Myxoid Pleomorphic Liposarcoma: A Review and Update

Clinical Features and Prognosis

MPLPS primarily occurs in children and young adults (<30 years old), with a slight female predominance. Some cases have been encountered in middle-aged to older adults (3, 6-8). MPLPS typically presents as a large, deep-seated soft-tissue mass and has a strong predilection for the mediastinum. Other less common locations include the head and neck, back, abdomen, perineum, cheek, orbit, and thigh (9). The median tumor size is 12.5 cm, with a range from 4.8 to 18.0 cm (7). The presenting symptoms are typically related to the location of origin. It is of interest that some cases are associated with Li-Fraumeni syndrome, involving germline mutations of the tumor protein p53 (TP53) gene (10-16) (Table I).

Of note, MPLPS pursues an aggressive clinical course, with a high local recurrence rate of 40-50% (2, 6, 7) and a high metastatic potential (9, 17). The most common sites of distant metastasis for MPLPS are lung, bone, and soft tissue (1). Alaggio et al. (2) reported that four out of 10 patients with available follow-up developed distant metastases and seven died of their disease within 36 months. Creytens et al. (6) reported that all six of their patients with available follow-up developed distant metastases and died of their disease within 40 months. Dermawan et al. (7) reported that four out of eight patients developed distant metastases, with five dying of their disease within 52 months. Overall mortality is estimated to be approximately 74% within a 52-month follow-up period (7) and MPLPS has the highest mortality rate of all pediatric LPSs (18). Compared with MLPS (including high-grade MLPS) and PLPS, MPLPS has significantly worse progression-free survival and overall survival (7).

Radiological Features

Descriptions of imaging characteristics dedicated to MPLPS are scarce. In the mediastinum, chest radiographs show a large mass shadow (19). Ultrasound with color Doppler demonstrates a hypoechoic lesion with internal vascularity (20, 21). Computed tomography usually reveals a large hypodense mass with heterogeneous enhancement (7, 10, 17, 19, 22, 23). Cross-sectional magnetic resonance imaging (MRI) is ideal for defining the extent of local disease before planned excision. On MRI, MPLPS may exhibit a heterogeneous soft-tissue mass with adipocytic and myxoid components (5, 7, 8, 17, 24, 25). Contrast-enhanced MRI demonstrates heterogeneous enhancement of the lesion (11, 24). To date, position-emission tomography features for MPLPS have been described in only one case (26). Integrated positron-emission tomography/computed tomography showed mild fluorodeoxyglucose uptake in the lesion, with the maximum standardized uptake value of 3.4. However, larger studies are needed to verify these imaging features in MPLPS.

Pathogenesis

Only one case of MPLPS has been cytogenetically characterized in the literature (5). MPLPS displays a hyperploid/hypotriploid karyotype with mainly numerical aberrations. Array comparative genomic hybridization and shallow whole-genome sequencing have shown complex profiles with numerous chromosomal imbalances, including recurrent large chromosomal gains in chromosomes 1, 6-8, and 18-21, and losses in chromosomes 13, 16, and 17 (4, 6). In addition, recurrent amplifications of chromosomes 1,19, and 21 have been identified in MPLPS (7). More interestingly, Tan et al. (23) reported that both MLPS-like and PLPS-like areas showed similarly complex copy-number alteration profiles, including widespread loss of heterozygosity (LOH) and amplification of chromosomes 1, 2, 7, 12, and 19-21. Genomic differences were also observed. Gains of chromosomes 3p25.1-22.3, 5q11.1-22.1, 6q, and 10q and loss of chromosome 14q11.2-24.3 were found only in the MLPS-like area. Small gains and losses in chromosome 6p were seen only in the PLPS-like area.

