Uncommon sarcoma subtypes

INTRODUCTION — Sarcomas are malignant tumors of skeletal and extraskeletal connective tissue that can arise from mesenchymal tissue at any body site. Soft tissue sarcomas (STS) are quite rare. In the United States, patients with STS represent less than 1 percent of all newly diagnosed malignant tumors [1].

Uncommon subtypes of sarcoma are especially challenging to diagnose and treat. These subtypes include epithelioid sarcoma, clear cell sarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, inflammatory myofibroblastic tumor, and undifferentiated embryonal sarcoma. Together these account for less than 5 percent of all sarcomas [2]. Diagnosis of these cancers is dependent on histology. Patients diagnosed with these uncommon subtypes of sarcoma should be referred to a sarcoma center of excellence.

The epidemiology, histology, risk factors, clinical presentation, and treatment approach for these rare sarcoma subtypes will be reviewed here. The diagnosis, staging, and general treatment approach to sarcomas are discussed separately:

●(See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

●(See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

●(See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

EPITHELIOID SARCOMA

Epidemiology and risk factors — Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, accounting for approximately 1 percent of all sarcomas [3,4]. There are two morphological variants: a classic type (also called distal type) and a proximal type. The reported overall peak incidence of ES is approximately 35 years of age. Classic-type ES is more frequently diagnosed and usually affects a younger (20 to 40 years of age) and more predominantly male population compared with proximal-type ES [3,4].

Risk factors for ES include prior radiation exposure and rare inherited cancer predisposition syndromes (such as Li-Fraumeni syndrome and retinoblastoma). Other risk factors have not been identified. (See "Radiation-associated sarcomas" and "Li-Fraumeni syndrome" and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)

Clinical presentation and natural history — Distal-type ES can present with superficial, slow-growing, painless firm nodules, leading to chronic nonhealing ulcers that most often affect the hands and arms. It can also present as deep-seated, slow-growing tumors in the extremities or in the tenosynovial tissues [3]. In contrast, proximal-type ES usually presents as a deep infiltrating soft tissue mass, affecting the axial proximal region of the body, and is generally considered to have a more aggressive clinical course. Notably, ES is one of the rare sarcoma subtypes that can regularly have lymph node spread. The disease is often characterized by multiple local recurrences and subsequent metastatic spread in 30 to 50 percent of cases [3].

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. On immunohistochemistry, the tumor cells are virtually always positive for cytokeratin and epithelial membrane antigen. Furthermore, in most cases coexpression of vimentin is present, and CD34 is expressed in 60 to 70 percent of cases. Tumor cells are usually negative for INI-1 (SMARCB1), S100, CD31, neurofilament protein, carcinoembryonic antigen, and factor VIII-antigen.

INI1 (SMARCB1) is a tumor suppressor gene located on 22q11 that encodes a subunit of the ATP-dependent SWI/SNF chromatin remodeling complex. Loss of INI1 plays a critical role in the pathogenesis of ES by impairing SWI/SNF function, causing aberrant PRC2 activity and tumor dependency on activating enhancer of zeste homolog 2 (EZH2) activity. Tazemetostat inhibits EZH2 and is used in the treatment of patients with advanced or metastatic disease. (See 'Tazemetostat' below.)

Due to a variety of appearances and immunophenotypes, the diagnosis of ES can be difficult to make, with the differential diagnosis including nodular fasciitis, fibrous histiocytoma, other reactive proliferations, desmoid tumor, sclerosing epithelioid hemangioendothelioma, as well as some melanomas and carcinomas [3,4].

Treatment of localized disease — Patients with localized disease are treated with complete surgical resection, with or without radiation [5]. Radiation may be administered preoperatively or postoperatively, and timing should be based on multispecialty input from a radiation oncologist and orthopedic or surgical oncologist with expertise in the treatment of ES, as data are limited for this approach. Postoperative radiation may be indicated for tumors larger than 5 cm, and positive or close surgical margins. For patients with treatment naïve-disease, preoperative radiation may be indicated if initial resection would result in significant postoperative morbidity or those in whom the morbidity of preoperative radiation therapy (RT) is expected to be less than postoperative RT. For those with a local recurrence, preoperative RT may be indicated if radiation was not previously administered and resection is expected to result in close negative or microscopically positive surgical margins.

The role of neoadjuvant or adjuvant chemotherapy in this histologic subtype is unclear, and we do not use it in this setting [3,6]. (See "Surgical resection of primary soft tissue sarcoma of the extremities".)

Treatment of advanced/metastatic disease

Initial therapy

Chemotherapy — For patients with locally advanced or metastatic ES who are not eligible for complete surgical resection, we suggest initial treatment with systemic chemotherapy rather than other agents (eg, tazemetostat). Tazemetostat, however, may be an acceptable alternative in select patients. (See 'Tazemetostat' below.)

Chemotherapy may be of particular benefit to those with aggressive disease who require a rapid treatment response. For patients who are eligible for anthracyclines, we offer doxorubicin, either as a single agent or in combination with ifosfamide. For those who are ineligible for anthracyclines, alternative treatment options include gemcitabine plus docetaxel or single-agent vinorelbine [7,8]. We offer this approach to patients irrespective of subtype of ES (classic versus distal), as data are also conflicting as to whether there is a differential sensitivity to chemotherapy between the two subtypes [9].

Supporting data are discussed below.

●Anthracyclines – In retrospective observational studies, anthracycline-based chemotherapy is associated with typical response rates of approximately 25 percent (but as high as 43 percent in one study), with the objective response rates of doxorubicin similar to that of doxorubicin plus ifosfamide (25 and 27 percent, respectively) [9,10]. However, anthracycline-based regimens have limited durable activity, with a median progression-free survival (PFS) between three and eight months [9-11].

●Non-anthracycline regimens – Gemcitabine plus docetaxel is an appropriate alternative for patients who are not eligible for anthracycline-based regimens, although data are limited. In an observational study of 12 patients with advanced ES treated with gemcitabine/docetaxel, the objective response rate was 58 percent, and median PFS was eight months [12]. In another observational study of 41 patients with advanced ES treated with gemcitabine-based regimens (with a majority receiving gemcitabine in combination with docetaxel), the objective response rate was 27 percent, and median PFS was four months [9].

Other chemotherapy options with clinical activity may include single agent vinorelbine [7,8] and platinum agents (eg, carboplatin) [10].

Tazemetostat — Tazemetostat, a small molecular inhibitor of EZH2, is approved by the US Food and Drug Administration (FDA) for treatment of unresectable ES in adult and pediatric patients (16 years of age or older) [13].

Although we typically prefer initial treatment with chemotherapy for patients with locally advanced or metastatic ES who are not eligible for complete surgical resection, tazemetostat is a reasonable alternative for those who are treatment naïve and have indolent, less bulky and/or asymptomatic disease. Clinicians offering tazemetostat as initial therapy should provide a risk-benefit discussion of this agent versus anthracycline-based chemotherapy, as the two treatment strategies have not been compared directly, and cross-trial comparisons suggest higher response rates with anthracycline-based chemotherapy. However, tazemetostat may be appealing because of the convenient oral route of administration and less cumulative adverse effects of treatment.

Tazemetostat is administered at 800 mg twice a day until evidence of disease progression or unacceptable treatment-related toxicity. Due to the potential teratogenicity of tazemetostat, male and female patients with reproductive potential should use effective contraception during and up to six months after treatment with tazemetostat.

