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Aberrant receptor tyrosine kinase signaling in lipofibromatosis : a clinicopathological and molecular genetic study of 20 cases

Al-Ibraheemi, Alyaa; Folpe, Andrew L.; Perez-Atayde, Antonio R.; Perry, Kyle; Hofvander, Jakob LU ; Arbajian, Elsa LU ; Magnusson, Linda LU ; Nilsson, Jenny LU and Mertens, Fredrik LU (2018) In Modern Pathology
Abstract

Lipofibromatosis is a rare pediatric soft tissue tumor with predilection for the hands and feet. Previously considered to represent “infantile fibromatosis”, lipofibromatosis has distinctive morphological features, with mature adipose tissue, short fascicles of bland fibroblastic cells, and lipoblast-like cells. Very little is known about the genetic underpinnings of lipofibromatosis. Prompted by our finding of the FN1-EGF gene fusion, previously shown to be a characteristic feature of calcifying aponeurotic fibroma (CAF), in a morphologically typical case of lipofibromatosis that recurred showing features of CAF, we studied a cohort of 20 cases of lipofibromatosis for this and other genetic events. The cohort was composed of 14 males... (More)

Lipofibromatosis is a rare pediatric soft tissue tumor with predilection for the hands and feet. Previously considered to represent “infantile fibromatosis”, lipofibromatosis has distinctive morphological features, with mature adipose tissue, short fascicles of bland fibroblastic cells, and lipoblast-like cells. Very little is known about the genetic underpinnings of lipofibromatosis. Prompted by our finding of the FN1-EGF gene fusion, previously shown to be a characteristic feature of calcifying aponeurotic fibroma (CAF), in a morphologically typical case of lipofibromatosis that recurred showing features of CAF, we studied a cohort of 20 cases of lipofibromatosis for this and other genetic events. The cohort was composed of 14 males and 6 females (median age 3 years; range 1 month–14 years). All primary tumors showed classical lipofibromatosis morphology. Follow-up disclosed three local recurrences, two of which contained calcifying aponeurotic fibroma-like nodular calcifications in addition to areas of classic lipofibromatosis, and no metastases. By FISH and RNA sequencing, four cases were positive for FN1-EGF and one case each showed an EGR1-GRIA1, TPR-ROS1, SPARC-PDGFRB, FN1-TGFA, EGFR-BRAF, VCL-RET, or HBEGF-RBM27 fusion. FN1-EGF was the only recurrent fusion, suggesting that some cases of “lipofibromatosis” may represent calcifying aponeurotic fibroma lacking hallmark calcifications. Several of the genes involved in fusions (BRAF, EGFR, PDGFRB, RET, and ROS1) encode receptor tyrosine kinases (RTK), or ligands to the RTK EGFR (EGF, HBEGF, TGFA), suggesting a shared deregulation of the PI3K–AKT–mTOR pathway in a large subset of lipofibromatosis cases.

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Modern Pathology
publisher
Nature Publishing Group
external identifiers
  • scopus:85054754156
ISSN
0893-3952
DOI
10.1038/s41379-018-0150-3
language
English
LU publication?
yes
id
4b59c0f2-3e6d-46bb-ae05-2b0643e5b9bf
date added to LUP
2018-11-13 09:55:53
date last changed
2019-01-06 14:14:42
@article{4b59c0f2-3e6d-46bb-ae05-2b0643e5b9bf,
  abstract     = {<p>Lipofibromatosis is a rare pediatric soft tissue tumor with predilection for the hands and feet. Previously considered to represent “infantile fibromatosis”, lipofibromatosis has distinctive morphological features, with mature adipose tissue, short fascicles of bland fibroblastic cells, and lipoblast-like cells. Very little is known about the genetic underpinnings of lipofibromatosis. Prompted by our finding of the FN1-EGF gene fusion, previously shown to be a characteristic feature of calcifying aponeurotic fibroma (CAF), in a morphologically typical case of lipofibromatosis that recurred showing features of CAF, we studied a cohort of 20 cases of lipofibromatosis for this and other genetic events. The cohort was composed of 14 males and 6 females (median age 3 years; range 1 month–14 years). All primary tumors showed classical lipofibromatosis morphology. Follow-up disclosed three local recurrences, two of which contained calcifying aponeurotic fibroma-like nodular calcifications in addition to areas of classic lipofibromatosis, and no metastases. By FISH and RNA sequencing, four cases were positive for FN1-EGF and one case each showed an EGR1-GRIA1, TPR-ROS1, SPARC-PDGFRB, FN1-TGFA, EGFR-BRAF, VCL-RET, or HBEGF-RBM27 fusion. FN1-EGF was the only recurrent fusion, suggesting that some cases of “lipofibromatosis” may represent calcifying aponeurotic fibroma lacking hallmark calcifications. Several of the genes involved in fusions (BRAF, EGFR, PDGFRB, RET, and ROS1) encode receptor tyrosine kinases (RTK), or ligands to the RTK EGFR (EGF, HBEGF, TGFA), suggesting a shared deregulation of the PI3K–AKT–mTOR pathway in a large subset of lipofibromatosis cases.</p>},
  author       = {Al-Ibraheemi, Alyaa and Folpe, Andrew L. and Perez-Atayde, Antonio R. and Perry, Kyle and Hofvander, Jakob and Arbajian, Elsa and Magnusson, Linda and Nilsson, Jenny and Mertens, Fredrik},
  issn         = {0893-3952},
  language     = {eng},
  month        = {10},
  publisher    = {Nature Publishing Group},
  series       = {Modern Pathology},
  title        = {Aberrant receptor tyrosine kinase signaling in lipofibromatosis : a clinicopathological and molecular genetic study of 20 cases},
  url          = {http://dx.doi.org/10.1038/s41379-018-0150-3},
  year         = {2018},
}