Andre M. Oliveira
Mayo Clinic and Mayo Foundation
65-year-old male with a 22 x 14 x 5 cm mass in the retroperitoneum and urinary
Case 1 - Figure 1 - Adipose tissue neoplasm with scattered medium size vessels (HE, 40X).
Case 1 - Figure 2 - Adipose tissue neoplasm showing scattered areas of perivascular fibrosis (HE, 40X).
Case 1 - Figure 3 - No apparent cytologic atypia is seen at medium magnification (HE, 100X).
10 Key Points to Remember
Case 1 - Figure 4 - Thin fibrous septa show bland spindle cells with no apparent cytologic atypia (HE, 100X).
Case 1 - Figure 5 - Thin fibrous septa show bland spindle cells with no apparent cytologic atypia (HE, 100X).
- The discrimination between ordinary lipoma
and atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) is a common diagnostic challenge
in diagnostic soft tissue pathology.
- Histologic, cytogenetic, and molecular
genetic data support the idea that these two major groups of adipose tissue tumors are distinct biologic
entities in spite of overlapping histologic features.
- Careful tissue sampling
and histologic examination are the major and simplest steps for the correct discrimination between
a lipoma and an ALT/WDL.
- Lipomas can be superficial or deep seated and are
histologically characterized by mature fat cells with no
cytologic atypia/hyperchromasia/pleomorphism. Occasionally, lipoblasts can be seen
in lipomas, especially near blood vessels. However, they do not exhibit cytologic
- ALT/WDL are histologically characterized by
the presence of mixed population of lipoblasts and lipocytes but more importantly by atypical
hyperchromatic pleomorphic cells. These tend to be more commonly found near blood vessels and within
fibrous septa. It is also important to note that the identification of lipoblasts is not a necessary
criterion for the diagnosis of an ALT/WDL.
- The discrimination between lipoma and
ALT/WDL becomes challenging when the diagnostic atypical hyperchromatic pleomorphic cells are rare or
have subtle atypical cytologic features. Many cell types or tissue artifacts can simulate these cells,
including lockhern artifact (intranuclear holes), activated fibroblasts/myofibroblasts, multinucleated
giant cells, and degenerated skeletal muscle fibers. However, in most instances these cells can be
correctly identified by careful examination. However, ALT/WDL cells with subtle cytologic features can
be very difficult to recognize by histologic exam. In these situations, ancillary studies may be
important to establish the correct diagnosis.
- Lipoma and ALT/WDL have very
distinct cytogenetic and molecular genetic characteristics:
- Lipomas are mainly characterized by rearrangements of chromosome
12q13~q15 with several partner chromosomes in approximately 50-60% of cases, especially chromosome 3
(figure 1). Lipomas without 12q13~q15 rearrangements frequently show
rearrangements of chromosome 6p21. Several lipoma fusion genes have been identified and the most common
is LPP-HMGA2, product of the t(3;12)(q27-q28;q14-a15). Interestingly,
lipomas grow relatively well in culture and, in our experience, 60-70% of them show abnormal
- ALT/WDL usually exhibit supernumerary ring or giant maker
chromosomes by standard cytogenetic analysis (figure 2). These abnormal
chromosomes are composed by amplified genomic material mainly derived from chromosome bands
12q13~q15. These bands contain several cancer genes, including MDM2, SAS,
CDK4 and HMGA2. MDM2 seems to be the most consistently amplified
gene in ALT/WDL (>99% of cases). Amplification of these genes is not observed in lipoma.
- In the clinical practice several ancillary techniques can be used to discriminate
lipomas from ALT/WDL: standard cytogenetics, molecular cytogenetics (fluorescence in situ hybridization
and chromogenic in situ hybridization), molecular genetics (polymerase chain reaction) and
immunohistochemistry. Table 1, which is not intended to be comprehensive, summarizes some of the
advantages and disadvantages for each of them (key papers are also listed in the suggested
Table 1. Advantages and disadvantages of ancillary techniques for the
discrimination between lipoma and ALT/WDL
- And why this discrimination is important?
This is a very important question that has not been fully answered but the overall experience is that
lipomas have a lower local recurrence that ALT/WDL. In addition, ALT/WDL may undergo dedifferentiation
into a high grade sarcoma, especially in the retroperitoneum.
- It is difficult
to propose universal guidelines on how to use these ancillary techniques in clinical practice but here
these are some of my general recommendations when dealing with a lipomatous tumor:
- Sample well the tumor. Common sense is the
best criteria to sample a large tumor. The 'one section/cm rule' is useful but it is just a guideline!
Use your common sense and your brain. Ex. whitish or fibrous areas are more likely to contain diagnostic
- Cytogenetics. 'Larger the tumor, larger the utility of a
cytogenetic analysis'. However, there is no biologically meaningful universal cut off to indicate when a
tumor should be sent to the cytogenetics laboratory! The simple reason is that a larger tumor is more
difficult to be adequately sampled. And this is one of the reasons some advocate a size of 10 cm or more
for sending a sample to the cytogenetics laboratory. However, there is no evidence that ALT/WDL should
be larger than lipomas.
- FISH (or CISH), IHC or real time PCR can be used for
paraffin-embedded tissues to confirm the diagnosis. Each one of these methodologies has advantages and
advantages. Their choice will depend on their availability, cost, institutional validation procedures,
and individual preferences. Some key references are listed at the end. I personally think that CISH
(chromogenic in situ hybridization) will be one of the most useful methodologies in a near future but
this is a matter of preference (figure 3).
opinion should always be considered in difficult cases.