In a single-arm, open-label phase II trial (EZH-202), 62 patients with locally advanced or metastatic ES with loss of INI1 were treated with tazemetostat [14]. Prior surgery and systemic chemotherapy were administered in 77 and 61 percent, respectively, of patients. In this study, the overall response rate was 15 percent, with approximately two-thirds of responses lasting greater than six months. The median time to response was four months. Median PFS and overall survival (OS) were 6 and 19 months, respectively. In comparison, the objective response rates for doxorubicin-based regimens are approximately 25 percent, with median PFS between three and eight months [9,10].

Treatment-related grade ≥3 toxicities for tazemetostat included anemia (13 percent), weight loss (6 percent), pleural effusion (5 percent), decreased appetite (5 percent), and cancer pain (5 percent). Additionally, there have been limited reports of secondary malignancies, including myelodysplastic syndrome (less than 1 percent) and T-cell lymphoblastic lymphoma.

Further studies are needed to confirm these improvements in response rates and to assess potential survival advantage with tazemetostat.

Subsequent therapy

●For those with progression on or poor tolerance of chemotherapy as initial therapy, tazemetostat is an appropriate subsequent-line treatment option. (See 'Tazemetostat' above.)

●For those with progression on tazemetostat as initial therapy, chemotherapy is an appropriate subsequent-line treatment option, if not received previously. (See 'Chemotherapy' above.)

●For patients who have progressed on chemotherapy (ie, doxorubicin and/or gemcitabine-based regimens) and tazemetostat, there are limited treatment options; patients should be encouraged to participate in clinical trials when available. Pazopanib may be offered as subsequent therapy to those who have progressed on multiple prior lines of therapy, including systemic chemotherapy and tazemetostat.

Data for the activity for pazopanib have been conflicting, with some observational studies reporting no responses to treatment [9] and others reporting response rates up to 22 percent, with durable disease control in up to 50 percent of patients [15]. Pazopanib has been studied only in heavily pretreated patients, which may explain the low response rates observed in some studies.

CLEAR CELL SARCOMA

Epidemiology and risk factors — Clear cell sarcoma (CCS) is a rare soft tissue sarcoma subtype, accounting for less than 1 percent of all sarcomas [16]. It was previously called "melanoma of soft parts" and has certain clinical features in common with melanoma, including distal limb distribution, in-transit disease, regional lymph node spread, and a tendency for local recurrence. In addition, CCS also has clinical characteristics of soft tissue sarcoma, including pulmonary metastatic spread and deep soft tissue primary location. This histologic subtype tends to affect young adults and has rarely been reported in the very young or older adults.

Risk factors include prior radiation exposure and rare inherited cancer predisposition syndromes (such as Li-Fraumeni syndrome and retinoblastoma). Other risk factors have not been identified. (See "Radiation-associated sarcomas" and "Li-Fraumeni syndrome" and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)

Clinical presentation and natural history — CCS has a predilection for the deep soft tissues of the lower extremity and typically involves the peripheral tendons and aponeuroses of young adults [16]. Females and males are equally affected. Despite optimal management of local disease, a large proportion of patients develop recurrent or metastatic disease. Five-year survival rate for patients with CCS is about 50 percent and is significantly lower for patients with stage 3 or 4 disease at diagnosis [17].

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. CCS displays a uniform pattern composed of fusiform rounded cells with clear or eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli [18]. Tumor cells are divided into nests by thin fibrous septa, which are contiguous with adjacent tendons or aponeuroses. The presence of large amounts of glycogen results in the clear cell appearance. Tumor cells almost always express S100 and most also express Melan-A and HMB-45. It is possible to distinguish CCS histologically from melanoma by the absence of a primary melanoma site or the absence of junctional activity within the overlying dermis.

This tumor is characterized by the translocation t(12;22)(q13;q12) and consequent fusion of the EWS and ATF1 genes [19]. This directly up-regulates the microphthalmia transcription factor (MITF). Notably, this translocation has not been documented in melanoma. Furthermore, CCS in the gastrointestinal tract has a variant fusion gene EWSR1-CREB1 [20]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Clear cell sarcoma'.)

Treatment of localized disease — Similar to other soft tissue sarcomas, the management of localized disease consists of complete surgical resection, with or without radiation therapy (RT). Radiation may be administered preoperatively or postoperatively, and timing should be based on multispecialty input from radiation oncology and orthopedic or surgical oncology with expertise in the treatment of CCS [16]. Although CCS is less sensitive to radiation therapy than other sarcoma subtypes, there are insufficient data to suggest that RT should be avoided in such patients. Therefore, following the general principles of radiation oncology for soft tissue sarcomas, postoperative RT may be indicated in patients with tumors greater than 5 cm or in those with positive or close surgical margins. For patients with treatment-naïve disease, preoperative radiation may be indicated if initial resection would result in significant postoperative morbidity or if the morbidity of preoperative RT is expected to be less than postoperative RT. For patients with a local recurrence, preoperative RT may be indicated if radiation was not previously administered and resection is expected to result in close negative or microscopically positive surgical margins. There is no established role for adjuvant systemic chemotherapy. (See "Surgical resection of primary soft tissue sarcoma of the extremities" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)

Treatment of advanced/metastatic disease — Despite optimal management of localized disease, a high proportion of patients develop metastatic disease [16]. For patients with locally advanced or metastatic CCS, the optimal systemic chemotherapy regimen has not been established, as retrospective studies of patients with metastatic CCS have shown limited sensitivity to anthracycline-based chemotherapy [21,22]. Referral for participation in clinical trials at a center with sarcoma specialists is encouraged.

There is a lack of effective systemic treatment options for patients who are ineligible for clinical trials. Targeted therapies such as MET kinase inhibitor (eg, crizotinib, cabozantinib) and inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway (eg, pazopanib and sunitinib), among others, have demonstrated low response rates in patients with advanced or metastatic disease.

●Crizotinib and cabozantinib – In a phase II trial (CREATE) of the MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib in a number of tumor types, including 34 patients with CCS, an objective partial response was observed in one patient with a MET positive tumor; median PFS was approximately four months [23].

Cabozantinib resulted in a partial response in one patient with CCS in a phase I trial [24].

●Tivantinib – A phase II trial of tivantinib, a selective, oral, non-adenosine triphosphate competitive, small molecular inhibitor of MET conducted in several tumor types (including CCS) achieved a partial response in 1 of 11 CCS patients, with a median PFS of two months [25].

●Pazopanib and sunitinib – Limited observational studies have suggested modest activity of pazopanib and sunitinib in those with CCS [22,26,27]. In one observational study of sunitinib, objective responses were seen in 3 of 10 patients (30 percent), and median PFS was four months [22].

ALVEOLAR SOFT PART SARCOMA

Epidemiology and risk factors — Alveolar soft part sarcoma (ASPS) is a very rare sarcoma subtype comprising approximately 0.5 percent of all soft tissue sarcomas [28,29]. This subtype affects young people with a median age at presentation of 25 years. ASPS is more common in females than males [30].

