Myxoid liposarcoma (MLS) is a subtype of liposarcoma that represents a distinct pathological entity characterized morphologically by tumor cells within a myxoid stroma with a rich, branching thin-walled vasculature, and focal lipomatous differentiation.
Myxoid liposarcoma is the second most common subtype (MLs). It accounts for 15–20% of liposarcomas and represents about 5% of all soft tissue sarcomas in adults. Histologically MLS shows a continuous spectrum of lesions with low-grade forms and others poorly differentiated round cell forms [rx]. The tumoral site (upper limb, lower limb, and trunk) did not result in a significant risk factor, even though the few numbers of patients with trunk localization could have hampered statistical significance. It is an important factor of this usually slow-growing, deep-seated tumor mainly located in the lower extremities is the propensity to metastasize to nonpulmonary soft-tissues as the retroperitoneum, the bone, or the contralateral limb [rx]. Furthermore, myxoid liposarcoma is particularly radiosensitive thus neoadjuvant radiation protocols may be very effective [rx–rx].
Causes of Myxoid Liposarcoma
Low grade:
- Atypical lipomatous tumor / well differentiated liposarcoma (ALT / WDL):
- ALT / WDL can be myxoid and focally indistinguishable from myxoid liposarcoma
- ALT / WDL usually has some degree of stromal atypia however and will lack the plexiform vasculature
- ALT / WDL has amplification of chromosome 12q14 (including the MDM2 gene) vs. the FUS rearrangement seen in myxoid liposarcoma
- Myxoid liposarcomas are also more likely to show a predilection for signet ring lipoblasts
- Extraskeletal myxoid chondrosarcoma (EMC):
- Composed of cords of epithelioid malignant cells set in a similar chondromyxoid matrix
- There are no cytoplasmic fat vacuoles and less prominent vasculature
- Immunohistochemical staining is not helpful (both are S100 positive)
- Cytogenetics can be helpful but care must be taken
- EMC have t(9;22)(q22;q12) gene rearrangements in most cases that result in an EWSR1-NR4A3 fusion
- EWSR1 FISH will be positive but can lead to confusion with the 2 – 5% of myxoid liposarcomas that rarely have EWSR1 rearrangements
- PCR applications can be particularly helpful in this setting
- In the lung, primary pulmonary myxoid sarcoma should be considered (Pathology 2017;49:792)
- Lipoblastoma / lipoblastomatosis:
- Can show similar histology but usually are present in patients less than 5 years old
- Will have PLAG1 gene rearrangements instead of FUS or EWSR1 rearrangements
- Lipoblastoma-like tumor of the vulva:
- This is a recently described entity that occurs in the vulva and shares remarkable histologic overlap with lipoblastoma and myxoid liposarcoma
- These lesions have been shown to have Rb loss like the spindle cell lipoma family of tumors
- They do not have PLAG1 or FUS rearrangements (Int J Gynecol Pathol 2018 Jan 3 [Epub ahead of print], Am J Surg Pathol 2015;39:1290)
- There is a significant difference in treatment and clinical outcome (only a limited ability to locally recur) and these lesions should be distinguished wherever possible
- Myxoid dermatofibrosarcoma protuberans (DFSP):
- Typically these are located superficially, which is uncommon in myxoid liposarcoma
- Look carefully to distinguish between entrapped fat versus true signet ring lip blasts
- Immunohistochemical staining and molecular testing can help
- DFSP will be CD34 positive, S100 negative, with the inverse seen in myxoid liposarcoma and DFSP, will harbor the t(17;22)(q22;q13) COL1A1-PDGFB gene fusion
- Some large reference labs offer PDGFB as a break-apart FISH assay
- Myxoma:
- Extremely paucicellular, lacks a prominent vascular component and no lipoblasts are found
- Associated with GNAS mutations (Mod Pathol 2009;22:718)
High grade:
- Myxofibrosarcoma:
- Older adults, often superficial, infiltrative and there are no true cytoplasmic fat vacuoles (although they can contain pseudolipoblasts)
- There is significantly more nuclear atypia, thicker curvilinear vessels and frequent mitotic figures can be found
- Pleomorphic liposarcoma (PLS):
- The entirely different entity that shares similarity in name only
- PLS is a high-grade pleomorphic sarcoma with scattered atypical lip blasts
- Atypia far in excess of what is seen in round cell liposarcoma, which retains its monotony (a clue to a tumor driven by a translocation)
- PLS typically has a complex karyotype
- Round cell sarcomas (Ewing, BCOR-CCNB3, CIC-DUX4, etc.):
- There are numerous round cell sarcomas that may morphologically resemble high-grade myxoid liposarcoma
- Low-grade areas and lip blasts can be particularly informative
- Immunohistochemical and molecular differences can also be exploited (Ewing sarcoma has different partner genes than does myxoid liposarcoma, a feature that can be taken advantage of via sequencing or PCR)
Symptoms of Myxoid Liposarcoma
Most patients with myxoid liposarcoma have no symptoms until the tumor is large and invades the neighboring organs or tissues, causing tenderness, pain, or functional problems.
