/m2 with mesna). MAID is discouraged (more myelosuppression from dacarbazine, minimal benefit).
• Neoadjuvant, Zaidi 2019 (US Sarcoma Collaborative, 770 pts): neoadjuvant chemo improved RFS and OS when high-grade tumors were ≥10 cm and extremity.
• Neoadjuvant, Gronchi phase 3: standard anthracycline/ifosfamide neoadjuvant chemo had better projected DFS at 46 mo (62% vs 38%) than histotype-tailored chemo; establishes standard anthracycline/ifosfamide over histotype-tailored regimens when neoadjuvant chemo is given (did not test chemo vs no chemo).

Retroperitoneal sarcoma (RPS)

• ~10% of all STS. Most common: well-differentiated / dedifferentiated liposarcoma, leiomyosarcoma, solitary fibrous tumor. Locoregional recurrence (30 to 50%) is the main pattern of failure in retroperitoneal liposarcoma and the primary cause of disease-related death.
• Surgery: aggressive en bloc resection at an expert center; margins are the key prognostic factor and offer the only cure.
• STRASS I: neoadjuvant RT then surgery vs surgery alone showed no benefit (3-yr abdominal RFS 60.4% vs 58.7%, P = .954). Exploratory liposarcoma subgroup may benefit (3-yr abdominal RFS 71.6% vs 60.4%; pooled STREXIT data localize the signal to well-differentiated and grade 1 to 2 dedifferentiated liposarcoma); no benefit for leiomyosarcoma.
• STRASS2 (ongoing): role of neoadjuvant chemo for grade 3 dedifferentiated liposarcoma and high-grade retroperitoneal leiomyosarcoma.
• Adjuvant chemo is not indicated for visceral or abdominal-site sarcoma; specific subtypes (synovial, high-grade myxoid/round cell liposarcoma) may benefit.

Resection of pulmonary metastases

• Complete pulmonary metastasectomy may be feasible for selected pts. Favorable factors: smaller / fewer metastases, longer disease-free interval, minimally invasive resection.
• Retrospective series (1996 to 2017) report 5-yr OS ranging 15 to 51% (bone or soft tissue histologies).

Metastatic / unresectable STS: systemic therapy

• Doxorubicin is the 1L SOC for most STS (mPFS ~5 mo, mOS ~12 mo) and remains standard for fit pts.
• Doxorubicin plus ifosfamide (AIM): ↑ ORR (26% vs 14% in EORTC 62012) but no OS advantage. Use when rapid response is needed. Santoro 1995 and Judson 2014 confirmed higher response/disease control but not OS.
• Doxorubicin plus dacarbazine: option for leiomyosarcoma (ORR ~30% in older studies).
• GeDDiS: gemcitabine plus docetaxel vs doxorubicin gave similar PFS (~23 wks) and OS (67 vs 76 wks); single-agent doxorubicin remains a reasonable standard.
• ANNOUNCE: olaratumab plus doxorubicin did not confirm the OS benefit seen in the phase 2 trial; olaratumab approval was withdrawn.

• Gemcitabine plus docetaxel: active in leiomyosarcoma and UPS; appropriate for anthracycline-ineligible pts (superior PFS 6 vs 3 mo, OS 18 vs 12 mo, ORR 16% vs 8% vs gemcitabine alone).
• Trabectedin (Yondelis): IV alkylating agent (DNA minor groove), especially active in FUS-DDIT3 myxoid liposarcoma and leiomyosarcoma. FDA Oct 23, 2015 for unresectable/metastatic leiomyosarcoma or liposarcoma after anthracycline. Can cause rhabdomyolysis: monitor CPK before each dose (↑ in ~1/3, can lead to renal failure).
• Eribulin: for liposarcoma (not leiomyosarcoma), superior to dacarbazine in liposarcoma (mOS 15.6 vs 8.4 mo). FDA-approved Jan 2016.
• Pazopanib (PALETTE): non-adipocytic STS, mPFS 4.6 vs 1.6 mo; FDA-approved 2012 (not for adipocytic STS). EPAZ: pazopanib vs doxorubicin in older pts had similar PFS/OS/ORR.
• Gemcitabine plus dacarbazine: salvage option after anthracycline; objective response or stable disease 49% vs 25% for dacarbazine alone.

Eribulin vs dacarbazine: randomized phase 3 (N = 452) in advanced/metastatic leiomyosarcoma or liposarcoma with ≥2 prior therapies. Benefit is confined to liposarcoma; eribulin is FDA-approved for unresectable/metastatic liposarcoma after an anthracycline.

