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hibernoma

Hibernoma

Hibernoma is a benign brown fat tumor with predilection for subcutaneous tissue of the thigh, upper trunk, and neck of middle-aged adults 1. Rare cases occurring in the axilla, groin, supraclavicular area, buttock, scalp, abdominal wall, breast, flank, pleura, adrenal, spine, larynx, bone, and spermatic cord have been described 1. In a comprehensive morphologic analyses of 170 hibernomas from the soft tissue registry of the Armed Forces Institute of Pathology, Furlong et al 2 found that hibernomas most commonly occur in the thigh (29%), followed by the shoulder (12%), back (10%), neck (9%), and chest wall (6%). In two smaller case series of hibernoma, the thigh was reported as the most common location (in 21% and 76% of cases, respectively) 3, 4. Other uncommon anatomic locations were also reported sporadically in case reports and small case series to include intraosseous spaces 5, breasts 6, mediastinum 7 and adrenal glands 8. Vulvar hibernoma is exceedingly rare with only one reported case in the literature 9. Hibernoma tumor has a peak incidence in the third decade of life with a slight male predominance 10.

Brown fat tissue is formed during the fetal stage and in newborns. The primary function of brown fat cells is nonshivering thermogenesis, brown adipose tissue produces energy and regulates the body temperature of newborn humans. Newborns utilize brown fat tissue for regulating their changing body temperature. Brown fat is physiologically present in newborn human, but it typically regresses with age comprising less than 0.1% of total body weight by the age of 70 years and is gradually replaced by white adipose tissue 11. Generally, brown fat tissue turns into white fat tissue as newborns grow 12, but in uncommon cases, brown fat tissue may become bigger in size and may grow into hibernoma. Brown fat persists, however, in varying amounts throughout adult life and may be found in the neck, armpit, mediastinum, and periaortic and perirenal zones 13. In the fetus, brown fat has also been identified in the interscapular area, posterior abdominal wall, suprailiac and peripancreatic adipose tissue, and near autonomic ganglia, in addition to the sites described in adults 13. It is not surprising, therefore, that hibernomas have often been reported to be present in these locations. Hibernomas arise from the vestiges of fetal brown fat; according to the largest series published to date, the thigh was the most commonly affected site 14. Other common sites include neck, back, armpit and shoulder. Hibernomas are most common in the third or fourth decades of life 14.

The term hibernoma was first described as “pseudolipoma” by Merkel in 1906 15 and was termed “hibernoma” by Gery in 1914 owing to its resemblance to the brown fat in hibernating animals, where large quantities were found 16. Hibernomas are composed of various proportions of brown fat cells with eosinophilic granular cytoplasm and microvacuolation (hibernoma cells), multivacuolated adipocytes, and mature univacuolated adipocytes. Four morphologic variants of hibernomas have been described: typical (82%), myxoid (8%), lipoma-like (7%), and spindle cell (2%) 10. Typical hibernomas are by far the most common subtype and contain mainly classic, multivacuolated brown fat cells. The myxoid subtype is notable for myxoid degeneration of the stroma and affects primarily males. The lipoma-like subtype predominantly contains mature, white fat cells with scattered brown fat cells (granular multivacuolated adipocytes). Finally, the spindle cell subtype most commonly occurs in the neck and has combined features of hibernoma and spindle cell lipoma to include bland spindle cells, ropey collagen, mast cells, and myxoid stroma. It is important to be aware of these rarer subtypes of hibernoma as the lipoma-like subtype of hibernoma could be mistaken for atypical lipomatous tumor or well-differentiated liposarcoma due to the presence of scattered multivacuolated adipocytes mimicking lipoblasts 10. The intra-abdominal location of these tumors and heterogeneous appearance on the contrast-enhanced CT or MRI are also features associated with well-differentiated liposarcoma, potentially adding to the diagnostic complexity. Recently, Al Hmada et al. 1 analyzed 64 atypical lipomatous tumor-like hibernoma cases and found histological features that favor hibernoma over atypical lipomatous tumor, including small nuclei without hyperchromasia or atypia, smaller vacuoles than true lipoblasts with minimal scalloping of nuclei, more numerous lipoblast-like cells as opposed to scattered true-lipoblasts in atypical lipomatous tumor or well-differentiated liposarcoma, and presence of adipocytes with granular eosinophilic cytoplasm. Distinction of hibernoma from atypical lipomatous tumor is clinically important as atypical lipomatous tumor requires complete resection and harbors a risk of local recurrence in ~30% of cases 1.

