Characterization of the myxoid variant of hibernoma

Hibernomas are rare benign neoplasms composed of brown adipose tissue. Although they were first mentioned in the literature almost a century ago, relatively few reports have documented their range of pathological features. Multivacuolated fat cells with small, central nuclei are typical features of hibernomas. Based on the nature of the stroma and the appearance of the multivacuolated cells, 4 categories of hibernomas are described: typical, lipoma-like, myxoid, and spindle cell. The myxoid variant is very rare. In this report, we present and characterize the spectrum of morphological features of the myxoid variant of hibernoma by describing the case of a 45-year-old white man who was referred to our hospital for treatment of an ovoid mass in the posterior segment of the right deltoid region. Histopathologic examination of the resected specimen revealed a multilobulated, tan-yellow, variegated tumor with a rubbery consistency that was separated by thick fibrous septa with interspersed collections of foamy histiocytes. The mass was initially diagnosed as schwannoma with degenerative changes, but workup revealed a myxoid variant of hibernoma. This report highlights recent advances that may help confirm the diagnosis and explain the differential diagnosis of this rare tumor. This is one of only a few cases of a myxoid variant of hibernoma reported in the literature.     

Deep-seated huge hibernoma of soft tissue: a rare differential diagnosis of atypical lipomatous tumor/well differentiated liposarcoma

Background: Hibernoma is a rare benign fat-forming soft tissue tumor that differentiates similar to brown fat, hence an origin from remnants of fetal brown adipose tissue has been proposed. Mainly young adults are affected, usually without significant clinical symptoms. Material and methods: We report on four patients with hibernomas, who were treated at our hospital during the last 10 years. The clinicopathologic and immunohistochemical features are presented and treatment and follow-up data discussed. Results: Patients were 2 women and 2 men aged 21-67 years (mean: 45 yrs) who presented with a slowly growing, painless mass. The anatomic location was the thigh, upper arm, lateral thoracic wall and paravertebral soft tissue. Two of them were diagnosed preoperatively through a percutaneous core needle biopsy and the other two underwent surgery because of high clinical and radiological suspicion of liposarcoma. The tumor’s size ranged from 7 cm to 15.5 cm (mean: 11 cm). All were deep-seated subfascial intramuscular masses. Histologically, all four tumors were of the typical variant. All patients underwent a R0-surgical resection of the tumor and they were recurrence-free at last follow-up (mean: 47 months; range: 25-87). Conclusion: Hibernoma may present as huge deep intramuscular soft tissue mass in adults, closely mimicking well differentiated liposarcoma and should be considered in the differential diagnosis of fatty soft tissue tumors in any location. Surgical excision is the treatment of choice. The tumor has no malignant or recurrence potential.     

11q13 alterations in two cases of hibernoma: large heterozygous deletions and rearrangement breakpoints near GARP in 11q13.5

Hibernomas are rare, benign tumors with a histological appearance resembling that of brown adipose tissue. The diagnosis of hibernomas may be difficult because some of them contain only a small number of the characteristic multivacuolated fat cells and can be mistakenly classified as well-differentiated liposarcomas. Cytogenetic information has been reported for 10 cases, showing that these tumors are characterized by structural rearrangements involving 11q13. Previous fluorescence in situ hybridization (FISH) studies revealed consistent and sometimes cryptic losses of the MEN1 region in 11q13.1. Here, we describe the molecular cytogenetic analysis of two new hibernoma cases. Both tumors showed complex rearrangements, simultaneously including translocations, inversions, and deletions affecting the pair of chromosomes 11. The translocation partners were chromosome 5 in one case and chromosomes 16 and 22 in the other case. The 11q13 region was concomitantly rearranged on both chromosomes 11. FISH studies revealed large heterozygous deletions within the 11q13 band, from 11q13.1 to 11q13.5. Genes such as PYGM, MEN1, CCND1, FGF3, ARIX, and GARP were deleted, showing that the size of the 11q13 altered region was larger than previously reported. Furthermore, both tumors had breakpoints in 11q13.5, one of them in the immediate proximity of the GARP gene. Our results suggest that rearrangements of GARP or a neighboring gene may be important for the pathogenesis of hibernomas.     

Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein.

AIM--To determine whether aP2 expression is a useful diagnostic marker in soft tissue tumour pathology. METHODS--A polyclonal antibody to aP2 was used to investigate the immunohistochemical expression of this protein in benign and malignant tumours of adipocytic differentiation and a wide variety of other neoplasms. RESULTS--aP2 was only expressed by lipoblasts (in all types of liposarcoma and in lipoblastomatosis) and by brown fat cells (in both hibernomas and normal periadrenal fetal fat). Other benign adipose tissue tumours and malignant connective tissue or epithelial tumours were distinguished from liposarcoma by the absence of staining for aP2. CONCLUSION--Identification of lipoblasts using markers of aP2 expression is of value in the differential diagnosis of benign and malignant adipose tissue tumours and in distinguishing liposarcomas from other malignant mesenchymal and epithelial neoplasms, some of which contain cells that morphologically resemble lipoblasts.     

