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Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities

JUN NISHIO, SHIZUHIDE NAKAYAMA, YOSHIRO CHIJIIWA and MIKIKO AOKI
Anticancer Research October 2023, 43 (10) 4295-4301; DOI: https://doi.org/10.21873/anticanres.16624

Abstract

Adipocytic neoplasms are frequently encountered in clinical practice. Atypical lipomatous tumor (ALT) is a locally aggressive but non-metastasizing adipocytic neoplasm that primarily occurs in the proximal extremities of middle-aged to older adults. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing and inflammatory subtypes. The sclerosing subtype is an unfavorable prognostic factor for local recurrence. ALT is characterized by supernumerary ring and/or giant rod chromosomes. These rings and giant markers invariably contain amplified sequences originating from the long arm of chromosome 12, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. Confidently differentiating deep-seated ALT from deep-seated ordinary lipoma is often difficult on imaging. Moreover, the sclerosing subtype may mimic a higher grade liposarcoma. Detection of MDM2 amplification by fluorescence in situ hybridization would be helpful diagnostically for ALT in more difficult cases. The standard treatment for deep-seated ALT is surgery. Although there is no consensus on the best surgical approach for deep-seated ALT of the extremities, the use of marginal resection is acceptable to preserve musculoskeletal function. This review provides an overview of the current knowledge on the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.

Key Words:

Adipocytic tumors are the most common mesenchymal neoplasms of the extremities and represent a biologically and histologically diverse group. Many of these tumors are atypical lipomatous tumor (ALT) or ordinary lipoma (1). ALT is a locally aggressive mesenchymal neoplasm composed entirely or in part of mature adipocytic proliferation demonstrating at least focal nuclear atypia in both adipocytes and stromal spindle cells. Deep-seated ALT of the extremities shows no potential for metastasis unless it undergoes dedifferentiation. ALT is characterized by the presence of supernumerary ring and/or giant rod chromosomes. These rings and giant markers are composed, exclusively or partly, of amplified 12q13-15 material, including the MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4) gene (2). MDM2 amplification is considered to represent one of the earliest events in the formation of ALT (3). In our experience, distinguishing ALT from ordinary lipoma can be challenging based on preoperative imaging features alone, especially if they occur in deep anatomical sites. Surgery is the mainstay of treatment for ALT. However, there is no consensus regarding the best surgical treatment for deep-seated ALT of the extremities. This review highlights the clinical and imaging characteristics, pathogenesis, histopathology, and management of deep-seated ALT of the extremities.

Clinical Characteristics

ALT can occur at any age but has a peak incidence in the fifth to seventh decades of life, with no sex predilection (3). It most frequently occurs in the deep soft tissue of the extremities, especially the thigh. The retroperitoneum, trunk and paratesticular area are also commonly involved (4). In our experience, occurrence in the superficial soft tissue is rare. ALT usually presents as a painless, slowly growing mass that can attain a very large size. In the retroperitoneum, ALT may be detected incidentally during radiological imaging. The diameter ranges from 2.0 to 35 cm (median of 18 cm) (5). The most important prognostic factor is its anatomical location. The local recurrence rates for ALT of the extremities have shown great variance in the literature (8-52%) (5-8). The median time to local recurrence is 48 months from the date of surgery (5). There is controversy regarding the appropriate length of follow-up. In our opinion, patients with deep-seated ALT of the extremities should be followed up for at least 5 years after surgery. The ultimate risk of dedifferentiation is probably less than 2% in the extremities (5). Deep-seated ALT of the extremities shows no potential for metastasis unless it undergoes dedifferentiation.

Imaging Features

Various imaging modalities have been applied for the detection and follow-up of ALT. Although the use of ultrasonography as a diagnostic modality is expanding, it is currently still limited. In our experience, magnetic resonance imaging (MRI) is the mainstay of imaging in ALT. It is essential to be familiar with the key imaging features of ALT for its accurate diagnosis and appropriate management.

Radiographs may depict the presence of a soft-tissue mass but are rarely specific. Calcification or metaplastic ossification can be seen in 10-32% of cases (9). Ultrasonography shows a heterogeneous, multilobulated, typically well-defined mass. The presence of hyperechoic foci suggests fat (9). Computed tomography (CT) reveals a predominantly fatty mass with thick irregular septa and/or nodular or patchy non-adipose components. In general, these lesions contain at least 75% adipose tissue (9). Contrast-enhanced CT demonstrates significant enhancement of the septa and non-adipose components. On MRI, ALT typically shows a multinodular, well-defined, predominantly fatty mass with thick septa (>2 mm) and/or nodular or patchy non-adipose components (10) (Figure 1). In contrast to ALT, ordinary lipoma usually lacks thick septa and associated nodular or globular areas (11). In our experience, the non-adipose components display a non-specific reduced signal intensity on T1-weighted images and variably increased signal intensity on T2-weighted images. Contrast-enhanced MRI demonstrates moderate to marked enhancement in the septa and non-adipose components (10). Gadolinium contrast enhancement patterns and degree may be helpful in distinguishing ALT from ordinary lipoma. Recently, Kawaguchi et al. reported that the maximum diameter, the proportion of non-adipose area on T1-weighted images and solid hyperintense area on fat-suppressed T2-weighted images were useful MRI features for differentiating ALT from spindle-cell lipoma (12). Position-emission tomography features for ALT have been described in the literature (13-16). Integrated positron-emission tomography/CT images show low fluorodeoxyglucose uptake by the lesion, with a maximum range of standardized uptake value (SUVmax) of 0.8-3.9 (15). However, there was no statistically significant difference between the mean SUVmax values of ALT and ordinary lipoma (15). In our opinion, differentiating between ALT and ordinary lipoma may be difficult even after good MRI due to their similar imaging appearance.

