Adipocytic Tumours in children
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1 Università degli Studi di Padova Dipartimento di Medicina Sezione di Anatomia Patologica Generale e Citopatologia Adipocytic Tumours in children Rita Alaggio Basel Seminars in Pathology Paediatric Pathology & Genetics Basel, June 22nd 25th, 2016
2 Outline Classification of adipocytic tumors Lipoblastoma Lipoblastoma: Differential Diagnostic Challenges Liposarcoma
3 WHO 2013 Classification BENIGN Lipoma Lipoblastomatosis Lipomatosis of Nerve Lipoblastoma Angiomyolipoma Myolipoma of soft tissue Chondroid lipoma Spindle cell/pleomorphic lipoma Hybernoma MALIGNANT Atypical lipomatous tumor Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma
4 WHO 2013 Classification BENIGN Lipoma Lipoblastomatosis Lipomatosis of Nerve Lipoblastoma Angiomyolipoma Myolipoma of soft tissue Chondroid lipoma Spindle cell/pleomorphic lipoma Hybernoma MALIGNANT Atypical lipomatous tumor Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma
5 Outline Classification of adipocytic tumors Lipoblastoma Lipoblastoma: Differential Diagnostic Challenges Liposarcoma
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7 Case 1 Multivacuolated and univacuolated lipoblasts
8 Clinical History Boy, 1.5 yr expanding mass in the paravertebral region Main diameter 3 cm Treatment: resection
9 Clinical History Boy, 1.5 yr expanding mass in the paravertebral region Main diameter 3 cm Treatment: resection Diagnosis: Lipoblastoma
10 Lipoblastoma Lipoblastoma, a benign neoplasm of embryonal white fat, is a localized or diffuse (lipoblastomatosis) tumor with a tendency for local recurrence if incompletely excised. - WHO, 2013
11 Lipoblastoma Clinical Features 90% before 3 years 40% 1 st year of life Rare in adolescents and adults Sex: male predilection Site: trunk, extremities Others: retroperitoneum, pelvis, abdomen, head/neck, organs (lung, heart) Benign clinical course 13-46% of relapse in incomplete resection
12 Lipoblastoma (Courtesy of C. Coffin)
13 Lipoblastomatosis (Courtesy of C. Coffin)
14 Lipoblastoma Histology Lobulated architecture with fibrovascular septa Lipoblasts in various stages of differentiation to mature fat with orientation from periphery to the center: primitive stellate or spindle cells multivacuolate lipoblasts signet ring cells Floret cells Hibernoma like cells Myxoid foci with plexiform vascular pattern, primitive mesenchymal cells Chronic inflammation, mast cells Fibrolipoma-like areas possible
15 Lipoblastoma Histology Lobulated architecture with fibrovascular septa Lipoblasts in various stages of differentiation to mature fat with orientation from periphery to the center: primitive stellate or spindle cells multivacuolate lipoblasts signet ring cells Floret cells Hibernoma like cells Myxoid foci with plexiform vascular pattern, primitive mesenchymal cells Chronic inflammation, mast cells Fibrolipoma-like areas possible
16 Lipoblastoma Histology Lobulated architecture with fibrovascular septa Lipoblasts in various stages of differentiation to mature fat with orientation from periphery to the center: primitive stellate or spindle cells multivacuolate lipoblasts signet ring cells Floret cells Hibernoma like cells Myxoid foci with plexiform vascular pattern, primitive mesenchymal cells Fibrolipoma-like areas (eg in maturing lipoblastoma) Chronic inflammation, mast cells
17 Abdominal Lipoblastoma, age 2 yr. Resection
18 Abdominal Lipoblastoma, age 2 yr. Recurrence, 5yr
19 Lipoblastoma Immunohistochemistry S100, CD34: positive nonspecific Desmin: in primitive mesenchymal cells: a potential pitfall PLAG1 protein: not liable p16: negative
20 p16 -ve Desmin p16 +ve (2 cases/30) S100 Lipoblastoma (Cappellesso et al Hum Pathol 2016)
21 Lipoblastoma Genetics Chromosome 8 aberrations typical, including extra copies in 10-15% Breakpoints cluster to 8q11-13 involving PLAG1 in 8q12.1 Translocation partners vary: 3q12-13, COL1A2 in 7q21.3 HAS2 in 8q24.13 rarely COL3A1 and RAB2A* others *Yoshida et al. Genes, Chromosomes & Cancer 53: (2014)
22 Lipoblastoma: Genetic Alterations Chromosomal Rearrangements Increase of PLAG1 copy number IGF2 Activation Adipocytes Proliferation
23 Chromosomal Rearrangements of PLAG1 HAS2 (hyaluronic acid synthase 2) Check and transport of Ialuronic Acid COL1A2 (collagen 1 alpha 2) Involved in the formation of the collagen in connective tissue, bone and tendons Potential role in the genesis of myxoid component? Potential role in collagen septae formation?