Hibernomas usually have been described as well delineated or encapsulated 17. However, infiltration of adjacent structures, particularly striated muscle may be present. Lowry and Halmos 18 described a case in which hibernoma tumor (located inferior to the scapula and deep to the latissimus dorsi) infiltrated striated muscle and was incompletely removed; postoperative irradiation was administered. Enterline et al 19 described a hibernoma located in the retropharynx; the mass surrounded parathyroid tissue and also isolated a small area of the thyroid, but was not deeply invasive. None of these tumors was reported to have recurred.

Hibernomas are generally asymptomatic, slow-growing and warm to touch owing to its hypervascularity 20. However, hibernoma tumors can sometimes be associated with pain and weight loss. It has been postulated that weight loss is attributed to the hypermetabolism of brown fat, but further studies are required to elucidate the underlying pathophysiology 20. It is recommended that patients should be made aware of the potential effect of weight gain following a removal of a large hibernoma 21. Owing to the insidious onset of hibernoma, the true incidence is unknown as most lesions often go undiagnosed.

Previous reports discourage preoperative core needle biopsy in suspected cases of hibernoma owing to the potential risk of bleeding resulting from its hypervascularity 22. Hibernomas are composed, in varying proportions, of three cell types which include large, finely vacuolated cells with eosinophilic granular cytoplasm (brown fat cells), cells with larger fatty vacuoles resembling lipoblasts, and mature adipocytes. In addition, rare myxoid, lipoma-like, and spindle cell variants of hibernoma have been described 2. Immunohistochemically, most hibernomas are positive for S- 100 protein and usually negative for CD34 2.

Hibernomas are benign tumors and complete excision results in cure in all reported cases and no metastases have been reported 2. Recurrence has not been reported in the literature, except in a case where complete excision was not possible owing to its location impinging on the brachial plexus and axillary vessels 23. The English literature contains only 1 report of recurrence, a sarcoma with hibernoma-like features that was described in an abstract by Teplitz et al 24. This tumor was described as being pseudoencapsulated, located in the interscapular region, and histologically resembling an anaplastic sarcoma with features of brown adipose tissue that were also noted on ultrastructural examination. The tumor recurred 4 weeks later with extensive involvement of the interscapular area, including the interfascicular planes of the trapezius muscle. No recurrence was observed during 2 years of follow-up and after radiotherapy with adjuvant chemotherapy. Two cases of recurrent hibernoma, referred to by Enterline et al 19, had “strips reminiscent of liposarcoma or polymorphocellular sarcoma” within the tumors.

Hibernoma types

There are four hibernoma variants 25.

Typical lobular hibernoma

The lobular hibernoma is the most common variant (82%), which appears as a mixture of pale cells, hibernoma cells, and eosinophilic cells.

  • The pale cell subtype has mostly pale, multivacuolated cells mixed with univacuolated adipocytes. This type is more common on the thigh and is most commonly intramuscular.
  • The mixed cell subtype has equal numbers of pale and eosinophilic multivacuolated cells. This type is more common on the trunk.
  • The eosinophilic subtype has a predominance of eosinophilic multivacuolated cells. This is more common on the upper extremities.

Myxoid hibernoma

  • A myxoid hibernoma contains a loose basophilic matrix and foamy histiocytes. It is more common in men and in the head and neck region (including the scalp and shoulder).

Lipoma-like hibernoma

  • Lipoma-like hibernoma has univacuolated white adipocytes with scattered hibernoma cells. It arises most commonly in the thigh.

Spindle cell hibernoma

  • Spindle cell hibernoma is the least common variant, accounting for 2% of hibernomas. It has features of spindle cell lipoma and hibernoma. Histology shows hibernoma cells, CD34+ spindle cells, thick collagen bundles, mast cells, myxoid stroma, and mature adipocytes. It is found on the scalp and posterior neck.

Hibernoma causes

The main function of brown adipose tissue is non-shivering thermogenesis (‘burning’ fat), which it accomplishes through fatty-acid dependent uncoupling of adenosine triphosphate (ATP) production in the mitochondria via the uncoupling protein UCP1 26. Brown fat deposits are typically found in infants 27 and were believed to disappear during adulthood 28. However, several reports indicate the existence of brown fat in adults 29, with debate over whether these deposits constitute classical brown fat or are ‘beige fat’ 30. Continuous growth of these vestiges of brown fat lead to the formation of a hibernoma.