Development of a monoclonal antibody to the aP2 protein to identify adipocyte precursors in tumours of adipose differentiation.

aP2 gene product (aP2 protein) expression has been shown to be a useful diagnostic marker for identification of lipoblasts and fetal fat cells in soft tissue tumours. A monoclonal antibody was developed by a mouse spleen cell-myeloma hybridoma technique to an 18 amino acid segment of the aP2 protein and was used to investigate the immunohistochemical expression of this protein in benign and malignant tumours of adipocytic differentiation and a wide variety of other soft tissue tumours. We found that aP2 protein was expressed by lipoblasts in liposarcomas and lipoblastomas and by brown fat cells in hibernomas and normal periadrenal fat. Other benign adipose tissue tumours and benign and malignant soft tissue tumours were distinguished from liposarcoma by absence of staining for aP2 protein. Immunohistochemical identification of the aP2 protein is likely to prove a useful means of distinguishing liposarcoma from other malignant mesenchymal and epithelial neoplasms, some of which contain cells that morphologically resemble lipoblasts.     

Pharmacological effects of nicotine on norepinephrine metabolism in rat brown adipose tissue: relevance to nicotinic therapies for smoking cessation

In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.     

Leptin and leptin receptor mRNA are widely expressed in tumors of adipocytic differentiation.

Adipose tissue is the principal source of leptin, a cytokine-like peptide with many biologic functions. Leptin binds to the leptin receptor, present in the hypothalamus and in many other tissues, and modulates energy balance and maintenance of body weight. The expression of leptin and leptin receptor in tumors of adipocytic differentiation has not been previously examined. Because normal adipose tissue is the principal source of leptin and expresses leptin receptor, we hypothesized that tumors of adipose tissue differentiation may also express leptin and/or the long functional form of the leptin receptor (OB-Rb). Leptin and OB-Rb were analyzed by immunohistochemistry, in situ hybridization, RT-PCR, and western blotting in 21 lipomas, 2 hibernomas, and 16 liposarcomas. Immunostaining and in situ hybridization showed leptin and OB-Rb mRNA expression in all cases of lipomas, hibernomas, and liposarcomas, including dedifferentiated and pleomorphic liposarcomas. RT-PCR analysis showed leptin and OB-Rb mRNA in both lipomas (n = 5) and liposarcomas (n = 5). Western blotting identified the 16 kDa leptin protein in a lipoma and a liposarcoma. No important difference in the expression of leptin and OB-Rb mRNA was found between lipomas and liposarcomas, although the level of leptin protein was higher in a lipoma than a liposarcoma by western blotting. These results show for the first time that leptin and OB-Rb mRNA are expressed in lipomas, hibernomas, and liposarcomas. The presence of leptin and its receptor may provide new insights into the pathobiology of these tumors.     

Mediastinal hibernoma: a case report

Hibernomas are rare benign tumours that arise most often in adults from the remnants of fetal brown adipose tissue. They usually affect muscle and subcutaneous tissue and are asymptomatic and slow growing. The distribution of this tumour follows the sites of persistence of brown fat. Out of more then 100 cases described in the word literature only three hybernomas were mediastinal. A recent clinicopathological study of 170 cases from the Armed Forces Institute of Pathology confirmed the exceptionality of the intrathoracic location. This report describes a very rare case of mediastinal hibernoma in a young man.     

Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study

Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.     

Brown adipose tissue: function and physiological significance

The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogenesis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.     

Effects of cold acclimation on the energetic metabolism of the staggerer mutant mouse

Staggerer mutant mice are lean despite their hyperphagia. Brown adipose tissue activity may be implicated in this phenomenon. The aim of this work is to determine the energetic metabolism and to detail some characteristics of the brown adipose tissue of Staggerer mutant mice born and reared either at 28 degrees C (within the thermoneutral zone) or 22 degrees C (cold temperature) compared to nonmutant control mice. In mutant mice reared at thermoneutrality the resting metabolism was found to be higher than that of controls, and further the activity of the brown adipose tissue increased as indicated in relative mass, composition and cytochrome oxydase activity. A stimulatory effect of cold exposure was observed in both mutant and nonmutant mice. It is suggested that Staggerer mice may provide a good model for the study of the cold-induced or diet-induced mechanisms of brown fat stimulation.     

