A lipoma is a benign tumor that can usually be treated conservatively1,7. Even if the tumor size is large, surgical treatment is not necessary as long as it remains asymptomatic. On the other hand, ALT/WDLS is the most common subtype of liposarcoma, and the treatment for these tumors is controversial1 because it is reported that 1–4% of them undergo dedifferentiation19–21 and may become malignant tumors2,8,19,22. If preoperative differential diagnosis between ALT/WDLS and lipoma is easy in ALT/WDLS patients, surgical resection is recommended before dedifferentiation1. The decision of the resection margin of ALT/WDLS is difficult because the local recurrence rate is high7. It has been reported that there was no significant difference in the recurrence rate between the wide and marginal resection in ALT23, and "conservative" surgery, aiming to preserve major vessels or nerves, may be recommended for deep-seated ALT/WDLS24–27. However, insufficient resection may increase the risk of recurrence and dedifferentiation and resulting in the need for more surgery to perform additional tissue resection. On the other hand, in recent years, Vos et al. reported that observation could be a reasonable option for selected patients with extremity WDLS28. For these reasons, it is crucial to make an accurate differential diagnosis between ALT/WDLS and lipoma for the preoperative plan of the appropriate resection margin and the appropriate selection of patients who can be observed.
For the differential diagnosis, previous studies reported critical factors such as clinical findings (older age13,29,30, tumor size [> 10cm]1,12,29,31, tumor site [lower extremity]12,29,31, and deep-seated location1) and MRI findings (thick septa [> 2mm]32,33, fat content less than 75%30, and contrast enhancement1). In this study, a multivariate analysis was performed to evaluate the predictive factors for ALT/WDLS, and there was a significant difference in tumor site (lower extremity), depth, size (> 11cm), thick septa, and enhancement of septa or nodular lesions. All of these were consistent with the previously mentioned factors, demonstrating high accuracy for the differential diagnosis of ALT/WDLS. MRI findings have high sensitivity but low specificity for the diagnosis of ALT/WDLS, and it has been reported that it may be difficult to decide the diagnosis of them by only MRI findings7,29. On the other hand, Brisson et al. reported that histopathological examination could be used to distinguish ALT/WDLS from lipomas29, so for adipocytic tumors, needle biopsies have been generally performed preoperatively to obtain the diagnosis2.
Histopathological findings in the multivariate analysis showed that lipoblasts were statistically significant for the diagnosis of ALT/WDLS. Traditionally, lipoblasts have been emphasized as a histopathological finding in the diagnosis of liposarcoma34. However, lipoblasts are also observed in benign lipogenic tumors such as spindle cell/pleomorphic lipoma. Furthermore, it has been reported that they are not always observed in ALT/WDLS35. Although the diagnostic accuracy of lipoblasts in the diagnosis of ALT/WDLS has not been clarified, our study revealed that their sensitivity was low (19.6%), but the specificity was very high (98.9%). Although only lipoblasts cannot make a definitive diagnosis of ALT/WDLS, they may be important factors in the diagnosis by comprehensive evaluations together with clinical and radiological examinations.
In this study, nuclear atypia had a significant difference in the differential diagnosis of ALT/WDLS by univariate analysis. ALT/WDLS features a mature adipocytic tumor showing atypical hyperchromatic nuclei2, which is consistent with our results. No nuclear atypia is found in lipoma, which is a benign tumor, so this characteristic is used for the rule out of the diagnosis of these tumors. The specificity of nuclear atypia was 100% in the diagnosis of ALT/WDLS in this study. However, needle biopsies may not provide enough sample for the identification of unequivocal atypical cells7,36, and the atypical stromal cells sometimes scatter throughout the lesion; therefore, in some cases, the difference between ALT/WDLS and lipoma may be subtle challenging the differential diagnosis process36. In addition, FISH examination for MDM2 and CDK4 gene amplification has provided the most accuracy for the diagnosis of ALT/WDLS9–13,15,16, and it is considered the gold standard for the differential diagnosis between ALT/WDLS and lipoma15. In this study, as well as previous studies, MDM2 and/or CDK4 amplification by FISH examination showed a significant difference as a predictive factor for ALT/WDLS. Furthermore, the specificity was 100%. MDM2 gene amplification in FISH examination has high sensitivity and specificity15, and this finding has been used for the definitive diagnosis of ALT/WDLS. However, similar to nuclear atypia, an insufficient sample and the selection of an inappropriate needle biopsy site might complicate the accurate exclusion of a diagnosis of ALT/WDLS due to the absence of MDM2 gene amplification. Furthermore, HE staining in the histopathological examination can be generally performed in many institutions, but FISH examination requires special equipment and reagents, which not all institutions are equipped to perform7. For these reasons, this study excluded the nuclear atypia and FISH examination used for the definitive diagnosis of ALT/WDLS.
Based on these results, in adipocytic tumors, the differential diagnosis should be evaluated based on a comprehensive assessment of clinical, radiological, and histopathological examinations. Although a few scoring systems for the differential diagnosis of ALT/WDLS based on radiological findings have been reported1,7, there is no diagnostic scoring system that includes histopathological findings. In the previous studies of similar scoring systems, Nagano et al. reported a sensitivity of 100% and specificity of 77%1, and Cheng et al. reported a sensitivity of 90% and specificity of 92.5%7. The diagnostic accuracy for ALT/WDLS of this scoring system is almost the same as in these studies. However, Nagano et al. study examined 48 lipomas and 12 ALTs, without including WDLS, and the case number was lower compared with our study1. In addition, this study investigated adipocytic tumors in all locations, but Cheng et al. investigated only deep-seated adipocytic tumors7. These limitations may have affected the difference in accuracy between our scoring system and those studies. Although the diagnostic accuracy of our combined scoring system for ALT/WDLS was slightly lower than that of FISH for MDM2, our scoring system will help to distinguish between ALT/WDLS and lipoma in general orthopedic surgeons at clinics where cannot perform FISH examination.
This study had a limitation that the evaluation of specimens of needle biopsy may be affected by the biopsy site and the amount of sample. If a preoperative needle biopsy can be performed with an accurate procedure, the diagnostic accuracy for ALT/WDLS of this scoring system may be higher, which makes it a very useful diagnostic tool for the preoperative differential diagnosis of adipocytic tumors.
In conclusion, we developed a new combined scoring system based on a comprehensive assessment of clinical, radiological, and histopathological examinations for the preoperative differential diagnosis between ALT/WDLS and lipoma. This scoring system had high diagnostic accuracy for differential diagnosis of ALT/WDLS and was a useful preoperative diagnostic tool that anyone can use easily in many medical institutions.