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

The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in... Hindawi Sarcoma Volume 2018, Article ID 1901896, 7 pages https://doi.org/10.1155/2018/1901896 Research Article The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing 1 1 1 1 1 Sean Ryan , Julia Visgauss, David Kerr, Joshua Helmkamp, Nicholas Said, 1 2 1 1 1 Emily Vinson, Patrick O’Donnell , Xuechan Li, Sin-Ho Jung , Diana Cardona, 1 1 William Eward, and Brian Brigman Duke University Hospital, 2301 Erwin Rd., Durham, NC 27710, USA Markey Cancer Center, University of Kentucky, 800 Rose St., Lexington, KY 40508, USA Correspondence should be addressed to Sean Ryan; sean.p.ryan@duke.edu Received 3 September 2017; Revised 27 January 2018; Accepted 1 March 2018; Published 19 March 2018 Academic Editor: Manish Agarwal Copyright © 2018 Sean Ryan et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Extremity lipomas and well-differentiated liposarcomas (WDLs) are difficult to distinguish on MR imaging. We sought to evaluate the accuracy of MRI interpretation using MDM2 amplification, via fluorescence in-situ hybridization (FISH), as the gold standard for pathologic diagnosis. Furthermore, we aimed to investigate the utility of a diagnostic formula proposed in the literature. Methods. We retrospectively collected 49 patients with lipomas or WDLs utilizing MDM2 for pathologic diagnosis. Four expert readers interpreted each patient’s MRI independently and provided a diagnosis. Additionally, a formula based on imaging characteristics (i.e. tumor depth, diameter, presence of septa, and internal cystic change) was used to predict the pathologic diagnosis. (e accuracy and reliability of imaging-based diagnoses were then analyzed in comparison to the MDM2 pathologic diagnoses. Results. (e accuracy of MRI readers was 73.5% (95% CI 61–86%) with substantial interobserver agreement (κ � 0.7022). (e formula had an accuracy of 71%, which was not significantly different from the readers (p � 0.71). (e formula and expert observers had similar sensitivity (83% versus 83%) and specificity (64.5% versus 67.7%; p � 0.659) for detecting WDLs. Conclusion. (e accuracy of both our readers and the formula suggests that MRI remains unreliable for distinguishing between lipoma and WDLs. lesions is recommended [2, 4, 5]. (us, the distinction be- 1. Introduction tween lipoma and WDL/ALT is important, as asymptomatic Lipomas are the most common soft tissue tumor and, unless lipomas need no treatment or follow-up. However, WDL/ALT of the extremity is appropriately treated with symptomatic, do not require surgical excision or formal surveillance when the provider is confident in the diagnosis. surgical excision and postoperative surveillance. Neverthe- However, the difference between a lipoma and well- less, the ability to distinguish between WDL/ALTand benign differentiated liposarcoma (WDL) is often difficult to de- lipomas using only MRI remains a diagnostic challenge. termine based solely on imaging [1–3]. Well-differentiated Numerous imaging features on MRI have been reported liposarcomas of the extremities have low metastatic potential to facilitate differentiation between these two entities. Lo- and are now also commonly referred to as atypical lipo- cation deep to fascia, septations>2 mm thick, heterogeneity, matous tumor (ALT), reflecting their benign biologic be- foci of high T2 signal, diameter>5 cm, stranding, nodularity, havior relative to WDLs of the mediastinum or retroperitoneum and cystic changes within the tumor have been reported [4]. However, given the potential for de-differentiation and as being more common in ALT/WDLs than in lipomas conversion to a higher grade liposarcoma, excision of these [1, 2, 6, 7]. A representative MR image of an ALT/WDL 2 Sarcoma (a) (b) Figure 1: Coronal T1 (a) and STIR (b) MRI of a 30 cm diameter ALT/WDL confirmed by MDM2 FISH which is deep to fascia, contains foci of T2 enhancement, heterogeneity, nodularity, and internal cystic changes. demonstrating common concerning features is shown have been incorrect. A recent study by Wang and colleagues in Figure 1. However, these features have not allowed experts constructed a scoring system for differentiating lipomas to reliably identify ALT/WDLs, and this uncertainty may from liposarcomas utilizing MRI findings. However, this lead to unnecessary patient concern and more invasive study also utilized the WHO histologic criteria without management. assessment of MDM2 amplification, and thus the resultant Gaskin and Helms previously reported an accuracy of scoring system also requires further review [7]. 83% in predicting the pathologic diagnosis based on MRI, To our knowledge, there is no study in the literature and noted that when a lesion was suspicious for ALT/WDLs, comparing the accuracy of MRI diagnosis to the new gold standard for pathologic diagnosis, MDM2. (erefore, the it was more likely (64%) to represent a benign lipoma [2] after final pathology. O’Donnell and colleagues similarly purpose of this study is (1) to evaluate the ability of expe- compared MRI evaluation between radiologists and or- rienced readers of MR imaging to distinguish between li- thopaedic oncologists, and found an accuracy of 69% in poma and ALT/WDLs in the era of MDM2 FISH, (2) to distinguishing lipoma versus ALT/WDLs, with no difference evaluate the agreement of MRI interpretations amongst across specialty [1]. (ese studies were performed using the experienced readers, (3) to evaluate the utility of the di- World Health Organization (WHO) pathologic criteria for agnostic formula proposed by Wang et al., and to determine diagnosis, and both recognized the need for a reproducible whether or not it is able to outperform the interpretation of method of determining the diagnosis without an invasive fellowship-trained readers, and (4) to determine which MRI surgical intervention. characteristics, if any, are most predictive of the diagnosis of (e difficulty identifying these tumors accurately with ALT/WDLs. Our hypothesis was that there would be an increase in the accuracy of MR imaging diagnosis given the imaging was rendered even more complex by the fact that the pathologic criteria for diagnosis were relatively sub- new pathologic criteria. We further hypothesized that the jective. In recent years, the gold standard for accurate weighted scoring system would provide the most accurate pathologic diagnosis has evolved with the discovery of and reproducible diagnosis compared to expert readers by murine double minute 2 (MDM2) gene amplification eliminating the inherent bias of readers to “overdiagnose” present in all ALT/WDLs. While most ALT/WDLs may be ALT/WDLs as shown in prior studies [1, 2]. correctly diagnosed histologically, the atypia required may be focal and missed on biopsy, or under/overinterpreted. 