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

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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; Arbajian, Elsa; Magnusson, Linda; Nilsson, Jenny; Mertens, Fredrik.

I: Modern Pathology, Vol. 32, Nr. 3, 2019, s. 423-434.

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Al-Ibraheemi, Alyaa ; Folpe, Andrew L. ; Perez-Atayde, Antonio R. ; Perry, Kyle ; Hofvander, Jakob ; Arbajian, Elsa ; Magnusson, Linda ; Nilsson, Jenny ; Mertens, Fredrik. / Aberrant receptor tyrosine kinase signaling in lipofibromatosis : a clinicopathological and molecular genetic study of 20 cases. I: Modern Pathology. 2019 ; Vol. 32, Nr. 3. s. 423-434.

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TY - JOUR

T1 - Aberrant receptor tyrosine kinase signaling in lipofibromatosis

T2 - Modern Pathology

AU - Al-Ibraheemi, Alyaa

AU - Folpe, Andrew L.

AU - Perez-Atayde, Antonio R.

AU - Perry, Kyle

AU - Hofvander, Jakob

AU - Arbajian, Elsa

AU - Magnusson, Linda

AU - Nilsson, Jenny

AU - Mertens, Fredrik

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s41379-018-0150-3

DO - 10.1038/s41379-018-0150-3

M3 - Article

VL - 32

SP - 423

EP - 434

JO - Modern Pathology

JF - Modern Pathology

SN - 1530-0285

IS - 3

ER -