Adipocytic tumors

2023-09-05 Paola Dal Cin, PhD Affiliation

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)

Classification

Definition

Fatty tumors are among the most common mesenchymal tumors, including a variety of benign lipomas and liposarcomas. Deeper tumors have a higher probability of malignancy. Most benign lipomas are superficial whereas deeper tumors have a higher probability of malignancy e.g. liposarcoma. Their wide histological spectrum and frequent morphological overlap between each subtype have made classification and diagnosis challenging. Molecular advances have significantly contributed to better understanding of the underlying biological mechanisms and the clinical and morphological spectra of adipocytic tumor subtypes, and have enabled more precise classification and management.^1-5

Adipocytic tumours	Genetics event(s)
Lipoma	Three distinct clustering breakpoints: 1) the major group involving 12q13-15 (65%), affecting every chromosomes ⁶, with several possible recurrent chromosome regions, 2) mainly deletion of 13q12-q22 (13%) and 3) 6p21-23 rearrangement (5%). Additional lipomas with other aberrations, ^7,8 including 1) ring chromosome/trisomy 12q ,associated with low-level amplification of sequences from 12q, suggesting that some intermediary forms exist between classical lipomas and classical WDLPS, ^9,10 and 2) 8q12 rearrangements. ⁸
	The target gene in 12q14.3, HMGA2 is a family member of the High Mobility Group (HMG) of protein. The most common gene fusion is HMGA2::LPP resulting from a t(3;12) (q27-28;q14.3), ¹¹ then t(1;12)(p32;q14.3)/ PPAP2::HMGA2, t(2;3)(q27;q14.3)/ ACKR3::HMGA2 , t(5;12)(q33;q14.3)/ EBF1::HMGA2, t(9;12){p22;q14.3/NFB::HMGA2, t(12;13)(q14.3;q13)} /HMGA2::LHFPL6 and t(12;18)(q14.3;q12/ HMGA2::SETBP1. ^12,13 However, several HMGA2 rearrangement in lipomas, e.g. t(4;12)(q27-28;q14-15) ,¹⁴ showed truncated forms HMGA2 separating 3 AT-hook domains from the 3'-untranslated region (3'-UTR). ^15-17
	Lipoma with 13q- show a minimal deleted region in 13q14, where only one gene SPRYD7 was found to be significantly underexpressed compared with control tissues. ¹⁸
	In lipoma with 6p21-23 rearrangement, the breaks occur adjacent to the coding sequences of HMGA1 a.k.a.HMGA1, another member of the same HMG family. ¹⁹ Generally 6p21 breakpoints are located at the 3' end of HMGA1 gene, and molecular analyses of the HMGA1 transcripts revealed common deletions of the C-terminal region and/or parts of the 3'UTR. ²⁰ A single t(3;6)(q27;p21) showed HMGA1 fused to a 139-kb genomic region between the LPP and TPRG1 loci. ²¹
Lipomatosis	Patients with multiple symmetrical lipomatosis have mutations in mitochondrial DNA genes. ²² Familial subtypes are recognized as Madelung disease. ²³
Lipomatosis of nerve	PIK3CA mutations are frequent events, irrespective of anatomic site or territory overgrowth. ^24,25
Lipoblastoma and lipoblastomatosis	8q12 /PLAG1 rearrangements (70%), sometime cryptic, seen mainly in pediatric population ²⁶, with several gene partners HAS2 ,COL1A2, RAD51B, COL3A1, RAB2A , BOC, ZEB, DDX6, KLF10, KANSLIL,RUNXT1,VCAN and SRSF3. ^27-30 PLAG1 overexpression in lipoblastoma with PLAG1 rearrangement is a result of a promoter swapping event. ³¹ PLAG1 staining as surrogate marker for PLAG1 rearrangement.³²
	Extra copies of chromosome 8 , with or without PLAG1 rearrangement have been also reported. ³³
	Alternately, HMGA2 can also be rearranged (8%).^28,30,34 Somatic PIK3CA (H1047R) mutation, in a single case negative for PLAG1 rearrangement. ³⁵
Angiolipoma	Normal karyotype in vast majority, ³⁶ rare cases with loss or structural rearrangement of chromosome 13. ³⁷ A single case with t(X;2)(p22;p12).³⁸
	Frequent low-level mutations of PRKD2 . ³⁹
	High frequency of the p.E545A PIK3CA mutation in both conventional and cellulalar variants .⁴⁰
Myolipoma of soft tissue	A single case t(9;12)p22;q14) associated with HMGA2::C9orf92. ⁴¹ HMGA2 nuclear staining in 60% of cases , suggesting HMGA2 rearrangement ⁴²
Chondroid lipoma	t(11;16)(q13.1;p13.12) associated with fusion between ZFTA, aka as C11orf95, and MRTKB .^43-45 A single case with ZFTA::NCOA1 gene fusion. ⁴⁶ Interesting , a ZFTA::RELA fusion has been reported in a distinct liposarcoma morphologically overlapping with chondroid lipoma, ⁴⁷ and ZFTA rearrangement have been reported in the majority of supratentorial ependymomas.⁴⁸
Spindle cell/plemorphic lipoma (SCPL)	Deletions or losses of 13q14 as -13/del(13q), including RB1 and its flanking genes RCBTB2, DLEU1, and ITM2B. have been identified in a significant subset of cases. ^49,50 SPRYD7 was the only gene to be significantly down-regulated in both lipoma and Spidle cell lipoma with 13q14 deletion. ⁵¹ Consistent absence of MDM2 or CDK4 amplification. ⁵²However, alternative genetic pathways exist for the development of spindle cell/pleomorphic lipoma. ⁵³
