Loss of the tumour suppressor gene <i>AIP</i> mediates the browning of human brown fat tumours

Magnusson, Linda; Hansen, Nils; Saba, Karim H.; Nilsson, Jenny; Fioretos, Thoas; Rissler, Pehr; Nord, Karolin Hansén

doi:10.1002/path.4945

Cited by 10 publications

(7 citation statements)

References 18 publications

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“…4,29 In tumors, AIP loss seems to play a role in brown fat differentiation, because the silencing of AIP results in UCP1 upregulation in vitro, and comparative gene expression profiling among adipose tumors showed that low expression levels of AIP are correlated with high expression levels of UCP1. 30 None of our patients studied here had pheochromocytoma, were subjected to β-adrenergic stimulator administration, or were severely ill, and AIP copy number analysis of these tumors might be an interesting future perspective. Although our study cohort comprised only 1.5% of WDLS cases with or without dedifferentiation, this could underestimate the true incidence of brown fat differentiation in these tumors, because we did not perform systematic screening using UCP1 immunohistochemistry.…”

Section: Discussionmentioning

confidence: 96%

“…Beige adipocytes develop from cellular origins distinct from myf5 + classical brown fat precursors or perhaps via the direct transdifferentiation of mature white fat cells 4,29. In tumors, AIP loss seems to play a role in brown fat differentiation, because the silencing of AIP results in UCP1 upregulation in vitro, and comparative gene expression profiling among adipose tumors showed that low expression levels of AIP are correlated with high expression levels of UCP1 30. None of our patients studied here had pheochromocytoma, were subjected to β-adrenergic stimulator administration, or were severely ill, and AIP copy number analysis of these tumors might be an interesting future perspective.…”

Section: Discussionmentioning

confidence: 99%

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Liposarcoma With Hibernoma-like Histology

Kojima¹,

Komiyama

Shinoda³

et al. 2022

American Journal of Surgical Pathology

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Hibernoma is an uncommon benign tumor of brown fat cells that consistently expresses uncoupling protein 1 (UCP1). Herein, we clinicopathologically characterized 16 liposarcomas, for which histology, at least focally, closely resembled that of hibernoma, including sheets of brown fat-like, finely multivacuolated-to-eosinophilic tumor cells with no or minimal nuclear atypia. The cohort consisted of 4 well-differentiated liposarcomas (WDLSs), 6 dedifferentiated liposarcomas with a concomitant WDLS component, and 6 myxoid liposarcomas (MLSs). For all dedifferentiated liposarcoma cases, hibernoma-like histology was present only in the WDLS component. All tumors presented as large, deep-seated masses. Hibernoma-like histology resembled the pale cell, mixed cell, eosinophilic cell, or spindle cell subtypes of hibernoma, and it was a focal observation, with conventional liposarcoma histology coexisting in all cases. However, a few biopsy samples were predominated by hibernoma-like patterns, and 1 case was initially interpreted as hibernoma. Hibernoma-like components in WDLS immunohistochemically coexpressed MDM2 and CDK4 in most cases and harbored MDM2 amplification in tested cases, whereas half of the cases expressed UCP1. The hibernoma-like components of MLS expressed DDIT3, and DDIT3 rearrangements were present in the tested cases, whereas only negative or equivocal UCP1 expression was observed. In summary, WDLS and MLS focally demonstrate hibernoma-like histology on rare occasions. These elements are neoplastic, and some such areas in WDLS likely represent true brown fat differentiation, as supported by UCP1 expression. This pattern requires recognition to avoid the misdiagnosis as hibernoma, especially in biopsies. A careful search for classic liposarcoma histology and additional work-ups for the MDM2/CDK4 or DDIT3 status will be helpful for an accurate diagnosis.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Liposarcoma With Hibernoma-like Histology

Kojima¹,

Komiyama

Shinoda³

et al. 2022

American Journal of Surgical Pathology

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“…Recently published data have shown that loss of AIP is likely responsible for the brown fat phenotype. 24…”

