Lipofibromatosis

Last updated
Lipofibromatosis
Specialty Pediatrics, pediatric dermatology, pediatric surgery
Treatment Surgical resection of the tumor
Prognosis Excellent
FrequencyVery rare

Lipofibromatosis (LPF) is an extremely rare soft tissue tumor which was first clearly described in 2000 by Fetsch et al as a strictly pediatric, locally invasive, and often recurrent (at the site of its surgical removal) tumor. It is nonetheless a non-metastasizing, i.e. benign, tumor. [1] While even the more recent literature has sometimes regarded LPF as a strictly childhood disorder, [2] [3] rare cases of LPF have been diagnosed in adults. [4] [5] The diagnosis of lipofibromatosis should not be automatically discarded because of an individual's age. [4] [5]

Contents

Based primarily on histopathologic (i.e. microscopic appearance of specially prepared tissue) analyses, lipofibromatosis was initially regarded as either a type of, or very similar to, aponeurotic fibroma (also termed calcifying aponeurotic fibroma), [6] fibrous hamartoma of infancy, [7] EWSRI-SMAD3-rearranged fibroblastic tumor (also termed EWSR1-SMAD3-positive fibroblastic tumor), [8] or infantile digital fibromatosis. [7] However, further analyses of these tumors' various differences, particularly in the gene abnormalities that their neoplastic cells express, led the World Health Organization in 2020 to classify LPF and each of the four other tumors as distinctly different forms in the category of fibroblastic and myofibroblastic tumors. [9]

Lipofibromatosis-like neural tumor was defined in 2016 as a disorder which initial studies regarded to be a variant of lipofibromatosis. [10] [11] However, more recent studies have emphasized critical differences in the clinical presentations and gene abnormalities between these two tumors. [12] Here, lipofibromatosis-like neural tumor is considered to be a distinct tumor form with its own article.

Presentation

LPF presents as an ill-defined, slow growing tumor mass located in or below the subcutaneous tissue (area of the skin below the dermis) of an extremity or, less commonly, the thigh, trunk, or head areas. [3] Rare single cases of these tumors have been reported in occur in the heart and eye socket. [4] These tumors are often painless [3] but in some cases become painful when manipulated during examination. [2] LPF tumors occur almost exclusively in children at birth (~18% of cases [1] ) up to age 8 years with most cases presenting before age 2 years; they are extremely rare in adults. [4] [5] The disorder has a 2:1 male predominance. [4] LPD tumors are usually 5 cm. or smaller and obvious on physical examination. Uncommonly, LPF tumors present after they have invaded adjacent underlying structures such as blood vessels, nerves, and muscles although significant functional impairment of the invaded tissues is uncommon. [3] Individuals have also presented with recurrences of these tumors at the site of surgery in up to 1/3 of all surgically treated cases. [1] [7]

Pathology

LPF is an infiltrative, poorly circumscribed tumor that on microscopic histopathological analysis consists of oval- or spindle-shaped fibroblast-like cells interspersed with muscle cells (as evidenced by the presence of the easily recognizable myofibril portions of muscle cells). [8] These cells give the appearance of infiltrating fat tissues. [1] This fat tissue is composed of adipocyte-like cells, some of which are distinctly abnormal [8] in that they contain one relative large vacuole, resemble lipoblasts (precursors to mature adipocytes), [8] and show considerable variations in their appearances. [8] The distinctly abnormal lipoblasts have been referred to as "pseudolipoblasts". [8] Overall, fat tissue represents >50% of the LPF tumors. [11] As detected by immunohistochemical analyses, LPF tumor tissues also contain scattered foci of cells that express the tumor marker proteins CD99, SMA (i.e. smooth muscle actin), CD34, and less frequently S100 and/or epithelial membrane antigen. [8]