	13q14/RB1 family of tumors includes spindle cell/pleomorphic lipoma, atypical spindle cell/pleomorphic lipomatous tumor, pleomorphic liposarcoma, myofibroblastoma, cellular angiofibroma, and acral fibromyxoma, which are considered benign lesions , except for pleomorphic liposarcoma , and mainly occurring in old adult population. ⁵⁴
Hibernoma	Cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. e.g.t(4;11)(q34;q13)⁵⁵ associated with concomitant deletions of AIP and/or MEN1. ^56,57 Association between hibernoma and MEN1 syndrome OMIM:131100. ⁵⁸ The white-to-brown phenotype switchs in brown fat tumours is mediated by the loss of AIP tumor supressor gene. ⁵⁹
Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT)/spindle cell liposarcoma	Deletions/losses of 13q14 RB1 and flanking genes RCBTB2, DLEU1, and ITM2B.^50,52,60 Similar findings reported in pleomorphic liposarcoma, but with less complex complex pattern of chromosomal gains and losses by array-based comparative genomic hybridization. ⁵⁰ Monosomy 7 and consistent absence of MDM2 and CDK4 amplification in 2 cases of spindle cell liposarcoma. ⁶¹
Atypical lipomatous tumor (ATL) /well-differentiated liposarcoma (WDLPS)	Ring /giant (rod) markers chromosomes associated associated with high-level amplifications of 12q13-15 region, which contain many genes, with MDM2 been consistently amplified and overexpressed with HMGA2, co-amplified withCDK4 in 70% of the cases , and less co-amplified with DDIT3. ⁶² The use of FISH to detect MDM2 amplification is a more sensitive and specific method than MDM2 immunohistochemistry in differentiating WDLPS from benign adipocytic lesion and atypical spindle cell/pleomporphic lipomatous tumor. ⁶³
	Case with double minute chromosomes harboring MDM2 amplification in a pediatric ALT. ⁶⁴
	Chromosome 12q13-q15 amplification is thought to occur over numerous breakage-fusion-bridge cycles, and addtional chromosomes regions can be co-amplified. ⁶⁵
	The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma, and occassionally myxofibrosarcomas, malignant peripheral nerve sheath tumors and undifferentiated sarcomas .⁶³ Anti-MDM2 therapy has become a reality: we actually know of molecules that block the MDM2-p53 interaction, and thus, reestablish wild type p53 activity. ⁶⁶ CDK4 inhibitor can also represent a potential therapeutic option. ⁶⁷
Dedifferentiated liposarcoma (DDLPS)	Beside 12q15 gain been the most frequent event inDDLPS, with MDM2, CPM and SLC35E3 been the most consistent genes gained; additional genomic alterations ,likely related to tumor progression and dedifferentiation, including co-amplifications of 1p32 JUN and 6q23 MAP3K5/MAP3K5, which are mutually exclusively. Recurrent chromosomal rearrangements involving mainly HMGA2 , CPM and DNM3OS are identified in a subset of DDLPS . ^63,68,69 A subset of DDLPS shows amplification of STAT6, resulting in STAT6 protein expression .⁷⁰
Myxoid liposarcoma (MLPS)	t(12;16) (q13;p11) ⁷¹ associated with FUS::DDIT3, ⁷² and less frequent t(12;22)(q13;q12) associated EWSR1::DDIT3 .⁷³ So far DDIT3 rearrangemet is unique for MLPS. ² Several nonrandom secondary aberrations have been identified, e.g. del(6q), +8, and der(16)t(1;16). ⁷² Be aware that both cryptic DDIT3 rearrangement , may ocurr. ⁷⁴
	DDIT3 immunohistochemistry (IHC) can distinguishes high-grade MLPS from other round cell sarcomas. ⁷⁵
	TERT promoter mutations in >50%, ⁷⁶ mutations activating PI3K/mTOR pathway in 25% .⁷⁷
Pleomorphic liposarcoma (PLPS)	Most aggressive subtype of liposarcoma. Extensive, complex karyotype with copy number alterations across the genome and more frequently gains than losses; non-specific molecular profile lacking the distinctive alterations of other liposarcomas and instead resembles undifferentiated liposarcma or myxofibrosarcoma. ^78,79 Dermal samples have a favorable prognosis compared to deeply seated POSL instead showed recurrent losses at the 13q14.2 including RB1 and DLEU2 , and deletion/disruption of the TP53 locus.⁸⁰
Myxoid pleomorphic liposarcoma (MPLPS)	Lacks FUS::DDIT3 or EWSR1::DDIT3 and MDM2 amp, but chromosomal alterations, including gains and lossed involving several chromsomes chromosomes. Losses in chromosome 13, in particular loss in 13q14 , including RB1, RCTB2, DLEU1, and ITM2B. ⁸¹ Genome-wide loss of heterozygosity co-existing with TP53 mutations as a characteristic genomic signature distinct from other liposarcoma subtypes. ⁸²
	Usually occurring in the mediastinum young patients with a female predominance.⁸³
	Association with Li-Fraumeni syndrome has been described. ^84,85

