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Atypical Lipomatous Tumor

Definition

  • Neoplasm of mature fat exhibitng at lest focal cytologic atypia occurring at sites other than the subcutis of posterior neck, back and shoulders

Alternate/Historical Names

  • Well differentiated liposarcoma
  • Lipoma-like liposarcoma
  • Atypical lipoma
  • Pleomorphic lipoma
  • Sclerosing liposarcoma
  • Inflammatory liposarcoma
  • Lymphocyte rich liposarcoma
  • Spindle cell liposarcoma

Diagnostic Criteria

  • Contains mature adipose tissue
    • Fat may appear grossly normal
    • Fat cell size may range from smaller to larger than normal
  • Atypical cells required for diagnosis
    • Atypical cells frequently located in fibrous areas
      • May also be located in fat, myxoid areas or in walls of blood vessels
      • Atypical cells usually scattered, not in nests or confluent
    • Large irregular nuclei should be visible at low magnification
      • Dense, smudgy chromatin
      • Frequent clear nuclear pseudoinclusions
    • Frequent floret cells, defined by a ring or semicircle of nuclei
    • Lipoblasts sufficient but not required for diagnosis (in the proper clinical context)
      • Atypical nuclei indented or scalloped by vesicles containing fat
      • Cytoplasmic vacuole(s) that indent and distort nucleus
  • Frequently contains fibrous or myxoid areas
    • Collagen may be fine or coarse
      • Frequently extends between adjacent lipocytes at edge of fibrotic areas
    • May predominate
      • Has been termed sclerosing liposarcoma or sclerosing variant
      • No clinical significance
    • Myxoid pattern may predominate and simulate myxoid liposarcoma
      • Primary retroperitoneal tumors with this appearance appear to be atypical lipomatous tumors genetically (de Vreeze)
  • Usually occurs in deep soft tissue, especially the retroperitoneum
    • By definition, it does not occur in the dermis or subcutis of the posterior neck, upper back or shoulders
      • Fatty tumors with atypia in those locations are termed pleomorphic lipoma
        • They do not recur aggressively or dedifferentiate
      • Atypical lipomatous tumor does occur rarely in other subcutaneous sites
  • If a high grade sarcomatous component is present, designate the process as dedifferentiated liposarcoma
  • Chronic inflammation may be prominent
    • Lymphocytes, plasma cells, germinal centers
      • May obscure underlying atypical lipomatous tumor
    • Fat necrosis may be present
    • Has been termed inflammatory or lymphocyte rich liposarcoma
      • No clinical significance
  • Foci of moderately increased cellularity and mitotic activity rarely may be seen
    • Non-lipogenic component with features of fibromatosis, low grade fibrosarcoma or hemangiopericytoma
    • Mitotic rate <5/10 hpf
    • No difference in survival from usual atypical lipomatous tumor
      • No metastases without recurrence as dedifferentiated liposarcoma
    • Has been termed low grade dedifferentiated liposarcoma
      • We do not use that term or separate them from usual atypical lipomatous tumors
      • Cellular atypical lipomatous tumor (Evans 2007) is an acceptable term
  • Spindle cell variant is predominantly composed of bland spindle cells
    • Fibrosarcoma-like lipomatous lesion has been proposed as an alternate term
  • Heterologous mesenchymal differentiation rarely may be seen
    • Cartilage
    • Bone
    • Smooth muscle
  • Well Differentiated Liposarcoma is an equivalent term, we generally designate such tumors, regardless of location as Atypical Lipomatous Tumor / Well Differentiated Liposarcoma

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting : 8/4/07
Last update: 12/28/13

Controversy about terminology:

Well Differentiated Liposarcoma vs. Atypical Lipomatous Tumor

As used, these are equivalent terms

Arguments in favor of the term Well Differentiated Liposarcoma

  • Historically these tumors were called well differentiated liposarcoma or lipoma-like liposarcoma
  • In deep locations, recurrences may be uncontrollable
  • These tumors may dedifferentiate and then metastasize

