JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2022

I-N14

 

Signalment (JPC 2325737):  Sprague-Dawley rat

 

HISTORY:  This rapidly growing mass is from the subcutis.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin and subcutis: Expanding the subcutis and elevating the overlying dermis and epidermis is a 2 x 1 cm, multilobulated, encapsulated, well demarcated, moderately cellular neoplasm composed of variably sized linear to coalescing cords of polygonal to spindle cells on a fine fibrovascular matrix. Neoplastic cells have distinct borders with a cytoplasm that is either abundant and microvacuolated, finely granular and eosinophilic, or occasionally expanded by larger, clear, round cytoplasmic vacuoles. Nuclei are centrally located and round with finely stippled chromatin and one to three prominent basophilic nucleoli. There are 5-6 mitotic figures per 2.37 mm². Multifocally, random lobules of well-differentiated adipocytes and fine connective tissue separate neoplastic cells. Scattered throughout the neoplasm are moderate numbers of lymphocytes, plasma cells, hemosiderin-laden macrophages, rare neutrophils, and mild to moderate hemorrhage. Multifocally within the adjacent and subjacent subcutis are low number of multinucleate giant cells (Langhans type). There are peritumoral infiltrates of plasma cells, lymphocytes, and occasional hemosiderin-laden macrophages; the dermis contains low numbers of similar inflammatory infiltrates.

 

MORPHOLOGIC DIAGNOSIS:  Haired skin and subcutis:  Hibernoma, Sprague-Dawley rat, rodent.

 

GENERAL DISCUSSION:  

• Animals have two types of adipose tissue: White and brown 
  • White adipose tissue stores energy as fat
  • Brown adipose tissue burns energy
• The hibernoma is a rare neoplasm of brown adipose tissue of humans and animals; typically benign, may be malignant and locally invasive
• Brown fat is more abundant in young animals, especially those that hibernate, hence the nickname ”hibernating gland”
  • Normally located around the neck, between the scapulae, in the mediastinum, and along the ventral surface of the vertebral column
• Brown fat is important for providing thermal maintenance in neonates or in periods of cold-induced stress; essentially, brown adipocytes convert fatty acids into energy (non-shivering thermogenesis)
  • Cold stress: sympathetic nerves release norepinephrine> binds receptors on brown adipocytes> intracellular signaling via adenylcyclase and cAMP> activation of lipoprotein lipase> beta-oxidation and liberation of free fatty acids, also inhibition of brown adipocyte apoptosis
  • Regulated by protein UCP1 (also known as thermogenin) that is found along the inner mitochondrial membrane
    • UCP1 uncouples fatty acid oxidation from phosphorylation of ADP, which results in the dissipation of oxidation energy as heat 
    • UCP1 is not specific for brown adipose; it is variably expressed in other tissues of mice (skeletal muscle, brain, thymocytes), rats (thymocytes), humans (hair follicles, sebaceous glands) and macaques (pancreatic islet cells)
• Some studies have shown that hibernomas are more prevalent in males

 

PATHOGENESIS:

• Unknown
• It has been suggested that prolonged cold stress, starvation or chronic hypoxemia may lead to hypertrophy/hyperplasia of brown adipose tissue via sympathetic release of norepinephrine and beta-adrenergic pathways

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Lobular aggregates of round to polygonal, eosinophilic adipocytes with centrally located nuclei; can have multiple, fine, intracytoplasmic vacuoles, a single intracytoplasmic vacuole (univacuolated), or eosinophilic granules; very vascular
• Thin connective tissue capsule and septae containing pigment-laden macrophages

 

ULTRASTRUCTURAL FINDINGS:  

• Brown fat cells contain abundant pleomorphic mitochondria with elongate transverse cristae and intramatrical granules, endoplasmic reticulum, a poorly developed Golgi apparatus, and numerous coalescing fat vacuoles
  • There is an inverse relationship between lipid droplet size and the number of mitochondria per unit of cytoplasm

 

ADDITIONAL DIAGNOSTIC TESTING: 

• Brown fat adipocytes exhibit positive immunohistochemical staining for UCP1 (Uncoupling Protein 1)   
• Recent studies in humans and dogs suggest that UCP1 is not absolutely specific for brown fat adipocytes:  a subset of liposarcomas express UCP1; this could represent transdifferentiation of white adipose to brown, aberrant expression of UCP1 on white adipose, or possibly cross-reactivity of the human UCP1 antibody with a different canine protein
• Brown adipose may also express myogenin, MyoD, and Myf5 (myogenic factors), which suggests a common origin for brown adipocytes and myocytes; like oxidative skeletal muscle, brown adipocytes specialize in catabolism of lipid rather than lipid storage as in white adipose

 

DIFFERENTIAL DIAGNOSIS:  

• Lipoma (I-N18A) – well-demarcated, expansile neoplasm of adipocytes with a single, large, clear vacuole that often peripheralizes the nucleus; usually less vascularized than hibernoma
• Liposarcoma (I-N18C) – infiltrative neoplasm composed of adipocytes and adipoblasts that often have multiple variably-sized intracytoplasmic clear vacuoles; cellular atypia and higher mitotic rate
• Xanthogranuloma – granulomatous component 

 

COMPARATIVE PATHOLOGY:  

• Dog:  
  • Report of seven cases of orbital hibernoma in adult dogs; there was also an increased prevalence in males in this study (Ravi Vet Pathol. 2014)
  • One previous report of a hibernoma in the omentum of a young dog 
• Rhesus monkey:  Two reported cases

 

REFERENCES:  

1. Bruner RH, Novilla MN, Picut CA, et al. Spontaneous hibernomas in Sprague-Dawley rats. Toxicol Pathol. 2009;37(4)547-552. 
2. Greaves P, Chouinard L, Ernst H, et. al.  Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle and mesothelium.  J Toxicol Pathol. 2013;26(3 Suppl):1S-26S.
3. Kiupel M, ed. Surgical Pathology of Tumors of Domestic Animals. Volume 3: Tumors of Soft Tissue. 3^rd ed. Gurnee, IL: Davis-Thompson DVM Foundation; 2018:138-140.
4. Labelle P. The eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1424.
5. LaDouceur EEB, Stevens SE, Wood J, Reilly CM.  Immunoreactivity of Canine Liposarcoma to Muscle and Brown Adipose Antigens.  Vet Pathol. 2017; 54(6): 885-891.
6. Malzahn J, Kastrenopoulou A, Papadimitriou-Olivgeri I, et al. Immunophenotypic expression of UCP1 in hibernoma and other adipose/non adipose soft tissue tumours. Clin Sarcoma Res. 2019; 9(8). 
7. Ravi M, Schobert CS, Kiupel M, Dubielzig RR. Clinical, morphologic, and immunohistochemical features of canine orbital hibernomas Vet Pathol. 2014:51(3):563-568.

Click the slide to view.

---