Role of epidural fat in the local milieu: what we know and what we don't.

PURPOSE: Traditionally, the epidural fat (EF) is known as a physical buffer for the dural sac against the force and a lubricant facilitating the relative motion of the latter on the osseous spine. Along with the development of the studies on EF, controversies still exist on vital questions, such as the underlying mechanism of the spinal epidural lipomatosis. Meanwhile, the scattered and fragmented researches hinder the global insight into the seemingly dispensable tissue. METHODS: Herein, we reviewed literature on the EF and its derivatives to elucidate the dynamic change and complex function of EF in the local milieu, especially at the pathophysiological conditions. We start with an introduction to EF and the current pathogenic landscape, emphasizing the interlink between the EF and adjacent structures. We generally categorize the major pathological changes of the EF into hypertrophy, atrophy, and inflammation. RESULTS AND CONCLUSIONS: It is acknowledged that not only the EF (or its cellular components) may be influenced by various endogenic/exogenic and focal/systematic stimuli, but the adjacent structures can also in turn be affected by the EF, which may be a hidden pathogenic clue for specific spinal disease. Meanwhile, the unrevealed sections, which are also the directions the future research, are proposed according to the objective result and rational inference. Further effort should be taken to reveal the underlying mechanism and develop novel therapeutic pathways for the relevant diseases.

Nevus lipomatosus superficialis: A series of six cases.

Nevus lipomatosus still imposes diagnostic, categorization, and etiologic challenges. Even though an intradermal adipose tissue is a histopathologic prerequisite, the lesions are clinically divided into classic multiple forms and a solitary variant, which some consider a separate so-called lipofibroma clinicopathologic entity. This further complicates the true prevalence, classification and etiopathogenesis of nevus lipomatosus. Case reports and series studies have reflected either consistent or variable and sometimes conflicting clinicopathologic findings. A few have reported electron microscopic findings. Immunohistochemistry is lacking. We report two multiple and four solitary forms of nevus lipomatosus in six patients, highlighting their salient histopathologic features and immunohistochemical profile. Both forms showed intradermal groups of perivascular S100+ lipogenic and CD34+ mesenchymal cells intermixed with scattered CD1a+ and FXIIIa+ dendrocytes, CD3 lymphocytic and CD117 mast cells in a fibromyxoid milieu. Epidermal nevoid and comedonal follicular alterations, attenuated dermal connective tissue and adnexal structures were variably present in both forms. We compared our findings with seven series of studies reporting classic and solitary forms. Both forms showed similar histopathologic findings, comparable clinicopathologic features, predominantly pelvic, and shoulder girdle distribution patterns in bimodal age onsets. Even though some lipomatous skin lesions clinically and histopathologically overlap with nevus lipomatosus, certain findings are helpful distinguishing features. Small intradermal islands of lipocytic fibroplasia have characteristic perivascular milieu that may function as a niche of preadipose CD34 mesenchymal stem cells. They are most likely represented in the dermis of the pelvic and shoulder areas in certain individuals prone to maintain these embryonic reservoirs, which are clinically manifested at different ages. Some may have unifocal or multifocal residues reflecting multiple and solitary forms.

Ultrasonographic findings in nevus lipomatosus cutaneous superficialis: What differentiates this tumor from other soft tissue tumors?

Nevus lipomatosus cutaneous superficialis is a rare, benign hamartoma characterized by mature adipocyte proliferation in the dermis. It is frequently difficult to distinguish clinically from soft tissue tumors, including lipoma, neurofibroma, venous malformation, and angiolipoma. Notably, the classical form, which shows multiple and sometimes enlarged nodules, is difficult to differentiate from liposarcoma based on clinical examination, computed tomography, and magnetic resonance imaging findings. Therefore, to ascertain the utility of ultrasonography in diagnosing nevus lipomatosus cutaneous superficialis, sonographic examinations were performed on eight patients with nevus lipomatosus cutaneous superficialis. All patients had ill-defined hyperechoic masses in the dermis or from the dermis to the subcutis, and the posterior echoes were attenuated in seven patients. Color Doppler sonography revealed no blood flow to the lesions. Ultrasound images were created using the reflections of ultrasound waves at interfaces with different acoustic impedances. Therefore, it is assumed that, in nevus lipomatosus cutaneous superficialis, the ultrasound beam is scattered by ectopic mature adipocytes intermingled with collagen bundles, which are shown as hyperechoic masses. Furthermore, the scattering of the ultrasound beam is thought to reduce tissue penetration, which may attenuate the posterior echo.

