Soft tissue

Adipose tissue tumors

Liposarcoma

Dedifferentiated liposarcoma

Topic Completed: 1 December 2017

Minor changes: 12 November 2021

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Table of Contents

Cite this page: Clay M. Dedifferentiated liposarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissuededifflipo.html. Accessed January 28th, 2022.

Definition / general

Well differentiated liposarcoma (WDL) with transition, either in the primary tumor or as a recurrence, to a sarcoma that is typically nonlipogenic
Although historically considered to only be high grade, variable grading is now recognized in dedifferentiated liposarcoma (DDL)

Essential features

Nonlipogenic sarcoma (typically) that arises from well differentiated liposarcoma
- Precursor well differentiated liposarcoma may or may not be identifiable in the background
Both low and high grade classifications are now recognized (see terminology below)
Molecularly characterized by ring or giant marker / rod chromosomes composed of material from 12q13-15
- Results in localized amplification of several neighboring genes, including MDM2
Rarely, the high grade component can be lipogenic and resemble pleomorphic liposarcoma (homologous lipoblastic differentiation, Am J Surg Pathol 2010;34:1122)
First tumor to consider in a high grade sarcoma of the retroperitoneum in an adult
- Retroperitoneal tumors historically regarded as inflammatory subtype of malignant fibrous histiocytoma (MFH) are now considered to represent a common morphologic pattern of dedifferentiation in dedifferentiated liposarcoma

Terminology

Although originally these tumors were all considered high grade, low grade dedifferentiation is now a recognized phenomenon
- Low grade dedifferentiation can be histologically indistinguishable from cellular well differentiated liposarcoma; the terminology that is used varies among practicing pathologists
- Although some report comparable prognosis for well differentiated and low grade dedifferentiated cases (Am J Surg Pathol 2007;31:1), others report an unfavorable outcome with any percentage or degree of dedifferentiation (Am J Surg Pathol 1997;21:271)
Minimal dedifferentiation: although controversial, some require macroscopic evidence of dedifferentiation (> 1.0 cm) to label a tumor as truly dedifferentiated
- Even cases with so called minimal dedifferentiation (< 1.0 cm) can still carry an inferior prognosis when compared to well differentiated liposarcoma; prolonged clinical follow up is recommended regardless of size

Epidemiology

Typically occur in older adults, with a slight predilection for men
Occurs in up to 10% of well differentiated liposarcomas, with more frequent dedifferentiation noted in retroperitoneal primaries

Sites

Most common site is the retroperitoneum, followed by the extremities
Other frequent sites include the spermatic cord
Rare in the head and neck
Extremely rare in the subcutis; as a general rule, subcutaneous atypical lipomatous tumors do not dedifferentiate

Case reports

23 year old woman with an orbital tumor (Int J Ophthalmol 2011;4:452)
53 year old man with a retroperitoneal tumor exhibiting a paraganglioma-like histologic pattern (Arch Pathol Lab Med 2004;128:788)
67 year old woman with a retroperitoneal tumor with leiomyosarcomatous differentiation and hCG production (Sarcoma 2008;2008:658090)
71 year old whose relapse had an extensive lymphoid component (Pathol Res Pract 2005;201:347)
71 year old woman with a thigh mass exhibiting osteosarcomatous dedifferentiation (Radiographics 2005;25:1082)
72 year old man with an arm tumor, G-CSF production and leukocytosis (World J Surg Oncol 2007;5:131)
76 year old woman with an abdominal mass (World J Gastrointest Oncol 2011;3:116)
85 year old woman with a soft tissue mass of buttock; dedifferentiated liposarcoma diagnosed by fine needle aspiration (Cytojournal 2010;7:5)
Three cases with rhabdomyoblastic dedifferentiation (Virchows Arch 2005;447:835)
Retroperitoneal tumor producing alpha fetoprotein (Virchows Arch 2006;448:517)
Two challenging cases resolved with molecular testing (BMC Clin Pathol 2014;14:36)

Prognosis and treatment

Better prognosis than other high grade pleomorphic sarcomas (Am J Surg Pathol 1994;18:1213) but still recurs in 40 - 75%, metastasizes in 10 - 15% and is associated with a 28% mortality rate (Am J Surg Pathol 1997;21:271)
Higher FNCLCC grade and myogenic differentiation are associated with worse clinical outcome (Am J Surg Pathol 2015;39:383)
Metastasis can occur in cases with low and high grade dedifferentiation and there is no minimal amount of dedifferentiation that mitigates this risk (Am J Surg Pathol 1997;21:271)
Cases with myxofibrosarcoma-like features are particularly aggressive (Mod Pathol 2005;18:976)
Retroperitoneal dedifferentiated liposarcoma has higher rates of local recurrence and disease specific death (Curr Opin Oncol 2011;23:373)
- If followed long enough, nearly all retroperitoneal tumors will recur
Must rule out dedifferentiated liposarcoma in any retroperitoneal sarcoma. Can be aided by:
1. Adequate sampling, particularly of peripheral areas
2. Cytogenetics
3. Immunostaining for MDM2 and CDK4 or molecular testing for 12q13-15 amplification