Arguments in favor of the term Atypical Lipomatous Tumor

  • In the absence of dedifferentiation, such tumors do not metastasize
  • In non-central locations, uncontrollable recurrence does not occur
  • Use of the term "sarcoma" for non-central lesions may result in over-aggressive surgery

Some use ALT for deep-seated lesions and WDL for superficial lesions

  • Lesions in both sites are histologically and genetically identical
  • Differences in behavior are basically a reflection of resectability

We prefer the term Atypical Lipomatous Tumor but frequently add the term Well Differentiated Liposarcoma in parentheses to avoid confusion

Supplemental studies

Immunohistology

  • p16 appears to be more sensitive for ALT/WDL than MDM2 or CDK4
    • CDK4 may be more specific
  • S100
    • Fat cells positive
    • Atypical cells and other cells negative
  • CD34
    • Atypical cells may be positive
    • Occasional dendritic cells positive
    • No widespread confluent positivity
  • Actin, keratin negative
  • MDM2 and CDK4 are markers amplified as a result of the supernumerary ring chromosomes described below

Immunohistochemistry of lipomatous tumors
  MDM2 CDK4 p16
Atypical lipomatous tumor 45-100% 84-92% 78-97%
Dedifferentiated liposarcoma 55-95 90-100 90
Myxoid / round cell liposarcoma 0-4 0-4 0
Pleomorphic liposarcoma 0 0 0
Lipoma 0-4 0-2 0
Spindle cell and pleomorphic lipoma 0-25 0-6 20
Angiomyolipoma 0 0  
Hibernoma 0 0 positive, variable
Lipoblastoma 0 (1 case) 0 (1 case) positive (1 case)

Genetic analysis

  • >60% have supernumerary ring chromosomes derived from 12q(13-15)
    • FUS/CHOP t(12;16)(q13;p11) and EWS/CHOP t(12;22)(q13;q12) rare
  • 16q13 abnormality rare
    • Common in spindle cell and pleomorphic lipomas
  • FISH and quantitative PCR (QPCR) for MDM2 amplification can be utilized for diagnosis
    • Appears useful for well differentiated lipomatous lesions vs lipoma
    • May be less specific for high grade lesions
FISH/PCR of lipomatous tumors
  MDM2 FISH MDM2 QPCR CDK4 FISH CDK4 QPCR
Atypical lipomatous tumor 90-100% 72-100% 75-100% 69-100%
Dedifferentiated liposarcoma 100% 100% 100% 100%
Myxoid liposarcoma 20%      
Spindle cell / pleomorphic lipoma Negative Negative Negative Negative
Angiolipoma Negative      
Lipoma, NOS Negative Negative Negative Negative
Sarcomas 0-40% 0% 0% 0%
  • Spindle cell / pleomorphic lipoma showed 89% chromosome 12 polysomy
  • Differential Diagnosis

     

    Lipoma vs Atypical Lipomatous Tumor (Well Differentiated Liposarcoma)

    • Diagnosis and behavior depends to a great extent on location
      • Dermis and subcutis of posterior neck, shoulders and upper back
      • Dermis and subcutis of all other sites
        • The vast majority are ordinary lipomas or angiolipomas
          • No cytologic atypia
        • Rare mature fatty neoplasms with cytologic atypia or lipoblasts are seen in these locations
          • Infrequent recurrences
          • Dedifferentiation is very rare
          • Natural (untreated) history is unknown
          • We designate such neoplasms as atypical lipomatous tumors but with a comment that aggressive behavior is rare in tumors arising in those sites
      • Deep soft tissues
        • Intramuscular, intermuscular and periosteal
          • Lipomas are well described in these locations
            • Must not have cytologic atypia or lipoblasts
            • Intramuscular lipoma may recur if incompletely excised
              • Rare large intramuscular lipomas have recurred with features of atypical lipomatous tumor
                • Genetic study for MDM2 amplification may be indicated in large or aggressively recurring intramuscular lipomas even in the absence of atypia
          • Atypical lipomatous tumor can occur in these locations
            • Infiltration is not relevant to the diagnosis
            • Requires cytologic atypia or lipoblasts
            • Frequent recurrences, rarely uncontrollable
            • Dedifferentiation rare
        • Retroperitoneum, spermatic cord, mediastinum
          • Vast majority of mature fatty neoplasms are atypical lipomatous tumors
            • (Most cord “lipomas” are merely pre-peritoneal fat squeezed through the inguinal ring, and not neoplasms)
            • Frequent recurrences, may be uncontrollable
            • May dedifferentiate and metastasize
          • Rare lipomas have been documented in the retroperitoneum (Macarenco)
            • Requires extensive sampling to exclude cytologic atypia and lipoblasts
            • Immunohistochemical and/or genetic studies are recommended before making this diagnosis
          • Myelolipoma frequently occurs in or around the adrenal
            • Megakaryocytes should not be confused with atypical cells of ALT
    • We consider atypical lipomatous tumor and well differentiated liposarcoma to be equivalent terms and primarily use the former, although both are acceptable (see discussion of these terms)
      • Some use WDL  for deep central tumors and ALT for those in other sites
    • Immunohistochemistry and/or in situ hybridization may be of use at any site
      • Lipomas are reported to be MDM2, CDK4, p16 negative
      • ALT are generally MDM2, CDK4, p16 positive
    • See subtypes of lipomas for specific differential diagnoses

