Shizuhide Nakayama

Epithelioid sarcoma (EPS) is an ultra-rare malignant mesenchymal neoplasm of uncertain differentiation that comprises two distinct clinicopathological subtypes: classic and proximal. Classic EPS most commonly occurs in the distal upper extremity of adolescents and young adults, whereas proximal-type EPS most often affects the truncal regions of young to middle-aged adults. Both classic and proximal-type EPSs exhibit aggressive clinical behavior, including a higher risk of local recurrence and regional lymph node or distant metastasis. Histologically, classic EPS is characterized by irregular nodules composed of epithelioid and spindled cells, while proximal-type EPS consists of multinodular distributions and sheets of large polygonal cells. EPS has a distinctive immunoprofile with characteristic expression of cytokeratins and epithelial membrane antigen. Loss of nuclear expression of SMARCB1 protein occurs in the vast majority of cases. Moreover, SMARCB1 homozygous deletions have also been observed in both subtypes. Surgery is the mainstay treatment approach for localized EPS. Systemic treatment options for metastatic or unresectable locally advanced disease are very limited. The withdrawal of tazemetostat has created a significant gap in available treatment options. In this review, we provide an overview of the current knowledge on the clinical and radiological features, histopathology, immunohistochemistry, pathogenesis, and management of EPS.

Histiocytic sarcoma (HS) is an ultra-rare hematopoietic neoplasm that frequently occurs in extranodal sites of adults. Clinically, HS demonstrates aggressive behavior and can arise de novo or in association with other hematological neoplasms. The median overall survival from the time of diagnosis is approximately six months. Histologically, HS is composed of sheets of large, round to oval cells with abundant eosinophilic cytoplasm and can be confused with a variety of benign and malignant conditions. Immunohistochemistry plays a crucial role in the diagnosis of HS, showing expression of CD163, CD68, lysozyme, and PU.1 and negative staining with follicular dendritic cell markers and myeloid cell markers. Recent studies have demonstrated a high rate of PD-L1 expression, suggesting a potential therapeutic target. Several genomic alterations have been identified in HS, including mutations involving the RAS/MAPK and PI3K/AKT/mTOR signaling pathways, CDKN2A mutations/deletions, and TP53 mutations. There is no standard protocol for the management of HS. Surgical resection with or without radiotherapy is the most common first-line treatment for unifocal/localized disease. The systemic treatment options for multifocal/disseminated disease are very limited. This review provides an overview of the current knowledge on the clinicoradiological features, histopathology, pathogenesis, and management of HS.

Atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT) is a rare and recently described adipocytic neoplasm that primarily occurs in the subcutis of the limbs and limb girdles, particularly of middle-aged adults. It has locally recurrent potential if incompletely excised but no risk for distant metastasis. ASCPLT is histologically similar to spindle cell/pleomorphic lipoma and atypical lipomatous tumor and shows a mixture of atypical spindle cells, adipocytes, lipoblasts, floret-like multinucleated giant cells, and/or pleomorphic cells. It has been recently recognized that ASCPLT can undergo sarcomatous transformation. However, the biological significance of morphological sarcomatous transformation in ASCPLT remains uncertain. Immunohistochemically, the tumor cells show variable expression of CD34, S-100 protein, and desmin. Loss of nuclear Rb expression is observed in the majority of cases. ASCPLT lacks MDM2 gene amplification but can show RB1 gene deletion in a significant subset of cases. Complete surgical excision is the treatment of choice. This review provides an overview of the current knowledge on the clinicoradiological features, pathogenesis, histopathology, and treatment of ASCPLT. In addition, we will discuss the differential diagnosis of this new entity.

Keratin-positive giant cell-rich tumor (KPGCT) is an extremely rare and recently described mesenchymal neoplasm that occurs in both soft tissue and bone, frequently found in young women. It has locally recurrent potential if incompletely excised but low risk for metastasis. KPGCT is histologically similar to conventional giant cell tumors of soft tissue but shows the presence of keratin-positive mononuclear cells. Interestingly, KPGCT also shares some morphological features with xanthogranulomatous epithelial tumors. These two tumors have recently been shown to harbor an HMGA2–NCOR2 fusion, arguing in favor of a single entity. Surgery is the treatment of choice for localized KPGCT. Therapeutic options for advanced or metastatic disease are unknown. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology, and treatment of KPGCT. In addition, we will discuss the differential diagnosis of this emerging entity.