Figure 1.
Figure 1.

Magnetic resonance imaging of atypical lipomatous tumor in the right thigh of a 70-year-old woman. Coronal T1-weighted image (A) revealed a large, well-defined, fatty mass with irregularly thickened, linear septa. Axial T1-weighted (B) and T2-weighted (C) images also demonstrated a lipomatous mass with prominent thickened and nodular septa.

Pathogenesis

ALT is characterized by supernumerary ring and/or giant marker chromosomes (Figure 2), usually as the sole anomaly or concomitant with a few other numerical or structural abnormalities (2). Random and nonrandom telomeric associations can be found (17). Both ring and giant marker chromosomes are mainly composed of amplified sequences from the 12q14–15 region, with MDM2 being the main driver gene. Other genes in this region are frequently co-amplified with MDM2, including CDK4, high mobility group AT-hook 2 (HMGA2), tetraspanin 31 (TSPAN31), carboxypeptidase M (CPM), YEATS domain containing 4 (YEATS4) and fibroblast growth factor receptor substrate 2 (FRS2) (2, 18-21). Interestingly, YEATS4 and CPM are known to be involved in the dedifferentiation process (22). In addition to 12q14-15 amplification, high-level amplification of 1q21–23 involving NBPF member 12 (NBPF12) and peptidylprolyl isomerase A like 4A (PPIAL4A) is frequently found in ALT (23). The functional significance of these genes remains unclear. Recently, Asano et al. reported that discoidin domain receptor tyrosine kinase 2 (DDR2) (1q23) was amplified in 26% of ALTs (24). Importantly, MDM2 (and/or CDK4) amplification is not seen in benign adipocytic tumors, and its detection can therefore be used as an ancillary diagnostic technique for the diagnosis of ALT.

Figure 2.
Figure 2.

Metaphase cell (GTG-banding) of atypical lipomatous tumor displaying a ring chromosome (arrow).

Histopathology

Grossly, ALT usually appears as a large (>10 cm), lobulated, well-circumscribed mass with a paler yellow cut surface (Figure 3). Fat necrosis may be seen in larger lesions. Histologically, ALT is divided into adipocytic (lipoma-like), sclerosing, and inflammatory subtypes (4), with lipoma-like ALT being predominant. In contrast to ordinary lipoma, ALT shows at least focal nuclear atypia in adipocytes or stromal cells. Lipoma-like ALT is composed of mature fat cells with a significant variation in size (Figure 4A) and atypical, hyperchromatic stromal spindle cells (Figure 4B). A variable number of lipoblasts may be seen (Figure 4C). Mitotic figures are rare. Sclerosing ALT occurs most often in the retroperitoneum and shows scattered bizarre stromal cells exhibiting marked nuclear hyperchromasia in an extensive fibrillary collagenous stroma. Inflammatory ALT is the rarest subtype and shows a dense, typically lymphoplasmacytic, chronic inflammatory infiltrate with lymphoid follicles within the adipocytic component. Immunohistochemically, diffuse nuclear expression of MDM2 (Figure 4D) and/or CDK4 is seen in the vast majority of ALTs (4). Use of the combination of staining for P16, MDM2, and CDK4 is helpful in distinguishing ALT from other adipocytic neoplasms, including ordinary lipoma (25). Recently, Jing et al. suggested that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT (26). In our opinion, fluorescence in situ hybridization for MDM2 remains the gold standard and the most recommended method to diagnose ALT (Figure 5).

Figure 3.
Figure 3.

Gross appearance of atypical lipomatous tumor showing a well-circumscribed, lobulated mass.

Figure 4.
Figure 4.

Histological and immunohistochemical features of atypical lipomatous tumor. A: The tumor was composed of mature adipocytes with a substantial variation in size (hematoxylin and eosin staining, original magnification ×100). B: Atypical, hyperchromatic stromal spindle cells are identified within fibrous septa (hematoxylin and eosin staining, original magnification ×200). C: A variable number of lipoblasts can be seen (hematoxylin and eosin staining, original magnification ×200). D: The tumor cells were focally positive for MDM2 proto-oncogene (original magnification ×200).

Figure 5.
Figure 5.

Dual-color interphase fluorescence in situ hybridization analysis using probes for MDM2 proto-oncogene (MDM2) (red signal) and centromere of chromosome 12 (green signal) demonstrating high-level amplification of MDM2. Nuclei were counterstained with 4′,6-diamidino-2-phenylindole and appear blue.