2. Materials and Methods MDM2, however, is consistently amplified and its detection using fluorescence in situ hybridization (FISH) has become (is study was performed in collaboration with radiology, the new gold standard for diagnosis [3, 8]. Using this new orthopaedic oncology, and surgical pathology. (e cohort diagnostic criterion, some tumors previously regarded as was retrospectively collected from the institutional database lipoma are now known to be ALT/WDLs and vice versa. (is and electronic medical records were reviewed for patient calls into question prior studies on the accuracy of MRI, as demographics, available MRI, and MDM2 pathologic di- the diagnosis based on the WHO histologic criteria may agnosis. Patients with extremity lesions superficial to fascia Sarcoma 3 and pathologic diagnosis based on WHO criteria were ex- Lastly, we used a stepwise regression model to select cluded from the study. Lesions outside of the extremity were significant imaging predictors associated with a diagnosis of excluded in part due to the subspecialties of the readers ALT/WDL. A significance level of 0.1 was required to allow (orthopaedic oncology and musculoskeletal radiology). a proposed imaging characteristic into the model. However, they were also excluded because WDL located in the mediastinum and retroperitoneum behave differently 3. Results than those in the extremities. Following exclusion, 49 pa- tients with deep extremity lipomas or ALT/WDLs remained. Of the 49 patients included, final pathologic diagnosis was Each patient’s MRI was interpreted by two fellowship- ALT/WDLs for 18 patients and lipoma for 31 patients. (ere trained orthopaedic oncologists and two fellowship-trained were six spindle cell lipomas and one lipoma with osseous musculoskeletal radiologists who were blinded to the final metaplasia included in the lipoma group. Pathologic di- diagnosis. All MR images reviewed contained T1-weighted agnosis was determined by MDM2 FISH for 44 patients and and T2-weighted or STIR sequences for evaluation, and all by immunohistochemistry for MDM2 and CDK4 for five MRI sequences were made available for reviewers at the time patients. of the study. All four reviewers independently interpreted Experienced readers of MR images were unable to ac- the images simultaneously, without time limitations, and curately and reliably distinguish between lipoma and were permitted to make measurements and analyze any ATL/WDL on MR imaging. Collectively, the readers had an desired sequence. accuracy of 73.5% based on 2 or more readers predicting Readers were surveyed for each case on whether margins ALT/WDL. Accuracy ranged from 73.5 to 79.6% for indi- were well or poorly defined, tumors were homogeneous or vidual observers. Expert readers showed an 83% sensitivity, heterogeneous, if there was stranding or nodularity, if thick 67.7% specificity, 73.5% accuracy, 60% PPV, and 87.5% NPV septa>2 mm were present, or if there were cystic changes or for interpreting the MRI for ALT/WDL when compared to foci of high T2 signal. (ey were then asked to make a final the final pathologic diagnosis (Table 1). imaging diagnosis of lipoma or ALT/WDL. Each categorical (e agreement of MR interpretation between readers variable, including the final diagnosis, was recorded pro- was variable for each imaging characteristic; however, spectively while interpreting the MR imaging. agreement was substantial when choosing a final diagnosis. Cohen’s Kappa coefficient were used to determine the Interobserver reliability for each imaging characteristic is interobserver agreement/reliability for the diagnosis and shown through use of Cohen’s kappa coefficient (Table 2) each categorical variable (margins, homogeneity, stranding, with foci of high T2 signal, nodularity, and final diagnosis nodularity, thickened septa, internal cystic change, foci of showing the most interobserver agreement. If the final di- high T2 signal, and final imaging diagnosis) for all four agnosis was lipoma, MR interpreters collectively chose the expert observers. Additionally, the sensitivity, specificity, correct diagnosis 68% (21/31) of the time, whereas if the final accuracy, positive predictive value (PPV), and negative diagnosis was ALT/WDL, the correct diagnosis was inter- predictive value (NPV) of the imaging diagnosis by the preted for 83% (15/18). (ere was no significant difference in expert observers were calculated based on the gold standard accuracy comparing expert observers against each other or MDM2 diagnosis. across subspecialty (orthopaedic oncology versus muscu- Next, we used the reviewer’s responses to predict the loskeletal radiology). For the final diagnosis, there was 100% diagnosis using the formula published by Wang et al. concordance across the four interpreters in 37/49 cases, 75% Z � 10X +X + 12X + 15X + 10X , where X is gender concordance in 5/49 cases, and 50% concordance in 7/49 1 2 3 4 5 1 (0 � female; 1 � male), X is tumor diameter (in cm), X is cases. 2 3 tumor depth (0 � superficial to fascia; 1 � deep to fascia), X During investigation of the formula proposed by is the presence of a septum or nodule (0 � absent septum or Wang et al. using their advocated cutoff score of 35 (>35 nodule; 1 � septum >2 mm or nodule >1 cm), and X is being considered a ALT/WDLs), we found the formula to internal cystic change (0 � no, 1 � yes). All tumors were deep be less accurate than previously described. Using this to fascia, meaning X was 1 for all patients included. X and threshold, the formula had an accuracy of 71% with 3 4 X were determined after all lesions had been reviewed and sensitivity 83%, specificity 64.5%, PPV 58%, and NPV were based on the majority opinion of the reviewers (i.e., if 2 87%. (ere was no significant difference in sensitivity or more expert observers felt there was a septum, nodule, or (p � 1.000), specificity (p � 0.659), accuracy (p � 0.708), PPV (p � 0.683), or NPV (p � 0.920) between the formula internal cystic change, then it was considered present for the formula). Of note, no reviewers had the formula available at and the expert interpreters. If the pathologic diagnosis the time of their MRI interpretation. A Z score of >35 was was lipoma, the formula correctly predicted the diagnosis considered consistent with ALT/WDL as described by Wang (score≤ 35) only 58% (18/31) of the time, whereas if the et al., who reported a 100% negative predictive value in their pathologic diagnosis was ALT/WDL, the formula cor- study. (erefore, 35 was used as the cutoff for testing their rectly predicted the