Risk factors include prior radiation exposure and the rare inherited cancer predisposition syndromes (such as Li-Fraumeni syndrome and retinoblastoma). Other risk factors have not been identified. (See "Radiation-associated sarcomas" and "Li-Fraumeni syndrome" and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)

Clinical presentation and natural history — This tumor usually presents as an indolent, slow-growing, painless, soft tissue mass, and the most common primary sites are muscles of the lower extremity [28]. Metastases can appear late in the course of the disease and frequently involve the lungs, bone, and brain. Metastases involving the lung usually precede metastases to the brain [31]. The rate of tumor progression is often very indolent, requiring months to years before symptoms develop. A minority of patients presenting with metastatic disease survive more than five years after diagnosis, although the survival rate may be improving substantially with more recently introduced treatment options [31-33].

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. ASPS has a characteristic appearance of nests of cells loosely arranged along fibrous septa, surrounded by capillaries. It is associated with a characteristic unbalanced t(x;17)(p11,q25) translocation, resulting in the ASPSCR1-TFE3 fusion gene [34]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Alveolar soft part sarcoma'.)

Treatment of localized disease — As for other soft tissue sarcomas, complete surgical resection is standard management for localized disease [28]. Adjuvant radiation is offered when wide surgical margins were not achieved, as this approach reduces the risk of local recurrence [35,36]. There is no established role for the use of adjuvant systemic chemotherapy. (See "Surgical resection of primary soft tissue sarcoma of the extremities" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)

Treatment of advanced/metastatic disease — The prognosis for locally advanced, unresectable, or metastatic ASPS is poor, and these patients are typically treated with palliative intent. The five-year overall survival (OS) is 20 percent, and median survival is approximately 40 months but may improve with advances in treatment [37].

Resectable primary site — For patients in whom a complete resection can be achieved with acceptable postoperative morbidity, particularly those who are symptomatic, we suggest surgical resection of the primary site. Patients who have undergone resection of the primary tumor and have appropriate wound healing and surgical recovery may subsequently be evaluated for systemic therapy, similar to those with unresectable or metastatic disease. (See 'Unresectable or metastatic disease' below.)

The rationale for resection of the primary site for those with metastatic ASPS is that it is an indolent disease and retrospective data suggest a clinical benefit from this approach. In one analysis of 251 patients initially diagnosed with ASPS in the Surveillance, Epidemiology and End Results (SEER) database between 1973 and 2012, resection of the primary tumor was associated with improved OS among the 58 percent of patients with metastatic disease who had resection of the primary tumor [35]. However, the large majority of patients in this series were treated before active drugs for treatment of ASPS were identified.

Unresectable or metastatic disease

Limited, stable disease burden — For treatment-naïve patients with unresectable or metastatic ASPS who have limited, stable disease burden and are asymptomatic, we suggest surveillance rather than immediate initiation of systemic therapy, given that patients with ASPS often experience an indolent disease course.

However, patients with brain metastases are an exception, regardless of the presence or absence of neurologic symptoms. Such patients should receive central nervous system (CNS)-directed therapy to prevent the development of devastating disease-related neurologic complications. (See "Overview of the treatment of brain metastases".)

Limited, progressive disease burden — For treatment-naïve patients with limited but progressive extracranial disease burden, we suggest single-agent immunotherapy rather than surveillance. Options include either atezolizumab or pembrolizumab. Either agent is acceptable, as there are no randomized trials directly comparing these treatments with each other or other agents. Data are as follows:

●Atezolizumab – Atezolizumab, a monoclonal antibody that inhibits programmed cell death 1 ligand (PD-L1) is effective and well-tolerated in patients with ASPS [38,39].

In a single-arm phase II trial, 52 adult and pediatric patients with unresectable or metastatic ASPS were treated with atezolizumab until disease progression or unacceptable toxicity [40]. Approximately half of patients had received at least one prior line of treatment. An objective response was seen in 37 percent of patients, most of which were partial responses. Median progression-free survival (PFS) was 21 months with a median duration of response of 25 months. Toxicity was similar to prior studies of atezolizumab. There were no grade 4 or 5 toxicities reported.

Based on these data, the US Food and Drug Administration (FDA) approved atezolizumab for the treatment of adult and pediatric patients with unresectable or metastatic ASPS [39].

●Pembrolizumab – Pembrolizumab, a programmed cell death-1 (PD-1) inhibitor, is another option for patients with metastatic ASPS. The efficacy of pembrolizumab is based on the following studies:

•In a phase II trial, 98 patients with various treatment-naïve or treatment-resistant advanced rare sarcomas received pembrolizumab [41]. Among the subgroup of 14 patients with ASPS, at a median follow-up of 13 months, partial and complete responses were seen in seven patients (50 percent) and one patient (7 percent); stable disease was seen in three patients (21 percent). The median duration of response was five months.

•In one observational study, 50 patients with advanced or metastatic sarcoma treated with various immunotherapy regimens, including pembrolizumab [42]. Among the four patients with ASPS, two had partial responses that were durable (lasting up to 12 months) and two had stable disease.

Heavy disease burden and/or rapidly progressive disease — For patients with extracranial tumor-related symptoms and/or rapidly progressive or bulky disease, we suggest combination therapy with pembrolizumab plus axitinib rather than chemotherapy. For patients who are ineligible for or unable to tolerate combination therapy, we offer antiangiogenic therapy alone with either pazopanib or sunitinib.

ASPS is responsive to pembrolizumab plus axitinib, with objective response rates of up to 55 percent in one phase II trial [43]. Conversely, there is very limited efficacy for chemotherapy (eg, doxorubicin, ifosfamide, dacarbazine, and trabectedin [44]) in this population. There are no randomized trials directly comparing pembrolizumab plus axitinib with other agents in ASPS.

Pembrolizumab plus axitinib was evaluated in a single-arm, phase II clinical trial of 36 patients with advanced or metastatic soft tissue sarcomas (STS), including 12 patients with ASPS [43]. In the ASPS cohort, at a median follow-up of 15 months, the objective response rate was 55 percent, and the three-month PFS was 75 percent. Grade ≥3 toxicities included hypertension (15 percent), nausea and vomiting, and seizures (6 percent each). Serious treatment-related adverse events were noted in seven patients (21 percent), including one patient with autoimmune colitis. No treatment-related deaths were reported.

For patients who are ineligible for or unable to tolerate the potential toxicities of combination immunotherapy and antiangiogenic therapy, options include pazopanib and sunitinib. These agents have demonstrated efficacy for metastatic ASPS in observational studies and early phase clinical trials, as follows:

●Pazopanib – Pazopanib has activity in patients with metastatic ASPS, with response rates ranging from 17 to 28 percent [44,45]. While pazopanib is approved by the US Food and Drug Administration (FDA) for patients with advanced sarcomas who have previously received chemotherapy, we offer it off label as initial therapy for select patients with ASPS.

●Sunitinib – Sunitinib has demonstrated activity in patients with advanced or metastatic ASPS in both observational studies and clinical trials [32,46-49]. Sunitinib was compared with cediranib in a randomized phase II trial of 29 evaluable patients with treatment-refractory metastatic ASPS [49]. Sunitinib had a similar objective response rate (7 percent each) and median PFS (6 versus 8 months) compared with cediranib. Stable disease rates were 79 and 87 percent, respectively. The low objective response rate for both drugs was attributed to the patient population, all of whom had progressive disease within six months preceding study enrollment.

Experimental agents — Antiangiogenic agents such as cediranib [37,49-52] and anlotinib [53] have demonstrated activity in ASPS [53]. Cediranib is not yet commercially available in any country, and its use remains investigational. Anlotinib is investigational in the United States and Europe but commercially available in China.

