Hibernoma arising in the breast is rare and may present as an asymptomatic mass or may be detected by screening mammography. Four histologic types have been identified: typical, myxoid variant, spindle cell variant, and the lipoma-like variant. The most common “typical variant” is composed of pale to eosinophilic multivacuolated cells with interspersed univacuolar cells. Hibernomas are universally benign and are not known to recur or have an aggressive behavior, even in incompletely excised lesions. Hence, their clinical importance lies in distinguishing them from other benign and malignant breast neoplasms as well as inflammatory conditions that come into the histologic or radiologic differential. This review discusses the clinical features, radiologic and histopathologic characteristics, ancillary studies, suggested pathogenesis, differential diagnosis, and treatment of and prognosis for these uncommon lesions.
Hibernoma is a benign lipomatous tumor made of brown fat, a specialized form of adipose tissue. Although these tumors can arise in various sites, mammary hibernomas remain extraordinarily uncommon, with fewer than 10 cases reported thus far in the English literature.1–5 This review discusses the clinical presentation, radiologic and histopathologic features, ancillary studies, pathogenesis, differential diagnoses, and treatment of and prognosis for this rare entity.
Hibernomas are seen mainly in adults, with a peak incidence during the third decade of life.1 In the largest series to date (170 cases from the Armed Forces Institute of Pathology [AFIP]), these tumors were seen over a wide age range of 2 to 75 years with a mean of 38 years.2 The most common sites were the soft tissues of the thigh, shoulder, back, neck, chest, arm, and abdominal cavity/retroperitoneum.2 Only 3 of 170 cases in this series were reported in the breast. Most Hibernoma cases, including mammary hibernomas, usually present as an asymptomatic, painless, slowly growing mass. However, they may also present as an incidental finding on screening mammography or other radiologic imaging or rarely cause symptoms due to compression of adjacent structures.4–7
Hibernomas arising in extramammary sites are usually radiolucent in contrast to the adjacent muscle; however, in fatty breast tissue, this mass is relatively radiodense. Mammary hibernoma appears as a well-defined, uniformly echogenic mass on breast ultrasonography and the radiologic differential includes other fatty lesions such as lipoma, interlobular stromal fibrous tissue, fibrolipoma, fibroadenolipoma, and early fat necrosis. Computed tomography (CT) scan usually demonstrates a solid, hypervascularized mass. On magnetic resonance imaging, hibernomas demonstrate signal intensity intermediate between that of skeletal muscle and subcutaneous fat on both T1- and T2-weighted images, and because of their hypervascularity show contrast enhancement. However, similar imaging features can be seen in other benign or malignant soft tissue neoplasms. Unlike conventional lipomas, given the abundant mitochondria, mammary hibernomas are metabolically active and therefore “hot” or “glucose-avid” on fluorodeoxyglucose CT–positron emission tomography (PET). The CT-PET findings of mammary hibernoma are indistinguishable from malignancy, often leading to a false-positive radiologic interpretation and requiring a biopsy to exclude a malignant etiology.4,6,7
The size of reported hibernomas ranges from 1 cm up to 24 cm, with 9 cm as average.2 Grossly, this tumor is a lobulated, well-circumscribed, partially encapsulated mass and typically is yellowish brown with a rubbery texture. Histologically, this tumor has a lobular configuration with breast tissue usually compressed at the periphery (Figure 1). Four histologic variants of hibernoma have been described in order of their frequency: typical, lipoma-like variant, myxoid variant, and spindle cell variant. The common feature is the presence of multivacuolated fat cells with small, central nuclei (Figures 2 and 3). The typical variant has cells ranging from multivacuolated pale cells to cells with deeply eosinophilic granular cytoplasm in varying proportions (Figures 2 and 3). Intermixed univacuolar cells are also seen with 1 or more large lipid droplets and peripherally placed nuclei (Figures 2 and 3). The lipoma-like variant contains a predominance of univacuolar cells with only few scattered multivacuolated pale or eosinophilic hibernoma cells. The myxoid variant is composed of multivacuolated hibernoma cells separated by myxoid stroma. The spindle cell variant has similar histologic features of a spindle cell lipoma (bland spindle cells, ropy collagen, interspersed mast cells, and mature fat cells) with admixed multivacuolated cells. No atypia or mitotic figures are seen. Hibernomas also show much more prominent vascular supply than is seen in lipomas.1,2,5