Bibliography

Reference Number	Pubmed ID	Last Year	Title	Authors
1	30709444	2019	Update on Lipomatous Tumors with Emphasis on Emerging Entities, Unusual Anatomic Sites, and Variant Histologic Patterns.	Chrisinger JSA et al
2	30853315	2019	A contemporary review of myxoid adipocytic tumors.	Creytens D et al
3	30857767	2019	Molecular updates in adipocytic neoplasms(✰).	Demicco EG et al
4	31501988	2020	What's new in adipocytic neoplasia?	Creytens D et al
5	34958506	2022	What's new in adipocytic neoplasia?	Thway K et al
6	21356192	2011	Translocation (Y;12) in lipoma.	Liang CW et al
7	9530339	1998	Comparison of chromosomal patterns with clinical features in 165 lipomas: a report of the CHAMP study group.	Willén H et al
8	17370328	2007	Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype.	Bartuma H et al
9	22137485	2011	HMGA2 and MDM2 expression in lipomatous tumors with partial, low-level amplification of sequences from the long arm of chromosome 12.	Mandahl N et al
10	17372913	2007	Gains and complex rearrangements of the 12q13-15 chromosomal region in ordinary lipomas: the "missing link" between lipomas and liposarcomas?	Italiano A et al
11	8812423	1996	LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family.	Petit MM et al
12	18383898	2008	Clinicopathological features of lipomas with gene fusions involving HMGA2.	Hatano H et al
13	26202160	2015	The recurrent chromosomal translocation t(12;18)(q14~15;q12~21) causes the fusion gene HMGA2-SETBP1 and HMGA2 expression in lipoma and osteochondrolipoma.	Panagopoulos I et al
14	27588119	2016	Molecular characterization of the t(4;12)(q27~28;q14~15) chromosomal rearrangement in lipoma.	Agostini A et al
15	19431195	2009	Identification of novel HMGA2 fusion sequences in lipoma: evidence that deletion of let-7 miRNA consensus binding site 1 in the HMGA2 3' UTR is not critical for HMGA2 transcriptional upregulation.	Wang X et al
16	19508721	2009	Expression levels of HMGA2 in adipocytic tumors correlate with morphologic and cytogenetic subgroups.	Bartuma H et al
17	24297246	2014	Rearrangements of chromosome bands 15q12-q21 are secondary to HMGA2 deregulation in conventional lipoma.	Macchia G et al
18	12494468	2003	Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors.	Dahlén A et al
19	9824199	1998	HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors.	Kazmierczak B et al
20	12970064	2003	A truncated HMGA1 gene induces proliferation of the 3T3-L1 pre-adipocytic cells: a model of human lipomas.	Pierantoni GM et al
21	19963137	2010	Fusion of HMGA1 to the LPP/TPRG1 intergenic region in a lipoma identified by mapping paraffin-embedded tissues.	Wang X et al
22	31912494	2020	Mitochondrial DNA pathogenic mutations in multiple symmetric lipomatosis.	López-Gallardo E et al
23	30283804	2018	Multiple Symmetric Lipomatosis (Madelung Disease) in a Large Canadian Family With the Mitochondrial MTTK c.8344A>G Variant.	Perera U et al
24	31481664	2020	PIK3CA mutations in lipomatosis of nerve with or without nerve territory overgrowth.	Blackburn PR et al
25	37067587	2023	PIK3CA mutation testing as a valuable molecular surrogate for lipomatosis of the median nerve: clinicopathological and molecular analysis of six cases.	Osterloh J et al
26	26319758	2015	Molecular cytogenetics of pediatric adipocytic tumors.	Dadone B et al
27	30857637	2019	Identification of a novel BOC-PLAG1 fusion gene in a case of lipoblastoma.	Nitta Y et al
