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Background: The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4 within the 12q13-15 chromosomal region. FRS2 gene was recently found to be consistently amplified in atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL), suggesting the detection of FRS2 amplification could be a diagnostic tool for ALT/WDL/DDLs. However, the expression of FRS2 protein and diagnostic value of FRS2 immunohistochemistry (IHC) has not been evaluated in a large cohort of ALT/WDL/DDLs., Methods: A SNOMED search of hospital surgical pathology files from January 2007 to July 2020 identified 182 ALT/WDL/DDLs with available materials. FRS2 fluorescence in situ hybridization (FISH) and IHC were performed on 182 ALT/WDL/DDLs and 64 control samples. The expression of FRS2 was also compared with that of classic immunomarkers (MDM2 and CDK4) of this tumor entity., Results: This study included 91 ALT/WDLs and 91 DDLs. The FISH results showed 172 of 182 (94.5%) cases were FRS2-amplified, and 10 cases were FRS2-nonamplified. Immunostaining results showed 171 (94.0%) ALT/WDL/DDLs were positive for FRS2 and 11 cases (6.0%) were FRS2-immunonegative. In 172 FRS2-amplified cases, 166 (96.5%) were FRS2-immunopositive, and 6 (3.5%) were negative. Among 10 FRS2-nonamplified ALT/WDL/DDL cases, 5 cases were FRS2-immunonegative, and 5 tumors displayed 1+ staining for this marker. In 64 control cases, none of them exhibited FRS2 amplification. Forty-seven (73.5%) control cases were negative for FRS2 immunostaining, while 17 cases (26.5%) were FRS2-immunopositive. Fifteen of these false positive samples (15/17, 88.2%) showed 1+ positivity and only 2 cases (2/17, 11.8%) displayed 2+ positivity. In ALT/WDL/DDLs, the sensitivity of FRS2 immunostaining was slightly lower than MDM2 (FRS2 vs. MDM2: 94.0% vs 100.0%) and CDK4 (FRS2 vs. CDK4: 94.0% vs 97.0%). However, the specificity of FRS2 (73.5%) was slightly higher than that of MDM2 (67.8%) and CDK4 (64.4%)., Conclusion: This study indicated that FRS2 IHC had relatively good consistency with FRS2 FISH, suggesting that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT/WDL/DDL. It must be emphasized that MDM2/CDK4/FRS2 especially MDM2 FISH remains the gold standard and the most recommended method to diagnose this entity., (© 2021. The Author(s).)

The incidence of pediatric liposarcoma is rare and most published cases lack systematic genetic analyses. We present clinicopathologic and genetic features of 23 liposarcomas aged <22 years. The study cohort comprised 10 males and 13 females (M:F=1:1.3) aged 11-21 years (median 17 years). The tumors predominantly occurred at the extremities (16/23; 69.6%), followed by the head/neck (2/23; 8.7%), chest (2/23; 8.7%), waist (2/23, 8.7%), and retroperitoneum (1/23; 4.3%). The tumor subtypes were sixteen myxoid liposarcoma (ML), one well-differentiated liposarcoma (WDL), two dedifferentiated liposarcoma (DDL), one pleomorphic liposarcoma (PL), and three myxoid pleomorphic liposarcoma (MPL) cases. Fluorescence in situ hybridization analysis identified MDM2/CDK4 amplification in all WDL/DDL cases (3/3; 100%) and DDIT3 rearrangement in all ML cases (13/13; 100%). Whole-exome sequencing indicated that one PL case and one MPL case exhibited RB1 loss. The two tested MPL cases had TP53 mutation and one of them harbored a TP53 germline mutation. Follow-up information was available for 20 patients (20/23; 87.0%) with a median follow-up duration of 42.5 months (range, 13-120 months). Three patients exhibited tumor progression (3/20;15.0%). Seventeen patients (17/20; 85.0%) survived with no evidence of disease. One MPL case (1/20; 5.0%) died of the disease. In conclusion, despite some overlaps, the occurrence, distribution of subtype, and prognosis of liposarcoma are overall different in children and adults. Most MLs and ALT/WDL/DDLs showed similar genetic aberrations with adult counterparts. Molecular features of MPL overlapped with those of conventional PL. The genetic characteristics including Tp53 status of MPL need further investigation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The aim of this study was to evaluate the frequency of FRS2 amplification and its relationship with the clinicopathological features of atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL)/de-differentiated liposarcoma (DDL)., Methods and Results: FRS2 and MDM2 fluorescence in-situ hybridisation (FISH) was performed on 146 tumours (70 ALT/WDLs and 76 DDLs). One hundred and eight control samples were included for FRS2 analysis. FRS2 amplification was detected in 136 of 146 (93.2%) ALT/WDL/DDLs, including 63 ALT/WDLs and 73 DDLs. A higher FRS2/CEP12 ratio was observed in DDLs than in ALT/WDLs (P = 0.0005). The FRS2/CEP12 ratio of peripheral tumours was lower than that of central tumours (P = 0.00004). All the ALT/WDL/DDLs showed MDM2 amplification (100%). The MDM2 + /FRS2 - series included seven ALT/WDLs and three DDLs. Four of seven (57.1%) MDM2 + /FRS2 - ALT/WDLs occurred in peripheral sites, slightly higher than the percentage of MDM2 + /FRS2 + ALT/WDLs (28 of 63, 44.4%). All the three MDM2 + /FRS2 - DDLs (100%) were peripheral tumours, a much higher proportion than that of MDM2 + /FRS2 + DDLs (10 of 73, 13.7%). A high percentage of homologous pleomorphic liposarcoma-like DDLs (two of three) were observed in the MDM2 + /FRS2 - group. In the control group all the parosteal osteosarcomas (five of five, 100%) were FRS2 amplified, whereas the remaining 103 samples were FRS2 non-amplified., Conclusions: These findings suggest that FRS2 is amplified consistently in ALT/WDL/DDLs and offer another avenue for the investigation of the biology of this tumour group. MDM2 + /FRS2 - cases seem to be associated with certain clinicopathological features, and further investigation is needed., (© 2018 John Wiley & Sons Ltd.)

Atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL)/dedifferentiated liposarcoma (DDL) is a common type of liposarcoma in late adulthood. However, pediatric ALT/WDL/DDL is extremely rare, and only 3 cases have been described in children younger than 10 years of age. Notably, none of these cases harbored MDM2 gene amplification. Here, we reported a sclerosing ALT/WDL in a 7-year-old Chinese girl. Histologically, in most areas, the neoplastic cells were embedded within the collagenous background, and typical lipogenic areas were inconspicuous throughout the sclerotic areas. In addition, scattered small foci of atypical osseous/chondrous elements were identified. Notably, a small typical lipoma-like ALT/WDL area was detected in the periphery of the mass. Immunohistochemically, all the neoplastic components demonstrated positivity for MDM2, CDK4, and p16. Fluorescence in situ hybridization revealed MDM2 gene amplification in all the tumor components. To the best of our knowledge, this is the first example of MDM2-amplified ALT/WDL in this age group., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Liposarcoma originating in the heart is extraordinarily rare. Herein, we report a dedifferentiated liposarcoma arising from the left atrium in a 59-year-old Chinese man. Histologically, the neoplasm predominantly consisted of undifferentiated pleomorphic sarcoma. In addition, the neoplasm exhibited lipoblastic differentiation and osteo-/chondrosarcomatous components. Immunohistochemically, the neoplastic cells were strongly positive for p16, MDM2, and CDK4. Fluorescence in situ hybridization showed MDM2 gene amplification in all of the tumor components. To the best of our knowledge, this is the first published example of cardiac dedifferentiated liposarcoma exhibiting homologous and heterologous differentiation without a well-differentiated liposarcoma component.

The incidence of pediatric liposarcoma is rare and most published cases lack systematic genetic analyses. We present clinicopathologic and genetic features of 23 liposarcomas aged <22 years. The study cohort comprised 10 males and 13 females (M:F=1:1.3) aged 11–21 years (median 17 years). The tumors predominantly occurred at the extremities (16/23; 69.6%), followed by the head/neck (2/23; 8.7%), chest (2/23; 8.7%), waist (2/23, 8.7%), and retroperitoneum (1/23; 4.3%). The tumor subtypes were sixteen myxoid liposarcoma (ML), one well-differentiated liposarcoma (WDL), two dedifferentiated liposarcoma (DDL), one pleomorphic liposarcoma (PL), and three myxoid pleomorphic liposarcoma (MPL) cases. Fluorescence in situ hybridization analysis identified MDM2/CDK4 amplification in all WDL/DDL cases (3/3; 100%) and DDIT3 rearrangement in all ML cases (13/13; 100%). Whole-exome sequencing indicated that one PL case and one MPL case exhibited RB1 loss. The two tested MPL cases had TP53 mutation and one of them harbored a TP53 germline mutation. Follow-up information was available for 20 patients (20/23; 87.0%) with a median follow-up duration of 42.5 months (range, 13–120 months). Three patients exhibited tumor progression (3/20;15.0%). Seventeen patients (17/20; 85.0%) survived with no evidence of disease. One MPL case (1/20; 5.0%) died of the disease. In conclusion, despite some overlaps, the occurrence, distribution of subtype, and prognosis of liposarcoma are overall different in children and adults. Most MLs and ALT/WDL/DDLs showed similar genetic aberrations with adult counterparts. Molecular features of MPL overlapped with those of conventional PL. The genetic characteristics including Tp53 status of MPL need further investigation. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate the frequency of FRS2 amplification and its relationship with the clinicopathological features of atypical lipomatous tumour (ALT)/well‐differentiated liposarcoma (WDL)/de‐differentiated liposarcoma (DDL). Methods and results: FRS2 and MDM2 fluorescence in‐situ hybridisation (FISH) was performed on 146 tumours (70 ALT/WDLs and 76 DDLs). One hundred and eight control samples were included for FRS2 analysis. FRS2 amplification was detected in 136 of 146 (93.2%) ALT/WDL/DDLs, including 63 ALT/WDLs and 73 DDLs. A higher FRS2/CEP12 ratio was observed in DDLs than in ALT/WDLs (P = 0.0005). The FRS2/CEP12 ratio of peripheral tumours was lower than that of central tumours (P = 0.00004). All the ALT/WDL/DDLs showed MDM2 amplification (100%). The MDM2+/FRS2− series included seven ALT/WDLs and three DDLs. Four of seven (57.1%) MDM2+/FRS2− ALT/WDLs occurred in peripheral sites, slightly higher than the percentage of MDM2+/FRS2+ ALT/WDLs (28 of 63, 44.4%). All the three MDM2+/FRS2− DDLs (100%) were peripheral tumours, a much higher proportion than that of MDM2+/FRS2+ DDLs (10 of 73, 13.7%). A high percentage of homologous pleomorphic liposarcoma‐like DDLs (two of three) were observed in the MDM2+/FRS2− group. In the control group all the parosteal osteosarcomas (five of five, 100%) were FRS2 amplified, whereas the remaining 103 samples were FRS2 non‐amplified. Conclusions: These findings suggest that FRS2 is amplified consistently in ALT/WDL/DDLs and offer another avenue for the investigation of the biology of this tumour group. MDM2+/FRS2− cases seem to be associated with certain clinicopathological features, and further investigation is needed. [ABSTRACT FROM AUTHOR]