Clinical images

Images hosted on other servers:

Intraoperative image of axillary tumor

Gross description

Large firm mass (may resemble fish flesh) with coarse lobulation that can be surrounded by the more grossly fatty appearing well differentiated component
Dedifferentiation can be discrete and nodular or more gradual
Look for foci of necrosis in the high grade component

Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description

High grade dedifferentiated liposarcoma:
- Well differentiated and dedifferentiated components are often both present and can have abrupt or gradual transitions
- Dedifferentiated component is a cellular and typically a nonlipogenic sarcoma with significant pleomorphism
- Although some propose a mitotic rate of > 5 mitoses/10 high power fields, this isn't uniformly adopted
- Often resemble malignant fibrous histiocytoma (MFH, now referred to as undifferentiated pleomorphic sarcoma or UPS) with short fascicles of pleomorphic spindled cells associated with mixed inflammatory infiltrate
- Can show a peculiar whirling pattern reminiscent of meningothelial structures (Histopathology 1998;33:414, Am J Surg Pathol 1998;22:945)
- Heterologous elements in 5 - 10%
  - Heterologous elements can easily mislead pathologists in poorly sampled cases, especially in metastatic sites
  - Can manifest as neural differentiation, leiomyosarcoma, osteosarcoma / chondrosarcoma, rhabdomyosarcoma or pleomorphic liposarcoma (homologous lipoblastic dedifferentiation)
  - Rhabdomyoblastic differentiation has been associated with worse outcome
  - Angiosarcomatous differentiation has been reported (Virchows Arch 2005;446:456)
Low grade dedifferentiated liposarcoma:
- Less common low grade tumor resembling fibromatosis or well differentiated fibrosarcoma
- Nonlipogenic (in contrast to well differentiated spindle cell liposarcoma, which contains atypical fat / lipoblasts)
- Considered by some to be the same as cellular atypical lipomatous tumor, although there is evidence even low grade dedifferentiation is associated with a poorer prognosis when compared to conventional atypical lipomatous tumor
- Now a recognized WHO classification

Pitfalls and tips:

Look at the edges of dedifferentiated liposarcoma to identify a rim of background well differentiated liposarcoma that may mimic compressed background fat with reactive change
Dedifferentiated liposarcoma often shows a significant amount of heterogeneity (multiple patterns of differentiation and growth) and the confusing nature of the tumor can be a clue to the right diagnosis
Imaging may show both a fatty and solid nonfatty component
Metastases often contain only the dedifferentiated component
When in doubt use ancillary testing to confirm either protein overexpression or gene amplification

Microscopic (histologic) images

Contributed by Michael R. Clay, M.D.

Dedifferentiated liposaroma (DDL):

Low grade component

Delicate branching vasculature

High grade component with entrapped lipoblasts

Meningothelial-like whirls

AFIP images

Soft tissue fascicle - third series:

Dedifferentiated liposarcoma

Fibrosarcoma-like areas

Hemangioperi-cytoma type pattern

MFH-like areas

Neural appearance

Rhabdomyo-sarcomatous elements

Storiform pattern

Images hosted on other servers:

Various images

Osteosarcomatous differentiation

H&E and MDM2 staining

Leiomyosarcomatous differentiation in retroperitoneal tumor with hCG production

Malignant fibrous histiocytoma (MFH)-like areas

Cytology description

Hypercellular with multinucleated, pleomorphic giant cells with abundant cytoplasm, small clusters of cells with high N/C ratio, spindled cells with elongated nuclei (Acta Cytol 2001;45:641)
Occasional osteoclast type giant cells (Cytojournal 2010;7:5)
Most samples are suitable for molecular confirmation

Cytology images

Images hosted on other servers:

FNAB of dedifferentiated liposarcoma

Positive stains

MDM2 and CDK4 are more sensitive in dedifferentiated liposarcoma than in well differentiated tumors given how cellular they are (Am J Surg Pathol 2005;29:1340)
- These stains are most useful in ruling out differential diagnoses that should be negative
- Addition of p16 to the above stains may increase sensitivity and specificity (Am J Surg Pathol 2012;36:462)
Also vimentin, p53, Rb (66%), PPAR gamma (Mod Pathol 2008;21:517), focal positivity for smooth muscle actin
Subset positivity for most antibodies isn't too shocking given the nature of this entity