28	32692992	2020	New molecular insights into the pathogenesis of lipoblastomas: clinicopathologic, immunohistochemical, and molecular analysis in pediatric cases.	Lopez-Nunez O et al
29	32918527	2021	Novel ZEB2-PLAG1 fusion gene identified by RNA sequencing in a case of lipoblastoma.	Krsková L et al
30	34455363	2021	The histological and molecular spectrum of lipoblastoma: A case series with identification of three novel gene fusions by targeted RNA-sequencing.	Gerhard-Hartmann E et al
31	10987300	2000	PLAG1 fusion oncogenes in lipoblastoma.	Hibbard MK et al
32	34601996	2022	PLAG1 Immunohistochemical Staining Is a Surrogate Marker for PLAG1 Fusions in Lipoblastomas.	Warren M et al
33	11549588	2001	PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms.	Gisselsson D et al
34	22223189	2012	Rearrangement of HMGA2 in a case of infantile lipoblastoma without Plag1 alteration.	Pedeutour F et al
35	33034408	2021	Lipoblastoma phenotype contains a somatic PIK3CA mutation.	Sudduth CL et al
36	9130991	1997	Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group.	Sciot R et al
37	29275363	2018	Consistent Involvement of Chromosome 13 in Angiolipoma.	Panagopoulos I et al
38	7515663	1994	Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors.	Mandahl N et al
39	28139834	2017	Frequent low-level mutations of protein kinase D2 in angiolipoma.	Hofvander J et al
40	32662895	2021	Frequent activating PIK3CA mutations in sporadic angiolipoma.	Saggini A et al
41	26857357	2016	Fusion of the HMGA2 and C9orf92 genes in myolipoma with t(9;12)(p22;q14).	Panagopoulos I et al
42	27635945	2017	Myolipoma of Soft Tissue: Clinicopathologic Analysis of 34 Cases.	Fukushima M et al
43	20607705	2010	C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma.	Huang D et al
44	22607659	2012	Chondroid lipoma: an update and review.	Thway K et al
45	23672313	2013	Presence of C11orf95-MKL2 fusion is a consistent finding in chondroid lipomas: a study of eight cases.	Flucke U et al
46	36734585	2023	Novel ZFTA::NCOA1 fusion in chondroid lipoma.	Zilla ML et al
47	36201637	2023	ZFTA::RELA fusion in a distinct liposarcoma morphologically overlapping with chondroid lipoma.	Sumida S et al
48	35378317	2022	ZFTA (Zinc Finger Translocation Associated) Fusion in Supratentorial Ependymomas: Low Prevalence in South Asians and No Correlation with Survival.	Goyal-Honavar A et al
49	28476785	2017	Cytogenetic Analysis of a Pseudoangiomatous Pleomorphic/Spindle Cell Lipoma.	Panagopoulos I et al
50	28877053	2017	"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).	Creytens D et al
51	21563233	2011	Gene expression and single nucleotide polymorphism array analyses of spindle cell lipomas and conventional lipomas with 13q14 deletion.	Bartuma H et al
52	32068239	2020	Atypical spindle cell/pleomorphic lipomatous tumor.	Lecoutere E et al
53	29695401	2018	Cytogenetics of Spindle Cell/Pleomorphic Lipomas: Karyotyping and FISH Analysis of 31 Tumors.	Panagopoulos I et al
54	33802620	2021	The Rapidly Expanding Group of RB1-Deleted Soft Tissue Tumors: An Updated Review.	Libbrecht S et al
55	17011989	2006	A (9;11)(q34;q13) translocation in a hibernoma.	Turaga KK et al
56	10393837	1999	Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region. Metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics.	Gisselsson D et al
57	21078971	2010	Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma.	Nord KH et al