diagnosis (score> 35) for 83% (15/18) formula in this study [7]. All diagnoses by the expert ob- of cases. servers were subsequently grouped, and compared against Lastly, we employed a stepwise variable selection pro- the diagnoses provided by the formula, using a 2-sample cedure to determine which MRI features were most asso- ciated with the diagnosis of ALT/WDL. A 10% significance paired binomial test. A p value< 0.05 was considered sta- tistically significant. level for both selection and deletion was used to identify 4 Sarcoma Table 1: Expert observer grouped interpretation of MRI compared to final pathologic diagnosis. Value 95% CI lower bound 95% CI upper bound Sensitivity 0.8333 0.6612 1 Specificity 0.6774 0.5129 0.8420 Accuracy 0.7347 0.6111 0.8583 Positive predictive value (PPV) 0.6000 0.4080 0.7920 Negative predictive value (NPV) 0.8750 0.7427 1 Table 2: Interobserver reliability amongst four expert readers of MRI for commonly reported imaging characteristics. Margins WD Internal cystic Foci of high Homogeneous Stranding Nodularity (ickened septa Imaging diagnosis versus PD change T2 signal Kappa 0.2331 0.6122 0.4552 0.7673 0.5890 0.3333 0.7959 0.7022 p value 0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 Table 3: Imaging parameter in stepwise model selection. Significance coefficient of 0.1 was required to remain in the model. 95% CI for OR Parameter Coefficient OR p value Lower Upper First selection Intercept −1.091 0.154 Margins (WD versus PD) −0.375 0.472 0.097 2.290 0.352 Homogeneous (yes versus no) −0.896 0.167 0.010 2.720 0.209 Stranding (yes versus no) 0.056 1.118 0.079 15.732 0.934 Nodularity> 1 cm (yes versus no) 0.001 1.002 0.155 6.486 0.998 (ickened septa > 2 mm (yes versus no) −0.620 0.289 0.019 4.290 0.367 Internal cystic change (yes versus no) −0.186 0.689 0.036 13.098 0.805 Foci of high T2 signal (yes versus no) 1.142 9.822 0.906 106.436 0.060 Second selection Intercept −0.9639 0.0215 Foci of high T2 signal (yes versus no) 1.3386 14.545 2.811 75.270 0.0014 imaging characteristics that were significantly correlated lipoma, increasing the accuracy of our readers and the with the final pathologic diagnosis. (is analysis is shown in formula (Figure 2). Table 3, and only foci of high T2 signal remains in the model (e final case is a 51-year-old female with a 10 cm li- following selection, indicating that it is most strongly as- pomatous lesion of the right thigh. All four expert observers sociated with the final diagnosis. Foci of high T2 signal was predicted the lesion to be an ALT/WDL, while the formula present in 16/18 (88.9%) ALT/WDLs and in 20/31 (64.5%) (with score of 22) predicted the lesion to be a benign lipoma. lipomas. Initial pathology report was read as ALT/WDL. Subsequent MDM2 FISH was negative for gene amplification, and given the histologic concern for atypia, the FISH was again re- 4. Case Illustrations peated and found to again be negative, confirming the di- agnosis of lipoma and changing the pathologic diagnosis (ree cases from this cohort were selected in order to (Figure 3). highlight the significance of MDM2 FISH and the difficult agreement between MRI interpretation and pathology. (e first is the case of a 42-year-old male with a 12 cm lipo- 5. Discussion matous tumor in the left shoulder. Based on MR imaging, 4/4 expert observers, in addition to the formula (score of 34), Liposarcomas represent approximately 20% of all soft tissue predicted the lesion to be a benign lipoma. Initial pathology sarcomas and are divided into various subtypes including was concerning ALT/WDL, which was subsequently over- atypical lipomatous tumors/well-differentiated liposarcomas turned following MDM2 FISH because there was no (ALT/WDLs), de-differentiated liposarcoma, myxoid lip- amplification of the MDM2 gene. (e second is the case of osarcoma, round cell liposarcomas, and pleomorphic lip- a 69-year-old male with a 2 cm lesion in the left arm. Again, osarcomas. ALT/WDLs are often difficult to distinguish all four expert observers and the formula (score of 24) from benign lipomas on MRI [1, 2, 6, 9, 10] and have predicted the lesion to be a benign lipoma, but pathology was different treatments as well as prognosis. On MRI, concerning ALT/WDL. Following MDM2 FISH, the path- ALT/WDLs are known for having thick septa, lack of capsule ologic diagnosis was subsequently confirmed to be a benign with less well-defined margins, nodularity, internal cystic Sarcoma 5 (a) (b) Figure 2: (a) Axial T1 MR of left shoulder with 12 cm lipomatous tumor. Formula and expert observers predicted benign lipoma, while initial pathology was concerning ALT/WDL. Lack of MDM2 amplification with FISH confirmed a diagnosis of benign lipoma. (b) Axial T1 MR of the left arm with 2 cm lipomatous tumor. Formula and expert observers predicted benign lipoma, which was later confirmed by lack of MDM2 amplification through FISH after initial pathology was concerning ALT/WDL. (a) (b) Figure 3: (a) Coronal T1 and (b) axial STIR MR images of the right thigh lipomatous tumor. Expert observers interpreted the lesion as heterogeneous, containing stranding, and having foci of high T2 signal. All four readers interpreted the tumor as ALT/WDL in addition to initial pathology interpreted as ALT/WDL. MDM2 amplification during FISH analysis confirmed benign lipoma on two separate occasions, illustrating the variability that can be seen within simple lipomas. changes, heterogeneity, and enhancement on T2-weighted however, found that there was a 60% local recurrence rate if imaging. Meanwhile, lipomas are characteristically homo- extremity tumors were treated with marginal excision, geneous and encapsulated lesions composed of pre- which decreased to 11% when treated with wide local dominantly mature adipose tissue. However, they may excision [5]. (e appropriate treatment remains debated, contain thin enhancing septa, be unencapsulated, or have however, as some advocate for marginal excision with or heterogeneity due to regions of fat necrosis, infarction or without radiation therapy given low rates of local re- nonfatty tissue, and creating concern for ALT/WDLs on currence and the morbidity associated with wide resection MRI interpretation [1, 2, 6, 9]. [4, 11, 12]. Importantly, many of these studies on local (e importance of distinguishing between lipoma and recurrence rates were not based on molecular analysis for ALT/WDLs preoperatively is well recognized. For many diagnosis, and therefore, may have had inaccurate cate- providers, ALT/WDLs receive wide local excision rather gorization of lipomatous tumors, leading to falsely low than marginal excision to decrease the risk of local re- recurrence rates if lipomas were regarded as ALT/WDLs. currence. Following surgery for ALT/WDLs, recurrence Furthermore, ALT/WDLs have the potential for delayed rates vary from 13.9 to 69% [2, 11]. Lucas and colleagues, malignant de-differentiation and subsequent metastasis. 