Soft tissue

• Malignant tumor composed of primitive nonlipogenic mesenchymal cells, signet ring lipoblasts and prominent myxoid stroma with a highly characteristic branching vascular pattern

• Although myxoid liposarcoma and round cell liposarcoma were initially described separately, both tumors have identical molecular alterations and clear evidence of cases with transition between the 2 morphologic patterns are easily found
  • Both tumors are now classified as myxoid liposarcoma with a secondary designation of high or low grade
• Percent of round cell component needed for this distinction is debated in the literature with most pathologists using either > 25% or > 5% indicating a high grade lesion
  • WHO currently lists 5%
• Cases with borderline round cell component (< 5%) are regarded as having areas of transition, a designation of unclear diagnostic significance

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Contributed by Jesse J. Jenkins, M.D. and AFIP

• t(12;16)(q13;p11.2) FUS::DDIT3 in most cases
• t(12;22)(q13;q12) EWSR1::DDIT3 very rarely (2 - 5%)
• Rearrangements can be complex and involve other chromosomes (Am J Clin Pathol 1995;103:20)
• DDIT3 was formerly known as CHOP (early literature will use the terminology FUS::CHOP)
• Can be identified via FISH, PCR, classic cytogenetics and sequencing

• Low grade:
  • Atypical lipomatous tumor / well differentiated liposarcoma (ALT / WDL):
    • Can be myxoid and focally indistinguishable from myxoid liposarcoma
    • Usually has some degree of stromal atypia, however, and will lack the plexiform vasculature
    • Has amplification of chromosome 12q14 (including the MDM2 gene) versus 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
    • 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 has 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 < 5 years old
    • Will have PLAG1 gene rearrangements instead of FUS or EWSR1 rearrangements
  • Lipoblastoma-like tumor of the vulva:
    • 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
    • Does not have PLAG1 or FUS rearrangements (Int J Gynecol Pathol 2019;38:204, 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 when 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 lipoblasts
    • 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 with no true cytoplasmic fat vacuoles (although they can contain pseudolipoblasts)
    • Significantly more nuclear atypia, thicker curvilinear vessels and frequent mitotic figures
  • Pleomorphic liposarcoma (PLS):
    • Entirely different entity that shares similarity in name only
    • High grade pleomorphic sarcoma with scattered atypical lipoblasts
    • 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)
    • Typically has a complex karyotype
  • Round cell sarcomas (Ewing, BCOR::CCNB3, CIC::DUX4, etc.):
    • Numerous round cell sarcomas that may morphologically resemble high grade myxoid liposarcoma
    • Low grade areas and lipoblasts 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)

The microscopic image above depicts the histologic appearance of a soft tissue mass resected from the thigh of a 37 year old man and is representative of the entire lesion. Which of the following is true regarding the diagnosis?

1. Immunohistochemical studies for MDM2 will show strong diffuse positive nuclear staining in the tumor cells
2. Majority of cases harbor t(7;16) FUS::CREB3L2 gene fusion
3. Majority of cases harbor t(9;22) EWSR1::NR4A3 gene fusion
4. Majority of cases harbor t(12;16) FUS::DDIT3 gene fusion
5. The lesion is classified as high grade if hypercellular solid sheets of back to back cells with round cell cytomorphology compose > 1% of the sampled tumor

D. Majority of cases harbor t(12;16) FUS::DDIT3 gene fusion. The microscopic image depicts a low grade myxoid liposarcoma characterized by a proliferation of bland stellate tumor cells embedded in a myxoid matrix with a prominent plexiform capillary network and scattered signet ring lipoblasts. There is no mitotic activity or pleomorphism. The majority of cases of myxoid liposarcoma harbor a t(12;16) FUS::DDIT3 gene fusion. Answers B and C are incorrect because the t(9;22) EWSR1::NR4A3 gene fusion is characteristic of extraskeletal myxoid chondrosarcoma and the t(7;16) FUS::CREB3L2 gene fusion is characteristic of low grade fibromyxoid sarcoma. Answer E is incorrect because classification of myxoid liposarcoma as high grade requires > 5% of the sampled lesion to consist of a hypercellular round cell component according to the WHO. Cases with borderline round cell component (< 5%) are regarded as having areas of transition, a designation of unclear diagnostic significance. Answer A is incorrect because immunohistochemistry for MDM2 is negative in myxoid liposarcomas.

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Reference: Myxoid liposarcoma

Which of the following features is characteristic of myxoid liposarcomas?

1. Hyalinized, thick walled vessels
2. Poor response to radiation therapy
3. Primary tumor in the retroperitoneum
4. Propensity to skip the lung and metastasize to other soft tissue sites
5. Marked nuclear atypia

D. Propensity to skip the lung and metastasize to other soft tissue sites. Myxoid liposarcomas have a unique propensity to metastasize to other soft tissue sites. Answers A and E are incorrect because these tumors tend to have bland nuclear features and arborizing plexiform vasculature. Answer B is incorrect because they have been found to be more radiosensitive than many other soft tissue tumor types. Answer C is incorrect because although myxoid liposarcomas can commonly metastasize to the retroperitoneum, primary retroperitoneal tumors are quite rare.

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Reference: Myxoid liposarcoma