Hibernoma

Etiology

Hibernomas are adipocytic tumors with histopathological features suggesting an origin from fetal brown fat tissue. Interestingly, these tumors rarely occur in infants, and they possibly represent an altered differentiation pathway of brown fat. Reciprocal translocations of chromosome 11 have been implicated.[2] Almost all hibernomas have breakpoints in the chromosome 11q arm. A clustering to 11q13 has also been described. The implicated rearrangements result in localization to regions involving tumor suppressor genes MEN1 and AIP. Of note, there is also an association of hibernomas with multiple endocrine neoplasia type 1.

Epidemiology

• Peak incidence at the third decade of life[3]
• Reported male versus female predilection differs amongst various authors. However, a slight male predilection is favored in the literature[4][5]
• Account for 1.6% of adipocytic tumors[6]
• The mean age of diagnosis is 38 years[3]

Histopathology

Hibernomas can have variable histopathologic composition depending on their histological subtypes of 1) typical, 2) lipoma-like, 3)myxoid, and 4) spindle cell variants. The typical subtype accounts for 82% of cases.[7] On gross analysis, these neoplasms can appear yellow, light brown, or grey in color. They can have a lobular appearance. The varied appearance of these neoplasms is secondary to their variable lipid content. On microscopy, these tumors appear as large multi-vacuolated cells and with mature adipose, often in abundance. Branching capillary vessels are also common. The lipoma-like subtype contains white fat. The typical subtype generally contains>70% brown fat. The brown fat marker gene UCP1 is strongly expressed. In brief, these neoplasms have the following histopathologic features:

• Contain a variable percentage of brown fat cells
• Demonstrate granular and multivacuolated cytoplasm of brown fat cells
• Demonstrate eosinophilic and polygonal brown fat cells
• Contain a variable component of univacuolated white fat cells
• May contain spindled cells and/or myxoid stroma
• Have a high concentration of cytochrome pigments
• Lack of high mitotic activity and nuclear atypia
• Cytology demonstrates small multivacuolated brown fat cells
  • On cytologic analysis, finely granular cytoplasm and bland round nuclei are typical features

History and Physical

Patients with hibernomas are often asymptomatic. Occasionally patients present with a "pressure" type of pain or discomfort related to mass effect. Hibernomas are also typically mobile and pliable.[8] Compression of adjacent nerves and associated pain may be an occasional feature on presentation. History and physical examination may contribute little to the evaluation of hibernomas especially in cases of asymptomatic patients. The history and physical exam should evaluate for features that may make the clinician suspect a more concerning alternative diagnosis such as a liposarcoma or other malignant tumor. Concerning features on history include:

• Rapid subjective growth of a soft tissue mass
• Associated axillary or inguinal pain indicating associated lymphadenopathy
• Known personal history of malignancy or family history of malignancy
• Unexpected weight loss

Physical exam also has a limited role in evaluating hibernomas. Hibernomas are often warm to touch owing to their vascularity, otherwise, the physical exam features of these neoplasms are nonspecific. A clinician should evaluate for the following when evaluating a subcutaneous mass:

• Size of the neoplasm
• Fixed or mobile nature of the mass on palpation
• Overlying ulceration of the skin
• Associated lymphadenopathy
• Evaluation for additional subcutaneous neoplasms

Evaluation

Imaging plays a key role in evaluating hibernomas.

Radiography

Like most non-mineralized soft tissue masses, radiographs are limited in the evaluation of hibernomas.  Subtle alteration of tissues plains may sometimes be noted in retrospect on radiographs when hibernomas are eventually identified on cross-sectional imaging. These lesions are typically radiolucent on radiographs about muscle and bone with a similar radiodensity to surrounding subcutaneous fat. Depending on their size and location, these neoplasms generally show a nonspecific prominence of subcutaneous soft tissues. Hibernomas identified on radiographs may be displacing another soft tissue structure or superimposed on an air-filled structure such as the lungs.  Intramuscular hibernomas and hibernomas involving the mediastinum, abdomen, and pelvis often cannot be identified on radiographs. Rare instances of intraosseous hibernomas can present as lytic lesions of the affected bone imaged.

Sonography

Sonography is most effective in evaluating hibernomas of the subcutaneous soft tissues. The utility of sonography is somewhat limited in the evaluation of intramuscular hibernomas as well as deeper lesions. On sonographic imaging, these neoplasms are generally encapsulated and well-circumscribed with similar echogenicity to surrounding fat. On occasion, these tumors can demonstrate mild hyperechogenicity or mild hypoechogenicity to surrounding subcutaneous fat.  A prominent vessel or vessels within these neoplasms can often be seen on color Doppler imaging. Adjacent prominent vascularity corresponding to a feeder vessel can also be identified.  These sonographic features are shared with both typical and atypical lipomas.