Other agents such as dasatinib (an oral inhibitor of the SRC family of kinases), crizotinib (an oral MET inhibitor), and trabectedin (a DNA-binding chemotherapy) all have minimal activity in ASPS [44,54,55].

EXTRASKELETAL MYXOID CHONDROSARCOMA

Epidemiology and risk factors — Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma subtype that generally has an indolent clinical behavior [56,57]. EMC is twice as common in males as females, with a median age at diagnosis of 52 years [58,59].

Risk factors include prior radiation exposure and the rare inherited cancer predisposition syndromes (such as Li-Fraumeni syndrome and retinoblastoma). Other risk factors have not been identified. (See "Radiation-associated sarcomas" and "Li-Fraumeni syndrome" and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)

Clinical presentation and natural history — The majority of patients present with bulky tumors in the extremities. In one study of 117 patients with EMC, the median tumor size was 7 cm (range 1.1 to 25 cm), and all tumors occurred in the deep subcutis or deeper soft tissues [59]. The primary tumor is located most commonly on the proximal extremities (80 percent) and less commonly on the trunk (20 percent).

Approximately one-half of patients with EMC are at risk for developing recurrent or metastatic disease. In one observational study, local recurrences occurred in 40 of 83 patients (48 percent), and metastatic disease in 35 of 76 patients (46 percent).

However, patients with metastatic disease often have indolent disease progression, and systemic treatment may be delayed for months to years until disease-related symptoms develop. The estimated 5-, 10-, and 15-year survival rates in patients with EMC are 90, 70, and 60 percent, respectively [59]. (See 'Treatment of advanced/metastatic disease' below.)

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. Morphologically, these tumors are characterized by multinodular growth of primitive chondroid cells in an abundant myxoid matrix. This tumor has a characteristic chromosomal translocation involving t(9;22)(q22;q12.2) fusing the EWSR1 and NR4A3 genes. In a minority of tumors, another translocation, t(9;17)(q22;q11.2), is present [60]. Some tumors may also be characterized by overexpression of RET [61]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Extraskeletal myxoid chondrosarcoma'.)

Treatment of localized disease — The standard management of localized disease consists of complete surgical resection, with or without radiation therapy (RT) [36,58,62]. Radiation may be administered preoperatively or postoperatively, and timing should be based on multispecialty input from radiation oncology and orthopedic or surgical oncology. Postoperative radiation may be indicated in tumors larger than 5 cm or in those with positive or close surgical margins. For those with treatment-naïve disease, preoperative radiation may be indicated if initial resection would result in significant postoperative morbidity or if the morbidity of preoperative RT is expected to be less than that of postoperative RT. For patients with a local recurrence, preoperative RT may be indicated if radiation was not previously administered and resection is expected to result in close negative or microscopically positive surgical margins. There are limited data to support the use of adjuvant systemic chemotherapy [36]. (See "Surgical resection of primary soft tissue sarcoma of the extremities" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)

In one retrospective observational study of 41 patients with localized EMC, combined modality treatment with surgery and RT (either preoperatively or postoperatively) was associated with improved 10-year local control versus surgery alone (100 versus 63 percent) [62].

Treatment of advanced/metastatic disease

Resectable primary site — For patients with metastatic disease who have a resectable primary tumor, we suggest surgical resection (with or without RT) using a similar approach to those with localized disease. Patients with EMC typically have indolent disease, and some patients who can achieve a complete surgical resection with minimal postoperative morbidity may benefit from this palliative surgical approach. (See 'Treatment of localized disease' above.)

Patients who have undergone resection of the primary tumor and have appropriate wound healing and surgical recovery may subsequently be evaluated for systemic therapy, similar to those with unresectable or metastatic disease. (See 'Unresectable disease' below.)

Unresectable disease

Limited disease burden — For treatment-naïve patients with limited disease burden who are asymptomatic, we suggest observation rather than immediate initiation of systemic therapy, given that patients with EMC often experience an indolent disease course.

Heavy disease burden and/or rapidly progressive disease — For those with indications to initiate therapy (ie, tumor-related symptoms and/or rapidly progressive disease), we suggest the use of antiangiogenic therapy with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors rather than anthracycline-based chemotherapy. Our preferred options include sunitinib and pazopanib.

EMC is responsive to antiangiogenic therapy with agents that target the vascular endothelial growth factor (VEGF) pathway but has limited sensitivity to anthracycline-based chemotherapy [58,63]. The optimal systemic therapy for patients with locally advanced or metastatic EMC has not been established, and participation in clinical trials is encouraged.

Data for antiangiogenic therapy are as follows:

●Sunitinib – In one retrospective observational study, 10 patients with metastatic EMC were treated with sunitinib [63]. At a median follow-up of nine months, objective responses were seen in six patients (60 percent). Further prospective clinical trials evaluating the efficacy of sunitinib are needed.

●Pazopanib – In a single-arm, open-label phase II trial, 26 patients with advanced, unresectable, or metastatic EMC were treated with pazopanib [64]. At a median follow-up of 27 months, objective responses were seen in 4 of 22 evaluable patients (18 percent). One- and two-year PFS were 74 and 40 percent, respectively.

Data are mixed for the utility of chemotherapy in patients with metastatic EMC. One observational study of 21 patients with metastatic EMC treated mainly with doxorubicin-based chemotherapy regimens demonstrated no clinical responses [58]. In contrast, another retrospective analysis suggested that doxorubicin-based therapy has clinical activity in this population [65].

EPITHELIOID HEMANGIOENDOTHELIOMA

Epidemiology and risk factors — Epithelioid hemangioendothelioma (EHE) is a vascular neoplasm composed of epithelioid or histiocytoid cells with endothelial characteristics. EHE is very rare, with an incidence of approximately one per one million. Although EHE can occur in both children and adults, it is usually diagnosed between 20 and 60 years of age [66]. The median age at diagnosis is likely affected by referral patterns and whether the EHE is primarily located in the lung (the most common site of disease in the pediatric population [67]), liver, or soft tissue. Women are more commonly affected than men [66-68].

There are no known risk factors for the development of EHE. Despite EHE occurring more frequently in women, there is no established association between hormonal factors and tumor development. Although Bartonella bacteremia was reported in two patients with EHE, chronic bacteremia has not been definitively associated with the development of disease [69].

Clinical presentation and natural history — Among patients with symptomatic disease, the most common reported symptom is pain. Cutaneous and soft tissue EHE often present as a painful mass and may cause thrombosis or occlusion in the affected vessel. In the majority of these cases, EHE is multifocal or metastatic at diagnosis.

EHE most frequently arises in the liver, followed by the lung and bones [70]. Intravascular bronchioloalveolar tumor (a sclerosing endothelial tumor) has also been reclassified as pulmonary EHE. EHE has also been reported to arise in skin, soft tissue, thyroid, spleen, stomach, prostate, ovary, and brain [66]. The extremities are the most common location for patients with cutaneous and soft tissue EHE.

Presenting symptoms are often based on disease site:

●Liver EHE may cause constitutional symptoms (eg, anorexia, weight loss, fatigue), nausea, abdominal pain, jaundice. It may appear on computed tomography (CT) or magnetic resonance imaging (MRI) as a solitary mass or multifocal masses.

