Recent Advances in the Diagnosis, Pathogenesis, and Management of Myxoinflammatory Fibroblastic Sarcoma.

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.

Biology and Management of High-Grade Myxofibrosarcoma: State of the Art and Future Perspectives.

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.

Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities.

Adipocytic neoplasms are frequently encountered in clinical practice. Atypical lipomatous tumor (ALT) is a locally aggressive but non-metastasizing adipocytic neoplasm that primarily occurs in the proximal extremities of middle-aged to older adults. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing and inflammatory subtypes. The sclerosing subtype is an unfavorable prognostic factor for local recurrence. ALT is characterized by supernumerary ring and/or giant rod chromosomes. These rings and giant markers invariably contain amplified sequences originating from the long arm of chromosome 12, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. Confidently differentiating deep-seated ALT from deep-seated ordinary lipoma is often difficult on imaging. Moreover, the sclerosing subtype may mimic a higher grade liposarcoma. Detection of MDM2 amplification by fluorescence in situ hybridization would be helpful diagnostically for ALT in more difficult cases. The standard treatment for deep-seated ALT is surgery. Although there is no consensus on the best surgical approach for deep-seated ALT of the extremities, the use of marginal resection is acceptable to preserve musculoskeletal function. This review provides an overview of the current knowledge on the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.

Spindle Cell Lipoma and Pleomorphic Lipoma: An Update and Review.

Spindle cell lipoma (SCL) is a benign adipocytic tumor that primarily occurs in the subcutis of the posterior neck, upper back, and shoulder, particularly of middle-aged males. SCL and pleomorphic lipoma (PL) represent a morphological spectrum of one disease process. The lesion typically presents as a relatively small (<5 cm), mobile, slow-growing, painless mass. Magnetic resonance imaging reveals the lesion to be a well-defined subcutaneous mass with a mixture of adipose and non-adipose components. Intense enhancement of the non-adipose component is seen after contrast administration. Histologically, SCL is composed of variable distributions of mature adipocytes, bland spindle cells and ropey collagen bundles and PL also contains pleomorphic and multinucleated floret-like giant cells. By immunohistochemistry, the spindle and pleomorphic/floret-like giant cells of SCL/PL are diffusely positive for CD34 and show loss of nuclear RB transcriptional corepressor 1 (RB1) expression. Recent cytogenetic and molecular genetic studies have shown heterozygous deletions of 13q14, including the RB1 gene. SCL/PL can be successfully treated with simple excision, with a very low recurrence rate. Knowledge of these peculiar tumors is important because it can mimic a variety of benign and malignant soft-tissue tumors. This review provides an updated overview of the clinical, radiological, histopathological, cytogenetic, and molecular genetic features of SCL/PL.

An Update on Clinicopathological, Imaging, and Genetic Features of Angioleiomyoma.

Angioleiomyoma is a benign, pericytic (perivascular) neoplasm that primarily occurs in the subcutis or dermis of the extremities. The lesion typically presents as a small, firm, slow-growing, painful nodule. Magnetic resonance imaging reveals the lesion to be a well-defined, round to oval mass with signal intensity similar to or slightly hyperintense to that of skeletal muscle on T1-weightwed sequences. A dark reticular sign on T2-weighted sequences appears to be a characteristic feature of angioleiomyoma. Prominent enhancement is usually seen after intravenous contrast. Histologically, the lesion consists of well-differentiated smooth muscle cells with many vascular channels. Based on vascular morphologies, angioleiomyoma is classified into three subtypes: solid, venous, and cavernous. By immunohistochemistry, angioleiomyoma is diffusely positive for smooth muscle actin and calponin and variably for h-caldesmon and desmin. Conventional cytogenetic studies have demonstrated relatively simple karyotypes characterized by one or few structural rearrangements or numerical aberrations. In addition, metaphase comparative genomic hybridization analyses have revealed recurrent loss of 22q and gain of Xq. Angioleiomyoma can be successfully treated with simple excision, with a very low recurrence rate. Knowledge of this peculiar neoplasm is important because it can mimic a variety of benign and malignant soft-tissue tumors. This review provides an updated overview of the clinical, radiological, histopathological, cytogenetic, and molecular genetic features of angioleiomyoma.

The reproducibility of MTV and TLG of soft tissue tumors calculated by FDG-PET: Comparison between the lower limit by the fixed value SUV 2.5 and that value by 30% of SUVmax.

