In this study, the aim was to elucidate the accuracy of the morphological diagnosis of lipoma and ALT/WDLPS. To this end, 109 patients who had been diagnosed with a lipomatous tumor before immunostaining became available for differentiating between lipoma and ALT/WDLPS were first identified retrospectively. Using tumor tissue specimens collected from these patients, immunostaining for MDM2 and CDK4, as well as FISH for their corresponding genes, was then performed. The results indicated that morphological diagnosis had low sensitivity and high specificity. In addition, the sensitivity of immunostaining was not particularly high, and its specificity was lower than that of morphological diagnosis. In addition, the present results showed the specific features of tumors that were definitively diagnosed as ALT/WDLPS based on the positive outcome of MDM2 FISH. According to these features, ALT/WDLPSs are: (1) often found in elderly patients, (2) larger in size, (3) located in the lower limb, and (4) frequently found in deep-seated regions.
Generally, MDM2 amplification identified by FISH is considered the gold standard for ALT/WDLPS diagnosis [16,17]. When this standard was applied to the present data, the sensitivity and specificity of morphological diagnosis were found to be 41.5% and 98.5%, respectively. To date, no studies have investigated the accuracy of the morphological diagnoses of lipoma and ALT/WDLPS that were made prior to the application of immunostaining in the differentiation between these two tumors. In the present study, of the 68 patients who had been morphologically diagnosed as having a lipoma, only one (1.5%) was positive for MDM2 amplification. This indicates that, in general, lipomas can be accurately diagnosed based on morphology, as long as the tumors exhibit their typical pathological characteristics. In contrast, of the 41 patients who had been morphologically diagnosed with ALT/WDLPS, 17 were positive for MDM2 FISH, and more than half (24) of the patients did not show MDM2 amplification. Based on this result, these 24 patients were re-diagnosed as having a lipoma. ALT/WDLPS is a soft tissue tumor of intermediate malignant behavior with a potential for dedifferentiation, and its recurrence rate is higher than that of lipoma. Therefore, it is imperative to avoid underdiagnosing ALT/WDLPSs as lipomas. In an attempt to circumvent this problem of underdiagnosis, certain benign tumors were presumably overdiagnosed as ALT/WDLPSs in our hospital during the period selected for this study. These benign tumors likely include: lipomas harboring lipoblast-like cells (including lipomas with degenerative changes); large lesions with the clinical appearance of malignant tumors; and deep-seated tumors. Thus, unless tumors can be clearly diagnosed as lipomas on the basis of morphology, the use of FISH for the confirmation of MDM2 amplification would be beneficial for preventing these overdiagnosis cases.
When the definitive diagnosis of ALT/WDLPS was made based on the positive results of MDM2 FISH, the sensitivity and specificity of MDM2 immunostaining were 55.6% and 87.0%, respectively. These values were both lower than those reported by Binh et al. [9]. Previous studies have found a high concordance rate between MDM2/CDK4 immunostaining and MDM2 FISH. However, according to Clay et al. [11], the reason for this high concordance rate is that these studies preferentially investigated cases where the diagnosis could be readily established histologically. They reported that, when they analyzed cases of lipomatous tumors with ambiguous histological features, immunostaining for MDM2 and CDK4 had a sensitivity of 45% and 41%, respectively, and a specificity of 98% and 92%, respectively. In the present study, the sensitivity of MDM2 immunostaining was low (55.6%), although it was higher than that of morphological diagnosis. The specificity of the staining was also low (87.0%), resulting in the underdiagnosis of ALT/WDLPS. Thus, due to their relatively low sensitivity, immunostaining for MDM2 and CDK4 is not a reliable tool for diagnosing ALT/WDLPS in routine clinical settings. Although MDM2/CDK4 immunostaining is a simple and easy technique, the use of FISH is strongly recommended in cases where the immunostaining cannot completely rule out the possibility of ALT/WDLPS.
When MDM2 amplification detected by FISH was used for definitively diagnosing ALT/WDLPS, the present study participants were found to include 91 lipoma and 18 ALT/WDLPS patients. Previous studies demonstrated that the predictive factors for ALT/WDLPS were: patient age (older) [18,19], depth (deep-seated) [13,20,21], and tumor location (lower limb) [18,21–23]. The present results are in line with these conclusions. It has also been shown that a large (≥ 10–15 cm) tumor is another indicator of ALT/WDLPS [11,18,21,22]. Consistent with this finding, the mean maximum diameter of ALT/WDLPSs in the present study was 150.1 mm, which was significantly larger than that of lipomas. On ROC curve analysis of the maximum tumor diameter, the optimal cut-off value for differentiating ALT/WDLPS from a lipoma was 125 mm. A similar cut-off value of 130 mm was previously obtained in a study that performed FISH on specimens from 113 patients with a lipomatous tumor [17]. Taken together, the present and previous studies show that MDM2 FISH should be conducted when lipomatous tumors display the clinical characteristics described above [i.e., older age, tumor location (deep-seated, lower limb), and large tumor size]. As for morphological diagnosis, clinical features suggesting ALT/WDLPS have been reported to be the presence of lipoblasts [20] and the existence of cytologic atypia [8]. The present study also showed that the morphological diagnosis of lipoma is largely reliable. Previously, Zhang et al. [20] suggested indications for performing FISH assays in diagnosing lipomatous tumors located in the trunk and extremities. They were: cytologic atypia, recurrent lipomas, retroperitoneal tumors, and deep-seated tumors without cytologic atypia larger than 15 cm. In the present study, only one ALT/WDLPS patient had been underdiagnosed as having a lipoma. Morphologically, the tumor in this patient contained multivacuolated lipoblast-like cells. However, there were no clear findings suggestive of malignancy. Since lipomas with degenerative changes are known to show characteristics similar to those of ALT/WDLPSs, the final diagnosis of this patient was an intramuscular lipoma. However, the patient was a 64-year-old woman, and the tumor was located in the femoral muscle. Furthermore, the maximum tumor diameter was 154 mm. Thus, there were clinical findings that suggested a diagnosis of ALT/WDLPS. The present study indicates that, when tumors are clearly diagnosed based on morphological features, they do not usually need to be investigated by FISH. However, as in the above case, certain clinical features [such as age (older), tumor location (lower limb), depth (deep-seated), and size (larger)] increase the likelihood of ALT/WDLPS. Preventing the underdiagnosis of ALT/WDLPS is critical in clinical practice. Thus, in the presence of these clinical features, lipomatous tumors should be examined by FISH, even when they do not exhibit cytologic atypia.
Limitations
The MRI findings analyzed in this study were limited to the maximum diameter and depth of tumors. There were no detailed investigations regarding other MRI characteristics, such as contrast effects and the presence or absence of septation and nonadipose components.