What’s new in adipocytic neoplasia?
Prof. dr. David Creytens, MD, PhD Department of Pathology Ghent University Hospital, Ghent University What’s new in adipocytic neoplasia? (1)
• Since the publication of the 2013 WHO classification, the most notable change in the category of adipocytic tumors has been made in the group of ‘atypical low-grade adipocytic neoplasms with spindle cell features’ • These tumors, first described by Dei Tos et al as ‘spindle cell liposarcoma’ are characterized by atypical spindle cells and a variably prominent adipocytic component, associated with a risk of local recurrence, but lack of dedifferentiation or distant metastasis • ‘spindle cell liposarcoma’ has been a confusing and evolving entity over the past few decades • In the WHO 2013 classification, ‘spindle cell liposarcoma’ was still considered as an uncommon morphologic variant of atypical lipomatous tumor/well-differentiated liposarcoma (but lacks the pathognomonic MDM2 gene amplification!) • It has become clear that these subset of adipocytic tumors (in the past also variably referred to as ‘well- differentiated spindle cell liposarcoma’, ‘fibrosarcoma-like lipomatous neoplasm’ and ‘atypical spindle cell lipoma’) does not seem to fit into any of the existing diagnostic categories of adipocytic tumors • Since the publication of the 2013 WHO classification, however, there have been substantial steps forward in the clinicopathologic and molecular (cyto)genetic characterization of this family of adipocytic tumors, for which the term atypical spindle cell/pleomorphic lipomatous tumor has been proposed What’s new in adipocytic neoplasia? (2)
• Another substantive change in the group of adipocytic tumors is the introduction of pleomorphic myxoid liposarcoma (myxoid pleomorphic liposarcoma) as an apparently novel subtype of aggressive liposarcoma, especially occurring in children and young adults with a predilection for the mediastinum Atypical spindle cell/pleomorphic lipomatous tumor Definition WHO 5th edition (2020)
Atypical spindle cell/pleomorphic lipomatous tumor is a benign adipocytic neoplasm, characterized by ill-defined tumor margins and the presence of variable proportions of mild to moderately atypical spindle cells, adipocytes, lipoblasts, pleomorphic multinucleated giant cells and a myxoid or collagenous extracellular matrix.
It has a low tendency for local recurrence if incompletely excised.
Unlike conventional atypical lipomatous tumours, there is no risk for dedifferentiation. Clinical features
• Persisting or enlarging soft tissue mass, nodule, or swelling, arising in the subcutis slightly more frequently than in deep (subfascial) somatic soft tissues (occasionally intracavitary or visceral locations) • Wide anatomic distribution, predominating in the limb and limb girdles • The most common locations: hands and feet, and the thigh, followed by the shoulder, upper arm, forearm, knee, lower leg, and buttock • Less common locations: head and neck, trunk, back, and genital area • Rare sites of involvement include retroperitoneum, mediastinum, larynx, trachea and appendix • Predominantly in middle aged adults with a peak incidence in the sixth decade of life (but can affect patients of any age); slight male predominance Pathologic features
• Grossly, these tumors are unencapsulated, show a nodular or multinodular growth pattern, and demonstrate ill-defined tumor margins • Tumor size is variable (range 0.5 to 28 cm, median 5 to 8.5 cm) • Histologically, a wide range of microscopic appearances can be observed, even regionally within the same lesion, depending on the relative proportions of atypical spindle cells, adipocytes, lipoblasts, pleomorphic (multinucleated) cells, and the variable amount of collagenous and/or myxoid extracellular matrix Pathologic features
