Spindle cell lipoma (SCL) is a relatively rare, benign adipocytic tumor composed of a variable mixture of mature adipocytes, bland spindle cells and ropey collagen bundles. Pleomorphic lipoma (PL) lies on a morphological spectrum with SCL and is characterized by pleomorphic spindle cells and multinucleated floret-like giant cells (1). The etiology of SCL/PL remains unknown. SCL/PL can show a morphological overlap with a variety of soft-tissue tumors, including atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT), atypical lipomatous tumor (ALT), solitary fibrous tumor (SFT), myxoid liposarcoma (MLS) and dedifferentiated liposarcoma (DDLS). In our opinion and experience, the imaging appearance of SCL/PL is not pathognomonic and reflects the histological composition of the lesion which contains variable amounts of adipose and non-adipose tissue. Advances in knowledge of the imaging, histopathology and genetics of SCL/PL are leading to more accurate diagnosis and appropriate treatment. This review highlights the clinical, radiological, histological, immuno-histochemical, cytogenetic and molecular genetic features of SCL/PL. In addition, we will discuss the differential diagnosis of SCL/PL.

SCL/PL can occur at any age but has a peak incidence in the fifth to seventh decades of life, with a marked male predominance (approximately 90%) (1). It typically presents as a solitary, mobile, slow-growing, painless, subcutaneous mass in the posterior neck, upper back, and shoulder (shawl distribution). Occasional lesions are multifocal or arise in a familial setting (2). Fascial and skeletal muscle involvement is uncommon. In women, SCL is more likely to occur outside the shawl distribution and in a younger age group (3). The diameter ranges from 1.0 to 14.0 cm (usually less than 5 cm) (4). Simple excision is the treatment of choice and prognosis is excellent. There is no metastatic potential and no reports of malignant transformation.

Various imaging modalities have been applied for the detection of SCL/PL. Although identification of fat within the lesion is the most important clue to make diagnosis of adipocytic tumors on imaging, it is recognized that SCL/PL may have minimal or no visible fat. It is essential to be familiar with the key imaging features of SCL/PL to avoid an unnecessary radical surgery.

Radiographs may be unremarkable or reveal a soft-tissue mass depending on the size and location of the lesion. Although cases of bone erosion have been described (5,6), the underlying bone is typically normal. Ultrasound shows non-specific soft-tissue echogenicity with moderate internal Doppler vascularity in the non-adipose component (7). Computed tomography (CT) reveals a well-defined soft-tissue mass with slightly increased attenuation compared with that of subcutaneous fat in the adipose component and slightly low attenuation compared with that of skeletal muscle in the non-adipose component (8). Contrast-enhanced CT demonstrates significant enhancement in the non-adipose component (7-10). In our experience, the non-adipose component is best detected and evaluated with magnetic resonance imaging (MRI). On MRI, the lesion is usually well-defined and contains variable amounts of adipose and non-adipose components (7-12) (Figure 1). In general, many lesions contain between 25% and 75% fat (10). However, a significant number of SCL/PLs may exhibit a “low-fat” or “fat-free” appearance that can mimic more aggressive tumors such as MLS, DDLS and non-adipocytic sarcomas (7,11,12). The non-adipose component displays isointense relative to skeletal muscle on T1-weighted images and variable signal intensity on T2-weighted images. Contrast-enhanced MRI demonstrates intense enhancement in the non-adipose component (10,12). 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 SCL/PL from ALT (13). To date, position-emission tomography (PET) features for SCL/PL have been described in only three cases (7). Integrated PET/CT images show increased uptake in the non-adipose component, with a standardized uptake value (SUV) range of 2.0-8.0. In our opinion, SCL/PL should be considered a possible diagnosis when a well-defined, complex, fatty mass is encountered in the subcutis of a middle-aged man.