Giant cell tumor of soft tissue (GCTST) is a locally aggressive mesenchymal neoplasm of intermediate malignancy that predominantly occurs in the superficial soft tissue of the extremities. It is histologically similar to a giant cell tumor of bone (GCTB) and shows a mixture of round to oval mononuclear cells and osteoclast-like multinucleated giant cells. Currently, immunohistochemistry plays a very limited role in the diagnosis of GCTST. Primary or secondary malignant GCTST has recently been described and tumors exhibiting high-grade histological features demonstrate higher rates of distant metastasis. GCTST lacks the H3-3A gene mutations that are identified in the vast majority of GCTBs, suggesting a different pathogenesis. Surgery is the standard treatment for localized GCTST. Incomplete surgical resection is usually followed by local recurrence. Radiation therapy may be considered when the close proximity of critical structures prevents microscopically negative surgical margins. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment for GCTST. In addition, we will discuss the differential diagnosis of this peculiar neoplasm.

Myxoinflammatory fibroblastic sarcoma (MIFS) is an infiltrative, locally aggressive fibroblastic neoplasm of intermediate malignancy that typically arises in the distal extremities of middle-aged adults. It can histologically be confused with a number of benign and malignant conditions. Recently, high-grade examples of MIFS have been described. Immunohistochemistry plays a very limited role in the diagnosis of MIFS. Several genetic alterations have been identified in MIFS, including a t(1;10)(p22;q24) translocation with TGFBR3 and/or OGA rearrangements, BRAF rearrangement, and VGLL3 amplification. Although it appears that VGLL3 amplification is the most consistent alteration, the molecular pathogenesis of MIFS remains poorly understood. A wide resection is considered the standard treatment for MIFS. Radiotherapy may be a viable option in cases with inadequate surgical margins or cases where surgery is likely to cause significant functional impairment. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment of MIFS.

Myxofibrosarcoma (MFS) is one of the most common adult soft tissue sarcomas, typically arising in the extremities. Histologically, MFS is classified into three grades: low, intermediate, and high. Histological grades correlate with distant metastases and tumor-associated mortality. The diagnosis of MFS is challenging due to a lack of well-characterized immunohistochemical markers. High-grade MFS displays highly complex karyotypes with multiple copy number alterations. Recent integrated genomic studies have shown the predominance of somatic copy number aberrations. However, the molecular pathogenesis of high-grade MFS remains poorly understood. The standard treatment for localized MFS is surgical resection. The systemic treatment options for advanced disease are limited. This review provides an updated overview of the clinical and imaging features, pathogenesis, histopathology, and treatment of high-grade MFS.

Myxofibrosarcoma (MFS) is a fibroblastic/ myofibroblastic neoplasm with a variably myxoid stroma. Histologically, MFS shows a wide spectrum of cellularity, pleomorphism and proliferative activity. Because of its variable morphology and lack of discriminatory markers, MFS can be difficult to distinguish from some benign soft-tissue tumors, especially nodular fasciitis (NF). Glucose transporter 1 (GLUT-1) is expressed in a variety of malignant mesenchymal tumors. In the current study, we evaluated GLUT-1 expression to determine its value in distinguishing MFS from NF. Tissue specimens from 14 MFS cases and 16 NF cases were sectioned and stained for GLUT-1 using immunohistochemistry. The percentage of GLUT-1-positive cells was scored as follows: 0 (no staining), 1+ (1-19%), 2+ (20-50%) and 3+ (>50%). Samples with a score of 1+ were defined as GLUT1-expressing samples. GLUT-1 expression was seen in all 14 MFS cases, whereas only 6 NF cases (37.5%) were positive for GLUT-1 and were scored 1+. Notably, 2-3+ GLUT-1 expression was found in 86% of MFS cases and 0% of NF cases. Our results indicate that GLUT-1 is a highly sensitive immunohistochemical marker for MFS and may be useful for the differential diagnosis of MFS and NF.

Although there is no evidence from prospective randomized controlled trials to support this practice, pulmonary metastases of sarcomas are often treated surgically if they are resectable. The purpose of this retrospective study was to evaluate the prognostic factors and outcome of pulmonary metastasectomy (PM) for soft tissue sarcomas (STSs) arising in the trunk wall and extremities in 66 consecutive patients. Prognostic factors associated with disease-specific survival after PM were evaluated using univariate and multivariate analyses. The patients included 38 men and 28 women, with a median age of 49 years. The median disease-specific survival after PM was 48 months, and the 5-year survival rate was 45%. No major perioperative complications occurred. Disease-free interval (<12 months), size of largest lung lesion (≥20 mm), and non-curative resection were independent prognostic factors in multivariate analysis. PM was effective in selected patients with pulmonary metastases from STSs arising in the trunk wall and extremities. Disease-free interval, maximum size of metastases, and resectability were identified as prognostic factors.

Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murinedouble minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.