Trabectedin vs dacarbazine (N = 518, after anthracycline): mOS 12.4 vs 12.9 mo (HR 0.87, P = .37); trabectedin improves PFS and is FDA-approved for leiomyosarcoma or liposarcoma after an anthracycline (may be less effective for dedifferentiated and pleomorphic liposarcoma).

Subtype-specific therapy (high-yield)

• Well-differentiated / dedifferentiated (MDM2 amplification, CDK4): retroperitoneum most common (extremity/trunk WD tumors are termed ALT); WD does not metastasize, dedifferentiated metastasizes in ~15 to 20% (mainly lung). Trabectedin, eribulin, doxorubicin, gemcitabine plus docetaxel; palbociclib per NCCN. 1L doxorubicin then 2L gemcitabine/docetaxel then 3L eribulin (preferred over dacarbazine and trabectedin for dedifferentiated).
• Brightline-1 (Schöffski Clin Cancer Res 2026; mPFS 8.4 vs 7.2 mo, HR 0.79): brigimadlin (BI 907828, oral MDM2 inhibitor) vs doxorubicin as 1L in advanced dedifferentiated liposarcoma did NOT meet the primary PFS endpoint. MDM2 inhibitors remain investigational for dedifferentiated liposarcoma.
• Myxoid / round cell (FUS-DDIT3, or EWSR1-DDIT3): exquisitely radiosensitive and very chemosensitive to trabectedin and anthracycline/alkylators (ifosfamide for neoadjuvant); do MRI spine and CT abdomen (↑ bone and abdominal mets).
• Pleomorphic: high-grade, TP53, closest to pleomorphic UPS; doxorubicin-based; ↑ liver/lung mets.
• Atypical lipomatous tumor (ALT): well-differentiated liposarcoma outside abdomen/retroperitoneum; en bloc resection with negative margins is sufficient; observation appropriate if fascia intact; adjuvant RT may ↓ local relapse but no OS benefit.

• Smooth muscle differentiation; extremities, IVC branches, GI tract, uterus (uterine LMS is distinct). Surgery is the mainstay (advanced disease is chemo-responsive (doxorubicin +/- dacarbazine, doxorubicin-trabectedin, gemcitabine-docetaxel)); ↑ hemorrhagic risk; rarely nodal; ER/PR positive in 40 to 70%.
• 1L: doxorubicin or doxorubicin plus dacarbazine.
• Doxorubicin plus trabectedin, LMS-04 (Pautier Lancet Oncol 2022 and NEJM 2024, PMID 39231341): 1L advanced/metastatic LMS (n=150); mPFS 12.2 vs 6.2 mo (HR 0.41), mOS 33 vs 24 mo. New 1L option in good-PS advanced LMS.
• 2L: gemcitabine plus docetaxel (ORR 17 to 50%), trabectedin (ORR 6 to 23%), eribulin (ORR 11%; not FDA-approved for LMS, no OS gain vs dacarbazine in LMS), pazopanib.

• Most common adult STS (the former "wastebasket" MFH); extremity or retroperitoneum; mostly high grade; metastatic rate 30 to 35% (lung); 5-yr OS 65 to 70%.
• High-grade UPS of bone is treated like high-grade osteosarcoma (neoadjuvant chemo per NCCN). NCCN category 1 1L regimens: cisplatin plus doxorubicin, and MAP.

• Most common STS of extremities in young adults; cell of origin unknown; monophasic and biphasic types. t(X;18)(p11;q11) fuses SS18 (formerly SYT) to SSX1, SSX2, or SSX4. SS18-SSX1 occurs in both monophasic and biphasic tumors; SS18-SSX2 is strongly associated with monophasic histology; fusion-partner type is not a validated independent prognostic factor.
• One of the most chemosensitive STS, especially to ifosfamide (AIM neoadjuvant and advanced; single-agent ifosfamide in advanced). Adjuvant chemo benefit is more pronounced than in other STS.
• Afami-cel (Tecelra), autologous MAGE-A4 TCR-T for MAGE-A4-expressing synovial sarcoma with HLA-A*02:01P/02:02P/02:03P/02:06P (exclude 02:05P), after prior chemo: FDA Aug 2, 2024, first engineered cell therapy approved for any solid tumor (SPEARHEAD-1, D'Angelo Lancet 2024; ORR 43%, mDOR 6 mo). Pazopanib is active.

• Ectodermal origin from peripheral nerves; ~50% arise in NF1 and are the leading cause of NF1 death (often from plexiform neurofibromas); trunk, extremities, head/neck; no characteristic translocation; S100 not uniform.
• Complete resection plus RT is potentially curative but high recurrence risk. Advanced: doxorubicin plus ifosfamide. Selumetinib (pediatric, and adults since Nov 2025) and mirdametinib (FDA Feb 2025, age ≥2 yr), both MEK inhibitors, are approved for NF1 plexiform neurofibromas; SARC031 studies selumetinib plus sirolimus in metastatic MPNST.