PURPOSE: We evaluated the reproducibility calculating volume-based FDG-PET/CT parameters, i.e., metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in soft tissue tumors. MATERIALS AND METHODS: Fifty-three cases with soft tissue tumors were analyzed retrospectively. The conditions determining the lower limit of MTV were fixed value SUV 2.5 or 30% of SUVmax. To investigate the agreement of the measurements by two radiologists, %difference, the correlation coefficients and Bland-Altman plot were analyzed. We compared these parameters in both intra- and inter-operator for evaluating the agreement in the measurements. RESULTS: The values of % difference were excellent, 0.2-3.5%, in the intra-operator in all calculated volume-based parameters. In both inter- and intra-operator analysis, the values of % differences were lower in the parameters calculated by SUV 2.5 fixed value as a lower threshold compared with those calculated by 30% of SUVmax as a lower threshold. The correlation coefficient in MTV30% for inter-operator were 0.84 or 0.87, those were lower than values by the intra-operator evaluation. Nevertheless, the correlation coefficients were higher than 0.84 in every parameter. Particularly, correlation coefficient in the parameters calculated by SUV 2.5 fixed value was better than those calculated by 30% of SUVmax. The Bland-Altman plot analysis showed good agreement for all parameters, particularly in the intra-operator examinations. However, in the inter-operator study, some variances were noted in every condition. CONCLUSION: In conclusion, the reproducibility of measuring volume-based FDG-PET/CT parameters of soft tissue tumors was good, particularly, in the measurement by fixed lower limit value SUV 2.5 in the intra-operator.

GLUT-1 expression is helpful to distinguish myxofibrosarcoma from nodular fasciitis.

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.

Arthroscopic Excision of Intra-articular AHRR-NCOA2- positive Angiofibroma of Soft Tissue of the Knee: A Case Report.

BACKGROUND/AIM: Angiofibroma of soft tissue (AFST) is a rare benign soft-tissue tumor that most frequently occurs in the lower extremities. It has a characteristic genetic feature with a balanced chromosomal translocation t(5;8)(p15;q13), resulting in a fusion of aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2). CASE REPORT: A 55-year-old woman presented with a 2-year history of left knee pain and recently noticed the development of a palpable mass. Magnetic resonance imaging exhibited a well-defined intra-articular mass with iso-signal intensity relative to skeletal muscle on T1-weighted sequences, heterogeneous high signal intensity on T2-weighted sequences and avid, diffuse enhancement on contrast-enhanced fat-suppressed T1-weighted sequences. After an ultrasound-guided core needle biopsy, the lesion was successfully treated by arthroscopically-assisted complete excision. Histologically, the tumor was composed of uniform bland spindle cells in a myxoid to collagenous stroma with a prominent vascular network. Immunohistochemically, the spindle cells were diffusely positive for CD163 and CD68 and focally positive for estrogen receptor. Moreover, AHRR-NCOA2 fusion gene was detected by reverse transcription-polymerase chain reaction. There has been no clinical evidence of local recurrence at 1-year follow-up. CONCLUSION: This is the first report of the detection of an AHRR-NCOA2 gene fusion associated with intra-articular AFST. AFST should be included in the extended differential diagnosis of an intra-articular soft-tissue mass, particularly if the mass is vascular.

t(1;2)-Positive Localized Tenosynovial Giant Cell Tumor With Bone Invasion.

BACKGROUND: Localized tenosynovial giant cell tumor (LTGCT) is one of the most common benign soft-tissue tumors of the foot. Although pressure erosion in the adjacent bone may be seen, intraosseous invasion of LTGCT is extremely rare. Recent molecular studies have identified the presence of pathognomonic translocation involving the colony stimulating factor 1 (CSF1) gene at 1p13. CASE REPORT: We present an unusual case of LTGCT mimicking a malignant tumor on imaging. The patient was a 16-year-old woman with no history of trauma who presented with a 2-year history of a slow-growing, painless mass in the left fourth toe. Physical examination revealed a 2-cm, elastic hard, immobile, nontender mass. Plain radiograph showed a lytic lesion with a partially sclerotic rim in the proximal phalanx of the fourth toe. Computed tomography demonstrated an expansile lesion with plantar cortical destruction. Magnetic resonance imaging revealed a nodular mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. The mass had intense contrast enhancement. Complete excision of the mass was performed, and the bone defect was repaired with calcium phosphate cement. Cytogenetic analysis revealed a t(1;2)(p13;q37) translocation as the sole anomaly. Fluorescence in situ hybridization demonstrated the presence of CSF1 rearrangements. CONCLUSION: Although extremely rare, LTGCT should be considered in the differential diagnosis of an intraosseous lesion near small joints, especially when seen in the toe.

Prognostic Factors of Pulmonary Metastasectomy for Soft Tissue Sarcomas Arising in the Trunk Wall and Extremities.

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.

Angiofibroma of soft tissue: Current status of pathology and genetics.