Gene abnormalities

A recent study found various fusion genes in the spindle-shaped cells of LPF tumors using fluorescence in situ hybridization, RNA sequencing, and real-time polymerase chain reaction analyses of formalin-fixed, paraffin-embedded tumor tissue. Fusion genes are abnormal and potentially tumor-inducing genes formed by mergers between parts of two different genes; they are results of chromosomal translocations, interstitial deletions, or inversions. The fusions genes in LPF were: FN1-EGF (i.e. part of the FN1 gene fused to the EGF gene), FN1-TGFA, HBEGF-RBM27, [13] EGR1-GRIA1, EGFR-BRAF, SPARC-PDGFRB, TPR [14] -ROS1, and VCL-RET. Of the twenty cases of lipofibromatosis tumors tested, the FNI-EGF fusion gene occurred in four cases, each of the other fusion genes occurred in just one case, and none of these fusion genes were detected in nine cases. Notably: 1) the EGFR, PDGFRB, and RET genes code for receptor tyrosine kinases, i.e. the epidermal growth factor receptor, platelet-derived growth factor receptor beta, and RET proto-oncogene receptor, respectively, all of which activate the PI3K/AKT/mTOR pathway; 2) the BRAF and ROS1 genes code for serine/threonine-protein kinase B-Raf [15] and proto-oncogene tyrosine-protein kinase, [16] respectively, both of which also activate the PI3K/AKT/mTOR pathway; and 3) products of the EGF gene, i.e. epidermal growth factor, HBEGF gene, i.e. heparin-binding EGF-like growth factor, and TGFA gene, i.e. transforming growth factor alpha are ligands for and activate the epidermal growth factor receptor. [7] Excessive activation of the PI3K/AKT/mTOR pathway is known to promote the development of various tumor types and may be involved in the development of at least some lipofibromatosis tumors. [7] [11]

Diagnosis

The diagnosis of LPF depends on its clinical presentation almost exclusively in newborn and young children and, most importantly, its histopathology as determined on biopsied intact tissue or fine-needle aspiration to obtain a sampling of the tumor's cells. Intact tissue samples typical show abundant mature-appearing adipose (i.e. fat) tissue [11] mixed with a minor component of oval-shaped or spindle-shaped fibroblast-like cells some of which have a pseudolipoblast-like morphology. [8] Needle biopsies should show these cells. However, LPF histopathology can vary widely between cases. The cited gene abnormalities in the above section are insufficient to support a diagnosis of LPF although further study of these and discoveries of other gene abnormalities may do so. [11] The histopathology of lipofibromatosis-like neural tumors (LPF-NT) can closely resemble LPF tumors. Unlike LPF tumors, however, LPF-NT tumors have been diagnosed in adults in more than 27% of cases with the remaining cases diagnosed in children not younger than 14 months/old. [17] Moreover, LPF tumor cells, but not LPF tumor cells, commonly express a fusion gene containing a part of the NTRK1 gene. [11]

Treatment and prognosis

Complete radical surgical resection is the recommended treatment for these rare tumors although modalities such as radiation have been attempted as adjuvant therapy for tumors that can not be totally removed. [2] For diffusely infiltrative LPF tumors, partial resection (i.e. debulking) with the lowest potential postoperative morbidity has been employed. [1] [2] [18] Incomplete surgical removal of the tumor, male sex, presence at birth, occurrence on the hands and feet, and a high mitotic index (i.e. rate of cell proliferation on microscopic tissue examination) are predisposing factors for recurrence. [1] Recurrent tumors, which may occur multiple times, have been successfully treated with repeated complete surgical resections aimed to remove all tumor tissue, incomplete local surgical resections to relieve symptoms, and in rare cases removal of the part of the limb containing the tumor. [1]

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Angiofibroma of soft tissue (AFST), also termed angiofibroma, not otherwise specified, is a recently recognized and rare disorder that was classified in the category of benign fibroblastic and myofibroblastic tumors by the World Health Organization in 2020. An AFST tumor is a neoplasm that was first described by A. Mariño-Enríquez and C.D. Fletcher in 2012.

Dermatofibrosarcoma protuberans, fibrosarcomatous (DFSP-FS), also termed fibrosarcomatous dermatofibrosarcoma protuberans, is a rare type of tumor located in the dermis. DFSP-FS tumors have been viewed as: 1) a more aggressive form of the dermatofibrosarcoma protuberans (DFSP) tumors because they have areas that resemble and tend to behave like malignant fibrosarcomas or 2) as a distinctly different tumor than DFSP. DFSP-FS tumors are related to DFSP. For example, surgically removed DFSP tumors often recur with newly developed fibrobosarcoma-like areas. Nonetheless, the World Health Organization (WHO), 2020, classified DFSP and DFSP-FS as different tumors with DFSP being in the category of benign and DFSP-FS in the category of rarely metastasizing fibroblastic and myofibroblastic tumors. This article follows the WHO classification: the 5-15% of DFSP tumors that have any areas of fibrosarcomatous microscopic histopathology are here considered DFSP-FS rather than DFSP tumors.