棕色脂肪形成的内分泌及环境影响因素研究

本文主要研究白色脂肪棕色化的内分泌调控及影响棕色脂肪变化的环境因素的最新研究成果,为其在代谢疾病中的治疗潜力提供证据。截至目前,对棕色脂肪的内分泌调控,低温及低氧环境暴露对棕色脂肪的影响,以及脂肪组织在高原上维持能量、代谢和热平衡的相互转化的研究依然较少。深入地了解BAT的潜在能力,能够更好地控制这些细胞,以改善系统能量代谢和葡萄糖稳态,为对抗人类肥胖和相关代谢紊乱提供新的治疗策略。     

Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse

AMPK (adenosine monophosphate-activated protein kinase), a key regulator of cellular energy metabolism and whole-body energy balance, is present in brown adipose tissue but its role in regulating the acute metabolic state and chronic thermogenic potential of this metabolically unique tissue is unknown. To address this, the AMPK signalling system in brown and white adipose tissue was studied in C57Bl/6 mice under control conditions, during acute and chronic cold exposure, and during chronic adrenergic stimulation. In control mice AMPK activity in brown adipose tissue was higher than in any tissue yet reported (3-fold the level in liver) secondary to a high level of expression of the α1 isoform. During the first day of cold, a time of intense non-shivering thermogenesis, AMPK activity remained at basal levels. However, chronic (>7 days) cold caused a progressive increase in brown adipose tissue AMPK activity secondary to increased expression of the α1 isoform. To investigate the signalling pathway involved, noradrenaline (norepinephrine) and the β₃-adrenergic-specific agonist CL 316, 243 were given for 14 days. This increased uncoupling protein-1 content in brown adipose tissue, but not AMPK activity. In white adipose tissue 15 days of cold increased α1 AMPK activity 98 ± 20%, an effect reproduced by chronic noradrenaline or CL 316 243. We conclude that chronic cold not only increases AMPK activity in brown and white adipose tissue, but that it does so via distinct signalling pathways. Our data are consistent with AMPK acting primarily as a regulator of chronic thermogenic potential in brown adipose tissue, and not in the acute activation of non-shivering thermogenesis.     

Diagnostic utility of aP2/FABP4 expression in soft tissue tumours

Adipocyte P2 (aP2), also known as fatty acid-binding protein 4 (FABP4), is a fatty acid-binding protein found in the cytoplasm of cells of adipocyte differentiation. In this study, we examined a large number of soft tissue tumours with a commercial polyclonal anti-aP2/FABP4 antibody and a newly developed mouse monoclonal antibody raised against this protein to determine the diagnostic utility of aP2/FABP4 as a marker of tumours of adipose differentiation. A mouse monoclonal antibody, clone 175d, was raised against a mixture of synthetic peptides corresponding to the amino acid sequence of residues 10–28 and 121–132 of the human aP2/FABP4 protein. Antigen expression with polyclonal and monoclonal antibodies was immunohistochemically determined in paraffin sections of normal adipose tissue and a wide range of benign and malignant primary soft tissue tumours (n?=?200). aP2/FABP4 was expressed around the cytoplasmic lipid vacuole in white and brown fat cells in benign lipomas and hibernomas. Immature fat cells and lipoblasts in spindle cell/pleomorphic lipoma, atypical lipomatous tumour/well-differentiated liposarcoma, myxoid/round cell liposarcoma and pleomorphic liposarcoma also reacted strongly for aP2/FABP4. No specific staining was seen in non-adipose benign and malignant mesenchymal and non-mesenchymal tumours. aP2/FABP4 is expressed by mature and immature fat cells and is a marker of tumours of adipose differentiation. Immunophenotypic aP2/FABP4 expression is useful in identifying lipoblasts, and immunohistochemistry with polyclonal/monoclonal anti-aP2/FABP4 antibodies should be useful in distinguishing liposarcoma from other malignancies, particularly round cell, myxoid and pleomorphic soft tissue sarcomas.     

PPARs信号通路参与肠道菌群和棕色脂肪组织的代谢调控肥胖

背景:肠道菌群与棕色脂肪组织之间存在着复杂的调控机制和广泛联系,但是目前机制尚未阐明。目的:揭示棕色脂肪组织与肠道菌群间的潜在关系,为接下来的研究提供实验思路。方法:由第一作者应用计算机以“brown adipose tissue,intestinal flora,obesity,peroxisome proliferator activated receptor family”为英文检索词,以“棕色脂肪组织,肠道菌群,肥胖,过氧化物酶体增殖物激活受体家族”为中文检索词在PubMed、万方、维普、知网数据库中检索1994-01-01/2020-06-01的相关文献,并对文献的相关内容进一步筛选、归纳分析与总结,最终纳入38篇相关文献进行综述。结果与结论:①肠道菌群失调会影响过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs),PPARs又可以影响棕色脂肪组织的代谢进而调控肥胖;PPARα、PPARβ和PPARγ都与脂肪代谢有关,可以被相应的激活剂激活促进棕色脂肪组织的表达,其中PPARγ在肠道菌群和棕色脂肪组织中的联系最为密切,肠道菌群代谢的变化可以上调PPARγ的表达,从而激活棕色脂肪组织达到减肥的目的;②调节肠道菌群与棕色脂肪组织的关系可以治疗肥胖症;③从棕色脂肪组织、PPARs信号通路两者中研究抵抗肥胖的相关药物前景可观。     

Accumulation of brown adipose tissue and nutritional status. A prospective study of 366 consecutive autopsies.