• Rare, aggressive; prognosis is stage- and site-dependent (localized 5-yr OS ~30 to 50%, much lower if metastatic). Sites: head/neck 31%, RT-associated 23%, visceral 15%, breast 10%. Risk factors: RT, lymphedema (Stewart-Treves post-mastectomy), vinyl chloride. IHC CD31 and factor VIII.
• Mutations: MYC amplification ~35% (90% in RT-associated), TP53 25%, PIK3CA ~21% overall, occurring predominantly in primary breast angiosarcoma (most PIK3CA-mutant tumors are breast primaries), KDR 7 to 22%, FLT4 amplification 5.5%.
• Tx: surgery then RT. Anthracycline-based chemo remains 1L (Young EJC 2014: doxorubicin plus ifosfamide improved PFS and OS vs single-agent anthracycline). Weekly paclitaxel is notably active (ANGIOTAX, Penel JCO 2008: PFS 74% at 2 mo, mOS 8 mo). Bevacizumab (alone or with paclitaxel) did not improve outcomes. IO active in cutaneous UV-mutated angiosarcoma.

• Slow-growing; pleura, pelvis, dura; can be huge. Metastatic risk assessed by the modified Demicco model (age, size, mitoses, necrosis); adverse mitotic threshold is ≥4/10 HPF; no single feature (size or hemorrhage alone) defines malignancy. Paraneoplastic refractory hypoglycemia from IGF-2 (resolves with resection). IHC CD34 positive; NAB2-STAT6 fusion. Mets to bone, liver, lung. Sunitinib is an option.

• Myxofibrosarcoma: if no neurovascular or bone involvement, limb-sparing resection can achieve negative margins (amputation not needed); consider adjuvant RT after limb-sparing resection.
• Pleomorphic dermal sarcoma (PDS): rare dermal tumor resembling atypical fibroxanthoma (AFX); distinguished from AFX by subcutaneous invasion, necrosis, lymphovascular invasion, or perineural infiltration.

• 1 to 6% of STS, ↑ in African Americans; intermediate-grade, low metastatic risk, high local recurrence; Bednar (pigmented) and fibrosarcomatous variants; accelerated growth in pregnancy; trunk 50%, extremities 35%, head/neck 15%.
• t(17;22)(q22;q13) fuses COL1A1 and PDGFB, upregulating PDGFB and autocrine PDGFRb activation. Tx: wide local excision or Mohs (recurrence 7.3% vs 1%). Imatinib for recurrent/unresectable/metastatic (ORR ~65% with the translocation).

• Definition: locally invasive, non-metastasizing fibroblastic neoplasm (~3% of sarcomas). Young adults (20s to 30s); can grow rapidly then stabilize or regress; spontaneous regression in ~20%; high local recurrence even after complete resection.
• Genetics: ~90% sporadic from CTNNB1 (beta-catenin) mutations; 5 to 15% in FAP from APC inactivation (desmoid plus FAP = Gardner syndrome). Wnt inhibits APC, raising beta-catenin, driving CYCD1/MYC and proliferation. IHC: nuclear beta-catenin, vimentin, SMA positive; desmin/cytokeratin/S100 negative. Refer FAP-associated cases to GI for colonoscopy.
• Sites: extremity, abdominal wall (pregnancy), mesenteric root (FAP, ↑ mortality, often unresectable).
• Management: active surveillance is first-line (many regress); surgery historically standard but high recurrence. Systemic therapy for symptomatic unresectable, enlarging, or repeatedly recurrent disease.
• Nirogacestat (Ogsiveo), gamma-secretase inhibitor: DeFi (Gounder NEJM 2023, PMID 37648347, 142 pts) PFS HR 0.29, mPFS not reached vs 15.1 mo, ORR 41%, CR 7%. FDA Nov 27, 2023, first systemic therapy for desmoid. Toxicity: diarrhea, rash, ovarian dysfunction.
• Other systemic: sorafenib (Gounder NEJM 2018, mPFS not reached vs 11.3 mo, HR 0.13), pazopanib, sunitinib, imatinib (rarely); single-agent doxorubicin or pegylated liposomal doxorubicin (ORR ~75%); doxorubicin plus dacarbazine (ORR 42 to 100%); weekly methotrexate plus vinblastine (ORR 26 to 87%, institutional SOC); NSAIDs and antihormonal therapy are no longer recommended as antitumor therapy (inadequate evidence); use active surveillance for mild/stable disease and NSAIDs for analgesia only; low-dose RT. Tegavivint (TBL1 inhibitor degrading nuclear beta-catenin) is investigational (ORR 25%). Doxorubicin-based regimens are limited to ~6 cycles by cardiotoxicity.

