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Although most cases of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) can be diagnosed solely on the basis of histologic features, those lacking diagnostic histologic features require ancillary studies for accurate classification. Fluorescent in situ hybridization (FISH) for amplification of MDM2 has been considered the gold standard for diagnosis in these situations. Immunostaining for MDM2 and/or CDK4 has been adopted as a surrogate method because of its high concordance rate with FISH and lower cost. However, studies examining the concordance of the 2 methods have been based preferentially on cases in which the diagnosis could be established histologically. No study has explored the concordance between the 2 methods in histologically ambiguous cases or in cases in which the diagnosis of ALT/WDL is not apparent after a review of all slides. To address this, we performed immunostaining for MDM2 and CDK4 on 183 well-differentiated lipomatous tumors that could not be diagnosed on purely histologic grounds and that were, therefore, subjected to FISH analysis. These included ALT/WDLs (n=56), lipomas (n=96), and lipoma variants (n=31). Staining for MDM2 and CDK4 was noted in 25/56 and 23/56 ALT/WDL, respectively, giving a sensitivity of 45% and 41% and a specificity of 98% and 92%. Staining was noted exclusively in the nuclei of atypical cells and not in the nuclei of adipocytes. Staining for MDM2 and CDK4 occurred in 2/125 and 10/117 benign lipomatous lesions, respectively. False-positive staining was equivalent in intensity to ALT/WDL. We conclude that MDM2 and CDK4 staining is a relatively insensitive method for diagnosing ALT/WDL in cases that are histologically ambiguous, as staining is restricted to neoplastic cells with atypia that are underrepresented in these cases. Therefore, in cases like ours that closely simulate clinical practice, FISH is the more reliable and cost-effective option.

Context: -High-molecular weight cytokeratins, such as cytokeratin 5 (CK5), are helpful to distinguish usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH) or low-grade ductal carcinoma in situ (DCIS). Few studies have looked at combining CK5 with estrogen receptor (ER) to differentiate UDH from ADH., Objective: -To evaluate the expression pattern of CK5 and ER as single or combined markers to separate UDH from ADH and low-grade DCIS., Design: -A total of 23 ADH, 10 low-grade DCIS, and 32 UDH whole-tissue slides were stained for ER, CK5, progesterone receptor (PR), and Bcl-2. Nuclear staining of ER and PR was scored as diffuse (>80%), focal (10%-80%), or negative (<10%). Cytoplasmic staining of CK5 and Bcl-2 was scored as diffuse (>60%), focal (10%-60%), or negative (<10%). Differences in staining patterns were evaluated., Results: -For ER staining: 94% of ADH/DCIS cases showed a diffuse staining pattern, whereas none of the 32 UDH cases showed diffuse staining. For CK5 staining: 96% of ADH/DCIS cases were negative or focally positive, whereas all 32 UDH cases had diffuse staining. The combination of ER and CK5 increased the sensitivity (94% to 97%). For PR staining: 11 of 23 ADH cases (48%), 6 of 10 DCIS cases (60%), and 4 of 32 UDH cases (13%) showed diffuse staining. Bcl-2 staining showed no statistical significance (P = .73)., Conclusions: -Although morphology remains the gold standard, ER and CK5 are useful makers to differentiate UDH from ADH. Progesterone receptor staining may have limited value, and Bcl-2 staining is not useful.

To discriminate lipomas from atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) we perform fluorescence in situ hybridization (FISH) for MDM2 amplification in several problematic situations: "lipomas" >10 cm, lesions with equivocal atypia, recurrent "lipomas," all retroperitoneal/pelvic/abdominal "lipomas", and in cases not fitting the above criteria but having worrisome clinical or radiologic features. To ascertain the validity of these criteria, we have reviewed our experience with 301 consecutive differentiated lipomatous tumors in which the diagnosis of ALT could not be established on the basis of histologic sections and in which FISH was performed on the basis of the above criteria. The final diagnosis was based on MDM2 amplification status. Given the nature of this study to evaluate difficult lesions, most cases included (74%) were received in consultation. This enhanced our study series for borderline cases, and the data presented may not be generalizable to adipocytic tumors seen outside a subspecialty setting. Of 301 cases, 108 proved to be ALT/WDL (36%). The most common test indication was size >10 cm (n=187), followed by equivocal atypia (n=145), retroperitoneal/pelvic/abdominal location (n=86), recurrence (n=33), and clinical concern (n=12). Of the tumors >10 cm, 68 (36%) proved to be ALT/WDL, whereas the remainder were interpreted as lipoma or its variants (eg, spindle cell or pleomorphic lipoma). The 2 groups did not differ statistically in size, although ALTs consistently occurred in patients above 50 years of age. Of the cases with equivocal atypia, 72 (50%) proved to be ALT/WDL. Those in the retroperitoneum/abdomen/pelvis were ALT/WDL in 30 cases (35%), and those that had recurred were ALT in 18 cases (55%). Recurrence, atypia, and having multiple indications for testing were more common in ALT than in benign lesions (P=0.02, 0.0001, 0.0012, respectively). No ALT/WDL occurred in the hands and feet, and only a single ALT/WDL was superficial (1 ALT/WDL vs. 60 lipoma/spindle cell or pleomorphic lipoma). Small (<10 cm) retroperitoneal tumors without additional features were always benign (n=9). On the basis of our results, FISH testing is recommended for: (1) recurrent lesions; (2) deep extremity lesions that are >10 cm in patients over 50 years of age; (3) in cases with equivocal atypia; (4) in lesions of the retroperitoneum/pelvis/abdomen, and in special clinical situations as directed by treating clinicians. Testing is low yield in superficial lesions, in small extremity lesions without additional indicators for testing, in large extremity lesions without additional features in patients under the age of 50, and in lesions arising in the hands/feet. More evidence is needed regarding testing in small retroperitoneal lesions without additional features. By adopting these criteria, we could have avoided testing 74 cases, missing a single superficial ALT/WDL.