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
    • Common in myxoid liposarcoma
• 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

Differential Diagnosis

• Benign lipomatous tumors
  • Lipoma
  • Pleomorphic lipoma
  • Hibernoma with predominant mature fat
  • Spindle cell lipoma
• Malignant lipomatous tumors
  • Myxoid liposarcoma
  • Pleomorphic liposarcoma
• Other lesions containing prominent fat
  • Fat necrosis
  • Angiomyolipoma
  • Subconjunctival herniated fat
  • Fat adjacent to renal cell carcinomas
• Spindle cell lesions that may be confused with ALT
  • Low grade fibromyxoid sarcoma
  • Low grade myxofibrosarcoma
• Other tumors containing atypical cells resembling those of ALT
  • Malignant fibrous histiocytoma

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
• Virtually all are lipomas
• Most are ordinary lipomas or spindle cell lipomas
• Mature fatty neoplasms with cytologic atypia or lipoblasts are designated pleomorphic lipomas in these locations only
• 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

Low Grade Myxofibrosarcoma	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

• Angiomyolipoma
• Hemosiderotic Fibrohistiocytic Lipomatous Lesion
• Hibernoma
• Lipofibromatosis
• Lipoma
• Lipomatosis
• Lipoblastoma / lipoblastomatosis
• Pleomorphic lipoma
• Spindle cell lipoma
• Atypical lipomatous tumor
• Liposarcoma
  • Dedifferentiated
  • Myxoid
  • Pleomorphic
  • Unclassified
• Atypical Spindle Cell Lipomatous Tumor

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