Atypical lipomatous tumor / well differentiated liposarcoma

Soft tissue

Adipose tissue tumors

Liposarcoma

Author: Michael R. Clay, M.D.

Topic Completed: 1 November 2017

Minor changes: 24 April 2020

Copyright: 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: (Atypical lipomatous tumor [title]) (well differentiated liposarcoma [title])

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Table of Contents

Cite this page: Clay M. Atypical lipomatous tumor / well differentiated liposarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissuewdliposarcoma.html. Accessed August 14th, 2020.

Definition / general

Locally aggressive mesenchymal tumor composed of mature adipocytes and stromal cells with at least focal cytologic atypia
Adipocytic component and background cellular constituents vary in concentration and lead to several recognizable morphologic subtypes

Essential features

Low grade lipogenic tumor with multiple morphologic subtypes and significant histologic variability
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
Behavior is dependent upon location, with deep seated lesions having the ability to dedifferentiate and subsequently metastasize
Terminology is based on location (see below)
Wide local excision with negative margins is often curative

Terminology

Use of the terminology "atypical lipomatous tumor" (ALT) and "well differentiated liposarcoma" (WDL) is based on a tumor's location in the body and primarily relates to resectability
- Tumors are morphologically and genetically identical, with the variation in terminology intended to avoid both undertreatment and overtreatment
Tumors located in the periphery have no risk of metastasis
- For such lesions complete resection is generally curative
- For these tumors the designation as sarcoma is inappropriate and the term "ALT" is preferred
If the tumor is deep seated (retroperitoneum, mediastinum, spermatic cord), the chance of achieving negative margins is significantly diminished and the risk of local recurrence, dedifferentiation (DDL) and death are increased
- Lesions are best regarded as true sarcomas and the terminology of "well differentiated liposarcom" is more appropriate
Suggestion: use of "atypical lipoma" is not recommended

Epidemiology

Most common adipocytic malignancy (40 - 45% of all liposarcomas)
Peak age in adults is between ages 40 - 60 years
Very rare in children (Hum Pathol 2017 Jul 10, [Epub ahead of print]) but can be associated with Li-Fraumeni syndrome (Pediatr Dev Pathol 2010;13:218)

Sites

Most common site is the deep thigh of the lower extremity, followed by retroperitoneum, trunk, head and neck region and spermatic cord
Numerous anatomic sites have been reported including the subcutis and skin

Case reports

36 year old woman with gluteal mass (World J Surg Oncol 2006;4:33)
43 year old woman with abdominal fullness and weight gain (Hinyokika Kiyo 2010;56:697)
73 year old man with mesenteric tumor (Case Rep Oncol 2011;4:178)
Multiple cases of oral and salivary gland liposarcomas (Mod Pathol 2002;15:1020)

Prognosis and treatment

Most important factor is anatomic location; surgical resection with widely negative margins is generally curative
Tumors do not metastasize unless they dedifferentiate, which is associated with significantly shorter overall survival (Am J Surg Pathol 2007;31:1)
Retroperitoneal or central body site tumors are difficult to resect with a clear margin, frequently recur, can dedifferentiate and cause death (J Surg Res 2012;175:12)
Positive margin status and sclerosing subtype are associated with reduced local recurrence free survival (Ann Surg Oncol 2004;11:78)
Subcutaneous or intramuscular tumors may recur but typically do not dedifferentiate or metastasize
Risk of dedifferentiation is directly related to location and duration of growth

Clinical images

Images hosted on other servers:

Pelvic tumor during surgery

Intraoperative image of axillary tumor

Gross description

Typically multilobulated and well circumscribed
Rarely grossly infiltrative
Marbled yellow cut surface in lipoma-like lesions, with more firm / fibrotic white areas grossly in lesions with less adipocytic differentiation
Fat necrosis in large lesions, especially at the periphery
Sample carefully to look for dedifferentiated component
- Dedifferentiated areas are nonlipogenic and can stand out as firm nodules or be more diffusely admixed with low grade areas

Gross images

Images hosted on other servers:

Mesenteric tumor

Pelvic tumor

Tumor of mesocolon

35 cm tumor weighing 9 kg

Retroperitoneal tumor

Dedifferentiated tumor in small bowel mesentery

Osteosarcomatous dedifferentiation

Microscopic (histologic) description

Depends on subtype, generally composed of mature fat with variably sized adipocytes and bands of fibrotic stroma containing spindle cells with enlarged, hyperchromatic nuclei
Can be markedly atypical
Cellularity is low and mitotic figures are uncommon
Atypical cells are more commonly found in fibrous septa and in a perivascular distribution
Rarely display heterologous differentiation (Hinyokika Kiyo 2010;56:697)
There are 3 histologic subtypes that have limited clinical significance (Semin Diagn Pathol 2001;18:258, Ann Surg Oncol 2004;11:78):
- Lipoma-like subtype:
  - Most common subtype
  - Scattered atypical cells may be diffuse or exceedingly rare
  - Frequently contain lipoblasts
  - Grossly can be indistinguishable from lipoma
- Sclerosing subtype:
  - Second most common subtype
  - Predilection for retroperitoneal or paratesticular location
  - Collagenous fibrous tissue with scattered adipocytes and atypical multinucleated stromal cells
  - Scant lipogenic component may be missed in small samples
- Inflammatory subtype:
  - Rare
  - Almost always in the retroperitoneum where it is confused for nonlipogenic tumors
  - Chronic inflammatory cells (B > T cells) with occasional lymphoid follicles scattered in a cellular fibrocollagenous stroma with sparse multinucleate atypical cells
  - May obscure adipocytes
- Mixed subtype:
  - Not uncommon to see an admixture of these subtypes with sufficient sampling
- Rarest variants:
  - Lipoleiomyosarcoma:
    - Liposarcoma with leiomyosarcomatous differentiation
    - Both components are low grade
    - Variable amount of the smooth muscle component, which can be seen in association with large vascular walls
    - Similar biology and can dedifferentiate
  - ALT / WDL with low grade osteosarcoma-like areas:
    - In contrast to osseous metaplasia, these lesions have foci reminiscent of parosteal osteosarcoma or low grade central osteosarcoma (Am J Surg Pathol 2010;34:1361)
Diagnostic updates:
- Spindle cell subtype:
  - Frequently subcutaneous and contains CD34 positive spindle cells in short fascicles set in a fibrous or fibromyxoid stroma
  - Histologic similarity to neural neoplasms with whorls or a storiforming growth pattern
  - Can have areas of traditional lipoma-like morphology
  - Do not contain MDM2 gene amplifications and instead have been reported to harbor RB1 gene deletions and loss of RB1 IHC staining (Mod Pathol 2010;23:729, Am J Surg Pathol 2017;41:234)
    - Favored diagnosis is atypical spindle cell lipomatous tumor
    - Locally recurrent potential
Pitfalls and tips:
- Nuclei with sharply outlined vacuoles (Lochkern cells) are enlarged and can appear hyperchromatic but are normal adipocytes cut in cross section
  - These do not qualify for the diagnosis; the same goes for atrophic skeletal muscle fibers, which can simulate atypia on an otherwise typical lipoma
- Histiocytes in areas of fat necrosis can simulate atypical cells
- Lipoblasts are neither necessary nor sufficient for diagnosis
  - When present they are generally multivacuolated vs. the signet ring lipoblasts commonly seen in myxoid liposarcoma
- Fatty differentiation may be very focal and difficult to differentiate from background adipocytes; when in doubt test molecularly (see molecular / cytogenetics description below)
- Lipomas do occur in the retroperitoneum (BMC Res Notes 2015;8:75) and the distinction with WDL may require molecular testing
  - Retroperitoneal WDL typically shows fat with an abnormal appearance on MRI ("stranding"), that represents the thick fibrous bands
- Avoid using subtypes as diagnoses (i.e. "inflammatory liposarcoma"); the preferred terminology would be "well differentiated liposarcoma," with the addition of "inflammatory subtype" (or that information conveyed in the comment)

Microscopic (histologic) images

Scroll to see all images:

Images hosted on PathOut servers:

Images contributed by Michael Clay, M.D.