6 Sarcoma musculoskeletal radiologists. Collectively, our expert ob- Due to this potential for delayed de-differentiation as well as the higher local recurrence rates compared to li- servers had an accuracy of 73% for predicting the final pathologic diagnosis, which is consistent with prior reports. pomas, the importance of continued surveillance post- operatively regardless of surgical margin is well established A PPV of 60% and NPV of 87.5% indicated a tendency to [1, 2, 6, 11–14]. overdiagnose ALT/WDL, as reported by prior authors [1, 2]. Previous publications have shown relatively poor ac- (e formula proposed by Wang et al. showed an accuracy of curacy for MRI predicting the pathologic diagnosis. 71.4% with a 57% PPV and 87% NPV, slightly under- O’Donnell and colleagues found a 69% overall accuracy performing our expert observer’’s interpretation. (is dif- for expert observers predicting the pathologic diagnosis ference, however, was not statistically significant. Unlike the study by Wang et al., all of the tumors included in our study based on the WHO criteria, while Gaskin and Helms found an 83% specificity and a 38% PPV [1, 2]. (ese studies were deep to fascia, making it more difficult to discern li- poma from ALT/WDLs. (is may account for the reduced noted a propensity for MRI interpreters to overdiagnose ALT/WDLs, leading to unnecessary patient worry and accuracy of the formula seen in our cohort. Of the various MRI features tested, foci of high T2 signal more invasive surgical intervention. In an effort to create a more objective interpretation of imaging findings, Wang intensity had the highest correlation with a diagnosis of and colleagues devised a scoring system based on MR ALT/WDL, unlike the study by Wang et al., which found imaging features which were found to be correlated to the internal cystic change, nodules, and thick septum to be more final pathologic diagnosis in their series [7]. In their study, predictable factors [7]. However, it is important to note that all ALT/WDLs had a Z score of >35 and 30/34 benign foci of high T2 signal were also present in 64.5% of benign lipomas had a Z score of≤35. (erefore, they proposed this lipomas. (is highlights the variability of these tumors and reveals a multitude of MRI findings based on a representa- scoring system as a potential alternative to invasive bi- opsies for preoperative decision-making. (ese authors, tive cohort. (is can be seen in other areas throughout the current literature; for example, O’Donnell and colleagues similar to others looking at the accuracy of MRI, utilized the WHO criteria for final pathologic diagnosis rather than focused on stranding, nodularity, and size as the de- terminant factors for diagnosis [1]. MDM2 amplification. (erefore, some tumors may have been misclassified, requiring revalidation of the scoring We continue to understand the utility of MR imaging for system. the generation of a differential diagnosis and preoperative Not only can it be difficult to determine lipoma from planning. However, based on our results, we do caution ALT/WDLs for the radiologist, it can also pose a challenge readers that MRI should not be used in isolation for di- to the pathologist. Histologically, the degree of atypia may agnosis. At this stage, despite numerous advances, we feel be overestimated or confounded by fat necrosis, especially that further study is required for alternative and less invasive means of diagnosis to guide appropriate management of in borderline cases [3, 8]. Furthermore, tumor heteroge- neity can lead to sampling error and inaccurate histologic these lesions preoperatively. Furthermore, we recognize that MDM2 FISH (or MDM2/CDK4 IHC) may not be available diagnosis. (is difficulty can be seen in our three case examples above, which all had concerning features on at all institutions, especially given its high cost. While all initial pathology. With advances in modern molecular lesions do not necessarily require MDM2 FISH, we agree analysis, however, the gold standard for pathologic di- with Clay and colleagues that when lesions are recurrent, agnosis of ALT/WDLs has changed. Specifically, murine deep and >10.0 cm, have equivocal atypia, and are con- double minute 2 (MDM2) has been found to be amplified cerning on MR imaging, they warrant investigation with in all ALT/WDLs [10]. (e use of immunohistochemistry MDM2 for definitive diagnosis [3]. (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 ter- 6. Conclusion tiary referral centers. However, for borderline cases, MDM2 FISH has been shown to be required for accurate While MDM2 FISH has affected the confidence with which pathologic diagnosis given the potential for sampling error pathologists can diagnose ALT/WDLs, it remains difficult on biopsy and subjective interpretation of MDM2 im- for expert observers to distinguish them from benign li- munohistochemistry [8, 15]. Meanwhile, MDM2 FISH has pomas on imaging. Based on the data presented here, been shown to have 100% sensitivity and specificity even on expert readers of MRI have an accuracy of 73% in dis- core needle biopsy [16]. (is new criterion was the focus of tinguishing lipoma from ALT/WDL, which is consistent the current study. (e goal was to reassess the ability of with prior reports. (e use of MDM2 FISH for pathologic expert observers to distinguish lipoma from ALT/WDL on diagnosis, while more reliable than the WHO criteria, has MRI, given the increased accuracy of pathologic diagnosis not changed the accuracy of MRI interpretation. Fur- of these tumors using MDM2 as the gold standard. As thermore, the proposed scoring system by Wang et al. was stated previously, 44 patients had final pathology de- found to have less utility than previously reported, with an termined by MDM2 FISH, and 5 patients had IHC for final accuracy of 71%. (erefore, while MRI is an important diagnosis. screening tool for differentiating these lesions, pathologic Our series showed agreement amongst expert in- confirmation with MDM2 FISH is still required for di- terpretation of MRI for both orthopaedic oncologists and agnostic certainty. Sarcoma 7 tumor location,” Journal of Surgical Research, vol. 175, no. 1, Conflicts of Interest pp. 12–17, 2012. [15] S. F. Kammerer-Jacquet, S. (ierry, F. Cabillic et al., “Dif- (e authors declare that there are no conflicts of interest ferential diagnosis of atypical lipomatous tumor/well- regarding the publication of this article. differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 im- References munohistochemistry,” Human Pathology, vol. 59, pp. 34–40, [1] P. W. O’Donnell, A. M. Griffin, W. C. Eward et al., “Can [16] J. Weaver, P. Rao, J. R. 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The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing

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Hindawi Publishing Corporation
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Copyright © 2018 Sean Ryan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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1357-714X
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1369-1643
DOI
10.1155/2018/1901896
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Hindawi Sarcoma Volume 2018, Article ID 1901896, 7 pages https://doi.org/10.1155/2018/1901896 Research Article The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing 1 1 1 1 1 Sean Ryan , Julia Visgauss, David Kerr, Joshua Helmkamp, Nicholas Said, 1 2 1 1 1 Emily Vinson, Patrick O’Donnell , Xuechan Li, Sin-Ho Jung , Diana Cardona, 1 1 William Eward, and Brian Brigman Duke University Hospital, 2301 Erwin Rd., Durham, NC 27710, USA Markey Cancer Center, University of Kentucky, 800 Rose St., Lexington, KY 40508, USA Correspondence should be addressed to Sean Ryan; sean.p.ryan@duke.edu Received 3 September 2017; Revised 27 January 2018; Accepted 1 March 2018; Published 19 March 2018 Academic Editor: Manish Agarwal Copyright © 2018 Sean Ryan et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Extremity lipomas and well-differentiated liposarcomas (WDLs) are difficult to distinguish on MR imaging. We sought to evaluate the accuracy of MRI interpretation using MDM2 amplification, via fluorescence in-situ hybridization (FISH), as the gold standard for pathologic diagnosis. Furthermore, we aimed to investigate the utility of a diagnostic formula proposed in the literature. Methods. We retrospectively collected 49 patients with lipomas or WDLs utilizing MDM2 for pathologic diagnosis. Four expert readers interpreted each patient’s MRI independently and provided a diagnosis. Additionally, a formula based on imaging characteristics (i.e. tumor depth, diameter, presence of septa, and internal cystic change) was used to predict the pathologic diagnosis. (e accuracy and reliability of imaging-based diagnoses were then analyzed in comparison to the MDM2 pathologic diagnoses. Results. (e accuracy of MRI readers was 73.5% (95% CI 61–86%) with substantial interobserver agreement (κ � 0.7022). (e formula had an accuracy of 71%, which was not significantly different from the readers (p � 0.71). (e formula and expert observers had similar sensitivity (83% versus 83%) and specificity (64.5% versus 67.7%; p � 0.659) for detecting WDLs. Conclusion. (e accuracy of both our readers and the formula suggests that MRI remains unreliable for distinguishing between lipoma and WDLs. lesions is recommended [2, 4, 5]. (us, the distinction be- 1. Introduction tween lipoma and WDL/ALT is important, as asymptomatic Lipomas are the most common soft tissue tumor and, unless lipomas need no treatment or follow-up. However, WDL/ALT of the extremity is appropriately treated with symptomatic, do not require surgical excision or formal surveillance when the provider is confident in the diagnosis. surgical excision and postoperative surveillance. Neverthe- However, the difference between a lipoma and well- less, the ability to distinguish between WDL/ALTand benign differentiated liposarcoma (WDL) is often difficult to de- lipomas using only MRI remains a diagnostic challenge. termine based solely on imaging [1–3]. Well-differentiated Numerous imaging features on MRI have been reported liposarcomas of the extremities have low metastatic potential to facilitate differentiation between these two entities. Lo- and are now also commonly referred to as atypical lipo- cation deep to fascia, septations>2 mm thick, heterogeneity, matous tumor (ALT), reflecting their benign biologic be- foci of high T2 signal, diameter>5 cm, stranding, nodularity, havior relative to WDLs of the mediastinum or retroperitoneum and cystic changes within the tumor have been reported [4]. However, given the potential for de-differentiation and as being more common in ALT/WDLs than in lipomas conversion to a higher grade liposarcoma, excision of these [1, 2, 6, 7]. A representative MR image of an ALT/WDL 2 Sarcoma (a) (b) Figure 1: Coronal T1 (a) and STIR (b) MRI of a 30 cm diameter ALT/WDL confirmed by MDM2 FISH which is deep to fascia, contains foci of T2 enhancement, heterogeneity, nodularity, and internal cystic changes. demonstrating common concerning features is shown have been incorrect. A recent study by Wang and colleagues in Figure 1. However, these features have not allowed experts constructed a scoring system for differentiating lipomas to reliably identify ALT/WDLs, and this uncertainty may from liposarcomas utilizing MRI findings. However, this lead to unnecessary patient concern and more invasive study also utilized the WHO histologic criteria without management. assessment of MDM2 amplification, and thus the resultant Gaskin and Helms previously reported an accuracy of scoring system also requires further review [7]. 83% in predicting the pathologic diagnosis based on MRI, To our knowledge, there is no study in the literature and noted that when a lesion was suspicious for ALT/WDLs, comparing the accuracy of MRI diagnosis to the new gold standard for pathologic diagnosis, MDM2. (erefore, the it was more likely (64%) to represent a benign lipoma [2] after final pathology. O’Donnell and colleagues similarly purpose of this study is (1) to evaluate the ability of expe- compared MRI evaluation between radiologists and or- rienced readers of MR imaging to distinguish between li- thopaedic oncologists, and found an accuracy of 69% in poma and ALT/WDLs in the era of MDM2 FISH, (2) to distinguishing lipoma versus ALT/WDLs, with no difference evaluate the agreement of MRI interpretations amongst across specialty [1]. (ese studies were performed using the experienced readers, (3) to evaluate the utility of the di- World Health Organization (WHO) pathologic criteria for agnostic formula proposed by Wang et al., and to determine diagnosis, and both recognized the need for a reproducible whether or not it is able to outperform the interpretation of method of determining the diagnosis without an invasive fellowship-trained readers, and (4) to determine which MRI surgical intervention. characteristics, if any, are most predictive of the diagnosis of (e difficulty identifying these tumors accurately with ALT/WDLs. Our hypothesis was that there would be an increase in the accuracy of MR imaging diagnosis given the imaging was rendered even more complex by the fact that the pathologic criteria for diagnosis were relatively sub- new pathologic criteria. We further hypothesized that the jective. In recent years, the gold standard for accurate weighted scoring system would provide the most accurate pathologic diagnosis has evolved with the discovery of and reproducible diagnosis compared to expert readers by murine double minute 2 (MDM2) gene amplification eliminating the inherent bias of readers to “overdiagnose” present in all ALT/WDLs. While most ALT/WDLs may be ALT/WDLs as shown in prior studies [1, 2]. correctly diagnosed histologically, the atypia required may be focal and missed on biopsy, or under/overinterpreted. 