24 Lipoblastoma Associated Conditions Developmental delay or abnormalities Congenital malformations Seizures Sturge-Weber syndrome Autism Familial lipomas
25 Outline Classification of adipocytic tumors Lipoblastoma Lipoblastoma: Differential Diagnostic Challenges Liposarcoma
26 Lipoblastoma Differential Diagnostic Challenges Lipoma and variants Primitive myxoid mesenchymal tumor of infancy Lipofibromatosis Fibrous Hamartoma Liposarcomas, especially myxoid and myxoid-pleomorphic Other fatty and myxoid tumors
27 Lipoma Hibernoma
28 Genetic aberrations in pediatric lipoma Similar to adult lipomas In literature less than 30 pediatric lipomas investigated: 11 with aberrations of the 12q14 q15 region, with rearrangement of the HMGA2 gene in 3, 1 with anomaly of 6p21 region, resulting in a rearrangement of HMGA1 NFIB identified as a fusion partner of HMGA2 in pediatric lipoma. NFIB is a regulator of adipocyte differentiation; its inhibition suppresses induction of adipogenic transcription factors, (PPARγ, C/EBPa etc), and reduces accumulation of lipids during differentiation. Cancer Genetics 208 (2015)
29 Lipoblastoma Differential Diagnostic Challenges Lipoma and variants Primitive myxoid mesenchymal tumor of infancy Lipofibromatosis Fibrous Hamartoma Liposarcomas, especially myxoid and myxoid-pleomorphic Other fatty and myxoid tumors
30 Vimentin Primitive myxoid mesenchymal tumor of infancy
31
32 Initial diagnosis of Lipoblastoma (2/30 cases in Italian series)
33 Lipoblastoma Differential Diagnostic Challenges Lipoma and variants Fibrous Hamartoma Primitive myxoid mesenchymal tumor of infancy Lipofibromatosis Liposarcomas, especially myxoid and myxoid-pleomorphic Other fatty and myxoid tumors
34
35
36 Fibrous Hamartoma In our series 2 originally diagnosed as lipoblastoma (out of 30 lipoblastomas) Slight male predilection Site: axilla, upper extremities, trunk, groin, external genitalia poorly circumscribed, nodular lesion Organoid lesion, 3 components Dense fibrous trabeculae Primitive mesenchymal cells in nests and bands in the context of a myxoid matrix Mature adipose tissue Rare multicentric cases
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40 Lipofibromatosis Histology Abundant adipose tissue (>50%) Slender fascicles of fibroblasts among the adipose lobules Myxoid component lipoblast-like cells at the periphery along the fibrous septae Infiltrative growth pattern with entrapment of nerve trunks and muscle Dendritic cells (occasional) DD with Lipoblastoma: more prominent connectival component and fibroblastic proliferation
41
42 Lipofibromatosis Clinical Features Myofibroblastic lesion in the past diagnosed as: fibrous hamartoma, fibromatosis, CIFS, lipoblastoma e calcifying aponeurotic fibroma Frequently congenital Site: extremities (frequent), thorax, abdomen, head (less frequent) Tendency to relapse Treatment: conservative surgery
43 Lipofibromatosis Molecular/Cytogenetic Features NTRK1 Associated Gene Fusions in Pediatric Fibroblastic / Myofibroblastic Neoplasms: A Molecular Study of 58 Cases 3 LPF with TPM3-NTRK1 NTRK1 by IHC strong expression 18 LPFs recurrent complex FISH abnormalities at the 1q locus (including NTRK1 and a number of known NTRK1-fusion partners in other cancers) 10/11 FHI recurrent abnormalities in the same 1q region. Agaram NP et al. USCAP 2016
44
45 LIPOSARCOMA
46 Outline Classification of adipocytic tumors Lipoblastoma Lipoblastoma: Differential Diagnostic Challenges Liposarcoma