    Pleomorphic Lipoma vs Atypical Lipomatous Tumor

    • The diagnosis of tumors composed of mature fat with atypia depends upon the location
      • In the dermis and subcutis of the posterior neck, upper back or shoulders, it is considered pleomorphic lipoma
      • In all other locations, it is considered atypical lipomatous tumor
    • Pleomorphic lipoma MDM2 and CDK4 negative, while most ALT are positive
    • Ropey collagen and extensive CD34 staining support pleomorphic lipoma

    Hibernoma with predominant mature fat Atypical Lipomatous Tumor
    Small, central bland nuclei in vacuolated cells Lipoblasts, if present, have atypical nuclei
    Lacks atypical nuclei Contains atypical nuclei
    Frequently superifcial Rarely superficial
    MDM2, CDK4, p16 negative MDM2, CDK4, p16 most positive

    Myxoid Liposarcoma Atypical Lipomatous Tumor
    No large atypical nuclei Large atypical nuclei present
    Prominent "chicken wire" vascular pattern Lacks "chicken wire" vascular pattern
    Rare as a primary lesion in retroperitoneum Frequently occurs in retroperitoneum
    MDM2 and CDK4 4% by immunohistology but 1/5 MDM2 by FISH MDM2 and CDK4 most positive

    Pleomorphic Liposarcoma Atypical Lipomatous Tumor
    Lacks mature fat Prominent mature fat
    Highly cellular Low cellularity
    Mitotic figures frequent Mitotic figures rare
    MDM2 and CDK4 negative MDM2 and CDK4 most positive

    Fat Necrosis Atypical Lipomatous Tumor
    Small central nuclei Large eccentric nuclei
    Nuclei not indented by vacuoles Vacuoles indent nuclei in lipoblasts
    Foamy cells frequently fill spaces of dead lipocytes Lipoblasts scattered

    Angiomyolipoma Atypical Lipomatous Tumor
    Large atypical blood vessels No large vascular component
    Large epithelioid cells No large epithelioid cells
    HMB45 positive HMB4 negative
    MDM2 and CDK4 negative MDM2 and CDK4 most positive

    Subconjunctival herniated fat and fat adjacent to renal cell carcinomas have been reported to simulate atypical lipomatous tumor

    • Awareness of the clinical situation should make the diagnosis apparent

    Spindle Cell Lipoma Spindle Cell Variant Atypical Lipomatous Tumor
    Restricted to back of neck, upper back, shoulders Various locations
    Bland spindle cells Mild to moderate atypia of spindle cells
    Ropy collagen bundles No ropy collagen
    Circumscribed May be infiltrative
    Uniformly strong CD34 CD34 only occasionally reactive
    MDM2 0-12% and CDK4 0-6% MDM2 and CDK4 most positive
    No areas of usual ALT pattern Areas of usual ALT pattern
    MDM2 and CDK4 figures given for usual ALT as no data for spindle cell variant