2. Materials and Methods MDM2, however, is consistently amplified and its detection using fluorescence in situ hybridization (FISH) has become (is study was performed in collaboration with radiology, the new gold standard for diagnosis [3, 8]. Using this new orthopaedic oncology, and surgical pathology. (e cohort diagnostic criterion, some tumors previously regarded as was retrospectively collected from the institutional database lipoma are now known to be ALT/WDLs and vice versa. (is and electronic medical records were reviewed for patient calls into question prior studies on the accuracy of MRI, as demographics, available MRI, and MDM2 pathologic di- the diagnosis based on the WHO histologic criteria may agnosis. Patients with extremity lesions superficial to fascia Sarcoma 3 and pathologic diagnosis based on WHO criteria were ex- Lastly, we used a stepwise regression model to select cluded from the study. Lesions outside of the extremity were significant imaging predictors associated with a diagnosis of excluded in part due to the subspecialties of the readers ALT/WDL. A significance level of 0.1 was required to allow (orthopaedic oncology and musculoskeletal radiology). a proposed imaging characteristic into the model. However, they were also excluded because WDL located in the mediastinum and retroperitoneum behave differently 3. Results than those in the extremities. Following exclusion, 49 pa- tients with deep extremity lipomas or ALT/WDLs remained. Of the 49 patients included, final pathologic diagnosis was Each patient’s MRI was interpreted by two fellowship- ALT/WDLs for 18 patients and lipoma for 31 patients. (ere trained orthopaedic oncologists and two fellowship-trained were six spindle cell lipomas and one lipoma with osseous musculoskeletal radiologists who were blinded to the final metaplasia included in the lipoma group. Pathologic di- diagnosis. All MR images reviewed contained T1-weighted agnosis was determined by MDM2 FISH for 44 patients and and T2-weighted or STIR sequences for evaluation, and all by immunohistochemistry for MDM2 and CDK4 for five MRI sequences were made available for reviewers at the time patients. of the study. All four reviewers independently interpreted Experienced readers of MR images were unable to ac- the images simultaneously, without time limitations, and curately and reliably distinguish between lipoma and were permitted to make measurements and analyze any ATL/WDL on MR imaging. Collectively, the readers had an desired sequence. accuracy of 73.5% based on 2 or more readers predicting Readers were surveyed for each case on whether margins ALT/WDL. Accuracy ranged from 73.5 to 79.6% for indi- were well or poorly defined, tumors were homogeneous or vidual observers. Expert readers showed an 83% sensitivity, heterogeneous, if there was stranding or nodularity, if thick 67.7% specificity, 73.5% accuracy, 60% PPV, and 87.5% NPV septa>2 mm were present, or if there were cystic changes or for interpreting the MRI for ALT/WDL when compared to foci of high T2 signal. (ey were then asked to make a final the final pathologic diagnosis (Table 1). imaging diagnosis of lipoma or ALT/WDL. Each categorical (e agreement of MR interpretation between readers variable, including the final diagnosis, was recorded pro- was variable for each imaging characteristic; however, spectively while interpreting the MR imaging. agreement was substantial when choosing a final diagnosis. Cohen’s Kappa coefficient were used to determine the Interobserver reliability for each imaging characteristic is interobserver agreement/reliability for the diagnosis and shown through use of Cohen’s kappa coefficient (Table 2) each categorical variable (margins, homogeneity, stranding, with foci of high T2 signal, nodularity, and final diagnosis nodularity, thickened septa, internal cystic change, foci of showing the most interobserver agreement. If the final di- high T2 signal, and final imaging diagnosis) for all four agnosis was lipoma, MR interpreters collectively chose the expert observers. Additionally, the sensitivity, specificity, correct diagnosis 68% (21/31) of the time, whereas if the final accuracy, positive predictive value (PPV), and negative diagnosis was ALT/WDL, the correct diagnosis was inter- predictive value (NPV) of the imaging diagnosis by the preted for 83% (15/18). (ere was no significant difference in expert observers were calculated based on the gold standard accuracy comparing expert observers against each other or MDM2 diagnosis. across subspecialty (orthopaedic oncology versus muscu- Next, we used the reviewer’s responses to predict the loskeletal radiology). For the final diagnosis, there was 100% diagnosis using the formula published by Wang et al. concordance across the four interpreters in 37/49 cases, 75% Z � 10X +X + 12X + 15X + 10X , where X is gender concordance in 5/49 cases, and 50% concordance in 7/49 1 2 3 4 5 1 (0 � female; 1 � male), X is tumor diameter (in cm), X is cases. 