Hibernoma is associated with chromosomal rearrangements in the long arm of chromosome 11 (11q13-21), which includes the multiple endocrine neoplasia type 1 (MEN1) region 31.

Loss of AIP and MEN1 genes are considered to be essential for hibernoma development 32. There are reports of hibernoma in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome 33. However, the cytogenetic pattern seen in hibernoma differs from those seen in MEN1-associated tumors and it is believed they progress via different mechanisms 31.

Two isolated cases of hibernoma have been reported with high expression of TP53, with the authors speculating that inactivation of the protein may be important for their development 34.

Hibernoma symptoms

Hibernoma presents as a progressive, slow-growing, painless subcutaneous mass 35. Hibernoma tends to grow slowly and are generally asymptomatic over time, even if the slow growth of the tumor may at some point, compress the adjacent structures 36. Hibernomas generally present with tenderness when the tumors growth compresses surrounding structures 37. However, symptoms related to the compression of adjacent structures rarely develop 38. Hibernomas are warm to touch owing to its hypervascularity 20. Hibernoma tumors can sometimes be associated with pain and weight loss 39. It has been postulated that weight loss is attributed to the hypermetabolism of brown fat, but further studies are required to elucidate the underlying pathophysiology 20. It is recommended that patients should be made aware of the potential effect of weight gain following a removal of a large hibernoma 21. Owing to the insidious onset of hibernoma, the true incidence is unknown as most lesions often go undiagnosed.

Hibernoma usually develops in the chest (thorax). Hibernoma can also develop in the trunk of the body, limbs and back of the abdomen (retroperitoneum). Hibernomas mostly occur in middle-aged adults (hibernoma is mostly seen in the third, fourth and fifth decades of life) with equal gender distribution, tend to be large with an average tumor size of 9.3 cm (range, 1–24 cm), and show a predilection for subcutaneous tissue of the thigh, upper trunk, and neck 2. Deep seated hibernomas account for <15% of cases 2.

Hibernoma, is often misdiagnosed or confused with lipoma 40. Yet, it is important to make the difference between lipoma and hibernoma since, to date, no case of malignant transformation of hibernoma has been reported, which is not the case of lipoma. The differentiation with lipoma is possible with MRI because hibernoma still remains more vascularized, with large septa (>2 mm; easily seen with contrast agent), and, unlike to lipoma, the hibernoma tissue can be differentiated to the fat with MRI STIR or T2 Fat Sar sequences 41.

Hibernoma complications

Complications of hibernoma are related to the rapid tumour growth and infiltration of neighbouring structures. Pressure on nerves can result in neuropathic pain.

  • A 36-year-old patient presented with carpal tunnel syndrome due to a hibernoma in the wrist 42.
  • A 55-year-old man had thoracic outlet syndrome from intrathoracic extension of an axillary hibernoma 43.
  • Sciatic neuropathy has been reported in a patient with a giant (27 cm) hibernoma of the thigh 44.
  • An intraosseous hibernoma is typically an incidental finding after a patient presents with back pain (vertebral hibernoma) or knee pain (femoral hibernoma) 45.
  • Mediastinal hibernoma was reported as the cause of chronic cough in a 33-year-old female 46.

Hibernoma diagnosis

Radiographic imaging is used when considering a diagnosis of hibernoma 47.

  • Computed tomography (CT) shows well-circumscribed mass with attenuation intermediate between subcutaneous fat and skeletal muscle.
  • Magnetic resonance imaging (MRI) shows well-circumscribed mass slightly hypointense to fat on T1- and T2- weighted images.
  • 18F-fluorodeoxyglucose (FDG) PET/CT shows high uptake due to high metabolic activity of brown adipocytes, with change in avidity on follow-up. Uptake values are often higher compared to liposarcoma.

The diagnosis of hibernoma is confirmed by histopathology on fine needle aspiration procedure or after the surgical excision 48. The histopathological findings include small, round, brown fat-like cells, variable numbers of mature fat cells with:

  1. uniform, small eosinophilic cytoplasmic vacuoles,
  2. regular, small, and round cell nuclei; and
  3. delicate branching capillaries.