Angiofibroma of soft tissue (AFST) is a new soft tissue tumor entity described in the 2020 World Health Organization Classification of Soft Tissue and Bone Tumors. It most often arises in the lower extremities of middle-aged adults and pursues a benign clinical course with a low rate of non-destructive local recurrence. Histologically, the lesion consists of uniform bland spindle cells in a fibromyxoid stroma with a prominent vascular network. The vascular component forms a complex arrangement of small, thin-walled branching blood vessels. By immunohistochemistry, AFST is variably positive for epithelial membrane antigen, desmin, smooth muscle actin, CD34, CD68, CD163 and estrogen receptor. The exact etiology of AFST remains unknown, but it appears genetically distinct, with a balanced t(5;8)(p15;q13) translocation resulting in a fusion of aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2). Knowledge of this recently described entity is important because it can mimic a variety of intermediate and malignant soft tissue tumors, including solitary fibrous tumor, low-grade fibromyxoid sarcoma, myxoid liposarcoma and low-grade myxofibrosarcoma. We review AFST, with an emphasis on the diagnostic spectrum, recent molecular genetic features and the differential diagnosis.

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives.

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.

Current Update on the Diagnosis, Management and Pathogenesis of Elastofibroma Dorsi.

Elastofibroma dorsi is an uncommon benign fibroblastic pseudotumor that typically occurs in the subscapular region of middle-aged or older individuals. The pathogenesis is still unclear and a matter of debate. Magnetic resonance imaging can be used as a first-line investigation of the lesion and reveals a lenticular soft-tissue mass with a signal intensity similar to that of skeletal muscle interlaced with strands of fat. Biopsy is not necessary if all pathognomonic criteria are present. A conservative "wait and see" attitude is reasonable and immediate surgery is no more the standard treatment of elastofibroma dorsi. This review provides an updated overview of the diagnosis, management and pathogenesis of elastofibroma dorsi. We also discuss recent advances in our understanding of genomic alterations in elastofibroma dorsi.

Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts.

Ubiquitin-specific peptidase 6 (USP6) is a hominoid-specific gene residing on chromosome 17p13 and serves as a deubiquitinating enzyme with a diverse set of functions including intracellular trafficking, inflammatory signaling, cell transformation and protein turnover. USP6 rearrangements were first identified in aneurysmal bone cysts, resulting in promoter swapping and over-expression of wild type USP6. Several morphologically overlapping fibroblastic/myofibroblastic tumors are known to harbor USP6 rearrangements, including nodular fasciitis, cellular fibroma of tendon sheath, myositis ossificans and fibro-osseous pseudotumor of digits. Over the past few years, fusions involving the USP6 gene and various partner genes have been described in these neoplasms. The current World Health Organization Classification of Tumors of Soft Tissue suggests that USP6-rearranged lesions are typically benign and usually self-limited in their growth. This review provides an updated overview of the clinical, histological and molecular genetic features of USP6-associated fibroblastic/myofibroblastic tumors and discusses how these lesions should be best classified.

An Update on Clinicopathological, Imaging and Genetic Features of Desmoplastic Fibroblastoma (Collagenous Fibroma).

Desmoplastic fibroblastoma (also known as collagenous fibroma) is an uncommon benign fibroblastic/myofibroblastic neoplasm that primarily arises in the subcutaneous tissue of upper extremity. Magnetic resonance imaging reveals a well-defined mass in intimate association with dense connective tissue and prominent low signal intensity on all pulse sequences. Peripheral and septal enhancement is usually seen after intravenous contrast. Histologically, the lesion is paucicellular and consists of spindle to stellate-shaped cells embedded in a collagenous or myxocollagenous stroma with low vascularity. Diffuse and strong nuclear immunoreactivity for FOS-like antigen 1 seems to be characteristic of desmoplastic fibroblastoma. Cytogenetic studies have demonstrated the presence of 11q12 rearrangements and an identical t(2;11)(q31;q12) translocation. This review provides an updated overview of the clinical, radiological, histological, cytogenetic and molecular genetic features of desmoplastic fibroblastoma and discusses the relationship to fibroma of tendon sheath.

Giant Cell Tumor of Tendon Sheath With a t(1;1)(p13;p34) Chromosomal Translocation.

BACKGROUND: Giant cell tumor of tendon sheath (GCTTS) is a benign soft-tissue tumor that occurs predominantly in the fingers, with the capacity for local recurrence. The cytogenetic hallmark of GCTTS is the presence of 1p13 rearrangement. Several chromosomal segments have been recognized as translocation partners to 1p13. Herein, we describe a novel cytogenetic finding of GCTTS arising in the right thumb of a 71-year-old man. CASE REPORT: Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Magnetic resonance imaging demonstrated a nodular mass with reduced signal intensity on both T1- and T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images showed intense heterogeneous enhancement of the mass. After a needle biopsy, complete excision was performed. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy cells, and inflammatory cells. Cytogenetic analysis revealed a reciprocal t(1;1)(p13;p34) translocation as the sole structural aberration. CONCLUSION: To the best of our knowledge, this is the first report of this tumor with t(1;1)(p13;p34).