Mammary hibernoma is typically diagnosed with hematoxylin-eosin stain and immunohistochemistry is rarely, if ever, needed. Immunohistochemically, hibernomas show focal to diffuse positivity for S100 protein. The spindle cell variant may show positive staining for CD34.1,5 Recently, hibernoma cells have been reported to be positive for CD31.5,8 Ultrastructural studies demonstrate round to tubular mitochondria in hibernoma cells, and these are more abundant, pleomorphic, and larger in brown fat than white fat.4,9,10 Cytogenetic aberrations seen in hibernomas include structural rearrangements of 11q13 and 11q21; however, these aberrations are also shared by other lipomatous neoplasms such as lipoma and myxoid liposarcomas and are not unique to hibernomas. Studies have found structural aberrations of 11q13 to be associated with deletions of multiple endocrine neoplasia 1 (MEN1) region in 11q13.1. Recent studies implicate rearrangements of the GARP gene on 11q13.5 or a neighboring gene to be important for the pathogenesis of hibernomas.1,11–13
Hibernoma is a neoplasm composed of brown fat. Brown fat is a specialized type of tissue designed to generate heat in response to exposure to cold (nonshivering thermogenesis) and with food ingestion (diet-induced thermogenesis). Unlike white fat in which fatty acids are metabolized to produce energy in the form of adenosine triphosphate, brown fat, owing to the presence of abundant mitochondria and uncoupling protein-1 (thermogenin), metabolizes these in the form of heat. In humans, brown fat is present in newborns and although its amount decreases with age, it still persists in adults as remnants and remains active to avoid hypothermia. Hibernoma typically occurs in adults at any site where brown fat persists.1,5–7,14–16
The differential diagnosis of a mammary hibernoma includes nonneoplastic inflammatory or reactive processes such as fat necrosis and xanthogranulomatous mastitis, other soft tissue tumors with lipomatous differentiation such as lipoblastomas, and some benign and malignant breast neoplasms such as granular cell tumor and histiocytoid carcinomas.1,5
Fat necrosis and xanthogranulomatous mastitis both exhibit abundant foamy CD68-positive histiocytes between mature adipocytes along with multinucleated giant cells and other inflammatory cells. The characteristic multivacuolated hibernoma cells or lobular architecture is not seen. Moreover, hibernoma cells, unlike histiocytes, are negative for CD68. There may be an accompanying clinical history of trauma or prior surgical resection in fat necrosis.17,18
Lipoblastoma is exceedingly rare in the breast. It is a neoplasm seen exclusively in infancy and childhood. It is composed of immature cells that resemble fetal adipose tissue in various stages of development, including spindle or stellate cells to univacuolated or multivacuolated cells and mature fat cells in a richly vascular myxoid matrix.19 Granular cell tumors are more uniformly granular and lack multivacuolated hibernoma cells or typical adipocytes. These tumors are also positive for S100, thus rendering this stain useless for this differential; however, granular cell tumors, unlike hibernomas, are also positive for CD68 and show complete absence of intracellular Oil Red O–positive lipid vacuoles.20 Lastly, a histiocytoid carcinoma of the breast typically shows atypia, mitotic figures, and evidence of epithelial differentiation, including positivity for cytokeratin stains, unlike hibernoma. Some breast carcinomas can show positive staining for S100 protein, thus rendering this stain less useful for this differential.5
TREATMENT AND PROGNOSIS
Hibernomas, including mammary hibernomas, are thought to be universally benign with no malignant counterpart described in the literature. Complete surgical excision is recommended to avoid recurrences; however, follow-up from the AFIP study revealed no local recurrences or evidence of aggressive behavior, even in cases of incompletely excised tumors.2
Mammary hibernoma is a rare entity, which can present either as palpable mass or incidental mass detected on imaging studies. These are benign lesions with no propensity for local recurrence or aggressive behavior even in incompletely excised lesions. The clinical significance lies in distinguishing these rare neoplasms from other primary breast and soft tissue neoplasms, both benign and malignant, that are in the differential diagnosis.
The authors have no relevant financial interest in the products or companies described in this article.