Hibernoma is a well-circumscribed, encapsulated, soft/rubbery mass that varies from yellow to red-brown when cut. Light microscopy shows typical hibernoma cells: multivacuolated brown fat cells with eosinophilic, slightly granular cytoplasm, a small central nucleus, and a single prominent nucleolus with evenly dispersed chromatin. These cells express high levels of cytoplasmic UCP1 49.

Hypervascularization combined with abundant mitochondria give hibernomas their color. Concerning the histopathological differential diagnosis with liposarcoma, some cytology features (i.e. admixture of multivacuolated and univacuolated fat cells; a rich, delicate, capillary-like vasculature) are known to lead to a misdiagnosis of liposarcoma and the pathologists must take into consideration these similar characteristics. To date, hibernoma can be classified by morphologic or histological characteristics such as the presence of multivacuolated or univacuolated cells found in brown fat or normal fat 48. Morphological, four variants of hibernoma are described: typical, myxoid, spindle cell, and lipoma-like 50. Typical hibernoma included eosinophilic, pale, and mixed cell types. The myxoid variant contained a loose basophilic matrix while the spindle cell hibernoma had features of spindle cell lipoma. The lipoma-like variant only contained scattered cells 48.

The imaging features of hibernomas are unfortunately, largely non-specific. MRI is the imaging modality of choice, as it provides superior characterization of tissue types and greater delineation of the margins of the lesion. There may be enhancing internal septations and vascularity within the lesion: in fact, branching flow voids in non-contrasted studies and enhancing vascular structures are considered a distinguishing feature that favors hibernoma over well-differentiated liposarcoma 51. In general, hibernomas are well-circumscribed, encapsulated masses, most frequently seen in areas where there is a preponderance of brown fat, such as thigh, shoulder, back, neck and mediastinum 14. Hibernomas are rarely seen in the retroperitoneum, despite brown fat being commonly found in the peripancreatic and suprarenal retroperitoneum 52. Differentiating hibernoma from simple lipoma on MRI is straightforward because the latter typically shows homogeneous T1 hyperintensity, signal loss on fat suppression, and uniform contrast enhancement pattern.

Table 1. Clinical and imaging characteristics of lipoma, liposarcoma and hibernoma

Clinical featuresLipomaLiposarcomaHibernoma
Size<5 cm (80% cases)>5 cm>5 cm
GrowthSlowSlow/moderate/highSlow/moderate/high
Age25-65 years>50 years30-50 years
ClinicAsymptomatic +++Asymptomatic ++Asymptomatic ++
Sex ratioMale = FemaleMale > FemaleFemale > Male
MR ImagingWell-homogeneousVariably homogeneousVariably homogeneous
CharacteristicsWell-circumscribedWell-circumscribedWell-circumscribed
Less vascularizedVariably vascularized (contrast +)Variably vascularized (contrast +)
No nodular lesionPossible nodular lesionPossible nodular lesion
T1: Hyper (as fat)T1: Hyper (less than fat/lipoma)T1: Hyper (less than fat/lipoma)
T2: Hyper (as fat)T2: HyperT2: Hyper
STIR/T2 Fat Sat: removing signalSTIR/T2 Fat Sat: no removing signalSTIR/T2 Fat Sat: no removing signal
Septa:<2 mm (C+)Septa:>2 mm (contrast +)Septa:>2 mm (contrast +)

Differentiating hibernoma from atypical lipomatous tumor or well-differentiated liposarcoma by imaging before tissue diagnosis can be a diagnostic dilemma. Both entities can be well circumscribed and show T1 hypointensity to the surrounding fat and incomplete fat saturation; both may contain thickened (>3 mm) and enhancing septation. Individual hibernoma of certain subtype may exhibit unique imaging characteristics. For example, the lipoma-like and spindle-cell subtypes may show internal serpiginous vascular structures, while the myxoid subtype may have non-specific high T2 signals due to its high water content 51. In contrast, well-differentiated liposarcoma often have an irregular capsule with decreased vascularity, sometimes with areas of mineralization which is not seen in hibernomas. In addition, more aggressive atypical lipomatous tumor can also show malignant behaviors, such as locoregional invasion, lymphadenopathy, and metastasis. When imaging fails to distinguish a benign hibernoma from a potentially malignant atypical lipomatous tumor, surgical excision remains the definitive diagnosis and treatment of choice.