●Pulmonary EHE may cause dyspnea, cough, hemoptysis, and clubbing. It may appear on CT of the chest as multiple parenchymal nodules, reticulonodular ground glass opacities, and/or pleural thickening, with or without fibrosis or effusion.

●Bone EHE may cause pain and pathologic fracture and typically appears on plain films or CT as lytic lesions with sclerotic border.

The natural history of EHE is variable. The clinical course can range from indolent disease (similar to those with benign hemangiomas) to aggressive disease (similar to those with angiosarcoma) [71].

●Asymptomatic or localized disease – A majority of patients (between 50 to 76 percent) with EHE are asymptomatic at diagnosis, and the disease is incidentally detected during radiographic imaging. The overall median survival of patients without symptoms is more than 10 years [66]. A small case series of less than 20 patients demonstrated a recurrence free survival of 65 months in patients who underwent surgery for localized disease [72]. A separate case series of over 150 patients with localized EHE found a 5 year overall survival of 82 percent [73].

●Symptomatic or metastatic disease – Patients with metastatic disease or adverse features have a worse prognosis. Adverse features include symptomatic disease, signs of inflammation, age over 55, effusions (eg, pleural and/or ascites), or male sex; these features have been associated with a more aggressive clinical course [70,73,74]. Certain pathologic features (eg, tumors >3 cm and with higher mitotic index [>3 per 50 high-power fields of view] or Ki-67 index [>10 percent]) are also adverse prognostic factors associated with worse overall survival (OS) [74].

A case series of over one hundred patients presenting with metastatic or multifocal disease reported a five-year OS rate of 62 percent [73]. Additional data have shown that prognosis can vary based on location and extent of disease. For instance, the median survival of patients with liver involvement has been reported to be 75 months, but is approximately one year for patients with adverse clinical prognostic factors [68].

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. EHE is comprised of atypical epithelioid endothelial cells arranged in cords in hyalinized, myxoid, and/or myxochondroid stroma [75,76]. Cells exhibit vacuoles within eosinophilic cytoplasm. Tumors expand involved vessel walls, spread into surrounding tissue, and may occasionally occlude vessel walls and/or cause thrombosis. Nuclear atypia and mitotic figures may be present but are not prominent. Tumor cells demonstrate expression of vascular markers, including von Willebrand factor, CD31, CD34, and ERG [76]. In a minority of cases, cytokeratins may be expressed. As a result of a recurring translocation between chromosomes 1 and 3 involving TAZ (WW domain-containing transcription regulator 1 [WWTR1]) and calmodulin-binding transcription activator 1 (CAMTA1), the fusion protein TAZ-CAMTA1 accumulates in the cytoplasm and is detected in the large majority of cases by immunohistochemistry using antibody to CAMTA1 [75]. Tumor expression of CAMTA1 is useful to distinguish EHE from epithelioid angiosarcoma that lacks expression of CAMTA1. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Epithelioid hemangioendothelioma'.)

Molecular studies have shown that multifocal EHE is a monoclonal process typically driven by fusion proteins [77]. Approximately 90 percent of tumors contain rearrangement of WWTR1 and CAMTA1 genes, which are not typically present in other vascular tumors [78,79]. The translocation results in expression of the TAZ-CAMTA1 fusion protein that disrupts transcriptional regulation and activates the mitogen-activated protein kinase (MAPK) pathway [80].

In tumors lacking rearrangement of CAMTA1, alternative molecular alterations have been reported. Examples include translocations between WWTR1 and FOSB [75] and expression of a yes-associated protein 1 (YAP1) and transcription factor E3 (TFE3) fusion protein [81]. Some studies suggest that YAP1-TFE3 fusion-positive tumors (which can be detected using immunohistochemistry) may be better classified as a distinct entity because they exhibit vascular formation and other cytologic features distinct from tumors that express the TAZ-CAMTA1 fusion [75].

Treatment of localized disease by organ involvement — Patients with localized disease are managed with surgery, and the treatment approach is guided by the involved organs. Complete surgical resection is offered to patients with unifocal disease or disease limited to a few organs (ie, lung, liver, or other viscera) where surgery would not be overly morbid. There are insufficient data to recommend use of adjuvant radiation or chemotherapy. Patients who undergo complete resection typically experience good outcomes, as detailed below.

The use of vascular embolization is variable based on sites of tumor involvement and institutional practice. It may be used preoperatively in patents with bone involvement and in select patients with a solitary liver tumor but is not required prior to resection of EHE involving the soft tissue or lungs.

●Soft tissue/skin – In one series of 49 patients with EHE in skin or soft tissue managed primarily by surgery, the five-year disease-specific survival was 81 percent. No patients with low-risk features (eg, tumor <3 cm and <3 mitotic figures per 50 high-power fields of view [HPF]) died of disease [74]. The five-year disease-specific survival of patients with a high-risk feature (eg, tumor >3 cm in size or >3 mitotic figures per 50 HPF) was 59 percent.

●Bone – For patients with bone involvement of EHE, we suggest treatment using preoperative selective vascular embolization, when feasible, because of the risk of intraoperative bleeding from highly vascular tumors; complete resection in cases with anticipated good functional outcome; and intralesional resection if wide resection would be overly morbid. We typically do not offer radiation of EHE involving the bone, as this approach is associated with risk of radiation-associated sarcoma and occurred in 8 percent of patients. (See "Radiation-associated sarcomas".)

In a series of 62 patients with EHE of bone treated with surgery, the 10-year survival rates for all patients, those with unifocal disease, and those with multifocal disease were 92, 97, and 74 percent, respectively [82]. Local 10-year recurrence-free survival rates for patients treated by wide resection or intralesional techniques were 94 and 68 percent, respectively, although all local recurrences appeared to occur within three years of the initial procedure.

●Liver – Patients with liver involvement of EHE with resectable disease are treated with hepatic resection. Patients with unresectable disease (ie, multifocal or diffuse liver involvement, or proximity to critical structures) that is symptomatic and/or progressive should be evaluated for orthotopic liver transplantation. Long-term outcomes are excellent with this approach, with 10-year survival rates of approximately 74 percent [83]. The benefit of liver transplantation in patients without symptoms or clear disease progression is not established.

In one registry study, 149 patients with liver involvement of EHE were treated with liver transplantation. At median follow-up of eight years after transplantation, 5- and 10-year OS rates were 80 and 74 percent, respectively; 5- and 10-year disease-free survival rates were 79 and 73 percent, respectively [83]. Early posttransplant mortality was low at 5 percent. Risk factors for EHE recurrence after transplant were pathologic evidence of macrovascular invasion, a waiting time from diagnosis to transplantation of less than 120 days, and invasion/involvement of hilar lymph nodes. The five-year disease-free survival rate was 94 percent in patients without adverse risk factors or with only lymph node involvement, compared with 39 percent in patients with macrovascular invasion and at least one other risk factor. The presence of extrahepatic involvement of EHE was not associated with worse outcomes. Patients who underwent transplant in 2000 or later also had a better prognosis, although this could be due to selection bias of patients with fewer risk factors for disease recurrence.

Treatment of advanced/metastatic disease — For patients with advanced/unresectable or metastatic disease who are also without symptoms or disease progression, we suggest observation, with initiation of systemic therapy at onset of new lesions, accelerated growth of existing lesions, or symptomatic disease.