Widespread LOH is a common characteristic of MPLPS (5, 7, 8, 23). In 2022, Dermawan et al. (7) investigated allele-specific copy-number alterations in seven MPLPS cases, nine PLPS cases, and 10 MLPS cases using the Fraction and Copy number Estimate from Tumor/normal Sequencing. The authors found that widespread LOH, affecting 80% of the genome on average, was seen in MPLPS but not in PLPS nor MLPS. These findings suggest that MPLPS may appear to show a haploid genome and can be distinguished from other LPS subtypes by widespread LOH.

In 2016, Hofvander et al. (5) reported that whole-exome sequencing showed six mutations in a single case, of which only one [lysine methyltransferase 2D (KMT2D)] was predicted to be pathogenetic. The most common genetic alteration is TP53 mutation in MPLPS (17). TP53 mutations were shown in an entire series of eight cases (7). TP53, located at chromosome 17p13.1, encodes a tumor-suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. It is of interest that TP53 mutations were also identified in 19 out of 23 (83%) of PLPS cases examined by Dermawan et al. (7). In addition, deletions of RB transcriptional co-repressor 1 (RB1) have been observed in 25-67% of cases (6, 7). RB1, located at chromosome 13q14.2, is an important tumor suppressor gene involved in the cell cycle. Creytens et al. reported that losses in chromosome 13q14 were seen in four out of the eight MPLPS cases analyzed, including RB1 and its flanking genes [RCC1 and BTB domain containing protein 2 (RCBTB2), deleted in lymphocytic leukemia 1 (DLEU1), and integral membrane protein 2B (ITM2B)] (6). It is known that RB1 deletions are also found in other benign and malignant adipocytic neoplasms, including PLPS, spindle-cell lipoma/pleomorphic lipoma, and atypical spindle-cell/pleomorphic lipomatous tumor (ASCPLT) (27-29). Moreover, ATRX chromatin remodeler (ATRX), cysteinyl leukotriene receptor 2 (CYSLTR2), and phosphatase and tensin homolog (PTEN) alterations were detected in 12%, 25%, and 12% of cases, respectively (7).

MPLPS displays a consistent absence of DDIT3 rearrangements and MDM2 proto-oncogene (MDM2) amplifications as shown by fluorescence in situ hybridization (3-6, 13, 15, 23). Amplifications of MYC proto-oncogene (MYC), CCAAT enhancer binding protein alpha (CEBPA), and cyclin E1 (CCNE1) have been identified in a significant subset of cases (7, 15, 23). Intriguingly, these gene amplifications are rarely found in PLPS and MLPS (7). However, the biological significance of gene amplification in MPLPS remains unclear.

In 2021, Creytens et al. (6) investigated methylation profiles in 12 MPLPS cases, 9 PLPS cases, and 31 MLPS cases using genome-wide DNA methylation profiling. The authors found a similar methylation profile in MPLPS and PLPS. These results suggest that MPLPS and PLPS may be closely related epigenetically.

Most recently, Shen et al. (8) detected two gene fusion/rearrangements in a single case, including cAMP responsive element binding protein 5 (CREB5)::telomerase reverse transcriptase (TERT) fusion and ETS variant transcription factor 1 (ETV1)::LFNG O-fucosylpeptide 3-N-acetylglucosaminyltransferase (LFNG) rearrangement.

Histopathological and Immunohistochemical Features

Grossly, MPLPS usually appears as an ill-defined, unencapsulated, multilobulated mass with a heterogeneous cut surface reflecting varied tissue types (1, 7).

Histologically, MPLPS typically shows infiltrative margins and is characterized by an admixture of MLPS-like areas and high-grade PLPS-like areas (1, 6, 7). MLPS-like areas, ranging from 10% to 75% of the lesion (2), are composed of relatively bland round to oval cells and scattered small lipoblasts in a myxoid stroma with plexiform or chicken wire-like vasculature. Lymphangioma-like myxoid pools may be present (4, 6). Mitotic activity is low (6). On the other hand, PLPS-like areas consist of moderately to markedly atypical spindle to oval cells with hyperchromatic nuclei and pleomorphic lipoblasts. In some cases, the pleomorphic lipoblasts show xanthoma-like foamy cytoplasm (7). Mitotic activity is high (>10-20 mitoses per 10 high-power fields) (7, 21, 23). Compared to low-grade MLPS-like areas, atypical mitoses are common, and tumor necrosis is occasionally present in high-grade PLPS-like areas. Interestingly, well-differentiated LPS-like areas with thin fibrous septa containing scattered hyperchromatic stromal spindle cells were also observed in two out of eight cases (7). Most recently, the presence of desmin-positive rhabdoid cells was also described (25).