SBDSR126T rescues survival of sbds -/- zebrafish in a dose-dependent manner independently of Tp53.

Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in SBDS, which encodes a ribosome assembly factor. Some individuals express a missense mutation, SBDS R126T , along with the common K62X mutation. We reported that the sbds-null zebrafish phenocopies much of SDS. We further showed activation of Tp53-dependent pathways before the fish died during the larval stage. Here, we expressed SBDS R126T as a transgene in the sbds -/- background. We showed that one copy of the SBDS R126T transgene permitted the establishment of maternal zygotic sbds-null fish which produced defective embryos with cdkn1a up-regulation, a Tp53 target involved in cell cycle arrest. None survived beyond 3 dpf. However, two copies of the transgene resulted in normal development and lifespan. Surprisingly, neutropenia persisted. The surviving fish displayed suppression of female sex differentiation, a stress response in zebrafish. To evaluate the role of Tp53 in the pathogenesis of sbds -/- fish phenotype, we bred the fish with a DNA binding deficient allele, tp53 M214K Expression of the loss-of-function tp53 M214K did not rescue neutropenia or survival in sbds-null zebrafish. Increased expression of cdkn1a was abrogated in the tp53 M214K/M214K ;sbds -/- fish. We conclude that the amount of SBDSR126T protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the sbds-null background, and cdkn1a up-regulation was dependent on WT tp53 We hypothesize that additional pathways are involved in the pathophysiology of SDS.

Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.

Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.

PIK3CA mutation testing as a valuable molecular surrogate for lipomatosis of the median nerve: clinicopathological and molecular analysis of six cases.

Lipomatosis of peripheral nerves (LPN, also known as fibrolipomatous or lipofibromatous hamartoma of peripheral nerves) is a very rare, benign, intraneural, tumorous lesion that predominantly involves the median nerve but may rarely affect any peripheral nerve. Recently, PIK3CA mutations have been reported in macrodactyly, a rare condition related to LPN, and in other localized lipomatous overgrowth syndromes. In this retrospective study, we report 6 cases of FPN involving the median nerve (4 of them identified among 570 patients with carpal tunnel syndrome who underwent surgical decompression at our center from 2012 to 2022 and two seen in consultation by one of the authors). All cases were diagnosed via biopsy or resection supplemented by MRI. Patients were 4 males and 2 females aged 23 to 60 years (mean 38 years). One patient with bilateral lesions had in addition extensive angiomatosis of the paravertebral region. Histological examination showed an abnormal amount of mature fatty tissue containing disordered fibrous bands, entrapping normal-looking nerve fibers with prominent perineurial and endoneurial fibrosis. Genetic analysis using snapshot assay constructed to detect hotspots mutations in PIK3CA revealed similar PIK3CA mutations (p.H1047R; c.3140A>G) in 5/6 cases (83.3%). Our study represents a further contribution to the literature on LPN and highlights the diagnostic value of PIK3CA mutation testing as surrogate tool in equivocal cases and in those lesions without associated macrodactyly, especially as the biopsy findings of this lesion are essentially nonspecific.

Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node.

Lymph node (LN) lipomatosis is a common but rarely discussed phenomenon associated with aging that involves a gradual exchange of the LN parenchyma into adipose tissue. The mechanisms behind these changes and the effects on the LN are unknown. We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that isolated medullary and CD34+ fibroblasts, in contrast to the reticular cells of the T-cell zone, display an inherently higher sensitivity for adipogenesis. Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting-like lymphatic vessels are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of naïve T-cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Is There any Link between Madelung Disease and Ischemic Stroke? A Case Report.

A 70-year-old man presented to the Emergency Department with left hemiparesis, slurred speech, and elevated blood pressure. A brain computed tomography scan revealed an ischemic lesion in the right frontal and parietal lobes. At clinical examination bilateral pseudo gynecomastia was detected together with the presence of multiple elastic, adipose bulging masses on the neck, trunk, and upper limbs. A type I-II Lanois-Bensaude syndrome was diagnosed. Ultrasonography confirmed their adipose nature. Multiple symmetric lipomatosis, also known as Lanois-Bensaude syndrome or Madelung disease, is a very rare condition with extreme variability in its clinical presentation. The simultaneous occurrence of ischemic stroke and lipomatosis in the same patient might be due to a mitochondrial function impairment, which could lead to abnormal fat tissue distribution and defective cellular energy production, thus resulting in neuronal sufferance and death. The possibility that, in our case, lipomatosis could have represented a further risk factor in promoting the stroke occurrence is discussed. In our opinion, multiple symmetric lipomatosis must be carefully evaluated to improve the patients' quality of life.

