well-differentiated liposarcoma

Definition: Atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLs) are one of the more frequent mesenchymal neoplasms in adults.

Images

 Well-differentiated liposarcoma

• https://twitter.com/WebPathology/status/721076890199592960
• https://twitter.com/smlungpathguy/status/880612355159273473

 pleomorphic lipoblasts in WLS

• https://twitter.com/smlungpathguy/status/880612355159273473
• https://twitter.com/JMGardnerMD/status/880707319407022081

WDLPS represents >40% of all diagnosed LPS and are subdivided in three main histological subtypes:
 adipocytic well-differentiated liposarcoma
 sclerosing well-differentiated liposarcoma
 inflammatory well-differentiated liposarcoma .

The three main locations are the limbs (50%), the retroperitoneum (30%) and the paratesticular area (20%).

Although these tumors do not metastasize, retroperitoneal and paratesticular ones are associated with a high risk of local recurrence (up to 90%) and a high a risk of dedifferentiation (up to 20%), whereas these risks are lower for tumors located in the limbs [9].

The preferred terminology for these lesions when arising at surgically amenable locations is ’atypical lipomatous tumour’, since these lesions have no potential to metastasize.

However, the term well-differentiated liposarcoma should be retained for those lesions arising in the retroperitoneum or mediastinum, since the overwhelming majority of the latter are ultimately associated with uncontrolled local recurrence and significant mortality, even in the absence of dedifferentiation.

The risk of dedifferentiation is much higher in the retroperitoneum than elsewhere, almost certainly as a consequence of the longer lesional duration and larger tumour size at this site.

This group of lesions has identical morphology and the same genetic abnormality (ring or giant marker chromosomes derived from 12q), irrespective of lesional depth or location.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and dedifferentiated liposarcoma (DDL) are reported to have murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) amplification as a characteristic genetic alteration.

Well-differentiated liposarcomas (WDLPS) are cytogenetically characterized by the presence of supernumerary ring or giant rod marker chromosomes.

These supernumerary chromosomes are composed of amplified sequences from chromosome 12 (12q14 approximately 15) in association with amplified segments from various other chromosomes, and contain alterations of the alpha satellite sequences.

Immunochemistry

 MDM2 overexpression by MDM2 amplification
 CDK4 overexpression by CDK4 amplification

Variants

 well-differentiated liposarcoma with low-grade osteosarcomatous component (20697254)

Cytogenetics

 Two subtypes according to their karyotype:

• Type D cells exhibit a near-diploid karyotype, with very few or no chromosome changes.
• Type H cells exhibit a near-tetraploid karyotype and many structural changes.

 giant marker chromosomes and/or supernumerary ring chromosomes containing 12q14-15-derived sequences (12q14-q15 amplification) (MDM2, SAS, CDK4 and HMGA2 amplification) (11734312)

 centrosome amplification (14695989)
 telomeric associations

Molecular biology

 MDM2 and CDK4 genic amplification

MDM2

CDK4

SAS

HMGA2

Reference

 Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor. Kashima T, Halai D, Ye H, Hing SN, Delaney D, Pollock R, O’Donnell P, Tirabosco R, Flanagan AM. Mod Pathol. 2012 Jun 15. PMID: 22699518

 Well-differentiated Liposarcoma With Low-grade Osteosarcomatous Component: An Underrecognized Variant. Yoshida A, Ushiku T, Motoi T, Shibata T, Fukayama M, Tsuda H. Am J Surg Pathol. 2010 Sep;34(9):1361-6. PMID: 20697254

 Sirvent N, Coindre JM, Maire G, Hostein I, Keslair F, Guillou L, Ranchere-Vince D, Terrier P, Pedeutour F. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol. 2007 Oct;31(10):1476-89. PMID: 17895748

 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 Sep;37(9):1123-9. PMID: 16938516

 Arrigoni G, Doglioni C. Atypical lipomatous tumor: molecular characterization. Curr Opin Oncol. 2004 Jul;16(4):355-8. PMID: 15187890

 Forus A, Bjerkehagen B, Sirvent N, Meza-Zepeda LA, Coindre JM, Berner JM, Myklebost O, Pedeutour F. A well-differentiated liposarcoma with a new type of chromosome 12-derived markers. Cancer Genet Cytogenet. 2001 Nov;131(1):13-8. PMID: 11734312