Differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 immunohistochemistry

Abstract

The differential diagnosis between atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) and dedifferentiated liposarcoma (DDLPS) from their morphologic counterparts is challenging. Currently, the diagnosis is guided by MDM2 and CDK4 immunohistochemistry (IHC) and is confirmed by the amplification of the corresponding genes. Recently, p16 IHC has been proposed as a useful diagnostic biomarker. The objective was to assess the utility of p16 IHC in the differential diagnosis of ALT/WDLPS and DDLPS. Our series included 101 tumors that were previously analyzed using fluorescence in situ hybridization for MDM2 and CDK4 amplification. We compared sensitivity and specificity of p16 IHC to MDM2 and CDK4 IHC in the differential diagnosis of ALT-WDLPS (n=19) versus benign adipocytic tumors (n=44) and DDLPS (n=18) versus mimicking sarcomas (n=20). In the differential diagnosis of ALT-WDLPS, p16 had a sensitivity of 89.5% but a specificity of 68.2%, which was impaired by false-positive lipomas with secondary changes, especially in biopsies. Likewise, in the differential diagnosis of DDLPS, p16 had a sensitivity of 94.4% and a specificity of 70%, which hampered its use as a single marker. However, adding p16 to MDM2 and/or CDK4 increased diagnostic specificity. Indeed, MDM2+/p16+ tumors were all ALT-WDLPS, and MDM2-/p16- tumors were all benign adipocytic tumors. Moreover, all MDM2+/CDK4+/p16+ tumors were DDLPS, and the MDM2-/CDK4-/p16- tumor was an undifferentiated sarcoma. Although the use of p16 as a single immunohistochemical marker is limited by its specificity, its combination with MDM2 and CDK4 IHC may help discriminate ALT-WDLPS/DDLPS.

The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing

“…The use of immunohistochemistry (IHC) for MDM2 and CDK4 has been proposed as a more cost-effective solution for determining the diagnosis and is widely available, while FISH is typically only used at tertiary referral centers. However, for borderline cases, MDM2 FISH has been shown to be required for accurate pathologic diagnosis given the potential for sampling error on biopsy and subjective interpretation of MDM2 immunohistochemistry [ 8 , 15 ]. Meanwhile, MDM2 FISH has been shown to have 100% sensitivity and specificity even on core needle biopsy [ 16 ].…”

High p16 Expression Is Associated with Malignancy and Shorter Disease-Free Survival Time in Solitary Fibrous Tumor/Hemangiopericytoma

“…2 As a potential downstream protein of EGR1, 6 p16, has been reported to be associated with malignancy and worse prognosis in multiple mesenchymal tumors. [7][8][9] We found that high p16 expression (defined as positivity ! 50% tumor cells) is significantly associated with malignancy (p ¼ 0.015) and shorter disease-free survival time (p ¼ 0.045) among all tumors (►Fig.…”

Paravertebral Well-Differentiated Liposarcoma with Low-Grade Osteosarcomatous Component: Case Report with 11-Year Follow-Up, Radiological, Pathological, and Genetic Data, and Literature Review

“…To help assess its tumoral nature, ancillary techniques such as MDM2/CDK4, HMGA2, or P16 immunohistochemistry can be helpful since all of these markers are frequently overexpressed in ALT/WDL/DL [14–16]. More recently, it has been reported that diffuse and intense P16 staining is highly sensitive for ALT/WDL/DL, although P16 lacks specificity and needs to be combined with MDM2/CDK4 for an accurate diagnosis [17, 18]. FISH can also be performed to confirm the presence of MDM2 amplification, especially on surgical margin in doubtful cases.…”