2 3 tumor depth (0 � superficial to fascia; 1 � deep to fascia), X During investigation of the formula proposed by is the presence of a septum or nodule (0 � absent septum or Wang et al. using their advocated cutoff score of 35 (>35 nodule; 1 � septum >2 mm or nodule >1 cm), and X is being considered a ALT/WDLs), we found the formula to internal cystic change (0 � no, 1 � yes). All tumors were deep be less accurate than previously described. Using this to fascia, meaning X was 1 for all patients included. X and threshold, the formula had an accuracy of 71% with 3 4 X were determined after all lesions had been reviewed and sensitivity 83%, specificity 64.5%, PPV 58%, and NPV were based on the majority opinion of the reviewers (i.e., if 2 87%. (ere was no significant difference in sensitivity or more expert observers felt there was a septum, nodule, or (p � 1.000), specificity (p � 0.659), accuracy (p � 0.708), PPV (p � 0.683), or NPV (p � 0.920) between the formula internal cystic change, then it was considered present for the formula). Of note, no reviewers had the formula available at and the expert interpreters. If the pathologic diagnosis the time of their MRI interpretation. A Z score of >35 was was lipoma, the formula correctly predicted the diagnosis considered consistent with ALT/WDL as described by Wang (score≤ 35) only 58% (18/31) of the time, whereas if the et al., who reported a 100% negative predictive value in their pathologic diagnosis was ALT/WDL, the formula cor- study. (erefore, 35 was used as the cutoff for testing their rectly predicted the diagnosis (score> 35) for 83% (15/18) formula in this study [7]. All diagnoses by the expert ob- of cases. servers were subsequently grouped, and compared against Lastly, we employed a stepwise variable selection pro- the diagnoses provided by the formula, using a 2-sample cedure to determine which MRI features were most asso- ciated with the diagnosis of ALT/WDL. A 10% significance paired binomial test. A p value< 0.05 was considered sta- tistically significant. level for both selection and deletion was used to identify 4 Sarcoma Table 1: Expert observer grouped interpretation of MRI compared to final pathologic diagnosis. Value 95% CI lower bound 95% CI upper bound Sensitivity 0.8333 0.6612 1 Specificity 0.6774 0.5129 0.8420 Accuracy 0.7347 0.6111 0.8583 Positive predictive value (PPV) 0.6000 0.4080 0.7920 Negative predictive value (NPV) 0.8750 0.7427 1 Table 2: Interobserver reliability amongst four expert readers of MRI for commonly reported imaging characteristics. Margins WD Internal cystic Foci of high Homogeneous Stranding Nodularity (ickened septa Imaging diagnosis versus PD change T2 signal Kappa 0.2331 0.6122 0.4552 0.7673 0.5890 0.3333 0.7959 0.7022 p value 0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 Table 3: Imaging parameter in stepwise model selection. Significance coefficient of 0.1 was required to remain in the model. 95% CI for OR Parameter Coefficient OR p value Lower Upper First selection Intercept −1.091 0.154 Margins (WD versus PD) −0.375 0.472 0.097 2.290 0.352 Homogeneous (yes versus no) −0.896 0.167 0.010 2.720 0.209 Stranding (yes versus no) 0.056 1.118 0.079 15.732 0.934 Nodularity> 1 cm (yes versus no) 0.001 1.002 0.155 6.486 0.998 (ickened septa > 2 mm (yes versus no) −0.620 0.289 0.019 4.290 0.367 Internal cystic change (yes versus no) −0.186 0.689 0.036 13.098 0.805 Foci of high T2 signal (yes versus no) 1.142 9.822 0.906 106.436 0.060 Second selection Intercept −0.9639 0.0215 Foci of high T2 signal (yes versus no) 1.3386 14.545 2.811 75.270 0.0014 imaging characteristics that were significantly correlated lipoma, increasing the accuracy of our readers and the with the final pathologic diagnosis. (is analysis is shown in formula (Figure 2). Table 3, and only foci of high T2 signal remains in the model (e final case is a 51-year-old female with a 10 cm li- following selection, indicating that it is most strongly as- pomatous lesion of the right thigh. All four expert observers sociated with the final diagnosis. Foci of high T2 signal was predicted the lesion to be an ALT/WDL, while the formula present in 16/18 (88.9%) ALT/WDLs and in 20/31 (64.5%) (with score of 22) predicted the lesion to be a benign lipoma. lipomas. Initial pathology report was read as ALT/WDL. Subsequent MDM2 FISH was negative for gene amplification, and given the histologic concern for atypia, the FISH was again re- 4. Case Illustrations peated and found to again be negative, confirming the di- agnosis of lipoma and changing the pathologic diagnosis (ree cases from this cohort were selected in order to (Figure 3). highlight the significance of MDM2 FISH and the difficult agreement between MRI interpretation and pathology. (e first is the case of a 42-year-old male with a 12 cm lipo- 5. Discussion matous tumor in the left shoulder. Based on MR imaging, 4/4 expert observers, in addition to the formula (score of 34), Liposarcomas represent approximately 20% of all soft tissue predicted the lesion to be a benign lipoma. Initial pathology sarcomas and are divided into various subtypes including was concerning ALT/WDL, which was subsequently over- atypical lipomatous tumors/well-differentiated liposarcomas turned following MDM2 FISH because there was no (ALT/WDLs), de-differentiated liposarcoma, myxoid lip- amplification of the MDM2 gene. (e second is the case of osarcoma, round cell liposarcomas, and pleomorphic lip- a 69-year-old male with a 2 cm lesion in the left arm. Again, osarcomas. ALT/WDLs are often difficult to distinguish all four expert observers and the formula (score of 24) from benign lipomas on MRI [1, 2, 6, 9, 10] and have predicted the lesion to be a benign lipoma, but pathology was different treatments as well as prognosis. On MRI, concerning ALT/WDL. Following MDM2 FISH, the path- ALT/WDLs are known for having thick septa, lack of capsule ologic diagnosis was subsequently confirmed to be a benign with less well-defined margins, nodularity, internal cystic Sarcoma 5 (a) (b) Figure 2: (a) Axial T1 MR of left shoulder with 12 cm lipomatous tumor. Formula and expert observers predicted benign lipoma, while initial pathology was concerning ALT/WDL. Lack of MDM2 amplification with FISH confirmed a diagnosis of benign lipoma. (b) Axial T1 MR of the left arm with 2 cm lipomatous tumor. Formula and expert observers predicted benign lipoma, which was later confirmed by lack of MDM2 amplification through FISH after initial pathology was concerning ALT/WDL. (a) (b) Figure 3: (a) Coronal T1 and (b) axial STIR MR images of the right thigh lipomatous tumor. Expert observers interpreted the lesion as heterogeneous, containing stranding, and having foci of high T2 signal. All four readers interpreted the tumor as ALT/WDL in addition to initial pathology interpreted as ALT/WDL. MDM2 amplification during FISH analysis confirmed benign lipoma on two separate occasions, illustrating the variability that can be seen within simple lipomas. changes, heterogeneity, and enhancement on T2-weighted however, found that there was a 60% local recurrence rate if imaging. Meanwhile, lipomas are characteristically homo- extremity tumors were treated with marginal excision, geneous and encapsulated lesions composed of pre- which decreased to 11% when treated with wide local dominantly mature adipose tissue. However, they may excision [5]. (e appropriate treatment remains debated, contain thin enhancing septa, be unencapsulated, or have however, as some advocate for marginal excision with or heterogeneity due to regions of fat necrosis, infarction or without radiation therapy given low rates of local re- nonfatty tissue, and creating concern for ALT/WDLs on currence and the morbidity associated with wide resection MRI interpretation [1, 2, 6, 9]. [4, 11, 12]. Importantly, many of these studies on local (e importance of distinguishing between lipoma and recurrence rates were not based on molecular analysis for ALT/WDLs preoperatively is well recognized. For many diagnosis, and therefore, may have had inaccurate cate- providers, ALT/WDLs receive wide local excision rather gorization of lipomatous tumors, leading to falsely low than marginal excision to decrease the risk of local re- recurrence rates if lipomas were regarded as ALT/WDLs. currence. Following surgery for ALT/WDLs, recurrence Furthermore, ALT/WDLs have the potential for delayed rates vary from 13.9 to 69% [2, 11]. Lucas and colleagues, malignant de-differentiation and subsequent metastasis. 