Figure 1. Lipoma with the classic t(3;12)(q27;q15).
Figure 2. ATL/WDL with the classic ring chromosome.
Figure 3. CISH image showing clusters of MDM2 amplification (brown) in an
- Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites. A follow-up study of 92 cases with analysis of the incidence of "dedifferentiation". Am J Surg Pathol 1992;16(11):1051-8.
- Sirvent N, Forus A, Lescaut W, Burel F, Benzaken S, Chazal M, et al. Characterization of centromere alterations in liposarcomas. Genes Chromosomes Cancer 2000;29(2):117-29.
- Sandberg AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: lipoma. Cancer Genet Cytogenet 2004;150(2):93-115.
- Rosai J, Akerman M, Dal CP, DeWever I, Fletcher CD, Mandahl N, et al. Combined morphologic and karyotypic study of 59 atypical lipomatous tumors. Evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group). Am J Surg Pathol 1996;20(10):1182-9.
- Pedeutour F, Forus A, Coindre JM, Berner JM, Nicolo G, Michiels JF, et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer 1999;24(1):30-41.
- Nilbert M, Rydholm A, Mitelman F, Meltzer PS, Mandahl N. Characterization of the 12q13-15 amplicon in soft tissue tumors. Cancer Genet Cytogenet 1995;83(1):32-6.
- Mandahl N, Akerman M, Aman P, Dal CP, De W, I, Fletcher CD, et al. Duplication of chromosome segment 12q15-24 is associated with atypical lipomatous tumors: a report of the CHAMP collaborative study group. CHromosomes And MorPhology. Int J Cancer 1996;67(5):632-5.
- Fletcher CD, Akerman M, Dal CP, De W, I, Mandahl N, Mertens F, et al. Correlation between clinicopathological features and karyotype in lipomatous tumors. A report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Am J Pathol 1996;148(2):623-30.
- Evans HL, Soule EH, Winkelmann RK. Atypical lipoma, atypical intramuscular lipoma, and well differentiated retroperitoneal liposarcoma: a reappraisal of 30 cases formerly classified as well differentiated liposarcoma. Cancer 1979;43(2):574-84.
- Dei Tos A, Pedeutour F. Atypical lipomatous tumour/well differentiated liposarcoma. In: Fletcher CD, Unni KK, Mertens F, eds. Tumours of Soft Tissue and Bone. 2nd ed. Lyon: IARCPress World Health Organization, 2002.
- Bassett MD, Schuetze SM, Disteche C, Norwood TH, Swisshelm K, Chen X, et al. Deep-seated, well differentiated lipomatous tumors of the chest wall and extremities: the role of cytogenetics in classification and prognostication. Cancer 2005;103(2):409-16.
- Arlotta P, Tai AK, Manfioletti G, Clifford C, Jay G, Ono SJ. Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J Biol Chem 2000;275(19):14394-400.
- Sandberg AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 2004;155(1):1-24.
- Pedeutour F, Suijkerbuijk RF, Forus A, Van GJ, Van de KW, Coindre JM, et al. Complex composition and co-amplification of SAS and MDM2 in ring and giant rod marker chromosomes in well-differentiated liposarcoma. Genes Chromosomes Cancer 1994;10(2):85-94.
- Coindre JM, Hostein I, Maire G, Derre J, Guillou L, Leroux A, et al. Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity. J Pathol 2004;203(3):822-30.
- Trahan S, Erickson-Johnson MR, Rodriguez F, Aubry MC, Cheville JC, Myers JL, Oliveira AM. Formation of the 12q14-q15 amplicon precedes the development of a well-differentiated liposarcoma arising from a nonchondroid pulmonary hamartoma. Am J Surg Pathol 2006;30(10):1326-9.
- Shimada S, Ishizawa T, Ishizawa K, Matsumura T, Hasegawa T, Hirose T. The value of MDM2 and CDK4 amplification levels using real-time polymerase chain reaction for the differential diagnosis of liposarcomas and their histologic mimickers. Hum Pathol 2006;37(9):1123-9.
- Hostein I, Pelmus M, Aurias A, Pedeutour F, Mathoulin-Pelissier S, Coindre JM. Evaluation of MDM2 and CDK4 amplification by real-time PCR on paraffin wax-embedded material: a potential tool for the diagnosis of atypical lipomatous tumours/well-differentiated liposarcomas. J Pathol 2004;202(1):95-102.
- Binh MB, Garau XS, Guillou L, Aurias A, Coindre JM. Reproducibility of MDM2 and CDK4 staining in soft tissue tumors. Am J Clin Pathol 2006;125(5):693-7.
- Binh MB, Sastre-Garau X, Guillou L, de PG, Terrier P, Lagace R, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29(10):1340-7.
- Adachi T, Oda Y, Sakamoto A, Saito T, Tamiya S, Masuda K, et al. Immunoreactivity of p53, mdm2, and p21WAF1 in dedifferentiated liposarcoma: special emphasis on the distinct immunophenotype of the well-differentiated component. Int J Surg Pathol 2001;9(2):99-109.
- Jacob E, Erickson-Johnson M, Wang X, Nascimento A, Oliveira A. Assessment of MDM2 amplification using fluorescence in situ hybridization on paraffin-embedded tissues discriminates atypical lipomatous tumors from lipomas. Lab Invest 2006; 86: 13A.