Section: Discussionmentioning

confidence: 99%

Hibernoma Mimicking Atypical Lipomatous Tumor

Hmada

Schaefer

Fletcher

2018

American Journal of Surgical Pathology

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Hibernoma is a benign adipocytic tumor with predilection for subcutaneous tissue of the thigh, upper trunk, and neck of middle-aged adults. 11q13 rearrangement resulting in MEN1/AIP codeletion is characteristic. Hibernomas are composed, in varying proportions, of brown fat cells, mature adipocytes, and microvacuolated lipoblast-like cells. Examples containing predominantly multivacuolated lipoblast-like cells are uncommon and distinction from atypical lipomatous tumor (ALT) is important for clinical management. We herein present the clinicopathologic features of 64 hibernomas histologically mimicking ALT. MDM2 and CDK4 immunohistochemistry as well as MDM2 fluorescence in situ hybridization were performed in a subset of cases. Clinical and follow-up information were obtained from referring pathologists. Thirty-four patients were male and 30 female, with a median age of 43 years (range, 24 to 78 y). The tumors were well circumscribed and mostly deeply located (53/64 cases, 83%) with a median tumor size of 12.9 cm (range, 3.5 to 23 cm) and predilection for the thigh (42/64 cases, 66%). Histologically, large cells with prominent lipoblast-like cytoplasmic fatty vacuoles and small central nuclei were present to a prominent degree in all cases, along with mature univacuolated adipocytes and smaller numbers of large, finely vacuolated cells with eosinophilic granular cytoplasm. Nuclear atypia and mitoses were absent. None of the 39 cases tested showed CDK4 and MDM2 overexpression or MDM2 amplification. Follow-up, available for 16/64 cases (median, 47 mo; range, 1 to 165 mo), revealed no recurrences or metastases. Hibernoma mimicking ALT shows predilection for deep soft tissue, especially in the thigh. These tumors behave in a benign manner and MDM2/CDK4 negativity may be useful in excluding ALT.

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“…However, these deletions are large and not limited to MEN1 . Importantly, in the Nord et al study ( 85 ), concomitant loss of the AIP gene, implicated in the syndrome of familial isolated pituitary adenomas, was also identified and a later study concluded that loss of AIP is responsible for the brown fat phenotype ( 86 ). Thus, it appears that a large deletion of 11q13 including both MEN1 and AIP is necessary for hibernoma development.…”

Section: Lipomas and Hibernomasmentioning

confidence: 99%

Beyond the “3 Ps”: A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1

Waguespack

2022

Front. Endocrinol.

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Multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominantly inherited tumor syndrome, is classically defined by tumors arising from the “3 Ps”: Parathyroids, Pituitary, and the endocrine Pancreas. From its earliest descriptions, MEN1 has been associated with other endocrine and non-endocrine neoplastic manifestations. High quality evidence supports a direct association between pathogenic MEN1 variants and neoplasms of the skin (angiofibromas and collagenomas), adipose tissue (lipomas and hibernomas), and smooth muscle (leiomyomas). Although CNS tumors, melanoma, and, most recently, breast cancer have been reported as MEN1 clinical manifestations, the published evidence to date is not yet sufficient to establish causality. Well-designed, multicenter prospective studies will help us to understand better the relationship of these tumors to MEN1, in addition to verifying the true prevalence and penetrance of the well-documented neoplastic associations. Nevertheless, patients affected by MEN1 should be aware of these non-endocrine manifestations, and providers should be encouraged always to think beyond the “3 Ps” when treating an MEN1 patient.

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Loss of the tumour suppressor gene AIP mediates the browning of human brown fat tumours

Cited by 10 publications

References 18 publications

Liposarcoma With Hibernoma-like Histology

Liposarcoma With Hibernoma-like Histology

Hibernoma Mimicking Atypical Lipomatous Tumor

Beyond the “3 Ps”: A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1

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