Computed tomography (CT)

On CT imaging, these neoplasms are hypoattenuating to muscle. Still, they can be mildly hyperattenuating compared to surrounding subcutaneous fat due to their vascularity and decreased percentage of white fat vacuoles. A feeding vessel or vessels can often be identified on contrast-enhanced imaging.

Magnetic Resonance Imaging (MRI)

On MRI imaging, hibernomas are often encapsulated and well-circumscribed. They are typically heterogeneous in signal and can be slightly hypointense or isointense to surrounding subcutaneous fat on T1 imaging.[9] Mildly increased T2 signal to surrounding subcutaneous fat is also often noted owing to increase vascularity compared to white fat, although isointensity to surrounding fat on T2 sequences can also be seen. These neoplasms sometimes show a lack of fat signal suppression on short-tau inversion recovery (STIR) imaging and fat-saturated T2 imaging. Gadolinium contrast enhancement can be seen and is proportional to brown fat composition.

Positron Emission Tomography (PET) Imaging

Owing to their composition of brown fat, which has high relative metabolic activity, hibernomas often show increased fluorodeoxyglucose-18 (FDG) activity on PET imaging.[7] Owing to their high metabolic activity, these neoplasms are often noted incidentally during FDG PET imaging acquisition.  When small hibernomas are found in the workup of malignancies, they can pose a diagnostic dilemma as their high metabolic activity can be mistaken for metastatic disease.  Hibernomas are discreet tumors and should be distinguished from some adult patients who retain stores of symmetric brown fat with increased metabolic activity.  Adult retained brown fat appearance on FDG PET is often non-mass, like symmetric regions of increased metabolic activity in the neck, supraclavicular or paraspinal regions.

Treatment / Management

Differentiating hibernomas and atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS) can be difficult. Intraabdominal hibernomas can also mimic WDLS, especially when heterogeneous in an appearance on CT and MR imaging. Branching flow voids and enhancing vascular structures can favor hibernoma over WDLS. Both ALT/WDLS and hibernomas can contain thick and enhancing septations. Aggressive ALT can present with local invasion, metastasis, and regional metastasis. When imaging is inconclusive, image-guided biopsy or open biopsy should be considered. Due to reported cases of arteriovenous shunting, it has been suggested that a core needle biopsy should be avoided in deep lesions.[8][10] (B3)

Surgical excision is the definitive treatment for these neoplasms. Differentiating hibernomas from lipomas on MR imaging is considered less of a diagnostic dilemma, considering lipomas tend to be more homogenous in their MR appearance with a reliable signal loss on fat suppression.

Differential Diagnosis

When subcutaneous in location, the differential diagnosis of a palpable hibernoma on the physical exam includes benign and malignant lesions.

Lipoma-like variants of hibernomas can resemble lipomas on imaging and histopathology, owning to their higher composition of white fat cells. When small, hibernomas can resemble other capillary-rich neoplasms, including hemangiomas and angiolipomas. Fat necrosis will appear as a complex fat-containing lesion and may have features of increasing fibrosis or calcification over time. Fibromatosis can be considered in the differential, although imaging can distinguish between these two entities. Hibernomas can be warm to touch on physical exam, and as such, an abscess can be considered in the differential diagnosis. In summary, benign common subcutaneous lesions in the differential diagnosis include:

• Lipomatous lesions (lipoma, ALT including angiolipoma)
• Fat necrosis
• Hemangiomas
• Fibromatosis
• Other primary malignancies
• Metastatic disease
• Abscess

On imaging, a liposarcoma can be difficult to distinguish from hibernomas. On rare occasions, hypervascular hibernomas can also resemble lymphoma on CT imaging. A history of malignancy should also raise the suspicion for metastasis. Cutaneous and subcutaneous metastasis often originate from melanoma, breast cancer, colorectal cancer, renal cell carcinoma, and lung cancer. Malignant subcutaneous lesions in the differential diagnosis include:

• Liposarcoma
• Lymphoma 
• Merkel cell carcinoma
• Subcutaneous metastases
• Dermatofibrosarcoma protuberans
• Angiosarcoma (radiation-induced)

Prognosis

The prognosis after excision of hibernomas is excellent owing to their benign behavior. Recurrence after local excision is rare. Chronic symptoms include mild to moderate pain from mass effect on adjacent neurovasculature and are most often noted in symptomatic cases.

Complications

The complications related to neoplasms typically are secondary to their regional mass effect. Patients can experience pain due to nerve compression. Hibernomas are most often asymptomatic. Complications can occur post-excision and include delayed wound healing, scarring, and hematoma/seroma formation.