Immunohistochemically, the tumor cells show diffuse expression of CD34 and p16 (6). Variable expression for S-100 protein is also observed (5, 14, 16, 21-23). Notably, loss of nuclear RB expression was seen in 12/12 of cases by Creytens et al. (6), in keeping with the deletion of chromosome 13q14, including the RB1 gene. Abnormal p53 immunostaining patterns (overexpression and null) have recently been identified in some cases with and without Li-Fraumeni syndrome (8, 13, 15, 21, 23). Immunostaining for MDM2 and cyclin dependent kinase 4 (CDK4) are typically negative (5, 6, 22, 25). These findings indicate that immunohistochemistry plays only a limited role in the diagnosis of MPLPS.

Management

Localized disease. Surgical excision followed by surveillance remains the mainstay of treatment for patients with localized MPLPS. The surgical procedure is wide excision with negative margins (R0, no microscopic residual tumor). However, R0 excision is more challenging for MPLPS due to the involvement of vital anatomic organs in the mediastinum. In selected cases, palliative debulking surgery may be an option to give symptomatic relief even if the entire tumor cannot be excised (30). It should be kept in mind that the rate of local recurrence for MPLPS is relatively high compared to other LPS subtypes.

RT can be used as a perioperative treatment strategy to improve local control of soft-tissue sarcoma (STS) (31). The role of RT in the management of MPLPS is controversial, although there are a few reports regarding the use of perioperative RT in patients with MPLPS (7, 13, 24). To date, no data is available from randomized trials comparing surgery alone with the combined treatment of RT and surgery in MPLPS. Further prospective randomized trials are required to better define optimal treatment approaches for localized MPLPS.

Advanced/metastatic disease. The development of unresectable, locally advanced or metastatic MPLPS is associated with a very poor prognosis (9, 17). Systemic therapy options for patients with advanced/metastatic STS include chemotherapy, tyrosine kinase inhibitors, targeted therapies, and immunotherapy (31). Currently, there is no standardized systemic treatment for advanced/metastatic MPLPS.

Doxorubicin-based chemotherapy (either as a single agent or with ifosfamide) is a standard first-line treatment for advanced/metastatic STS (31). There are a few reports regarding doxorubicin-based chemotherapy of patients with MPLPS (7, 14, 16, 26). Chitikela et al. (14) reported a pediatric case of MPLPS of the neck that developed unresectable, recurrent disease after wide excision. The patient received a combination of doxorubicin and ifosfamide for 6 cycles. The authors suggested that the doxorubicin and ifosfamide combination therapy might be a feasible approach in the treatment of advanced MPLPS.

The combination of gemcitabine and docetaxel has activity in patients with metastatic STS (32). There is a single case report concerning this combination therapy in an adult patient with MPLPS with Li-Fraumeni syndrome who had multiple local recurrences and developed bone metastasis (12). In this case, at the most recent follow-up, the patient was tolerating the treatment well and had no evidence of local recurrence or metastatic disease.

Trabectedin can be administered effectively and safely to patients with advanced or metastatic LPS at a second- or later-line setting (33, 34). Rao et al. (26) reported the use of trabectedin in a 32-year-old man with recurrent MPLPS of the mediastinum. Local recurrence of disease occurred 5 months after completing 6 cycles of doxorubicin and ifosfamide adjuvant chemotherapy for positive surgical margins. Trabectedin was administered as a second-line treatment; however, the patient developed excessive fatigue and had disease progression after 2 cycles.

