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Atypical lipomatous tumor / well differentiated liposarcoma


Michael R. Clay, M.D.

Last author update: 1 November 2017
Last staff update: 20 April 2022

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PubMed Search: Atypical lipomatous tumor / well differentiated liposarcoma


Michael R. Clay, M.D.
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Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Case reports | Prognosis and treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1
Cite this page: Clay M. Atypical lipomatous tumor / well differentiated liposarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissuewdliposarcoma.html. Accessed August 14th, 2022.
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 Terminology)
  • 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 liposarcoma" is more appropriate
  • Suggestion: use of "atypical lipoma" is not recommended
Epidemiology
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
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

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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

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Mesenteric tumor

Pelvic tumor

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)

  • 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

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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



AFIP images

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



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Immunostains

Inflammatory subtype

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
Molecular / cytogenetics description
Molecular / cytogenetics images

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(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:
    • 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:
    • 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):
    • 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
Board review style question #1
Which of the following is true about atypical lipomatous tumor / well differentiated liposarcomas (ALT / WDL)?

  1. Frequently present in the upper trunk / back of the neck in adults.
  2. Have genomic alterations at 8q11-13.
  3. Lack the ability to metastasize.
  4. Must contain lipoblasts.
  5. Show a predilection to metastasize to other soft tissue sites.
Board review style answer #1
C. Lack the ability to metastasize; ALT / WDL cannot metastasize unless it progresses to a dedifferentiated liposarcoma.

  1. Incorrect, spindle cell lipomas show this predilection.
  2. Incorrect, lipoblastomas have PLAG1 gene fusions, which is located at 8q11-13.
  1. Incorrect, remember they neither need nor always have lipoblasts.
  2. Incorrect, myxoid liposarcoma shows the unusual predilection amongst fatty tumors to metastasize to other soft tissue sites.


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