Atypical Lipomatous Tumor

Not clinically relevant

ALT is characterized by supernumerary ring and giant marker chromosomes, typically as the sole change or concomitant with a few other numerical or structural abnormalities. Telomeric associations are frequently observed and may give a false impression of complexity to ALT karyotypes. Both supernumerary rings and giant markers invariably contain amplified sequences originating from the 12q14-q15 region. MDM2 (12q15) being the main driver gene. Several other genes located in the 12q14-q15 region, including TSPAN31, CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4, CPM, and FRS2 (12q15), are frequently coamplified with MDM2. In addition to 12q14-q15–amplified sequences, they always contain coamplification of at least one other genomic segment. The chromosomal origin of these coamplified regions varies. The most frequent is 1q21-q25. Another striking feature of ALT supernumerary chromosomes is that they consistently contain a neocentromere. Although the generation of a neocentromere is a very rare event in tumor cells, it is a specific hallmark of ALT ring and marker chromosomes. The mechanism of formation of these peculiar chromosomes is not elucidated. They might be generated by chromothripsis. Overexpression of MDM2 protein resulting from genomic amplification inactivates p53; MDM2 targets p53 degradation towards the proteasome and inhibits p53-mediated transactivation.

ALT usually consists of a large, well-circumscribed, lobulated mass. Variable consistencies are present, from firm gray to gelatinous areas, depending on the proportion of fibrous and myxoid components. Larger retroperitoneal tumors appear more heterogeneous, often containing foci of fat necrosis and punctate hemorrhages.

ALT/WDLPS can be subdivided morphologically into three main subtypes: adipocytic (lipoma-like), sclerosing, and inflammatory. The presence of more than one morphological pattern in the same lesion is common, particularly in retroperitoneal tumors.

Lipoma-like ALT/WDLPS is composed of mature adipocytes in which, unlike in benign lipoma, substantial variation in cell size is appreciated alongside nuclear atypia in fat cells or stromal spindle cells. Scattered hyperchromatic stromal spindle cells are easily identified within fibrous septa or blood vessel walls. Occasionally, fat cells assume hibernoma-like features. A varying number of lipoblasts (from many to none) may be found. Importantly, the mere presence of lipoblasts neither makes nor is required for a diagnosis of liposarcoma.

Sclerosing ALT/WDLPS ranks second in frequency. This pattern is most often seen in the retroperitoneum or spermatic cord. The main histological finding is the presence of scattered bizarre stromal cells, exhibiting marked nuclear hyperchromasia and set in an extensive fibrillary collagenous stroma. Multivacuolated lipoblasts can be observed. The fibrous component may overshadow lipogenic areas, which can therefore be easily missed in a small sample.

Inflammatory ALT/WDLPS represents the rarest subtype, occurring most often in the retroperitoneum. A chronic inflammatory infiltrate predominates to the extent that the adipocytic nature of the neoplasm can be obscured. When dealing with cases in which the adipocytic component is scarce, the presence of bizarre multinucleated stromal cells represents a useful diagnostic clue.

A rare finding in ALT/WDLPS is the presence of mature heterologous differentiation, which can be osseous or myogenic, but does not of itself imply dedifferentiation. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases. In lipoma-like ALT/WDLPS, MDM2 and CDK4 expression may prove difficult to evaluate, making FISH a valid alternative. A major pitfall is represented by MDM2 nuclear positivity in histiocytes in fat necrosis. ALT/WDLPSs associated with Li–Fraumeni syndrome are MDM2-negative; however, they express p53.

Cytology is not clinically relevant in most cases, with reported appearances in keeping with histology in 85% in one series.

WDLPS shows no potential for metastasis unless it undergoes dedifferentiation, therefore justifying the introduction of the term “atypical lipomatous tumor” for lesions arising at anatomical sites for which complete surgical resection is curative. For lesions arising in anatomical sites such as the retroperitoneum, spermatic cord, and mediastinum, which have shown greater potential for disease progression, retention of the term “well-differentiated liposarcoma” can be readily justified.

The most important prognostic factor is anatomical location. Lesions located in surgically amenable anatomical regions do not recur after complete excision. Tumors occurring in deep anatomical sites such as the retroperitoneum, spermatic cord, or mediastinum tend to recur repeatedly and eventually cause death as a result of uncontrolled local effects or less often as a result of systemic spread subsequent to dedifferentiation. In the retroperitoneum, multivisceral resections may increase relapse-free survival. The ultimate risk of dedifferentiation varies according to site and lesional duration and is probably > 20% in the retroperitoneum but < 2% in the limbs. Overall, 10-year to 20-year mortality rates range from essentially 0% for ALT of the extremities to > 80% for WDLPS occurring in the retroperitoneum. The median time to death is 6–11 years.

Detection of MDM2 (and/or CDK4) amplification serves to distinguish ALT from benign adipose tumors.

Essential: lipoma-like ALT/WDLPS: variation in adipocytic size associated with nuclear atypia in stromal and/or adipocytic cells; sclerosing ALT/WDLPS: hyperchromatic bizarre stromal cells set in a fibrillary sclerotic background; inflammatory ALT/WDLPS: scattered atypical stromal cells scattered in a chronic inflammatory background; lipoblasts are not required for diagnosis.

Desirable (in selected or challenging cases): MDM2 and/or CDK4 nuclear expression or evidence of MDM2 and/or CDK4 gene amplification.