58	28478946	2017	Hibernoma and multiple endocrine neoplasia type 1 syndrome: A non-fortuitous association? A case report and literature review.	Marchand L et al
59	28722204	2017	Loss of the tumour suppressor gene AIP mediates the browning of human brown fat tumours.	Magnusson L et al
60	35332938	2022	Histopathologic and genetic findings in atypical spindle cell/pleomorphic lipomatous tumors and atypical pleomorphic fibromas.	Kouhsari LM et al
61	18617058	2008	Monosomy 7 and absence of 12q amplification in two cases of spindle cell liposarcomas.	Italiano A et al
62	30852045	2019	Well-differentiated liposarcoma and dedifferentiated liposarcoma: An updated review.	Thway K et al
63	33799733	2021	MDM2 Amplified Sarcomas: A Literature Review.	Sciot R et al
64	30887579	2019	Double minute chromosomes harboring MDM2 amplification in a pediatric atypical lipomatous tumor.	Dadone-Montaudié B et al
65	10805796	2000	Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity.	Gisselsson D et al
66	32651541	2020	MDM2 inhibition: an important step forward in cancer therapy.	Konopleva M et al
67	32593094	2020	Targeting CDK4 (cyclin-dependent kinase) amplification in liposarcoma: A comprehensive review.	Assi T et al
68	29610390	2018	Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin.	Beird HC et al
69	31831742	2019	Integrated exome and RNA sequencing of dedifferentiated liposarcoma.	Hirata M et al
70	24457460	2014	STAT6 is amplified in a subset of dedifferentiated liposarcoma.	Doyle LA et al
71	7805034	1995	Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.	Knight JC et al
72	21566924	1994	Nonrandom secondary chromosome-aberrations in liposarcomas with t(12, 16).	Mandahl N et al
73	8637704	1996	Fusion of the EWS and CHOP genes in myxoid liposarcoma.	Panagopoulos I et al
74	36379683	2023	A cryptic EWSR1::DDIT3 fusion in myxoid liposarcoma: Potential pitfalls with FISH and cytogenetics.	Ibstedt S et al
75	33731886	2021	Nuclear expression of DDIT3 distinguishes high-grade myxoid liposarcoma from other round cell sarcomas.	Baranov E et al
76	24726063	2014	TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities.	Koelsche C et al
77	30787173	2019	Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma.	Trautmann M et al
78	30852046	2019	Pleomorphic liposarcoma: Updates and current differential diagnosis.	Anderson WJ et al
79	35876778	2023	Pleomorphic Liposarcoma Revisited.	Hadjimichael AC et al
80	32525520	2020	A Reappraisal of Superficial Pleomorphic Liposarcoma.	Berg SH et al
81	34168281	2021	Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma.	Creytens D et al
82	35672466	2022	Myxoid pleomorphic liposarcoma is distinguished from other liposarcomas by widespread loss of heterozygosity and significantly worse overall survival: a genomic and clinicopathologic study.	Dermawan JK et al
83	19194281	2009	Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age.	Alaggio R et al
84	31559875	2020	Recurrent Pleomorphic Myxoid Liposarcoma in a Patient With Li-Fraumeni Syndrome.	Zare SY et al
85	36514176	2022	Comprehensive genomic profiling of a unique liposarcoma arising in a patient with Li-Fraumeni syndrome and the novel detection of c-myc amplification: a case report.	Watanabe H et al

External Links

Citation

Paola Dal Cin

Adipocytic tumors

Atlas Genet Cytogenet Oncol Haematol. 2023-09-05

Online version: http://atlasgeneticsoncology.org/solid-tumor/209206