For patients who are symptomatic or have progressive disease, we suggest initial therapy with antiangiogenic therapy using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (eg, pazopanib) rather than cytotoxic chemotherapy. For patients who are ineligible for VEGFR tyrosine kinase inhibitors (ie, those with liver dysfunction), we offer cytotoxic chemotherapy, such as single-agent gemcitabine.

Antiangiogenic agents have demonstrated objective response rates ranging from 13 to 29 percent in observational studies, whereas the efficacy of chemotherapy is not clearly established. Limited prospective data exist to guide the optimal treatment approach for this rare tumor, and patients are encouraged to enroll in clinical trials, where available.

●Pazopanib – Pazopanib has demonstrated activity, with some case reports demonstrating long-term disease control [84,85]. In one observational study of 10 patients with progressive EHE treated with pazopanib, objective responses were seen in two patients (20 percent) [86]. Median progression-free survival (PFS) and OS were approximately 26 months.

Pazopanib is approved by the US Food and Drug Administration (FDA) for patients with soft tissue sarcomas who have progressed on prior cytotoxic chemotherapy. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Pazopanib'.)

●Chemotherapy – Data are conflicting for the efficacy of cytotoxic chemotherapy in patients with advanced or metastatic EHE [87]. While some case reports have reported near complete responses for gemcitabine [88], carboplatin plus etoposide [89] and carboplatin, pemetrexed, and bevacizumab [90], other observational studies have demonstrated limited response rates for doxorubicin-based chemotherapy [91] and low-dose (metronomic) oral cyclophosphamide [92].

●Other agents – The efficacy of other targeted agents in the treatment of EHE is unclear, and further studies are needed. The use of these treatments in patients with EHE remains investigational.

•Vascular endothelial growth factor receptor (VEGFR) inhibitors – Bevacizumab and sorafenib have also demonstrated modest clinical efficacy in phase II trials, with objective responses ranging from 13 to 29 percent [93,94].

•Trametinib – Trametinib is an inhibitor of mitogen-activated protein (MEK) kinase. In preliminary results of a phase II trial of 41 patients with EHE, single-agent trametinib demonstrated objective tumor responses in 4 out of 41 patients (9.5 percent) in preliminary results of a phase II trial [95]. Median PFS and OS were 8 and 22 months, respectively. Patients reported a significant reduction in pain within four weeks of initiating therapy.

•Sirolimus – Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR) serine/threonine kinase, had an objective response rate of approximately 11 percent in one retrospective study and was not active in those with pleural or peritoneal effusions [96,97].

•Lenalidomide – Lenalidomide, an immunomodulatory agent, demonstrated long-term disease stability up to three years in some case reports [98-100].

INFLAMMATORY MYOFIBROBLASTIC TUMOR

Epidemiology and risk factors — Inflammatory myofibroblastic tumor (IMT) is a very rare mesenchymal neoplasm that tends to occur in children and young adults, with a mean age of 9 to 10 years [101]. However, patients can present at any age, from newborn infants to over the age of 70 years. Its incidence in children is significant, representing 20 percent of all primary lung tumors in this age group [101,102]. A large retrospective series reported no gender difference in the incidence of IMT, but another study reported a male-to-female ratio of 3:4 [103-105].

There are no known risk factors for the development of IMT. Clinical factors associated with recurrence include larger tumor size, abdominopelvic location, and older age.

Clinical presentation and natural history — Patients can present with a mass or symptoms including cough, chest pain, and abdominal pain [101]. Approximately 15 to 30 percent of patients will experience a constitutional syndrome consisting of malaise, fever, and weight loss. The most common sites of disease include the lungs, abdomen, pelvis, and retroperitoneum, although any site may be involved (eg, soft tissues, bone, larynx, uterus, liver, kidney, and central nervous system).

The outcome of these tumors can vary depending on anatomic location, with lung and bladder tumors typically having a more favorable outcome. However, IMTs may locally recur in 25 percent of patients with abdominopelvic tumors. Additionally, patients may rarely develop metastatic disease; common sites include the lung, liver, bone, and brain.

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. IMT is characterized by a spindle cell proliferation and an inflammatory infiltrate. These tumors are relatively well circumscribed and composed of bland to mildly atypical, spindled myofibroblasts and intermixed inflammatory cells [101,106]. The spindled myofibroblasts have large, oval, and vesicular nuclei with small nucleoli and variable amounts of eosinophilic cytoplasm. A prominent intermixed inflammatory infiltrate (composed of lymphocytes and plasma cells) can also be a feature of IMT. These tumors usually have a low mitotic count, and atypical mitoses are rare [101,106]. It has been reported that three basic histologic features can be observed with the same tumor: a hypocellular fibrous (fibromatosis-like), a myxoid/vascular, and compact spindle-cell pattern.

Tumor cells are usually positive for smooth muscle actin (80 to 90 percent of cases), and calponin and desmin (60 to 70 percent of cases). Furthermore, approximately one-third of these tumors have focal keratin expression. Malignant transformation is rare and characterized by cellular proliferation of atypical epithelioid cells with vesicular nuclei and prominent nucleoli with atypical mitoses [101,106].

The anaplastic lymphoma kinase (ALK) gene has a critical role in the biology of many IMTs. Approximately 50 percent of IMTs contain a translocation of the ALK gene, resulting in constitutive tyrosine kinase activation [101]. A number of different ALK fusion partner genes have been reported, including TPM3, TPM4, ATIC, CLTC, CARS, RANBP2, and SEC31L1 [101]. Additionally IMTs may harbor mutations in neurotrophic tyrosine receptor kinase (NTRK) genes at intermediate frequencies [107,108]. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Common cancers with low to intermediate frequency of TRK fusions'.)

Treatment of localized disease — Patients with localized IMT are initially treated with complete surgical resection as the standard of care. Patients with locally recurrent disease may be offered re-resection, depending on the anatomic location and the tempo of disease [9]. There are limited data to support the use of radiation or systemic chemotherapy.

Treatment of advanced/metastatic disease — Patients with advanced/unresectable or metastatic IMT are typically resistant to standard chemotherapy agents [109]. All patients should undergo molecular sequencing of their tumors for actionable targets such as mutations in ALK or NTRK, which influences available treatment options.

ALK-mutated tumors

●Initial therapy – For adult and pediatric patients with tumors harboring an ALK gene rearrangement, we suggest initial treatment with crizotinib rather than other systemic therapies, based on the high objective response rates seen with this agent in phase I and II trials [109-111].

For adults, we administer crizotinib at 250 mg orally twice a day. For pediatric patients, we administer crizotinib at 280 mg/m² orally twice a day, based on body surface area.

Based on initial studies [109], the efficacy of crizotinib was evaluated in an open-label, single-arm phase II trial of 20 patients with advanced, unresectable IMT [110]. At median follow-up of approximately 29 months, 6 of 12 patients with ALK-positive tumors (50 percent) achieved an objective response versus one of seven patients with ALK-negative tumors (14 percent). Similarly, in a separate open-label, single-arm phase Ib trial (Study A8081013) of adult patients with unresectable, recurrent, or refractory ALK-positive IMT, the objective response rate for crizotinib was 71 percent (five of seven patients), including one complete response [111].

Crizotinib is also effective with durable responses in pediatric patients with ALK-positive IMT. In a single-arm, open-label phase I/II trial of crizotinib (Study ADVL0912) that included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT, objective responses were seen in 12 patients (86 percent), including five complete and seven partial responses. Treatment response to crizotinib was also durable (lasting one year or longer) in 7 of 12 responders (58 percent) [111].