• The adipocytic component has a predominantly mature morphology with variation in adipocytic size and shape • The morphology of the lipoblasts can vary from small univacuolated, or bivacuolated to larger multivacuolated (‘pleomorphic’) lipoblasts • Bizarre, hyperchromatic, and sometimes pleomorphic multinucleated cells are often scattered within the spindle cell or adipocytic components • Mitotic figures are often present, but mostly scarce • Tumor necrosis is absent • A rare finding is heterologous (metaplastic) differentiation, including presence of smooth muscle, cartilaginous, and/or osseous elements Pathologic features
• The morphology of these tumors can best be described as a broad spectrum defined by 2 dissimilar extremes: ‘low-cellularity end’ and ‘high-cellularity end’ of the morphological spectrum
• Other peculiar growth patterns: -presence of staghorn-like vessels in a collagenous-rich background (solitary fibrous tumor-like growth pattern) -the presence of a prominent branching capillary network (soft tissue angiofibroma-like growth pattern) -presence of abundant myxoid matrix and prominent capillary chickenwire-like vascular network (myxoid liposarcoma-like growth pattern) -striking perivascular location of the atypical spindle cell/pleomorphic cells (pericytic mimicry)
‘Fat-rich’ (spindle cell-poor) variant of atypical spindle cell/pleomorphic lipomatous tumor Creytens D, Mentzel T, Ferdinande L, van Gorp J, Van Dorpe J, Flucke U. Int J Surg Pathol 2019 Creytens D, Mentzel T, Ferdinande L, van Gorp J, Van Dorpe J, Flucke U. Am J Surg Pathol 2019
Creytens D, van Gorp J, Savola S, Ferdinande L, Mentzel T, Libbrecht L. Virchows Arch 2014;465:97-108
A B
C D ‘Pericytic mimicry’ in atypical spindle cell/pleomorphic lipomatous tumor
Creytens D, Mentzel T, Ferdinande L, van Gorp J, Van Dorpe J, Flucke U. Int J Surg Pathol 2019 Immunohistochemistry and genetic/molecular studies • The tumor cells show variable expression for CD34, S100, and desmin • Weak and/or focal expression for MDM2 or CDK4 can be rarely seen; however the combination of MDM2 and CDK4 expression is not encountered • Loss of nuclear Rb expression is observed in around 50-70% of cases • Deletions/losses of 13q14 (including RB1 and its flanking genes RCBTB2, DLEU1, ITM2B) in a significant subset of cases • Consistent absence of MDM2/CDK4 amplification CD34 MDM2
Rb Rb Prognosis and prediction
• Mostly indolent behavior with local recurrence occurring in 10-15% of patients
• No reported distant metastasis or death of disease
• No documented risk for dedifferentiation
• Most patients will have an excellent prognosis if the lesion is completely excised Differential diagnosis
-spindle cell/pleomorphic lipoma -’classical’ atypical lipomatous tumor/well-differentiated liposarcoma -diffuse neurofibroma -mammary-type myofibroblastoma -solitary fibrous tumor -dermatofibrosarcoma protuberans (DFSP) -low-grade malignant peripheral nerve sheath tumor (MPNST) -’low-grade’ dedifferentiated liposarcoma -pleomorphic liposarcoma Dei Tos AP, Mentzel T, Newman PL, et al. Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma. Analysis of six cases. Am J Surg Pathol. 1994 Sep;18(9):913-21. Italiano A, Chambonniere ML, Attias R, et al. Monosomy 7 and absence of 12q amplification in two cases of spindle cell liposarcomas. Cancer Genet Cytogenet. 2008 Jul;184(2):99-104. Mentzel T, Palmedo G, Kuhnen C. Well-differentiated spindle cell liposarcoma ('atypical spindle cell lipomatous tumor') does not belong to the spectrum of atypical lipomatous tumor but has a close relationship to spindle cell lipoma: clinicopathologic, immunohistochemical, and molecular analysis of six cases. Mod Pathol. 2010 May;23(5):729-36. Deyrup AT, Chibon F, Guillou L, et al. Fibrosarcoma-like lipomatous neoplasm: a reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other liposarcomas. Am J Surg Pathol. 