Inflammatory ALT 4x

Inflammatory ALT 20x

Lipoma-like ALT

Recurrent ALT with ropey collagen 4x

Recurrent ALT with ropey collagen 20x

Sclerotic ALT 4x

Sclerotic ALT 20x

Images from AFIP Third Series

Morphologic variability:

Enlarged, dense irregular nuclei

Bizarre shaped cells

Lipoblasts are multivacuolated with atypical nuclei

Atypical cells within fibrous tissue

Lochkern cells with sharply outlined nuclear vacuoles

Floret cells

Thick collagen fibers

Thin collagen fibers

Moderately cellular (but not dedifferentiated)

Atypical cells within blood vessel walls

Metaplastic change:

Metaplastic bone

Metaplastic smooth muscle

Inflammatory subtype

Images hosted on other servers:

Immunostains

Various images

Inflammatory subtype:

Various images

Cytology description

Large cells with multilobulated nuclei and mature appearing adipocytes
May have bizarre tumor cells (Acta Cytol 2000;44:459)

Positive stains

MDM2, CDK4 and p16 together have 71% sensitivity and 98% specificity for detecting WDL and DDL (Am J Surg Pathol 2012;36:462, Appl Immunohistochem Mol Morphol 2009;17:51)
Pitfalls:
- MDM2 and CDK4 can falsely stain endothelial cells, foamy macrophages and multinucleated giant cells; this means fat necrosis may be positive
- Care should be taken in problematic well differentiated lipomatous tumors (lipoma-like WDL vs. lipoma), where sensitivity is particularly low (Am J Surg Pathol 2016;40:1647); in such cases FISH testing is preferred by some
S100 (adipocytes in 2/3 of cases)
CD34 (some spindle cells)
Desmin (rare cells are often identified)

Negative stains

HMB45

Molecular / cytogenetics description

Ring or giant marker/rod chromosomes derived from 12q13-15 in almost all cases
Amplifications of the 12q12-21 (Virchows Arch 2012;461:67)
MDM2 and CDK4, by FISH or real time PCR, can differentiate from other sarcomas (Hum Pathol 2006;37:1123, Am J Surg Pathol 2007;31:1476)
- See Am J Surg Pathol 2015;39:1433 for recommendations on when to utilize FISH in well differentiated tumors
Carboxypeptidase M amplification has also been reported (Mod Pathol 2009;22:1541)
Other rearrangements include amplifications of 10p11-14 (Virchows Arch 2012;461:67) and complex rearrangements involving chromosomes 8 and 12 (Oncol Rep 2005;13:649)

Molecular / cytogenetics images

Images hosted on other servers:

(A) Ring chromosome
(B) Giant marker chromosome
(C) Anaphase bridge

Differential diagnosis

Inflammatory subtype of ALT / WDL
- Castleman disease:
  - No well differentiated liposarcomatous component
  - Absence of 12q13-15 amplification
- Hodgkin lymphoma:
  - No well differentiated liposarcomatous component, CD30 and CD15 positive Reed-Sternberg cells
  - Absence of 12q13-15 amplification
- Inflammatory myofibroblastic tumor:
  - No well differentiated liposarcomatous component
  - Usually see a highly cellular proliferation of SMA positive myofibroblasts associated with a dense lymphoplasmacytic infiltrate
  - Predilection for children and lack MDM2 gene amplification
  - Nearly 1/2 are positive for ALK immunostaining secondary to ALK gene rearrangements (Mod Pathol 2001;14:569)
- Sclerosing mesenteritis or idiopathic retroperitoneal fibrosis:
  - No well differentiated liposarcomatous component, lack MDM2 gene amplification
  - Beware fat necrosis, which can give the false impression of liposarcoma in this setting
  - Look for increased IgG4 positive plasma cells to evaluate for IgG4 related disease (Mod Pathol 2012;25:1181)
Lipoma-like subtype of ALT / WDL
- Lipoblastoma:
  - Usually age 3 or younger, (Virchows Arch 2002;441:299)
  - Lobular growth pattern with delicate branching vessels and myxoid change are characteristic
  - Negative for 12q13-15 amplification
- Classic lipoma:
  - Typically superficial, lack atypical nuclei
  - Use FISH in deep seated lesions where atypia may be sparse
    - Molecular confirmation is particularly useful (Am J Surg Pathol 2015;39:1433):
      - Recurrent tumors
      - Deep extremity lesions > 10 cm in patients over the age of 50
      - Cases with equivocal cytologic atypia
      - Lesions in the retroperitoneum, pelvis or abdomen
- Lipomatous angiomyolipoma:
  - HMB45+ epithelioid cells, negative for 12q13-15 amplification (Pathol Int 2006;56:638)
- Massive localized lymphedema:
  - Clinically very different, localized in the proximal thigh of morbidly obese individuals
  - Fat separated by widened edematous fibrous septa, with no cytologic atypia
  - Also see other areas of compromised lymphatic drainage such as lymphangiectasia in the overlying skin
  - Lacks molecular findings of ALT / WDL (Am J Surg Pathol 1998;22:1277)
- Myxoid liposarcoma:
  - Morphology may be similar but negative for 12q13-15 amplification (Mod Pathol 2009;22:223)
  - Tends to have more lobular growth, delicate plexiform vasculature and signet ring lipoblasts
  - Characterized by FUS gene rearrangements
- Paraffinoma:
  - History of paraffin injection, no atypical nuclei, negative for 12q13-15 amplification (Br J Radiol 2003;76:264)
- Spindle cell / pleomorphic lipoma:
  - Frequently seen in the head and neck or other superficial soft tissues, look for ropey collagen and absence of fibrillary stroma
  - Have deletions of 16q / 13q and do not have amplification of 12q13-15 (Am J Surg Pathol 2012;36:1119)
  - loss of RB1 by IHC staining (Am J Surg Pathol 2012;36:1119)
Sclerosing subtype of ALT / WDL
- Atypical spindle cell lipomatous tumor (Am J Surg Pathol 2017;41:234):
  - See diagnostic update under microscopic (histologic) description
- Dedifferentiated liposarcoma:
  - Nonlipogenic high grade sarcoma, that still retains molecular characteristics of WDL
  - Typically shows abrupt transition between well differentiated and dedifferentiated components
  - Rarely can have homologous lipoblastic differentiation where the dedifferentiated component morphologically resembles pleomorphic liposarcoma (Histopathology 2013;62:702)
    - Concept of low grade dedifferentiation is controversial but generally has cellularity between that seen in WDL and DDL (Pathol Int 2001;51:392)
- Lipomatous hemangiopericytoma (solitary fibrous tumor with fatty differentiation) (Am J Surg Pathol 1999;23:1201):
  - Morphologically distinct with the patternless pattern of growth, round to spindle cell morphology and characteristic hemangiopericytomatous vasculature
  - Has NAB2-STAT6 gene fusions (diffuse STAT6 and CD34 IHC positivity) and negative for 12q13-15 amplification

Additional references

Stanford University: Atypical Lipomatous Tumor [Accessed 10 November 2017]

Board review style question #1

Which of the following is true about atypical lipomatous tumor / well differentiated liposarcomas (ALT / WDL)?

Frequently present in the upper trunk / back of the neck in adults.
Have genomic alterations at 8q11-13.
Lack the ability to metastasize.
Must contain lipoblasts.
Show a predilection to metastasize to other soft tissue sites.

Board review answer #1

C. Lack the ability to metastasize; ALT / WDL cannot metastasize unless it progresses to a dedifferentiated liposarcoma.

Incorrect, spindle cell lipomas show this predilection.
Incorrect, lipoblastomas have PLAG1 gene fusions, which is located at 8q11-13.

Incorrect, remember they neither need nor always have lipoblasts.
Incorrect, myxoid liposarcoma shows the unusual predilection amongst fatty tumors to metastasize to other soft tissue sites.