Molecular / cytogenetics description

12q14 amplification, often due to supernumerary ring or giant chromosome derived from 12q13-15 region
Degree of copy number change has been correlated with progression to higher grade tumors (Am J Clin Pathol 2014;141:334)
Pitfalls - beware of other tumors that have MDM2 gene amplification, including:
- Intimal sarcoma (majority, Cancer Genet Cytogenet 2007;179:146)
- Parosteal osteosarcoma, low grade central osteosarcoma (Arch Pathol Lab Med 2014;138:694)
- Malignant peripheral nerve sheath tumor (MPNST, 20%, Arch Pathol Lab Med 2012;136:95)
- Endometrial stromal sarcoma (5%, Int J Gynecol Pathol 2015;34:576)
- Sclerosing rhabdomyosarcoma (Sarcoma 2013;2013:520858)

Molecular / cytogenetics images

Images hosted on other servers:

FISH studies performed on FNA cell block sections of DDL

Differential diagnosis

Leiomyosarcoma:
- Even in pleomorphic cases there are usually areas with morphology distinctive of well differentiated leiomyosarcoma
- There is no background well differentiated liposarcomatous component and no 12q13-15 amplification
- Immunostaining can be supportive but beware of desmin / actin expression in dedifferentiated liposarcoma
Malignant peripheral nerve sheath tumor (MPNST):
- No well differentiated liposarcomatous component
- History of neurofibromatosis can be helpful
- Be wary of molecular / immunohistochemical testing as 20% of MPNST can have MDM2 gene amplification and protein overexpression
- More commonly located in the deep soft tissues of the extremities than in the retroperitoneum
- Typically more uniform in growth pattern than dedifferentiated liposarcoma, although the distinction may be very difficult
Melanoma:
- Look for a clinical history of melanoma
- Immunohistochemical staining can be informative with S100 being consistently positive, although other melanocytic markers are frequently negative (HMB45 and MelanA)
Pleomorphic liposarcoma (PLS):
- Has lipoblasts set in the background of a pleomorphic sarcoma
- Only way to distinguish PLS from dedifferentiated liposarcoma with secondary homologous differentiation is to either identify background well differentiated liposarcoma or verify MDM2 overexpression or amplification by ancillary studies (Cancer Cytopathol 2014;122:128)
  - This is an important distinction as pleomorphic liposarcoma has a significantly worse prognosis
Rhabdomyosarcoma:
- No well differentiated liposarcomatous component, no 12q13-15 amplification or MDM2 protein overexpression
- Rhabdomyoblastic stains can be unreliable given heterologous differentiation in dedifferentiated liposarcoma
Other sarcoma subtype infiltrating background adipose tissue:
- Try to look in areas outside of the main tumor bulk to identify a well differentiated liposarcoma component, imaging can be particularly useful in showing a well differentiated fatty component associated with the higher grade sarcoma
- Molecular and immunohistochemical studies are helpful
  - This may be particularly necessary when the background entrapped fat takes on a reactive appearance with fat necrosis, as this can closely mimic an underlying well differentiated liposarcoma
Sarcomatoid carcinoma:
- Look for epithelial markers (EMA / cytokeratin) and clinical history indicative of a primary epithelial malignancy
- No well differentiated liposarcomatous component, no 12q13-15 amplification
Sarcomatoid mesothelioma:
- Similar age group but often have a clinical history of asbestos exposure, even in peritoneal disease (Am J Surg Pathol 2015;39:1568)
- Variably positive for mesothelial markers (cytokeratin in 93%, calretinin only 31%; Mod Pathol 2010;23:470)
- There is no well differentiated liposarcomatous component and no 12q13-15 amplification
Undifferentiated pleomorphic sarcoma (UPS) / malignant fibrous histiocytoma (MFH):
- Retroperitoneal tumors are dedifferentiated liposarcoma until proven otherwise
  - Be very wary of this diagnosis in that location
- Although UPS may have a complex karyotype, MDM2 gene amplification would indicate the diagnosis of dedifferentiated liposarcoma (Mod Pathol 2003;16:256)

Additional references

Stanford University: Dedifferentiated Liposarcoma [Accessed 19 December 2017]

Board review style question #1

Which of the following is not associated with an adverse prognosis in patients with dedifferentiated liposarcoma?

Advanced clinical stage
Amount of the dedifferentiated component
Heterologous differentiation into rhabdomyosarcoma
Myxofibrosarcomatous morphology
Retroperitoneal location

Board review style answer #1

B. The amount of the dedifferentiated component is not associated with clinical outcome in patients with dedifferentiated liposarcoma.