As previously mentioned, most patients are diagnosed with myxoid liposarcoma do not have any early symptoms and it can go unnoticed during the initial and primary stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function.
- It can sometimes be noticed as a deep-seated mass to touch.
- Myxoid liposarcoma, as with all other cancers, can present with non-specific symptoms such as fevers, chills, fatigue, night sweats, anorexia, and weight loss.
- If the tumor is retroperitoneal in location, it can present with specific symptoms in the abdomen, including abdominal pain, constipation, gastritis, or flank pain, swelling, and constipation or the sensation of feeling full sooner than expected after eating.
- The well-differentiated type tumor is less aggressive and tends to be a large painless mass found in deeper tissues and in the retroperitoneum.
- Myxoid, round cell and pleomorphic types tend to be in the arms and legs, whereas dedifferentiated tend to be in the retroperitoneum and often associated with the well-differentiated variety.
- Specifically, pleomorphic liposarcoma is the least common subtype with a high rate of recurrence and poor outcomes.
- Patients usually present with progressive dysphagia with weight loss
- A new or growing lump beneath your skin, especially around or behind your knees or on your thighs
- Pain or swelling
- Weakness in an arm or leg that has the lump
- Feeling full soon after you start eating
- A new lump anywhere on your body, or an existing lump that grows persistently
- Painful swelling or numbness in the area around your lump
- Blood in your stool, or black or tarry stool (an indication of blood)
- Blood in your vomit
- Abdominal pain or cramping
- Constipation
- Poop that has blood or looks black or tarry
- Cramping
- Bloody vomit
- Your belly gets larger
- Recurrent molecular alteration with either t(12;16)(q13;p11.2) FUS-DDIT3 or very rarely (~2%) t(12;22)(q13;q12) EWSR1-DDIT3 rearrangements
- Includes a spectrum of disease including high-grade lesions, which were formerly regarded as “round cell liposarcoma”
- Has an unusual propensity to present with the first metastasis to another soft tissue or bony site (such as from one leg to the contralateral leg or to the retroperitoneum or spine
- Prominent myxoid stroma with branching vasculature (so-called chicken wire vasculature)
- The majority of the tumor can be nonlipogenic with only scattered lip blasts that often have a characteristic signet ring morphology
Diagnosis of Myxoid Liposarcoma
Microscopic (histologic) description
Low grade:
- Paucicellular with monomorphic, stellate, or fusiform shaped cells without atypia; striking in their blandness, so much so that any significant pleomorphism should cause one to pause
- Prominent plexiform vasculature (delicate thin-walled arborizing and curving capillaries that form a network reminiscent of chicken wire fencing)
- These are so striking because of the overall background paucicellularity and are still present but much less obvious in high-grade tumors
- Numerous signet ring lip blasts, particularly at the periphery of lobules
- This imparts a lipoblastoma-like appearance
- Mucoid matrix is rich in hyaluronic acid that may form large mucoid pools (so called pulmonary edema pattern)
- Will be positive for stromal mucin stains such as Alcian blue
- Rarely metaplastic cartilage or bone can be seen
- Metaplastic components retain the same molecular alteration without progressive molecular change (no support that these foci represent dedifferentiation) (J Clin Oncol 2018;36:151, Appl Immunohistochem Mol Morphol 2007;15:477)
- Typically there is no significant mitotic activity
- There are many rare morphologic variants; an excellent review of the spectrum of histologic features can be found at Am J Clin Pathol 2012;137:229
High grade:
- Hypercellular solid sheets of back to back cells with round cell or primitive cytomorphology in greater than 5% of the sampled tumor
- Cells can have a small amount of hypereosinophilic cytoplasm, a finding of no clinical significance but of significant diagnostic confusion, especially in a limited sample
Pitfalls and tips
- Round cell features of high-grade tumors are so cellular you can typically “walk” across nuclei in a high power field without “stepping” in matrix
- When in doubt, especially in a small sample, pursue molecular testing (typically fluorescent in situ hybridization) for FUS gene rearrangement