Eribulin is currently licensed for use in patients with unresectable or metastatic LPS following prior doxorubicin-containing therapy (35, 36). There is a single report concerning the use of eribulin in the above case of Rao et al. (26). After discontinuing trabectedin, eribulin was started as a third-line treatment. Follow-up computed tomography after 4 cycles of eribulin showed a partial response. The patient completed 7 cycles of eribulin, and clinical response was maintained. On the basis of these findings, we speculate that the use of eribulin in treating advanced/metastatic MPLPS may show promise.

Immunotherapy is an emerging treatment for several cancer types with promising outcomes (37). Studies have shown that immunotherapy is a promising approach to treat LPS [reviewed in (38)], despite its limited role in LPS. There is a single case report concerning the use of AVM0703 in a young woman with advanced MPLPS of the abdomen and pelvis (16). The patient underwent adjuvant chemotherapy with doxorubicin and ifosfamide due to large tumor size and high tumor grade. After 2 cycles of doxorubicin and ifosfamide combination chemotherapy, the patient had local disease progression without distant metastasis. Subsequently, the patient received systemic therapies, including AVM0703. Unfortunately, however, the patient continued to have intra-abdominal disease progression. Further studies are needed to verify the efficacy and safety of immunotherapy in patients with advanced/metastatic MPLPS.

Differential Diagnosis

The differential diagnosis of MPLPS is wide and includes benign and malignant mesenchymal neoplasms such as ASCPLT, MLPS, PLPS, dedifferentiated liposarcoma (DDLPS), and myxofibrosarcoma (MFS). Recent advances in molecular genetics have contributed greatly to our understanding of these neoplasms. The corresponding clinicopathological and molecular characteristics of these entities are summarized in Table II.

ASCPLT is a benign adipocytic neoplasm that usually arises in the subcutis of the limbs and limb girdles. Unlike MPLPS, ASCPLT predominantly occurs in middle-aged adults and shows a male predominance (29, 39). Most importantly, unlike MPLPS, there is no metastatic potential in ASCPLT. Histologically, ASCPLT usually shows infiltrative margins and contains varying proportions of atypical spindle cells, predominantly mature adipocytes, and floret-like multinucleated giant cells. In contrast to MPLPS, mitotic figures are scarce, and tumor necrosis is absent (39). ASCPLT and MPLPS share similar immunohistochemical phenotypes, including CD34 and p16 positivity and loss of nuclear RB expression. Positive staining for S-100 protein and desmin may be seen in a subset of cases (40, 41). Cytogenetic and molecular cytogenetic studies have shown loss of chromosome 7 in some cases (40, 42). Like MPLPS, RB1 deletions and TP53 alterations have been detected in a significant subset of cases (40, 43-45).

MLPS is a malignant adipocytic neoplasm that usually arises in the deep soft tissue of the extremities, especially the thigh. Although MLPS has a peak incidence in the fourth to fifth decades of life, it is the most common subtype of LPS in children and adolescents (46). There is no sexual predominance. Importantly, unlike MPLPS, conventional MLPS appears to have an excellent prognosis in pediatric patients (2). Histologically, MLPS is composed of uniform, small ovoid cells admixed with small lipoblasts in a prominent myxoid stroma. The presence of delicate chicken wire-like vasculature is characteristic of MLPS. A subset of MLPS shows histological progression to hypercellular and round cell morphologies, which are associated with a significantly poor prognosis (46). Immunohistochemically, MLPS shows diffuse and strong nuclear expression of DDIT3 (47-49). There is no immunohistochemical expression of MDM2 or CDK4 (50). Unlike MPLPS, MLPS is characterized by translocation t(12;16)(q13;p11) in about 95% of cases, resulting in an FUS RNA binding protein (FUS)::DDIT3 gene fusion. A variant translocation t(12;22)(q13;q12) has also been identified in about 3% of cases, resulting in an EWS RNA binding protein 1 (EWR1)::DDIT3 gene fusion (46). Most recently, Kojima et al. (51) described a rare variant of MLPS with nuclear pleomorphism, resembling MPLPS. These tumors, in addition to the classic histology of MLPS, showed moderately to severely pleomorphic cells, bizarre giant cells, and multinucleated cells. Interestingly, all three tumors had TP53 mutations, harbored FUS::DDIT3 fusions, and exhibited DDIT3 expression. These findings suggest that molecular genetic testing for DDIT3 rearrangements or DDIT3 immunohistochemistry is helpful to distinguish MLPS with nuclear pleomorphism from MPLPS.