Grossly, SCL/PL appears as an oval or discoid, well-circumscribed mass with a yellow or grayish white cut surface (1). Histologically, SCL is composed of variable distributions of mature adipocytes, bland spindle cells and ropey collagen bundles (Figure 2). The ratio of the spindle cells and mature adipocytes is variable, but the great majority of cases have significant amounts of both components. In the other end of the spectrum, PL is characterized by the presence of pleomorphic spindle cells and multinucleated floret-like giant cells. Occasional lipoblasts can be present in a significant subset of cases (14). Mitotic figures are rare, and necrosis is absent. There is relatively sparse vascularity, of small to medium-sized thick-walled, sometimes hyalinized vessels. A variety of variants of SCL have been described including low-fat, fat-free, (pseudo)angiomatous, fibrous, myxoid and plexiform subtypes (1,15-19). Immunohistochemically, the spindle, pleomorphic and multinucleated floret-like cells are diffusely positive for CD34 (Figure 3) and show loss of nuclear RB transcriptional corepressor 1 (RB1) protein expression (20). Immunostainings for S-100 protein, desmin and smooth muscle actin (SMA) are typically negative.

SCL and PL show similar cytogenetic aberrations which are usually more complex than conventional lipoma (21). SCL/PL displays unbalanced karyotypes, mostly hypodiploid, with multiple partial losses. Structural rearrangements, mainly deletions, of chromosome arm 13q or losses of whole chromosome 13 are the most common cytogenetic aberrations (22). The related region (13q14) contains the RB1 gene. Fluorescence in situ hybridization (FISH) analyses have revealed a heterozygous deletion of RB1 in a subset of SCL/PLs (22,23). Single nucleotide polymorphism array analyses have identified two minimally deleted regions in 13q14 in SCL (24). The first region includes RB1, lysophosphatidic acid receptor 6 (LPAR6), RCC1 and BTB domain containing protein 2 (RCBTB2) and cysteinyl leukotriene receptor 2 (CYSLTR2). The second region lies between the genes fibronectin type III domain containing 3A (FNDC3A) and transmembrane phosphoinositide 3-phosphatase and tensin homolog 2 pseudogene 3 (TPTE2P3, formerly LOC220115) and harbors 34 genes including SPRY domain containing 7 (SPRDY7, formerly C13orf1), dehydrogenase/reductase 12 (DHRS12), ATPase copper transporting beta (ATP7B), ALG11 alpha-1,2-mannosyltransferase (ALG11) and vacuolar protein sorting 36 homolog (VPS36) and the two microRNA genes miR-15a and miR-16-1. Recently, Uehara et al. reported that SCL/PL expressed decreased levels of forkhead box O1 (FOXO1) and RB1 and showed the activation of p38 mitogen-activated protein kinase (MAPK) pathway induced by oxidative stress (25). In addition to 13q deletions, SCL/PL also shows chromosome 16q losses with partial monosomy (26). The involved genes have not been specifically identified in this region. In our extensive experience, SCL/PL lacks amplification of murine double minute 2 (MDM2).

Deletion of RB1 is shared with a group of morphologically similar spindle cell tumors with variable admixed fat and immunohistochemically overlapping features, including SCL/PL, ASCPLT, mammary-type myofibroblastoma and cellular angiofibroma (CAF) (27). RB1 loss has also been described as a recurrent finding in other mesenchymal neoplasms such as pleomorphic fibroma (28) and superficial acral fibromyxoma (29). The current World Health Organization classification of soft-tissue tumors suggests that these lesions are typically benign and are mainly seen in the older adult population. It is of interest that RB1 has been implicated in the regulation of adipocyte differentiation (30,31).

The differential diagnosis for SCL/PL is broad due to its varying morphology and includes benign, intermediate, and malignant soft-tissue tumors such as ASCPLT, CAF, ALT, fat-forming SFT, MLS and DDLS (Table I).