- If you are particularly certain and FUS is negative, proceed to EWSR1
- Sample these tumors extensively; you likely will not see small amounts of round cell progression grossly
- Can contain large areas of mature adipocytic differentiation
- If the clinical or radiologic picture is concerning, sample additional tumor or do molecular testing
- Location (extremity) and age of the patient (young adult) can be helpful clues in the differential diagnosis
- Most of the diagnostic clues are helpful in the appropriate context but individually can be seen in many other tumor types
- Plexiform vasculature and cells that look like signet rings can be found in a diverse variety of tumors
- Combination of a number of clinical, radiologic, histologic and if needed, molecular features will make the diagnosis
Imaging
- CT scan, magnetic resonance imaging (MRI) – If you have symptoms of MRCLS, your doctor will use imaging scans such as CT and MRI to look at where the tumor is and how big it is. They will also check for signs that the tumor has spread to other parts of the body. Although none of these techniques is specific, CT scan and MRI can be more helpful in narrowing down the differential diagnosis as both modalities can detect the percentage of a lipomatous component of the tumor. Higher fat content is associated with benign lipoma, while less fat is consistent with atypical lipoma or sarcoma. A definitive diagnosis can only be achieved by tissue examination. And in the majority of the cases, complete resection of the tumor is needed for a correct diagnosis [rx].
- Removing a sample of tissue for testing – During a biopsy procedure, your doctor removes a small sample of tissue to test for cancer cells. Your tumor’s location determines how the tissue sample is removed.
- Using advanced lab tests to determine the kinds of cells involved in cancer – Doctors who specialize in analyzing blood and body tissue (pathologists) will study your biopsy samples using specialized laboratory tests, such as immunohistochemistry, cytogenetic analysis, fluorescence in situ hybridization, and molecular genetic testing. These tests provide information about your liposarcoma that helps your doctor determine your prognosis and your treatment options.
- Biopsy – To check if the tumor is MRCLS, your doctor will do a biopsy, taking a small sample from the tumor with a needle. An expert, called a pathologist, will study cells from the sample under the microscope to see what kind of tumor it is.
Treatment of Myxoid Liposarcoma
A standard fraction schedule was used: 2 Gy per fraction, 5 days a week.
Chemotherapy was performed in patients with more than two of these unfavorable prognostic factors: high-grade disease, tumor size > 5 cm, deep sited tumors, and positive surgical margins. Chemotherapy consisted of three or five cycles of epirubicin (60 mg/m2, Days 1-2) and ifosfamide (3 g/m2, Days 1–3) administered every 21 days.
Treatments for liposarcoma include
- Surgery – The goal of surgery is to remove all of the cancer cells. Whenever possible, surgeons work to remove the entire liposarcoma. If a liposarcoma grows to involve nearby organs, removal of the entire liposarcoma may not be possible. In those situations, your doctor may recommend other treatments to shrink the liposarcoma to make it easier to remove during an operation.
- Radiation therapy – Radiation therapy uses powerful energy beams, such as X-rays and protons, to kill cancer cells. Radiation may be used after surgery to kill any cancer cells that remain. Radiation may also be used before surgery to shrink a tumor in order to make it more likely that surgeons can remove the entire tumor.
- Chemotherapy – Chemotherapy uses drugs to kill cancer cells. Not all types of liposarcoma are sensitive to chemotherapy drugs. Careful analysis of your cancer cells by an expert pathologist can determine whether chemotherapy is likely to help you. Chemotherapy may be used after surgery to kill any cancer cells that remain or before surgery to shrink a tumor. Chemotherapy is sometimes combined with radiation therapy.
Newer drugs for
Halaven® (eribulin) and Yondelis® (trabedectin) are approved for people who have not responded to earlier treatment, have widespread liposarcoma, or have cancers that cannot be removed via surgery.