2013 Sep;37(9):1373-8. Creytens D, van Gorp J, Savola S, et al. Atypical spindle cell lipoma: a clinicopathologic, immunohistochemical, and molecular study emphasizing its relationship to classical spindle cell lipoma. Virchows Arch. 2014 Jul;465(1):97-108. Mariño-Enriquez A, Nascimento AF, Ligon AH, et al. Atypical Spindle Cell Lipomatous Tumor: Clinicopathologic Characterization of 232 Cases Demonstrating a Morphologic Spectrum. Am J Surg Pathol. 2017 Feb;41(2):234-244. Agaimy A. Anisometric cell lipoma: Insight from a case series and review of the literature on adipocytic neoplasms in survivors of retinoblastoma suggest a role for RB1 loss and possible relationship to fat-predominant ("fat-only") spindle cell lipoma. Ann Diagn Pathol. 2017 Aug;29():52-56. Creytens D, Mentzel T, Ferdinande L, et al. "Atypical" Pleomorphic Lipomatous Tumor: A Clinicopathologic, Immunohistochemical and Molecular Study of 21 Cases, Emphasizing its Relationship to Atypical Spindle Cell Lipomatous Tumor and Suggesting a Morphologic Spectrum (Atypical Spindle Cell/Pleomorphic Lipomatous Tumor). Am J Surg Pathol. 2017 Nov;41(11):1443-1455. Creytens D, Mentzel T, Ferdinande L, et al. Atypical multivacuolated lipoblasts and atypical mitoses are not compatible with the diagnosis of spindle cell/pleomorphic lipoma. Hum Pathol. 2018 Apr;74():188-189. McCarthy AJ, Chetty R. Tumours composed of fat are no longer a simple diagnosis: an overview of fatty tumours with a spindle cell component. J Clin Pathol. 2018 Jun;71(6):483-492. Creytens D, Ferdinande L, van Gorp J, et al. Atypical Spindle Cell Lipomatous Tumor With Benign Heterologous (Metaplastic) Cartilaginous Differentiation. Int J Surg Pathol. 2018 Oct;():1066896918809189. Creytens D. A contemporary review of myxoid adipocytic tumors. Semin Diagn Pathol. 2019;36:129-141. Creytens D, Mentzel T, Ferdinande L, et al. Atypical mitoses are present in otherwise classical pleomorphic lipomas-reply. Hum Pathol. 2018 Nov;81():300-302. Bahadır B, Behzatoğlu K, Hacıhasanoğlu E, et al. Atypical spindle cell/pleomorphic lipomatous tumor: A clinicopathologic, immunohistochemical, and molecular study of 20 cases. Pathol Int. 2018 Oct;68(10):550-556. Creytens D, Mentzel T, Ferdinande L, et al. "Fat-rich" (Spindle Cell-poor) Variants of Atypical Spindle Cell Lipomatous Tumors Show Similar Morphologic, Immunohistochemical and Molecular Features as "Dysplastic Lipomas": Are They Related Lesions? Comment on Michal et al (2018). Am J Surg Pathol. 2019 Feb;43(2):288-289. Creytens D, Mentzel T, Ferdinande L, van Gorp J, Van Dorpe J, Flucke U. ‘Fat-rich’ (spindle cell-poor) variant of atypical spindle cell/pleomorphic lipomatous tumor: striking mimic of ‘classical’ atypical lipomatous tumor/well-differentiated liposarcoma. Int J Surg Pathol 2019. Pleomorphic myxoid liposarcoma (myxoid pleomorphic liposarcoma) Definition WHO 5th edition (2020)
Pleomorphic myxoid liposarcoma is an exceptionally rare, aggressive adipocytic neoplasm, typically occurring in children and adolescents. Pleomorphic myxoid liposarcoma shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma Pleomorphic myxoid liposarcoma lacks the gene fusions and amplifications of myxoid liposarcoma, atypical lipomatous tumour and dedifferentiated liposarcoma. Clinical features
• Tumor generally manifests as a large, deep-seated soft tissue mass • Predilection for the mediastinum • Other reported locations include the thigh, head and neck, back, abdomen, and perineum • Tumors occur predominantly in children and adolescents; patient age in the large majority of published cases is under 30 years old with a female predominance • Association with Li-Fraumeni syndrome has been described Pathologic features
• Grossly, these tumors are non-encapsulated with ill-defined margins • Histologically, these tumors show variable proportions of conventional myxoid liposarcoma-like areas (abundant myxoid matrix; relatively bland primitive round to oval cells; scattered lipoblasts; delicate curvilinear to plexiform capillary network; “lymphangioma-like” myxoid pools) • Pleomorphic spindled to ovoid cells with hyperchromatic nuclei may be scattered within the myxoid component, with a progressive transition into more cellular, solid, sheet-like, high-grade pleomorphic liposarcoma-like areas (severe cytological atypia; pleomorphic lipoblasts; increased mitotic activity; atypical mitoses; and occasional necrosis)