ASCPLT is a new entity of benign adipocytic neoplasm that usually presents as an enlarging or persistent mass in the extremities and limb girdles, sometimes with tenderness. It can occur at any age but has a peak incidence in the sixth decade of life, with a slight male predominance. The diameter ranges from 0.5 to 28.0 cm (32). ASCPLT has a low rate of non-destructive local recurrence (10-15%) (32). Importantly, there is no risk for dedifferentiation or metastasis. There is only limited description of the imaging appearance of ASCPLT (33-35). On MRI, the lesion displays variable signal intensity on T1- and T2-weighted images. ASCPLT and SCL/PL tend to have similar enhancement patterns on T1-weighted images (33). Preoperative imaging diagnosis is difficult, and histopathological and molecular evaluations are required for a definite diagnosis. Histologically, ASCPLT shows infiltrative margins and demonstrates atypical hyperchromatic spindle cells, pleomorphic lipoblasts and bizarre pleomorphic (multinucleated) cells with mitotic activity in contrast with SCL/PL. ASCPLT typically lacks ropey collagen bundles. ASCPLT and SCL/PL share similar immunohistochemical features such as CD34 positivity and loss of RB1 protein expression (50-70%) (32). In addition, ASCPLT shows variable expression of S100 protein and desmin. Weak and/or focal expression of MDM2 or cyclin-dependent kinase 4 (CDK4) may be seen, but the combination of MDM2 and CDK4 expression is not compatible with a diagnosis of ASCPLT (36). Molecular studies have shown that deletions of 13q14 in ASCPLT are more extensive and complex than in SCL/PL, including multiple functionally important exons of RB1 and its adjacent genes RCBTB2, deleted in lymphocytic leukemia 1 (DLEU1) and integral membrane protein 2B (ITM2B) (37). Moreover, monosomy 7 has been described in a subset of ASCPLTs (36,38). MDM2 or CDK4 amplification is absent in ASCPLT.

CAF is a benign fibroblastic tumor that usually presents as a slow-growing, painless, subcutaneous mass in the vulvovaginal region for women and the inguinoscrotal region for men. It has a peak incidence in the fifth decade of life in women and the seventh in men, with no sex predilection. The diameter ranges from 0.6 to 25.0 cm (39). Simple excision is the treatment of choice and local recurrence is uncommon. On MRI, the lesion is well-defined and displays intermediate or low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images (40). Contrast-enhanced MRI demonstrates intense heterogeneous enhancement. The presence of intralesional fat has been reported in up to 56% of CAF (41). CAF has some morphological overlap with SCL/PL. Histologically, the lesion consists of uniform, short spindle-shaped cells in an edematous to fibrous stroma. Mature adipocytes are observed in close to 50% of cases (39). In contrast with SCL/PL, there are numerous small to medium-sized thick-walled blood vessels, often with perivascular fibrosis or hyalinization. CAF and SCL/PL share similar immunohistochemical features such as CD34 positivity (30-60%) and loss of RB1 protein expression (39). Moreover, CAF shows expression for estrogen receptor and progesterone receptor (42). Variable expression of SMA and desmin is seen in a minority of cases (39). Genetically, loss of 13q14, including RB1, is characteristic of CAF as well as SCL/PL (27,43-46).

ALT is an intermediate (locally aggressive) mesenchymal neoplasm that usually presents as a deep-seated, painless mass in the lower extremities, trunk, and retroperitoneum. It most commonly occurs in middle-aged and older adults, with no sex predilection (47). Unlike SCL/PL, ALT shows a significant propensity for local recurrence and can dedifferentiate to DDLS (incidence up to 10%) (48). Radiographs may depict the presence of a soft-tissue mass. Calcification is seen in 10-32% of cases (49). Ultrasound reveals a heterogeneous, multilobulated, typically well-defined mass. The presence of hyperechoic foci suggests fat (49). On CT and MRI, ALT shows a predominantly adipose mass with irregularly thickened, linear, swirled and/or nodular septa. Generally, the lesion contains at least 75% adipose tissue (49). In our experience, the non-adipose component displays non-specific decreased signal intensity on T1-weighted images and variably increased signal intensity on T2-weighted images. Contrast-enhanced MRI usually demonstrates significant enhancement in the non-adipose component (50). Histologically, ALT may be indistinguishable from fat-rich SCL/PL. However, the spindle cells seen in ALT contain more irregular, enlarged, hyperchromatic nuclei. In contrast to SCL/PL, ALT usually lacks ropey collagen bundles. Immunohistochemically, nuclear expression of MDM2 and/or CDK4 is seen in most cases (47). Unlike SCL/PL, ALT is cytogenetically characterized by the presence of one or more supernumerary ring and/or giant marker chromosomes containing amplified chromosome 12 sequences (21). Moreover, MDM2 and/or CDK4 amplification is present in ALT. Detection of MDM2 (and/or CDK4) amplification by fluorescence in situ hybridization (FISH) serves to distinguish ALT from SCL/PL.

