LC-02-005: Molecular testing: how and when to screen fatty tumors?
Prof. Dr. David Creytens, MD, PhD
Department of Pathology, Ghent University Hospital, Ghent, Belgium
Adipocytic tumors are the most common soft tissue neoplasms. These lesions, which can occur at every age and at almost any anatomical location, are part of the daily practice of every surgical pathologist. The classification of adipocytic tumors has evolved considerably in the past three decades, largely due to advances in understanding the pathogenetic basis of many of these adipocytic tumors. The identification of characteristic molecular alterations for many adipocytic tumor types has led to reproducible and uniform diagnostic criteria, as well as the development of useful ancillary diagnostic tests. Compared to the 2013 World Health Organization (WHO) classification of soft tissue and bone tumors, the principal changes in the group of adipocytic tumors in the 2020 WHO classification have been the introduction of the entities ‘atypical spindle cell/pleomorphic lipomatous tumor’ (characterized by recurrent/pathognomic RB1 gene deletions) and ‘myxoid pleomorphic liposarcoma’. The 2020 WHO classification of soft tissue and bone tumors recognizes in the group of adipocytic tumors five major liposarcoma subtypes: atypical lipomatous tumor/well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma and myxoid pleomorphic liposarcoma. The first 3 entities are characterized by diagnostic recurrent genetic changes, more specifically, MDM2/CDK4 gene amplifications in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and FUS/EWSR1-DDIT3 gene fusions in myxoid liposarcoma. Pleomorphic liposarcomas and
myxoid pleomorphic liposarcomas demonstrate complex alterations with chromosomal gains and losses. Fluorescence in situ hybridization (FISH) is the most commonly employed diagnostic molecular test to detect gene rearrangements and gene amplifications/deletions in adipocytic tumors, and is currently available in a large number of histopathology diagnostic laboratories. Fusion-targeted RNA sequencing and copy number variation sequencing of formalin-fixed, paraffin-embedded material are more recently described, reliable and alternative molecular techniques to screen for gene fusions and copy number alterations, respectively.
One of the most common challenges in diagnostic soft tissue pathology is the distinction between lipoma and atypical lipomatous tumor/well-differentiated liposarcoma.
Discrimination is important not only because atypical lipomatous tumor/well-differentiated liposarcoma is more likely to locally recur than a lipoma, but more importantly because of the potential for atypical lipomatous tumor/well-differentiated liposarcoma to dedifferentiate into a high-grade sarcoma, particularly for lesions in the retroperitoneum/abdomen. In my consultation practice, differentiated lipomatous lesions are most often referred for a second opinion because the question of atypia. Evaluating the quality of atypia is inherently subjective. Pathologists tend to overestimate the presence of atypia most often mistaking changes in areas of fat necrosis as atypia (e.g. lochkern morphology, secondary changes such as inflammation, fibrosis, necrosis and secondary muscle atrophy). Another main clinicopathological scenario in which (gene amplification) molecular analysis can help resolve a diagnostic challenge (and could alter significantly the clinical managment of the patient) is the setting of a high-grade sarcoma in the retroperitoneum/abdomen/pelvis when the differential diagnosis includes a dedifferentiated liposarcoma. Dedifferentiated liposarcomas may be difficult to distinguish from a high-grade
pleomorphic sarcoma or other poorly differentiated sarcomas, especially with small biopsies.
Areas of dedifferentiation in dedifferentiated liposarcomas may resemble myxofibrosarcoma, myxoid liposarcoma, solitary fibrous tumor, ‘fibrosarcoma’,… Heterologous differentiation of rhabdomyosarcomatous, osteosarcomatous, and leiomyosarcomatous elements might also be present in dedifferentiated liposarcoma. In other words, dedifferentiated liposarcoma can mimic any type of sarcoma and MDM2 immunohistochemistry/FISH should be part in any sarcoma, certainly if it is undifferentiated/pleomorphic and arising in the retroperitoneum/abdomen/pelvis.
In conclusion, H&E morphology together with the clinical context (size, superficial vs deep localisation, topography, age,…) should set the stage for interpretation and the decision for molecular testing in lipomatous tumors. Indications for molecular analysis of lipomatous tumors are: 1. Recurrent lesion; 2. Deep extremity lesion larger than 10 cm in patients over 50 years of age; 3. Lesion with equivocal atypia; 4. Lesion in the retroperitoneum/abdomen/pelvis; 5. Lesions not fitting the above criteria but having worrisome clinical and radiological features.
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