Ongoing and Upcoming Clinical Trials of Targeted Therapy and Immunotherapy for Liposarcoma
| Drug Name/Code | Targets | Pathological subtypes of liposarcoma | Recruitment | Phase | ClinicalTrials. gov ID |
|---|---|---|---|---|---|
| APX005M | CD40 | Well/Dedifferentiated liposarcoma | Not yet recruiting | II | NCT03719430 |
| Ribociclib/LEE011 | CDK4/6 | All | Recruiting | Ib | NCT03009201 |
| Abemaciclib | CDK4/6 | Dedifferentiated liposarcoma | Recruiting | II | NCT02846987 |
| Ribociclib/LEE011 | CDK4/6 | Well/Dedifferentiated liposarcoma | Recruiting | II | NCT03096912 |
| Ribociclib/LEE011+Everolimus | CDK4/6+mTOR | Dedifferentiated liposarcoma | Recruiting | II | NCT03114527 |
| Regorafenib | c-Kit, B-Raf, Raf-1, RET, VEGFR1-3, PDGFR β etc. | All | Recruiting | II | NCT02048371 |
| Sitravatinib/MGCD516 | c-Kit, PDGFR α-β, c-Met, Axl etc. | Well/Dedifferentiated liposarcoma | Recruiting | II | NCT02978859 |
| Selinexor/KPT-330 | CRM1 | Dedifferentiated liposarcoma | Recruiting | II/III | NCT02606461 |
| Selinexor/KPT-330+Ixazomib | CRM1+20S proteasome | Dedifferentiated liposarcoma | Not yet recruiting | I | NCT03880123 |
| Itacitinib/INCB39110 | Jak1 | Myxoid/round cell liposarcoma | Not yet recruiting | I | NCT03670069 |
| MAGE-A4ᶜ¹º³²T cells | MAGE-A4 | Myxoid/round cell liposarcoma | Recruiting | I | NCT03132922 |
| HDM201+Ribociclib/LEE011 | MDM2+CDK4/6 | Well/Dedifferentiated liposarcoma | Active, not recruiting | Ib/II | NCT02343172 |
| CD8+ NY-ESO-1-Specific T Cells+LV305±CMB305 | NY-ESO-1 | Myxoid liposarcoma | Recruiting | I | NCT03450122 |
| NYCE T Cells | NY-ESO-1 | Myxoid/round cell liposarcoma | Recruiting | I | NCT03399448 |
| CMB305±Atezolizumab | NY-ESO-1±PD-L1 | Myxoid/round cell liposarcoma | Active, not recruiting | II | NCT02609984 |
| NY-ESO-1ᶜ²⁵⁹T cells | NY-ESO-1 | Myxoid/round cell liposarcoma | Recruiting | II | NCT02992743 |
| Pembrolizumab | PD-1 | All | Not yet recruiting | II | NCT03899805 |
| Pembrolizumab | PD-1 | Myxoid/round cell liposarcoma | Recruiting | II | NCT03063632 |
| Nivolumab+Nab-rapamycin | PD-1+mTOR | All | Recruiting | Ib | NCT03190174 |
| Nivolumab±Ipilimumab | PD-1±CTLA-4 | Dedifferentiated liposarcoma of the retroperitoneum | Recruiting | II | NCT03307616 |
| Olaratumab | PDGFR α | All | Active, not recruiting | III | NCT02451943 |
| Olaratumab | PDGFR α | Myxoid/round cell, pleomorphic or dedifferentiated liposarcoma | Recruiting | II | NCT02584309 |
| Efatutazone | PPAR-γ | Myxoid liposarcoma | Active, not recruiting | II | NCT02249949 |
| Pazopanib | VEGFR 1-3, c-Kit & PDGF-R | All | Recruiting | II | NCT01532687 |
| Pazopanib | VEGFR 1-3, c-Kit & PDGF-R | Dedifferentiated, or myxoid liposarcoma | Recruiting | II | NCT02357810 |
| Lenvatinib | VEGFR 2/3 | Dedifferentiated, myxoid, or pleomorphic liposarcoma |
References
- https://www.ncbi.nlm.nih.gov/books/NBK538265/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010855/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930414/
- https://www.ncbi.nlm.nih.gov/books/NBK482343/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011058/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859402/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236966/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678127/
- https://www.cancer.gov/publications/dictionaries/cancer-terms/def/liposarcoma
- https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-soft-tissue-tumors/myxoid-round-cell-liposarcoma
- https://rarediseases.info.nih.gov/diseases/6913/liposarcoma/cases/29493
- https://rarediseases.org/rare-diseases/liposarcoma/
- https://en.wikipedia.org/wiki/Bone_tumor
- https://en.wikipedia.org/wiki/Myxoid_liposarcoma
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