Etiologies and Outcomes of Spinal Epidural Lipomatosis: Systematic Review of the Literature and Meta-Analysis of Reported Cases.

STUDY DESIGN: This was a systematic review of the literature. OBJECTIVE: The aim was to examine the contemporary demographics, etiological factors, treatment options and outcomes of spinal epidural lipomatosis (SEL) in adults. SUMMARY OF BACKGROUND DATA: SEL is primarily seen in obese patients as well as those on steroid therapy. Much regarding the etiology and treatment outcomes of SEL is unknown. METHODS: We reviewed Ovid MEDLINE, PubMed, SCOPUS, and Google Scholars databases from 1990 through August 2020 to identify cases of SEL. Data collected included patient characteristics, disease associations, level of pathology, treatment, and clinical outcomes. RESULTS: Ninety articles (145 individual cases) were included in the analysis. The median age was 54 years and 79% were males. Obesity-associated SEL constituted the largest proportion (52%) of our cohort. 22% of SEL cases were related to steroid use, while 26% cases were considered to be idiopathic. Lumbosacral SEL was the most frequently reported level of disease (68.9%), followed by the thoracic level (26.2%). The mean age of cases who underwent surgical intervention was 55 years, as compared with 48 years in those who received conservative management ( P =0.03). 95% of patients reported some degree of symptomatic improvement regardless of the treatment modality. Logistic regression suggested a possible superior outcome associated with those undergoing surgical treatment. CONCLUSION: In contrast to historical comparisons, contemporary articles support that obesity has become the major contributing factor for SEL. Logistic regression of the existing cases suggests that there may be a role for surgical intervention in select patients.

Spinal epidural lipomatosis: a rare and frequently unrecognized complication of Cushing syndrome.

CONTEXT: Spinal Epidural Lipomatosis (SEL) is a rare and frequently unrecognized complication of Cushing syndrome (CS). Only nine previous cases of SEL have been described in CS. Here, we present a case of severe SEL and review the literature. CASE REPORT: A 29-year-old man who had severe CS secondary to an ACTH-secreting pituitary macroadenoma. He presented with progressive lower limb weakness over a 2-year period leading to complete paraplegia in the last 4 months. In addition, he had classic symptoms and signs of severe CS. His evaluation confirmed the diagnosis of CS with a 4-fold increase in his daily free urinary cortisol (1190 mg/day), a positive 1-mg dexamethasone suppression test (AM cortisol 729 nmol/l) and an elevated ACTH of 196 ng/dl (10-65). Magnetic resonance imaging (MRI) revealed a 20-mm pituitary adenoma and extensive fat accumulation in the spinal canal extending from C7 to S5 with significant spinal cord compression from T2-T10. The patient underwent an urgent spinal cord decompression surgery. He showed an immediate improvement and was able to walk with crutches 3 weeks later and independently 3 months later. About 13 days after the spinal surgery, he underwent a trans-sphenoidal surgery resulting in eucortisolemia. CONCLUSION: SEL is a rare and serious complication of CS. It should be considered in any patient with CS, especially when there is neurological symptoms or disproportionate weakness of the lower limbs. Its management should be individualized but prompt surgical decompression should be considered even in patients with relatively long history of paraparesis.

Nevus Lipomatosus Cutaneous Superficialis of Hoffmann and Zurhelle: a rare cutaneous hamartoma.

Nevus lipomatosus cutaneous superficialis (NLCS) is a rare idiopathic cutaneous hamartoma characterized by ectopic clusters of mature adipose tissues in dermis. It is classified into two types. Classical type presenting as multiple lesions with onset at birth or within third decade of life and solitary type with onset between third to sixth decade of life. Here we present a case of 45 years female with adult onset, asymptomatic, grouped, skin colored, soft sessile growth in zosteriform pattern on left buttock. We here intend to report rare case of classical Nevus Lipomatosus Cutaneous Superficialis.

Graft-versus-host disease-associated angiomatosis with striking lipomatous metaplasia.