Increased amounts of brown adipose tissue have been reported to occur in association with several diseases. The objective of the present study was to determine whether brown adipose tissue accumulation is related to nutritional status. Histologic sections of periadrenal tissue prospectively obtained at consecutive autopsies from 366 adults were examined. The cases were separated into three groups: malnourished (101 autopsies), normotrophic (128 autopsies), and obese (137 autopsies), according to the Quetelet index. Of these patients, 89 had brown adipose tissue accumulation, 35 were malnourished, 32 were normotrophic, and 22 were obese. The results showed a correlation between brown adipose tissue and patient nutritional status and a higher brown adipose tissue accumulation in malnourished patients. Cardiovascular disease was the most common type of illness present in the cases with brown adipose tissue accumulation.     

Hamartoma of the breast--a case report

A 45 year old female presented with a discrete palpable mass in the right breast. Repeated fine needle aspiration of the mass yielded only adipose tissue and was reported as lipoma - breast. Microscopic features of the resected mass were evaluated in conjunction with the clinical and gross pathologic finding and a diagnosis of hamartoma was established. The histological concept of hamartoma of the breast as described in the literature is reviewed. Here we report this rare case of mammary hamartoma with an unusual abundance of adipose tissue Repeated yield of only adipose tissue in an aspirate from a discrete palpable breast mass should suggest the possibility of a hamartoma.     

Fat metabolism in brown adipose tissue in vivo

1. Noradrenaline infusions (I.V. for 30 min) in new-born and 1-week-old unanaesthetized rabbits caused a rapid and sustained rise in oxygen consumption and an increase in blood glucose, free fatty acid and glycerol concentrations. Similar changes occurred in anaesthetized 1-week-old rabbits.2. A simple direct method was used to measure the net exchange of metabolites across brown adipose tissue in anaesthetized young rabbits. It was found that the brown adipose tissue of rabbits reared from birth in a thermoneutral environment and studied when their next feed was due took glucose from and released fatty acids and glycerol into the circulation.3. Similar rabbits kept unfed for a further 48 hr in a warm environment released fatty acids and glycerol from their brown adipose tissue at a far greater rate, but the rate of glucose uptake was reduced.4. On the other hand the brown adipose tissue of rabbits kept unfed in a cold environment (20 degrees C) took up circulating free fatty acids as well as glucose and did not release glycerol. The brown adipose tissue of these rabbits was depleted of fat.5. The rate of blood flow through brown adipose tissue and the exchange of all three metabolites increased fourfold during noradrenaline infusion in the three groups of rabbits.6. It is concluded (i) that brown adipose tissue releases significant amounts of fatty acids and glycerol into the circulation and that this contribution is greatly increased with noradrenaline infusion and presumably cold exposure, and (ii) that brown adipose tissue depleted of fat produces heat by drawing free fatty acids as well as glucose from the circulation.     

Adenolipoma of the thyroid gland: report of a case with diagnosis by fine-needle aspiration cytology

Adenolipomas are rare benign neoplasms composed of mature adipose tissue and thyroid follicles. The preoperative fine-needle aspiration cytology of such lesion has rarely been cited. Approximately 12 cases have been reported in the literature worldwide, diagnosed solely on histopathology. A 65-year-old woman presented with a 4-month history of a thyroid nodule. A FNA cytology specimen showed a few benign follicular cells with adipose tissue. Right lobectomy was performed and the specimen revealed a solid yellowish mass measuring 3 x 2.5 cm. Microscopic findings showed a solid tumor predominantly composed of mature adipose tissue intermixed with thyroid follicles. The pathological diagnosis was adenolipoma of the thyroid gland. The presence of adipose tissue is a common finding within the cytologic specimen, especially in obese individuals or with inadequate sampling. But suspicion may be possible if excess amounts of adipose tissue are present in the submitted sample.     

Chromosome changes in a case of hibernoma.

Cytogenetic analysis of a rare adipose tissue tumor, hibernoma, a benign proliferation of the brown fat, is presented for the first time. A complex translocation involving bands 1p36, 2q33, 5q22, and 11q13 was found as the sole chromosome abnormality.