In these studies, patients experienced side effects commonly associated with crizotinib and similar to those seen in patients receiving crizotinib for other tumors, such as non-small cell lung cancer and anaplastic lymphoma. Dose interruptions and/or reductions may be necessary and are more frequent in pediatric patients. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Management of toxicities associated with ALK inhibitors'.)

Based on these data, the US Food and Drug Administration (FDA) approved crizotinib for the treatment of adult and pediatric patients one year of age and older with unresectable, recurrent, or refractory IMT that is ALK positive [111].

●Subsequent therapy – For those who progress on crizotinib, we offer subsequent therapy with ceritinib as an off-label agent, as observational studies suggest activity of ceritinib in tumors that develop resistance to crizotinib [112,113]. As an example, in one case report, ceritinib was used to successfully treat a patient with IMT with crizotinib resistance whose tumor harbored an ALK G1269 mutation [112].

Although data are limited, other ALK inhibitors, such as brigatinib [114], lorlatinib [115-118], and alectinib [116,119], are also active in treatment-refractory IMT [120].

TRK mutations — For patients with tumors containing NTRK gene fusions, we offer initial treatment with larotrectinib or entrectinib [107]. The efficacy of these agents in sarcomas and other tumor histologies is discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)

Other agents — Observational studies have reported some activity for a number of systemic therapies, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chemotherapy (eg, anthracycline-based regimens, vinca alkaloids (vinorelbine or vinblastine) alone or in combination with methotrexate, oral cyclophosphamide, gemcitabine plus docetaxel, and methotrexate plus cisplatin), and the anti-tumor necrosis factor (TNF) alpha antibody infliximab [121-124].

UNDIFFERENTIATED EMBRYONAL SARCOMA

Epidemiology and risk factors — Undifferentiated embryonal sarcoma (UES) of the liver is a very rare sarcoma subtype that occurs mainly in children between 5 and 12 years of age, with equal gender distribution [125-127]. It has been rarely reported in adults, with a female predominance [128,129]. After hepatoblastoma and hepatocellular carcinoma, UES of the liver is the third most common pediatric liver cancer, accounting for approximately 9 to 13 percent of all cases [130].

There are no known risk factors associated with undifferentiated embryonal sarcoma.

Clinical presentation and natural history — UES of the liver commonly arises from the right lobe of the liver; as a result, patients can present with an abdominal mass, with or without abdominal pain [126]. Patients can also experience other symptoms including fever, weight loss, anorexia, vomiting, diarrhea, fatigue, constipation, and respiratory distress. There have been reports of spontaneous tumor rupture as a result of rapid tumor growth. Liver function tests are usually normal in these patients, although slightly elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels may be seen. Rarely, increased levels of alpha-fetoprotein and CA-125 have been documented.

UES of the liver is a clinically aggressive tumor [126]. In initial reports of the disease, most children affected died within 12 months of diagnosis from tumor progression or local recurrence in liver, local regional recurrence in the abdomen and/or pulmonary and peritoneal metastases [125]. In a subsequent review, those treated with surgery and chemotherapy had a median overall survival (OS) of approximately 12 months and a three-year disease-free survival of approximately 38 percent [131].

Diagnosis and histology — Diagnosis is made by histologic findings on biopsy. On macroscopic evaluation, there is usually a single, well-circumscribed lesion as a result of a fibrous pseudocapsule of compressed liver parenchyma. This tumor most often occurs in the right lobe of the liver, although it can occur in both lobes. The tumor typically consists of both solid and cystic components [126]. Microscopic evaluation reveals cords and clusters of hepatocytes within the pseudocapsule and at the peripheral margin of the tumor. The solid component consists of spindle- or stellate-shaped cells with inconspicuous nucleoli and ill-defined cell borders. Multinucleated and bizarre-shaped cells with hyperchromatic nuclei are often seen between the sarcomatoid cells. Eosinophilic globules are seen in the tumor cell cytoplasm and extracellular matrix [126].

On immunohistochemistry, UES does not have a specific immunophenotype [126]. These tumors can have variable expression of muscle, histiocytic, and epithelial markers. Myogenin, CD34, CD117, PE10, ALK-1, S100, and hepatocyte paraffin 1 are negative in most cases; these negative markers are critical in excluding other diagnoses.

Treatment of resectable disease — UES of the liver has an aggressive clinical behavior but is potentially treatable with multimodality therapy including chemotherapy, surgery, radiation, and in select cases, orthotopic liver transplantation [126]. The treatment approach is dependent on the patient's eligibility for surgical resection. Patients should undergo multidisciplinary evaluation at a sarcoma center of excellence.

For patients with localized, resectable disease, we suggest neoadjuvant chemotherapy followed by hepatic resection with curative intent. Active chemotherapy regimens include doxorubicin plus ifosfamide; cyclophosphamide plus doxorubicin plus vincristine; and ifosfamide plus etoposide [132].

Patients often present with very large tumors or tumors adjacent to critical vascular structures that are unresectable [132]. Surgical resection alone results in poor outcomes, with an estimated OS of 37 percent [126]. Neoadjuvant chemotherapy often reduces tumor burden and facilitates complete resection. The addition of neoadjuvant chemotherapy has improved outcomes over surgery alone, with OS ranging between 70 and 100 percent in some case series [126,132].

Although we prefer neoadjuvant chemotherapy followed by hepatic resection in most patients, adjuvant chemotherapy (with or without radiation) is an alternative treatment option in select patients who undergo initial hepatic resection without neoadjuvant chemotherapy [126,133]. As an example, one study reported the efficacy of this approach in five patients treated with surgical resection (with or without radiation) and adjuvant chemotherapy using a vincristine, actinomycin D, and cyclophosphamide (VAC) regimen, developed through the Intergroup Rhabdomyosarcoma Study IV [133]. At median follow-up of 53 months, all five patients were alive and in first disease remission, including two patients with high-risk disease (one with metastatic disease and the other with tumor rupture).

Treatment of unresectable or advanced/metastatic disease — Patients with localized disease who are not eligible for hepatic resection are typically treated with neoadjuvant chemotherapy followed by evaluation for orthotopic liver transplantation, as clinically indicated [130,132]. Liver transplantation may also be offered to those with disease that is recurrent or refractory to previous initial therapy (ie, chemotherapy and/or surgery) [126,130]. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Liver transplant'.)

For patients with unresectable disease who are not candidates for liver transplantation or those with distant metastases, systemic chemotherapy is indicated. Chemotherapy options (typically doxorubicin-based regimens) that are active for those with localized, resectable disease may also be offered as initial therapy in this patient population. (See 'Treatment of resectable disease' above.)

SUMMARY AND RECOMMENDATIONS

●Uncommon sarcoma subtypes – Sarcomas are rare malignant tumors of skeletal and extraskeletal connective tissue. Uncommon subtypes of sarcoma that are especially challenging to diagnose and treat include epithelioid sarcoma (ES), clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), extraskeletal myxoid chondrosarcoma (EMC), epithelioid hemangioendothelioma (EHE), inflammatory myofibroblastic tumor (IMT), and undifferentiated embryonal sarcoma (UES). Patients diagnosed with these rare tumors should be referred to sarcoma centers of excellence for management and evaluation for clinical trials. (See 'Introduction' above.)