SFT is an intermediate (rarely metastasizing) mesenchymal neoplasm that usually presents as a slow-growing, painless mass in the pleura, abdominal cavity, extremities and head and neck. It most commonly occurs in middle-aged adults, with no sex predilection (51). Wide excision is the current treatment mainstay. Local recurrence occurs in 10-40% of cases and distant metastases develop in up to 35-45% of cases (51,52). Dedifferentiation can occur at the end of the transforming histological stage of SFT. Radiographs may reveal a non-specific soft-tissue mass. Calcification is rare, occurring in about 9% of cases (53). Ultrasound generally shows a heterogeneous, well-defined, hypoechoic mass (54). CT reveals a well-defined, occasionally lobulated mass of similar attenuation to that of skeletal muscle. Contrast-enhanced CT demonstrates mild to marked heterogeneous enhancement (54). On MRI, the lesion is well-defined and displays isointense signal intensity on T1-weighted images and variable signal intensity on T2-weighted images (55). Contrast-enhanced MRI demonstrates strong focal or diffuse enhancement. In our experience, the presence of prominent collateral feeding vessels is a useful distinguishing imaging feature of SFT. Histologically, the lesion consists of uniform ovoid to spindle-shaped cells with a patternless architecture embedded in a variably collagenous stroma. Some SFTs contain a component of mature adipose tissue (56). This SFT variant (fat-forming SFT) can be confused with SCL/PL. In contrast with SCL/PL, SFT typically contains branching and hyalinized staghorn-like blood vessels. Immunohistochemically, SFT typically shows diffuse expression of CD34, CD99 and BCL2 (57). Importantly, immunostaining for signal transducer and activator of transcription 6 (STAT6) reliably distinguishes SFT from SCL/PL (58). The discovery of a NGFI-A binding protein 2 (NAB2)-STAT6 fusion gene has recently led to more precise diagnosis of SFT (59). Unlike SCL/PL, SFT is not characterized by deletion of RB1 and corresponding nuclear loss of expression for RB1 (20,60).

MLS is a malignant adipocytic neoplasm that typically presents as a large, painless mass in the proximal lower extremities. It has a peak incidence in the fourth to fifth decades of life, with no sex predilection (61). Wide excision with or without radiotherapy is the treatment of choice. Local recurrence occurs in 12-25% of cases and distant metastases develop in about 30-60% of cases (61). The presence of a round cell component is associated with a significant higher rate of metastasis and an overall adverse outcome. Unlike other soft-tissue sarcomas, MLS shows a high incidence of extrapulmonary metastasis to the soft tissues and bones. Radiographs may be normal or reveal a non-specific soft-tissue mass. Calcification is uncommon. Ultrasound shows a heterogeneous, well-defined, hypoechoic but solid, non-cystic mass with posterior acoustic enhancement (49). CT reveals a well-defined, lobular mass with low attenuation compared with that of skeletal muscle (49). On MRI, the lesion is well-defined and displays low to intermediate signal intensity with lacy, linear, or amorphous high signal intensity foci on T1-weight images and predominantly high signal intensity on T2-weight images (62). Contrast-enhanced MRI typically demonstrates avid heterogeneous enhancement. Histologically, MLS consists of uniform ovoid cells and a variable number of small lipoblasts in a prominent myxoid stroma. Unlike SCL/PL, there is a delicate, arborizing capillary vascular network. DNA damage-inducible transcript 3 (DDIT3) positivity by immunohistochemistry is a sensitive marker for MLS and is expected to be negative in SCL/PL (63). MLS is genetically characterized by a FUS RNA binding protein (FUS)-DDIT3 gene fusion, resulting from a balanced translocation t(12;16)(q13;p11). A variant EWS RNA binding protein 1 (EWSR1)-DDIT3 gene fusion has also been identified in approximately 3% of MLS (61). Detection of these fusion transcripts would be helpful in distinguishing MLS from other adipocytic neoplasms including SCL/PL (64).