PLPS is a highly malignant adipocytic neoplasm that typically occurs in older adults, with a peak incidence in the seventh decade of life and shows a slight male predominance. Unlike MPLPS, pediatric cases are exceptional (52). PLPS has a significant metastatic potential, with 21.4-42.5% of cases exhibiting metastasis (53-56). Histologically, PLPS usually shows infiltrative margins and consists of diffuse sheets of markedly atypical spindle cells with variable amounts of pleomorphic lipoblasts. Mitotic figures and tumor necrosis can be observed. Approximately half of cases contain MFS-like areas (52, 56), mimicking MPLPS. Immunohistochemically, PLPS is focally positive for CD34, S-100 protein, smooth muscle actin, and desmin, (53, 54). In addition, p16 expression was found by Ghadimi et al. in all 40 cases studied by immunohistochemistry (55). It is notable that PLPS can show loss of nuclear RB expression (43, 55). Cytogenetically, PLPS is characterized by highly complex karyotypes without pathognomonic structural alterations (57). Array comparative genomic hybridization analysis has demonstrated that loss of 13q is the most common cytogenetic alteration (43, 58). Recent multiplex ligation-dependent probe amplification assay of 21 cases showed loss of RB1 and its flanking gene RCBTB2 (43), suggesting genetic overlap between PLPS and MPLPS. Like MPLPS, TP53 mutations have been detected in 17-60% of cases (55, 59).

DDLPS is a malignant adipocytic neoplasm that primarily occurs in middle-aged and older adults, with a peak incidence in the sixth to seventh decades of life and shows no sexual predominance. Unlike MPLPS, pediatric cases are rare (60). The most common location for DDLPS is in the retroperitoneum, followed by the extremities (61). DDLPS has a metastatic potential, with 15-30% of cases (62, 63). The histological hallmark of DDLPS is the transition from atypical lipomatous tumor/well-differentiated LPS to non-adipocytic sarcoma (61). Mitotic activity is variable and usually lower than that seen in MPLPS. Immunohistochemically, diffuse nuclear expression of MDM2, CDK4, and p16 is seen in the vast majority of cases (64). Cytogenetically, unlike MPLPS, DDLPS is characterized by supernumerary ring chromosomes or giant marker chromosomes (60). It is of interest that the dedifferentiated components show LOH of the RB1 gene in a significant subset of cases (65). Most notably, detection of MDM2 amplification by fluorescent in situ hybridization is helpful to distinguish DDLPS from MPLPS.

MFS is a malignant mesenchymal neoplasm that typically arises in the subcutaneous tissue of the extremities, with a slight male predominance. Unlike MPLPS, MFS predominantly occurs in older adults and rarely occurs in the mediastinum (66, 67). MFS has a high propensity for local recurrence and a metastatic potential, with 16-38% of cases (66). Histologically, MFS usually shows infiltrative margins and consists of atypical spindle cells in a variably myxoid stroma. Bizarre, pleomorphic giant cells can be seen in high-grade MFS. Immunohistochemically, MFS shows a strong expression of CD248 (also known as tumor endothelial marker 1) (68, 69). Cytogenetically, high-grade MFS is characterized by highly complex karyotypes without pathognomonic structural alterations. Like MPLPS, TP53 mutations and RB1 deletions are the most frequent aberrations in MFS (66).