●Approach to localized, resectable disease – Patients with specific histologies (eg, ES, CCS, ASPS, EMC, IMT) and localized, resectable disease are typically treated with surgery. Certain patients (ie, those with ES, CCS, or EMC) may also benefit from postoperative (adjuvant) radiation therapy (RT; eg, those with tumors larger than 5 cm, positive or close surgical margins) or preoperative RT (eg, patients with treatment-naïve disease in whom initial resection would result in significant postoperative morbidity, or those in whom the morbidity of preoperative RT is expected to be less than postoperative RT; patients with a local recurrence in whom radiation was not previously administered and resection is expected to result in close negative or microscopically positive surgical margins). However, given the rarity of these tumors, these patients should be referred to a center with specialists in the management of sarcoma. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

●Epithelioid sarcoma – Epithelioid sarcoma (ES) occurs in young patients and has two morphological variants: classic (distal) and proximal type. (See 'Epithelioid sarcoma' above.)

•For patients with locally advanced or metastatic ES who are not eligible for complete surgical resection, we suggest initial treatment with chemotherapy rather than tazemetostat (Grade 2C). (See 'Treatment of advanced/metastatic disease' above.)

-When using chemotherapy, we typically suggest an anthracycline-based rather than non-anthracycline-based regimen (Grade 2C), provided there are no contraindications. For those who are ineligible for anthracyclines, alternative treatment options include gemcitabine plus docetaxel or single-agent vinorelbine. (See 'Chemotherapy' above.)

In patients with indolent, less bulky and/or asymptomatic disease, other experts may offer tazemetostat as an alternative to chemotherapy as initial therapy. (See 'Tazemetostat' above.)

●Clear cell sarcoma – Clear cell sarcoma (CCS) occurs in young adults and typically arises in deep soft tissue of extremity. (See 'Clear cell sarcoma' above.)

•For patients with locally advanced or metastatic disease, we refer for participation in clinical trials due to the lack of effective systemic treatment options. (See 'Treatment of advanced/metastatic disease' above.)

●Alveolar soft part sarcoma – Alveolar soft part sarcoma (ASPS) is a clinically indolent tumor that occurs in young patients and is more common in females than males. (See 'Alveolar soft part sarcoma' above.)

•Resectable disease – For patients with locally advanced or metastatic disease and a resectable primary, we suggest resection of the primary site, if this can be achieved with acceptable risk of postoperative morbidity (Grade 2C). (See 'Resectable primary site' above.)

•Unresectable or metastatic disease – For most treatment-naïve patients with unresectable or metastatic disease, selection of therapy is based upon disease burden and/or symptoms. (See 'Unresectable or metastatic disease' above.)

-For asymptomatic patients with limited, stable disease burden limited to extracranial sites, we suggest surveillance rather than systemic therapy (Grade 2C), given that ASPS typically has an indolent disease course. The exception is patients with brain metastases who should receive central nervous system (CNS)-directed therapy, regardless of symptoms, which is discussed separately. (See 'Limited, stable disease burden' above and "Overview of the treatment of brain metastases".)

-For those with limited but progressive extracranial disease burden, we suggest single-agent immunotherapy with either atezolizumab or pembrolizumab rather than surveillance (Grade 2C). (See 'Limited, progressive disease burden' above.)

-For those with extracranial tumor-related symptoms and/or rapidly progressive or bulky disease, we suggest pembrolizumab plus axitinib rather than chemotherapy (Grade 2C). For patients who are ineligible for or unable to tolerate combination therapy, we offer antiangiogenic therapy alone with either pazopanib or sunitinib. (See 'Heavy disease burden and/or rapidly progressive disease' above.)

●Extraskeletal myxoid chondrosarcoma – Extraskeletal myxoid chondrosarcoma (EMC) is a clinically indolent tumor that occurs in middle-aged patients and is more common in males than in females. (See 'Extraskeletal myxoid chondrosarcoma' above.)

•For patients with metastatic disease, we suggest resection of the primary site (with or without RT) if this can be achieved with minimal postoperative morbidity. (See 'Resectable primary site' above.)

•For treatment-naïve patients with advanced or metastatic disease and limited disease burden who are asymptomatic, we suggest observation rather than upfront systemic therapy (Grade 2C). (See 'Limited disease burden' above.)

For those with tumor-related symptoms and/or rapidly progressive disease, we suggest antiangiogenic therapy with VEGFR tyrosine kinase inhibitors rather than anthracycline-based chemotherapy (Grade 2C). Our preferred options include sunitinib and pazopanib. (See 'Heavy disease burden and/or rapidly progressive disease' above.)

●Epithelioid hemangioendothelioma – Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular neoplasm occurring in both children and adults. The clinical course is variable and ranges from indolent to aggressive disease. (See 'Epithelioid hemangioendothelioma' above.)

•Patients with localized disease are managed with surgical resection, depending on the site of disease. Patients with unresectable liver disease that is symptomatic or progressive should be evaluated for orthotopic liver transplantation. (See 'Treatment of localized disease by organ involvement' above.)

•For patients with advanced/unresectable or metastatic disease who are without symptoms or disease progression, we suggest observation (Grade 2C), with initiation of systemic therapy at onset of new lesions, accelerated growth of existing lesions, or symptomatic disease. (See 'Treatment of advanced/metastatic disease' above.)

For patients who are symptomatic or have progressive disease, we suggest initial therapy with antiangiogenic therapy using VEGFR inhibitors rather than cytotoxic chemotherapy (Grade 2C). Patients are encouraged to enroll in clinical trials, where available.

●Inflammatory myofibroblastic tumor – Inflammatory myofibroblastic tumor (IMT) is a very rare mesenchymal neoplasm that tends to occur in children and young adults (mean age of presentation 9 to 10 years of age). (See 'Inflammatory myofibroblastic tumor' above.)

•For adult and pediatric patients with advanced or metastatic disease harboring an anaplastic lymphoma kinase (ALK) gene rearrangement, we suggest initial treatment with crizotinib rather than other systemic therapies (Grade 2C). For those who progress on crizotinib, we offer subsequent therapy with ceritinib. (See 'Treatment of advanced/metastatic disease' above.)

For those with tumors expressing neurotrophic tyrosine receptor kinase (NTRK) gene fusions, we offer initial treatment with larotrectinib or entrectinib, which is discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

●Undifferentiated embryonal sarcoma – Undifferentiated embryonal sarcoma (UES) of the liver is an aggressive sarcoma that occurs mainly in pediatric patients and rarely in adults. (See 'Undifferentiated embryonal sarcoma' above.)

•For patients with localized, resectable disease, we suggest neoadjuvant chemotherapy and hepatic resection rather than hepatic resection alone (Grade 2C). Since patients often present with very large tumors or tumors adjacent to critical vascular structures, chemotherapy is often administered neoadjuvantly to reduce tumor burden and facilitate complete resection. However, adjuvant chemotherapy (with or without radiation therapy) is an alternative treatment option in select patients who undergo initial hepatic resection without neoadjuvant chemotherapy. (See 'Treatment of resectable disease' above.)

•Patients with localized, unresectable disease are typically treated with neoadjuvant chemotherapy followed by evaluation for orthotopic liver transplantation. (See 'Treatment of unresectable or advanced/metastatic disease' above.)

•For those with unresectable disease who are not candidates for liver transplantation or those with distant metastases, systemic chemotherapy is indicated.