Management

The standard treatment for ALT is surgery. There is controversy regarding optimal surgical margins for deep-seated ALT of the extremities. Several authors have proposed the use of marginal resection for deep-seated ALT of the extremities (8, 27-30). Chang et al. showed that the postoperative complication rate was higher in the wide resection group than in the marginal resection group, and the local recurrence rate was similar in these two groups (27). If the tumor occurs in close proximity to vessels or nerves essential for function, wide resection may result in severe surgical morbidity. Furthermore, Olson et al. found that microscopically positive margins were not associated with an increased risk of local recurrence (30). On the other hand, Kito et al. reported that the local recurrence and dedifferentiation rates were both 0% for the wide resection group but 23% and 3% for the marginal resection group, respectively (31). They have suggested that wide resection is necessary to prevent local recurrence, dedifferentiation, and residual tumor. However, a recent systematic review revealed that the local recurrence rate was not significantly higher in the marginal resection group (32). A scheduled R1 marginal resection is easy because the tumor capsule is completely individualized. In our opinion, marginal resection is acceptable for deep-seated ALT of the extremities. It should be kept in mind that the sclerosing subtype is an unfavorable prognostic factor for local recurrence and may be associated with an increased propensity for dedifferentiation (33-35).

Radiation therapy (RT) can be used as an adjuvant treatment strategy to improve local tumor control. Although the role of RT in management of deep-seated ALT of the extremities is controversial, several studies have shown that RT in combination with surgery is associated with a lower risk of local recurrence (36-39). Radiation doses typically range from 50 to 70 Gy (39). Long-term risk of radiation-induced sarcomas has not been reliably assessed in these studies. Kang et al. suggested that a combination of re-resection and RT might provide long-term local control with acceptable morbidity for recurrent or residual diseases (36). Similarly, Fonseca et al. showed that RT was associated with a lower rate of second recurrence and suggested that it should be considered in ALT patients with recurrent diseases (37). The French Sarcoma Group reported that the 5-year local recurrence-free survival rates were 98.3% versus 80.3% in patients treated with and without adjuvant RT, respectively (p<0.001) (38). More recently, Lawrenz et al. indicated that adjuvant RT after primary resection of ALT of the extremities was associated with a significantly reduced risk of local recurrence but a three-fold increase in the rate of complications requiring medical or surgical management (39). On the other hand, Sommerville et al. have suggested that RT should not be used for deep-seated ALT of the extremities because dedifferentiation is extremely rare and RT may play a role in its causation (7). It has also been shown that recurrent disease is almost always amenable to re-resection (29). Further clinical trials are needed to better define optimal treatment approaches for deep-seated ALT of the extremities.

There is a question as to whether all deep-seated ALT of the extremities need to be removed. Sometimes, this disease appears to stop growing or give minimal or no symptoms (1). Recently, Vos et al. reported the natural history of 24 patients with ALT of the extremities (40). Of these 24 patients, four eventually underwent surgery after a period of active surveillance (range=14-52 months) because of symptoms or tumor growth. The remaining 20 patients were under active surveillance (median follow-up of 26 months). They concluded that active surveillance was a reasonable option for selected patients with deep-seated ALT of the extremities, in particular for elderly patients with comorbidities and no/minimal symptoms. However, further prospective studies are required to assess the safety of active surveillance as a treatment option in patients with deep-seated ALT of the extremities.

Conclusion

ALT is an intermediate (locally aggressive) mesenchymal neoplasm characterized by the presence of supernumerary ring and/or giant marker chromosomes. Deep-seated ALT of the extremities shows no potential for metastasis unless it undergoes dedifferentiation. ALT should be considered a possible diagnosis when a large (>10 cm), predominantly fatty mass with thick septa (>2 mm) and septal enhancement is seen in the deep soft tissue of the lower extremities, especially in middle-aged to older adults. The sclerosing subtype may mimic a higher grade liposarcoma on imaging and this is an unfavorable prognostic factor for local recurrence. Detection of MDM2 amplification by fluorescent in situ hybridization would be helpful diagnostically for ALT in more difficult cases. We believe that marginal resection is a reasonable surgical approach for deep-seated ALT of the extremities because this disease has a relatively good prognosis and local recurrence can be managed with re-resection.

Acknowledgements

This study was supported in part by the Japan Society for the Promotion of Science KAKENHI (21K09336).

Footnotes

  • Authors’ Contributions

    JN searched the literature and drafted the article. SN and YC reviewed the article. MA performed the histopathological evaluations. All Authors read and approved the final article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest associated with this article.

  • Received July 10, 2023.
  • Revision received August 1, 2023.
  • Accepted August 4, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Biology and Management of Deep-seated Atypical Lipomatous Tumor of the Extremities
JUN NISHIO, SHIZUHIDE NAKAYAMA, YOSHIRO CHIJIIWA, MIKIKO AOKI
Anticancer Research Oct 2023, 43 (10) 4295-4301; DOI: 10.21873/anticanres.16624
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