Low-grade myofibroblastic sarcoma (LGMS) is a subtype of the malignant sarcomas. As it is currently recognized, LGMS was first described as a rare, atypical myofibroblastic tumor by Mentzel et al. in 1998. Myofibroblastic sarcomas had been divided into low-grade myofibroblastic sarcomas, intermediate‐grade myofibroblasic sarcomas, i.e. IGMS, and high‐grade myofibroblasic sarcomas, i.e. HGMS based on their microscopic morphological, immunophenotypic, and malignancy features. LGMS and IGMS are now classified together by the World Health Organization (WHO), 2020, in the category of intermediate fibroblastic and myofibroblastic tumors. WHO, 2020, classifies HGMS as a soft tissue tumor in the category of tumors of uncertain differentiation. This article follows the WHO classification: here, LGMS includes IGMS but not HGMS which is a more aggressive and metastasizing tumor than LGMS and consists of cells of uncertain origin.

References

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  6. ↑ John I, Fritchie KJ (January 2020). "What is new in pericytomatous, myoid, and myofibroblastic tumors?". Virchows Archiv. 476 (1): 57–64. doi:10.1007/s00428-019-02700-y. PMID   31705190. S2CID   207941071.
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  9. ↑ Sbaraglia M, Bellan E, Dei Tos AP (April 2021). "The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives". Pathologica. 113 (2): 70–84. doi:10.32074/1591-951X-213. PMC   8167394 . PMID   33179614.
  10. ↑ Agaram NP, Zhang L, Sung YS, Chen CL, Chung CT, Antonescu CR, Fletcher CD (October 2016). "Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors". The American Journal of Surgical Pathology. 40 (10): 1407–16. doi:10.1097/PAS.0000000000000675. PMC   5023452 . PMID   27259011.
  11. 1 2 3 4 5 6 Malik F, Santiago T, Newman S, McCarville B, Pappo AS, Clay MR (June 2020). "An addition to the evolving spectrum of lipofibromatosis and lipofibromatosis-like neural tumor: Molecular findings in an unusual phenotype aid in accurate classification". Pathology, Research and Practice. 216 (6): 152942. doi:10.1016/j.prp.2020.152942. PMID   32299759. S2CID   215803522.
  12. ↑ Panse G, Reisenbichler E, Snuderl M, Wang WL, Laskin W, Jour G (February 2021). "LMNA-NTRK1 rearranged mesenchymal tumor (lipofibromatosis-like neural tumor) mimicking pigmented dermatofibrosarcoma protuberans". Journal of Cutaneous Pathology. 48 (2): 290–294. doi:10.1111/cup.13772. PMID   32519338. S2CID   219562066.
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  14. ↑ "TPR translocated promoter region, nuclear basket protein [Homo sapiens (Human)] - Gene - NCBI".
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  16. ↑ Sudhagar S, Sathya S, Lakshmi BS (September 2011). "Rapid non-genomic signalling by 17β-oestradiol through c-Src involves mTOR-dependent expression of HIF-1α in breast cancer cells". British Journal of Cancer. 105 (7): 953–60. doi:10.1038/bjc.2011.349. PMC   3185958 . PMID   21897387.
  17. ↑ Crumbach L, Descotes F, Bringuier PP, Poulalhon N, Balme B, Juliet T, Lopez J, Harou O (November 2020). "Lipofibromatosis-Like Neural Tumor: A Case Report and Review of the Literature". The American Journal of Dermatopathology. 42 (11): 881–884. doi:10.1097/DAD.0000000000001734. PMID   32618702. S2CID   220327572.
  18. ↑ Costa Dias S, McHugh K, Sebire NJ, Bulstrode N, Glover M, Michalski A (May 2012). "Lipofibromatosis of the knee in a 19-month-old child". Journal of Pediatric Surgery. 47 (5): 1028–31. doi:10.1016/j.jpedsurg.2012.02.009. PMID   22595596.
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