Other modalities including positron emission tomography (PET) have also been utilized to characterize hibernomas. Fluoro-labelled 2-deoxyglucose PET scan (FDG-PET) is commonly utilized as a diagnostic imaging tool to detect metabolically active tumors based on their FDG uptake. It has been proven that brown fat has a high level of FDG uptake 53. Brown fat cell expresses unique mitochondrial uncoupling protein (UCP1), which functions to generate heat instead of adenosine triphosphate production 54. Several studies have attempted to use standardized uptake values (SUV) in 18-fluoro-2-deoxy-D-glucose (18 FDG)-PET to differentiate between hibernoma and other atypical lipomatous tumors. A landmark study based on 3640 consecutive FDG PET and PET/CT scans demonstrated that the biopsies of the FDG-avid regions have the histological and molecular characteristics of brown fat remnants, including UCP1. The lack of FDG enhancement helps in differentiating lipomas from other lesions, such as hibernomas, liposarcomas and myolipomas. Hibernomas show increased FDG avidity more than expected for other lipomatous lesions, which can suggest the diagnosis 55. In general, an FDG-PET SUV in excess of 2.0–2.5 is considered concerning for malignancy. An extremely high level of FDG-PET avidity may be considered even excessive for sarcomas and may be suggestive of hypermetabolic brown fat, i.e. hibernoma. For example, hibernoma was shown to have intense FDG uptake greater than 7.9, while liposarcomas have low to intermediate uptake values between 0.8 and 6.0 depending on the tumor grade; simple lipomas usually have low uptake values less than 2.0 56. However, subsequent case reports showed intermediate SUV less than 6.7 for hibernomas, overlapping with the range of liposarcoma uptake values 57. These findings suggest different subtypes of hibernoma may show different FDG metabolic activities depending on the proportions of their brown fat contents. Smith et al. 58 in their analyses of three incidental hibernomas further postulated that the fluctuations in SUVs, rather than the actual SUVs, maybe a better biomarker for hibernoma. Hoshi et al 59 and Charest et al 60 concluded that FDG PET/CT lacks the specificity required to differentiate benign from malignant soft tissue tumors. In addition, FDG-PET may not be sufficiently sensitive in detecting myxoid liposarcoma owing to the limitation in discerning metabolically active cells within the myxoid matrix 61. The value of FDG-PET in soft tissue tumors may lie in its accuracy in discriminating low- and high-grade sarcomas 60. If an FDG-PET imaging is obtained, experts recommend that hibernomas should be considered prospectively in the work-up of lipomatous tumours with high SUV levels, since an excision without adjuvant therapy is curative owing to their benign nature. Previous studies demonstrated that a single dose of oral propranolol (a non-selective beta-blocker) can reduce FDG avidity in brown fat, since brown fat contains beta-adrenergic receptors 62.

Hibernoma differential diagnosis

The differential diagnosis for hibernoma includes benign and malignant tumors 35.

Benign soft tissue tumors

Benign soft tissue tumors that could be interpreted as hibernoma include:

  • Lipoma — a homogenous mass with no contrast enhancement on imaging
  • Hemangioma — calcifications, T2-hyperintensity, and internal vasculature forming a lump under the skin
  • Angiolipoma — T2-hyperintensity and internal vasculature forming a lump under the skin.

Malignant soft tissue tumors

Malignant soft tissue tumors that could be interpreted as hibernoma include:

  • Well-differentiated liposarcoma — presents with thickened septa, decreased vascularity, and areas of T2-hyperintensity
  • Myxoid liposarcoma — a malignant tumour with t(12;16) translocation and characteristic branching vascularisation
  • Rhabdomyosarcoma — a malignant and aggressive cancer associated with bone destruction
  • Lymphoma — isoattenuated (weakened to the same degree as background tissue) CT pattern.

Hibernoma treatment

The definitive and curative treatment of hibernoma is surgical excision. No recurrence of hibernoma after excision has been reported in the literature. For patients who cannot tolerate surgery, routine surveillance may be considered. Since hibernomas are almost never malignant 63, no treatment is required if the patient is asymptomatic. Following a benign diagnosis, follow-up information was available for only 16/64 (25%) cases with a median follow-up time of 47 months (range, 1–165 months) and revealed that none of the patients developed local recurrence or metastasis, emphasizing the benign behavior of hibernoma 1. At the time of follow-up, all patients were alive without evidence of disease. Most patients had not been seen again after initial treatment.

Hibernoma prognosis

Hibernoma is excellent following a complete surgical excision. Local hibernoma recurrence does not occur and there are no reported hibernoma cases with metastases 35.

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