DDLS is a malignant adipocytic neoplasm showing transition from ALT to non-lipogenic sarcoma of variable histological grades. It usually presents as a large (>10 cm), painless mass in the retroperitoneum, extremities and paratesticular region. DDLS has a peak incidence in the sixth to seventh decades of life, with no sex predilection (65). Wide excision is the standard treatment for DDLS. Local recurrence occurs in about 40% of cases and distant metastases develop in 15-30% of cases (66). The most important prognostic factor for DDLS is anatomical location. DDLS shares radiological features with ALT or SCL/PL, and dedifferentiation is usually suggested by the presence of a focal, nodular, non-lipomatous region greater than 1cm in size (49). Radiographs may reveal a non-specific soft-tissue mass. Calcification is uncommon. Ultrasound shows a solid, heterogeneous mass with both hypo- and hyperechoic areas (49). CT usually reveals a well-circumscribed, round, or lobulated mass with slightly increased attenuation compared with that of subcutaneous fat in the adipose component and tissue attenuation similar to or slightly lower than that of skeletal muscle in the non-adipose component (67). Contrast-enhanced CT demonstrates definite enhancement in the non-adipose component. MRI typically shows the coexistence of adipose (ALT) and juxtaposed non-adipose (dedifferentiated) components (68,69). The non-adipose component usually displays low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-weighted images. Hemorrhage and necrosis may be seen within the high-grade non-adipose component. Contrast-enhanced MRI demonstrates variable enhancement in the non-adipose component (66). Recently, Parkes et al. have suggested that PET/CT is a sensitive and specific diagnostic tool to identify the presence of dedifferentiation within the tumor (70). Histologically, DDLS typically shows an abrupt transition between well-differentiated and dedifferentiated components. The well-differentiated component consists of mature adipocytes with a significant variation in size and atypical, hyperchromatic stromal spindle cells. A varying number of monovacuolated or multivacuolated lipoblasts may be seen. The dedifferentiated component exhibits a wide morphological spectrum but most frequently resemble myxofibrosarcoma or undifferentiated pleomorphic sarcoma (71). Immunohistochemically, diffuse nuclear expression of MDM2 and/or CDK4 is seen in the vast majority of DDLSs. In addition, DDLS shows variable expression of CD34, SMA and desmin (48). The combination of p16 with CDK4 and MDM2 is helpful in distinguishing DDLS from other adipocytic neoplasms including SCL/PL (72). DDLS cytogenetically overlaps with ALT and is characterized by the presence of ring and giant marker chromosomes composed mainly of amplified chromosome 12 sequences (66). Unlike ALT, high-level amplifications of 1p32 and 6q23 are found in DDLS and are associated with a worse prognosis (66). Of note, MDM2 and/or CDK4 amplification is typically present in DDLS. DDLS can therefore be distinguished from SCL/PL by FISH for MDM2 (and/or CDK4) amplification.

SCL/PL is a distinctive, benign, adipocytic neoplasm and simple excision is usually curative. The morphologic spectrum of this peculiar neoplasm is surprisingly diverse. SCL/PL should be considered a possible diagnosis when a well-defined, complex, fatty mass is encountered in the subcutis of a middle-aged man. Structural rearrangements, mainly deletions, of 13q are prominent in SCL/PL. Detection of loss of the RB1 gene would be helpful diagnostically for SCL/PL in selected cases. Further investigations are required to better delineate the relationship between SCL/PL and ASCPLT.

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

YO collected the data and searched the literature. JN searched the literature and drafted the article. KK and MA performed the histopathological evaluations. SN and TY reviewed the article. All Authors read and approved the final article.

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