Sclerodermatous graft-versus-host disease (GvHD) is one of the many clinicopathological variants of chronic GvHD. One of the rarest forms of this variant is GvHD-associated angiomatosis (GvHD-AA). We describe the case of a 62-year-old male with sclerodermatous GvHD who presented, in consecutive years, two different lesions that showed characteristics of GvHD-AA. The first lesion fitted perfectly with the previously known features of this rare entity. However, the second lesion was more interesting, as the angiomatoid lesion was surrounded by newly appeared adipocytes, something not previously described. The appearance of this peculiar adipose tissue may be explained as related to an important dermal atrophy, as a concomitant appearance of a lipomatous nevus and GvHD-AA, or, finally, as mature adipose tissue related to a previous inflammatory process, that is, lipomatous metaplasia. Both lesions were diagnosed as GvHD-AA, and the second one was considered to be associated with dermal lipomatous metaplasia. We also considered whether hypoxia could be related to both lesions. In the present report, we review previously published cases of GvHD-AA and discuss the different hypotheses that could explain the appearance of metaplasia associated with the second lesion.

Bilateral symmetric lipomatosis of the orbit in Madelung's disease.

Madelung's disease is a rare benign systemic lipomatosis, which often presents in the head, neck and upper trunk regions. The appearance of symmetrical, excessive adipose tissue in the subcutaneous layer is its clinical characteristic. Orbital involvement is unusual with only a few cases reported previously. In this study, we describe the clinical and radiological features of Madelung's disease in the orbits. A 42-year-old man with alcohol addiction presented with chronic bilateral masses of the lower eyelids and proptosis. Computed tomography (CT) scan showed excessive symmetrical non-encapsulated fat deposition in the orbital fat, lower eyelids, salivary glands, subcutaneous tissue along the neck and under the sternocleidomastoid muscles and supraclavicular areas bilaterally. Histopathological study of the orbital masses revealed mature adipose tissue interspersed with thin fibrous septae. He developed recurrent lipomatosis 1 year after surgical excision.

Clustered yellow papules in the posterior axilla of a middle-aged woman.

Naevus lipomatosus cutaneous superficialis (NLCS) of Hoffman-Zurhelle is a rare hamartomatous benign condition first described in 1921. Two clinical variants have been described: a classical form of multiple yellow papules that coalesce to form larger plaques with segmental distribution, and a solitary form also known as pedunculated lipofibroma. We present a case of early-stage NLCS with characteristic histopathological and dermoscopic features.

Concurrent thyrolipomatosis and thymolipoma in a patient with myasthenia gravis: a case report and review of the literature.

We present a case of a man with a background of myasthenia gravis who presented with a neck lump, which was diagnosed as thyrolipomatosis in continuity with a very large thymolipoma. Following removal of these lesions, the patient's myaesthenic symptoms improved. While thymolipomas are often seen in the context of myasthenia gravis, thyrolipomatosis is a rare entity and to our knowledge the concurrent finding of both lesions with myasthenia gravis has never been reported. We highlight the important imaging features of both entities and the clinical importance of recognising them.

What's known and what's new in adipose lesions of peripheral nerves?

BACKGROUND: Adipose lesions of nerve primarily include intra- and extraneural lipomas and lipomatosis of nerve (LN). This paper will summarize the advances that have been made in the past decade, particularly related to LN and nerve territory overgrowth that have improved our understanding of the natural history, genetic background, diagnosis, imaging features, and clinical management. METHODS AND MATERIALS: Articles about adipose lesions of nerve were reviewed from 2011, when the last comprehensive review on this topic was published. Papers reporting advances on natural history, genetic background, diagnosis, imaging features, and clinical management were screened using PubMed and Google Scholar databases and then analyzed. Case reports and small case series were included only if they reported model examples of discussed pathologies, as these types of articles were summarized in recent systematic reviews on intraneural lipomas and LN. All eligible papers were assessed by the authors, who are subject matter experts. RESULTS: The first screen revealed 404 articles. After careful evaluation, a total of 53 articles were analyzed which includes advances in diagnosis (especially imaging), classification of the lesions, the role of somatic mutations in PIK3CA in LN, and treatment approaches for all adipose lesions of the peripheral nerve. CONCLUSION: Many advances have been made in the understanding of adipose lesions of nerve in the past decade. These pathologic entities are more readily recognized as a spectrum of lesions that share common phenotypic features.

Lumbar cystic epidural lipomatosis with mass effect. Report of an unusual case.

We present a rare case of symptomatic cystic lumbar spinal epidural lipomatosis that required surgical treatment via a minimally invasive tubular laminectomy. To our knowledge this is the first pathology confirmed report of compressive cystic lumbar spinal epidural lipomatosis available in literature.