Immunohistochemistry and genetic/molecular studies • Nonspecific immunophenotype • Negativity for MDM2 and CDK4; and variable expression for S100 are reported • Genetic data are scarce and the molecular characteristics have so far only been explored in small series and case reports • PML lacks the FUS/EWSR1-DDIT3 gene fusions seen in conventional myxoid liposarcoma, and MDM2/CDK4 amplifications present in well- differentiated/dedifferentiated liposarcoma • Additional aCGH studies have revealed a complex pattern of chromosomal gains and losses; inactivation of RB1 tumor suppressor gene is pathogenetically important in this tumor type • PML lacks the complexity of conventional pleomorphic liposarcoma alterations, which typically involve focal copy number changes, rather than whole gains and losses Rb Prognosis and prediction
• Extremely aggressive tumor type
• High recurrence rate; metastasis to lung, bone, and soft tissue; and poor survival rates Pleomorphic myxoid liposarcoma (myxoid pleomorphic liposarcoma) • Based on the particular clinical presentation (usually occurring in young patients), the distinctive histological features and the molecular features (no FUS/EWSR1-DDIT3 gene fusions; differences in aCGH findings), PML must be differentiated from conventional myxoid liposarcoma and pleomorphic liposarcoma and may represent a new and separate subtype of liposarcoma. Differential diagnosis
• Myxoid liposarcoma
• Pleomorphic liposarcoma
• Dedifferentiated liposarcoma Alaggio R, Coffin CM, Weiss SW, et al. Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age. Am J Surg Pathol. 2009 May;33(5):645-58.
Coffin CM, Alaggio R. Adipose and myxoid tumors of childhood and adolescence. Pediatr Dev Pathol. 201215(1 Suppl):239-54.
Boland JM, Colby TV, Folpe AL. Liposarcomas of the mediastinum and thorax: a clinicopathologic and molecular cytogenetic study of 24 cases, emphasizing unusual and diverse histologic features. Am J Surg Pathol. 2012 Sep;36(9):1395-403.
Creytens D, van Gorp J, Ferdinande L, et al. Array-based comparative genomic hybridization analysis of a pleomorphic myxoid liposarcoma. J Clin Pathol. 2014 Sep;67(9):834-5.
Hofvander J, Jo VY, Ghanei I, et al. Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene. Histopathology. 2016 Jul;69(1):141-147.
Sinclair TJ, Thorson CM, Alvarez E, et al. Pleomorphic myxoid liposarcoma in an adolescent with Li-Fraumeni syndrome. Pediatr Surg Int. 2017 May;33(5):631-635.
Putra J, Al-Ibraheemi A. Adipocytic tumors in Children: A contemporary review. Semin Diagn Pathol. 2019;36:95-104.
Anderson WJ, Jo VY. Pleomorphic liposarcoma: Updates and current differential diagnosis. Semin Diagn Pathol. 2019;36:122-128.
Creytens D. A contemporary review of myxoid adipocytic tumors. Semin Diagn Pathol. 2019;36:129-141.
Demicco EG. Molecular updates in adipocytic neoplasms. Semin Diagn Pathol. 2019;36:85-94. conclusion
• 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 tumors • The identification of characteristic molecular alterations for many tumor types has led to reproducible and uniform diagnostic criteria, as well as the development of useful ancillary diagnostic tests (e.g. MDM2 overexpression/amplification in well-differentiated/dedifferentiated liposarcoma) • Since the 2013 WHO classification the principal changes in the group of adipocytic tumors have been the introduction of atypical spindle cell/pleomorphic lipomatous tumor and pleomorphic myxoid liposarcoma (myxoid pleomorphic liposarcoma) as novel emerging entities, which will be incorporated in the upcoming new edition of the WHO classification of soft tissue and bone tumors.