• Atezolizumab, FDA Dec 9, 2022 for unresectable/metastatic ASPS in pts ≥2 yr (ML39345; ORR 24%, mDOR NR). First IO with specific approval in ASPS. TKIs (sunitinib, cediranib, pazopanib) also active.

• 0.6 to 1.0% of sarcomas; painless slow-growing distal-extremity mass in young adult males; locally invasive, metastasizes to nodes and lung in 40 to 50%. >90% lack INI-1 (SMARCB1), letting EZH2 drive oncogenesis.
• Tazemetostat (oral EZH2 inhibitor, 800 mg twice daily): FDA-approved for unresectable ES (≥16 yr); EZH-202 phase 2 ORR 15% with ~2/3 of responses >6 mo. Anthracycline-based chemo has ORR ~25% (mPFS 3 to 8 mo); gemcitabine plus docetaxel if anthracycline-ineligible. Teratogenic: contraception during and up to 6 mo after.

• Vascular malignancy of bone, liver, lung; endothelial markers Fli-1 and CD31; defined by WWTR1-CAMTA1 fusion from t(1;3)(p36;q25), present in ~90% of cases (a YAP1-TFE3 subset makes up most of the rest) and absent in other vascular neoplasms.

• NTRK fusion sarcoma: larotrectinib or entrectinib (tumor-agnostic; high response in infantile fibrosarcoma).
• Inflammatory myofibroblastic tumor: ALK fusion (~50%); crizotinib (also ceritinib), both NCCN options.
• Tenosynovial giant cell tumor (TGCT, formerly PVNS): CSF1 rearrangement, locally aggressive; surgery first-line (diffuse-type recurs). Pexidartinib (Turalio), FDA Aug 2, 2019 (ENLIVEN), REMS and boxed warning for hepatotoxicity. Vimseltinib (Romvimza), selective CSF1R TKI, FDA Feb 14, 2025 (MOTION, Gelderblom Lancet 2024; ORR 40% vs 0% placebo), 30 mg PO twice weekly, no REMS/boxed warning, better tolerated.
• Rhabdomyosarcoma: pediatric/AYA; embryonal (favorable), alveolar (PAX3/7-FOXO1, aggressive), pleomorphic (adult): manage as high-grade adult-type STS (surgery +/- RT, individualized anthracycline-based therapy), not routine VAC; VAC applies to embryonal/alveolar RMS.
• Kaposi sarcoma: HHV-8; AIDS-related, classic, endemic, iatrogenic. ART for AIDS-related; liposomal doxorubicin or paclitaxel for advanced; pomalidomide approved after HAART failure and in HIV-negative KS.

Immunotherapy for advanced STS

• SARC028: single-arm phase 2 pembrolizumab (N = 86); objective response in 7/40 STS pts (18%), mainly UPS and liposarcoma.
• Alliance A091401: nivolumab vs nivolumab plus ipilimumab (N = 85); ORR 5% (nivo) vs 16% (nivo/ipi); responders included UPS, LMS, angiosarcoma, myxofibrosarcoma.

High-yield STS pearls

• Refer to a sarcoma center; surgical expertise improves OS. MRI before biopsy.
• Doxorubicin is 1L SOC for advanced/metastatic STS.
• Trabectedin for myxoid liposarcoma and LMS (FUS-DDIT3 highly susceptible); eribulin for liposarcoma (not LMS).
• LMS-04: doxorubicin plus trabectedin is a new 1L option in good-PS advanced LMS.
• Atezolizumab for ASPS (FDA Dec 2022); nirogacestat for desmoid (FDA Nov 2023).
• Afami-cel (Tecelra), FDA Aug 2, 2024, first solid-tumor TCR-T (synovial sarcoma, HLA-A*02 / MAGE-A4).
• Vimseltinib (Romvimza), FDA Feb 14, 2025, preferred CSF1R inhibitor for TGCT.
• Imatinib for DFSP (COL1A1-PDGFB); NTRK fusion to larotrectinib/entrectinib; NF1 with MPNST; Stewart-Treves = angiosarcoma in chronic lymphedema.
• STRASS I: neoadjuvant RT did not improve abdominal RFS overall; exploratory/pooled (STREXIT) data suggest possible benefit in well-differentiated and grade 1 to 2 dedifferentiated liposarcoma (individualize), not leiomyosarcoma.
• Brightline-1: brigimadlin (MDM2 inhibitor) negative in dedifferentiated liposarcoma; MDM2 inhibitors remain investigational.