    Neurofibroma Spindle Cell Variant Atypical Lipomatous Tumor
    Hypocellular Moderated cullularity
    No mitotic figures Occasional mitotic figures
    No nuclear pleomorphism Mild to moderate atypia
    S100 positive Spindle cells S100 negative

    Dermatofibrosarcoma Protuberans Spindle Cell Variant Atypical Lipomatous Tumor
    No cytologic atypia Mild to moderate atypia
    Entrapped fat at periphery Fat integral to lesion
    No lipoblasts Lipoblasts frequently present
    CD34 may be extensive CD34 only in scattered cells

    Spindle Cell Atypical Lipomatous Tumor Low Grade Fibromyxoid Sarcoma
    Adult fat integral to lesion No fat component
    Lipoblasts may be present No lipoblasts
    Abnormal mitotic fibures may be present No abnormal mitotic figures
    Areas may be histologically identical

    Low Grade Myxofibrosarcoma Spindle Cell Variant Atypical Lipomatous Tumor
    No lipoblasts Lipoblasts frequently present
    Hypocellular Moderate cellularity
    Perivascular grouping of cells No perivascular pattern
    May have atypical mitotic figures No atypical mitotic figures
    May have marked pleomorphism Mild to moderate atypia

    MFH and other pleomorphic sarcomas vs Atypical Lipomatous Tumor

    • Various neoplasms may have atypical cells resembling those of ALT
    • The diagnosis of ALT is made by identifying mature fat integral to the lesion
    • This requires appropriate surgical and pathological sampling of fatty areas
      • Fatty areas of neoplasm may be confused grossly with normal fat if the level of suspicion is not high
    • ALT is positive for MDM2 and CDK4 while MFH is infrequently positive (11 and 3%)

    Clinical

    • Predominantly middle age and older
      • Very rare under age 20
    • Location
      • Central body
        • Retroperitoneum, spermatic cord, mediastinum
        • Frequent recurrences, may be uncontrollable
        • Initial specimen or recurrences may exhibit dedifferentiation
      • Intramuscular / intermuscular
        • Thigh, arm, buttock
        • Frequent recurrences, rarely uncontrollable
        • Dedifferentiation rare
      • Subcutaneous
        • By definition does not occur in posterior neck, upper back or shoulders
        • Infrequent recurrences, never uncontrollable
        • Dedifferentiation very rare
      • Viscera
        • Larynx most common, other sites extremely rare
        • Recurrences frequent, never uncontrollable
        • Dedifferentiation very rare
    • General behavior
      • Local recurrences
      • No metastases unless dedifferentiated

    Grading / Staging / Report

    According to the guidelines of the ADASP, atypical lipomatous tumor is considered low grade

    French Federation of Cancer Centers System grading scheme for adult sarcomas

    • Tumor differentiation score = 1 for atypical lipomatous tumor
    • Mitotic index
      • Score 1 0-9 mitoses per 10 hpf (0.1744 sq mm)
      • Score 2 10-19 mitoses per 10 hpf
      • Score 3 >19 mitoses per 10 hpf
    • Tumor cell necrosis
      • Score 0 No necrosis on any slide (one slide per 2 cm tumor diameter)
      • Score 1 <50% of tumor is necrotic on slides examined
      • Score 2 >50% of tumor is necrotic on slides examined
    • Final Grade (add the three scores above)
      • Grade 1 Sum of scores = 2 or 3
      • Grade 2 Sum of scores = 4 or 5
      • Grade 3 Sum of scores = 6 or more

    Use TNM Staging

    The surgical pathology report should contain or address the following:

    • Location
    • Type of resection or biopsy
    • Histologic diagnosis
    • Managerial category IIb (Local recurrence common; metastasis vanishingly rare unless tumor dedifferentiates to a process in group III)
    • Extent of tumor cell necrosis
    • Grade
    • Stage
    • Size
    • Depth (dermis, subcutis, below fascia, body cavity)
    • Margins
      • Involved
      • Not involved
        • If under 2 cm give all such distances and sites
        • If over 2 cm give minimum distance and site
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient

     

    Lists

    Lipogenic tumors

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