6 Sarcoma musculoskeletal radiologists. Collectively, our expert ob- Due to this potential for delayed de-differentiation as well as the higher local recurrence rates compared to li- servers had an accuracy of 73% for predicting the final pathologic diagnosis, which is consistent with prior reports. pomas, the importance of continued surveillance post- operatively regardless of surgical margin is well established A PPV of 60% and NPV of 87.5% indicated a tendency to [1, 2, 6, 11–14]. overdiagnose ALT/WDL, as reported by prior authors [1, 2]. Previous publications have shown relatively poor ac- (e formula proposed by Wang et al. showed an accuracy of curacy for MRI predicting the pathologic diagnosis. 71.4% with a 57% PPV and 87% NPV, slightly under- O’Donnell and colleagues found a 69% overall accuracy performing our expert observer’’s interpretation. (is dif- for expert observers predicting the pathologic diagnosis ference, however, was not statistically significant. Unlike the study by Wang et al., all of the tumors included in our study based on the WHO criteria, while Gaskin and Helms found an 83% specificity and a 38% PPV [1, 2]. (ese studies were deep to fascia, making it more difficult to discern li- poma from ALT/WDLs. (is may account for the reduced noted a propensity for MRI interpreters to overdiagnose ALT/WDLs, leading to unnecessary patient worry and accuracy of the formula seen in our cohort. Of the various MRI features tested, foci of high T2 signal more invasive surgical intervention. In an effort to create a more objective interpretation of imaging findings, Wang intensity had the highest correlation with a diagnosis of and colleagues devised a scoring system based on MR ALT/WDL, unlike the study by Wang et al., which found imaging features which were found to be correlated to the internal cystic change, nodules, and thick septum to be more final pathologic diagnosis in their series [7]. In their study, predictable factors [7]. However, it is important to note that all ALT/WDLs had a Z score of >35 and 30/34 benign foci of high T2 signal were also present in 64.5% of benign lipomas had a Z score of≤35. (erefore, they proposed this lipomas. (is highlights the variability of these tumors and reveals a multitude of MRI findings based on a representa- scoring system as a potential alternative to invasive bi- opsies for preoperative decision-making. (ese authors, tive cohort. (is can be seen in other areas throughout the current literature; for example, O’Donnell and colleagues similar to others looking at the accuracy of MRI, utilized the WHO criteria for final pathologic diagnosis rather than focused on stranding, nodularity, and size as the de- terminant factors for diagnosis [1]. MDM2 amplification. (erefore, some tumors may have been misclassified, requiring revalidation of the scoring We continue to understand the utility of MR imaging for system. the generation of a differential diagnosis and preoperative Not only can it be difficult to determine lipoma from planning. However, based on our results, we do caution ALT/WDLs for the radiologist, it can also pose a challenge readers that MRI should not be used in isolation for di- to the pathologist. Histologically, the degree of atypia may agnosis. At this stage, despite numerous advances, we feel be overestimated or confounded by fat necrosis, especially that further study is required for alternative and less invasive means of diagnosis to guide appropriate management of in borderline cases [3, 8]. Furthermore, tumor heteroge- neity can lead to sampling error and inaccurate histologic these lesions preoperatively. Furthermore, we recognize that MDM2 FISH (or MDM2/CDK4 IHC) may not be available diagnosis. (is difficulty can be seen in our three case examples above, which all had concerning features on at all institutions, especially given its high cost. While all initial pathology. With advances in modern molecular lesions do not necessarily require MDM2 FISH, we agree analysis, however, the gold standard for pathologic di- with Clay and colleagues that when lesions are recurrent, agnosis of ALT/WDLs has changed. Specifically, murine deep and >10.0 cm, have equivocal atypia, and are con- double minute 2 (MDM2) has been found to be amplified cerning on MR imaging, they warrant investigation with in all ALT/WDLs [10]. (e use of immunohistochemistry MDM2 for definitive diagnosis [3]. (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 ter- 6. Conclusion tiary referral centers. However, for borderline cases, MDM2 FISH has been shown to be required for accurate While MDM2 FISH has affected the confidence with which pathologic diagnosis given the potential for sampling error pathologists can diagnose ALT/WDLs, it remains difficult on biopsy and subjective interpretation of MDM2 im- for expert observers to distinguish them from benign li- munohistochemistry [8, 15]. Meanwhile, MDM2 FISH has pomas on imaging. Based on the data presented here, been shown to have 100% sensitivity and specificity even on expert readers of MRI have an accuracy of 73% in dis- core needle biopsy [16]. (is new criterion was the focus of tinguishing lipoma from ALT/WDL, which is consistent the current study. (e goal was to reassess the ability of with prior reports. (e use of MDM2 FISH for pathologic expert observers to distinguish lipoma from ALT/WDL on diagnosis, while more reliable than the WHO criteria, has MRI, given the increased accuracy of pathologic diagnosis not changed the accuracy of MRI interpretation. Fur- of these tumors using MDM2 as the gold standard. As thermore, the proposed scoring system by Wang et al. was stated previously, 44 patients had final pathology de- found to have less utility than previously reported, with an termined by MDM2 FISH, and 5 patients had IHC for final accuracy of 71%. 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