47 Liposarcoma in children Extremely rare in pediatric patients (2% of sarcomas) Distribution among soft tissue sarcomas: 5%, 6%, 22%, and 66% in age categories: <5 years, 5 9 years, years, and years, respectively (SEER data). Most frequent histotype represented by Myxoid Liposarcoma (MLPS)* Prognosis for conventional MLPS in young patients very favorable* Progression to Round cell-lps very uncommon in MLPS in young patients A subset of LPS show features of a Pleomorphic-MLPS, is typical of mediastinal region, with aggressive clinical behaviour. Spindle cell-lps also present (not clear if they belong to MLPS) Lipoma-like and pleomorphic LPS exceptional in children *Alaggio R, Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age.am J Surg Pathol May;33(5):
48 Myxoid Liposarcoma (60 cases: 10-22y, M:F=2:1)
49
50
51 Atypical lipomatous tumor (4 cases: 12-19y, M:F=1:1)
52
53 Pleomorphic Liposarcoma (2 cases: 5-21y, M:F=1:1)
54 Male, 10 year-old Familiar/Personal history negative Mass in the back noted few months before and recently increased in size.
55 MRI solid lesion deeply located in the subcutis, strongly adherent to the fascia.
56 Treatment Primary excision with macroscopic residual disease. After the histological diagnosis, the child underwent a primary re-excision.
57 The mass (main diameter 3.6 cm) was completely excised The child is alive and diseasefree after 8 yr.
58 Spindle cell Liposarcoma (6 cases: 11-17y, M:F=1:5)
59
60
61 Important differential diagnosis Spindle cell lipoma Typical of adult age Bland cytology Nuclear palisading Ropey collagen bundles Mastocytes CD34+++
62 Pleomorphic Myxoid Liposarcoma (10 cases: 10-22y, M:F=2:3)
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69 Outcome M/RCLPS P-MLPS SC-LPS ALT/DL PLPS Follow-up 31/60 ( mos; median 72 mos) 6/10 (8-108 mos; median 36 mos) 4/6 ( mos; median 42 mos) 4/4 ( mos; median 72 mos) 1/2 (72 mos) ANED 29/31 (94%) 1/6 (17%) 3/4 (75%) 4/4 (100%) 1/1 (100%) AWD 1/31 (3%) 1/6 (17%) 1/4 (25%) 0/4 (0%) 0/1 (0%) DOD 1/31 (3%) 4/6 (67%) 0/4 (0%) 0/4 (0%) 0/1 (0%) LR 3/31 (9%) 3/4 (75%) 1/4 (25%) 2/4 (50%) 0/1 (0%) Mets 0/31 (0%0 2/4 (50%) 1/4 (25%) 0/4 (0%) 0/1 (0%)
70 Pediatric Liposarcoma Genetic aberrations
71
72 CONCLUSIONS
73 Differential Diagnosis between Lipoblastoma and Liposarcoma may be challenging Lipoblastoma Myxoid LPS Usual age: Newborn-5 yr Adults Lobules Well-defined Indistinct Mature fat Central Peripheral, sparse Mucin pools Cellularity Focal Low More abundant Higher (focal) Atypia Absent Present (focal) Mitoses Genetics: Normal (if any) 8q11-13 PLAG1 t(7;8) Abnormal 12q13 DDIT3 t(12;16) or t(12;22) Courtesy of Cheryl Coffin
74 Lipoblasts do not mean liposarcoma in children Liposarcoma in children differs from its adult counterpart with minor aggressivity and peculiar histology -myxoid with pleomorphic cells -spindle cell
75 Fig.14-case 14; mixed myxoid round cell liposarcoma. At the right a myxoid area with intermingled round cell lipoblasts. At the left an area where the cells simulate the appearance and arrangement of a fibrosarcoma Arthur Purdy Stout. Annals of Surgery, January 1944 in some tumors (myxoid liposarcomas) areas showing a distinct spindle cell pattern were present. Unlike the spindle cells of the pleomorphic type, however, the cells were small and slender and generally oriented along a single plane Enzinger &Winslow Virch Arch Path Anat, 1962
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