AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENT SYSTEM

October 2019

I-N18

 

Slide A

Signalment (JPC # 1647900): Age and breed unspecified, dog

 

HISTORY: A slow growing soft subcutaneous mass

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, subcutis: Expanding the subcutis and compressing the underlying skeletal muscle is a 1.5 cm diameter, well-circumscribed, partially encapsulated, moderately cellular neoplasm composed of mature adipocytes arranged in indistinct lobules on a fine fibrovascular stroma. Neoplastic adipocytes have distinct cell borders and a single, 60-130 micron, clear vacuole (lipid) that compresses and peripheralizes a flattened and hyperchromatic nucleus. Anisocytosis is marked depending on vacuole size of the, but anisokaryosis is minimal. Mitoses are not seen. There are two small, focal areas of hemorrhage, fibrin, and edema within the neoplasm with associated dark brown to golden globular pigment (hemosiderin).

 

MORPHOLOGIC DIAGNOSIS: Subcutis: Lipoma, breed not specified, canine.

 

Slide B

Signalment (JPC # 1958368): Age and breed unspecified, dog

 

HISTORY: A large, soft, subcutaneous mass

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, subcutis, and panniculus carnosus: Expanding the subcutis; elevating the overlying dermis and epidermis; widely separating adnexa; and separating, surrounding, and replacing skeletal muscle bundles is a poorly circumscribed, infiltrative neoplasm composed of densely packed, mature adipocytes with distinct cell borders and a single, clear, 50-80 um, cytoplasmic vacuole that compresses and peripheralizes a flattened and hyperchromatic nucleus. Mitoses are not observed. Skeletal muscle fibers are often either replaced or are shrunken with angular margins (atrophy) or swollen with pale, vacuolated sarcoplasm (degeneration). Multifocally, apocrine glands are mildly ectatic.

 

MORPHOLOGIC DIAGNOSIS: Haired skin, subcutis: Infiltrative lipoma, breed not specified, canine.

 

Slide C

Signalment (JPC #1900656): Age and breed unspecified, dog

 

HISTORY: A firm subcutaneous mass from the shoulder

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Effacing the subcutis, elevating the overlying dermis, and extending to the deep margins is an infiltrative, unencapsulated, multilobulated neoplasm composed of polygonal to spindle cells that are arranged in solidly cellular areas or short streams separated by a fine fibrovascular stroma. Neoplastic cells have indistinct cell borders and a moderate amount of eosinophilic cytoplasm that often contains one large (up to 80 um), distinct, clear vacuole (lipocyte) or several small (10-15 um), distinct vacuoles (lipoblast). Nuclei are round to oval, vesiculate, and occasionally centrally located with a single prominent magenta nucleolus. Mitoses average 2 per 10 400X HPF. There is marked anisokaryosis and anisocytosis. The center of the neoplastic lobule, affecting approximately 30% of this section, is characterized by loss of differential staining with retention of architecture (coagulative necrosis). Multifocally there is mild hemorrhage, fibrin, and edema admixed with few hemosiderin-laden macrophages.

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis, shoulder (per contributor): Liposarcoma, breed not specified, canine.

 

SYNONYMS: Soft tissue sarcoma favor liposarcoma

 

GENERAL DISCUSSION:

Lipoma

·      Common benign neoplasm of adipocytes (also known as lipocytes)

·      Reported more frequently in cocker spaniels, dachshunds, weimaraners, Doberman pinschers, miniature schnauzers, labrador retrievers and small terriers

·      Higher incidence in obese female and middle-aged to older dogs and cats

·      Common sites include the subcutis of the thorax, abdomen, proximal limbs, and brisket; often multiple; reports of canine primary cardiac/pericardial lipomas

·      Intramuscular lipomas of the thigh region of dogs: Usually occur between the fascial planes of the semitendinosus and the semimembranosus muscles, are not infiltrative, and have an excellent prognosis following surgical excision

·      Occasionally, hemangiosarcomas/mast cell tumors arise from lipomas, suggesting that lipomas may provide a beneficial environment for tumor development

Infiltrative Lipoma

·      Uncommon variant of lipoma characterized by intramuscular invasion

·      Most common in dogs and horses

·      Doberman pinschers, Labrador retrievers, and standard schnauzers may be predisposed (according to one study)

·      Common sites include the subcutis of the extremities, thorax, and neck

·      Usually occur in middle-aged dogs

·      Not associated with obesity

·      Locally invasive, and often recur following incomplete excision

·      Usually do not metastasize

Liposarcoma

·      Rare malignant tumor of lipocytes; may also arise from fat cell precursors in the bone marrow

·      Locally invasive and may recur, but rarely metastasize

·      Common sites include the subcutis of the ventral thorax, abdomen and proximal limbs; have also been reported in mammary gland of dogs

·      Dachshunds, Shetland sheepdogs and Brittany spaniels are predisposed

·      Usually occur in older dogs

·      Liposarcomas are included in the group “cutaneous/subcutaneous soft tissue sarcomas;” these are graded (I-III) using a scale which assesses differentiation, mitotic index, and degree of necrosis (Dennis Vet Pathol 2011, Mauldin 2016)

 

PATHOGENESIS:

·      A study of dog liposarcomas found that platelet-derived growth factor receptor-beta (PDGFR-beta) is expressed at a higher level in more mitotically active liposarcomas, suggesting that PDGFR-beta-mediated pathways may have a role in the progression of canine liposarcoma (Avallone Vet Pathol 2017)

·      PPARs (peroxisome proliferator-activated receptors) are nuclear receptors that are important in adipocyte differentiation; they are also involved in insulin resistance and diabetes

·      There are three major PPARs: PPAR-alpha, PPAR-gamma, PPAR-delta

·      PPAR-alpha agonists affect triglyceride and HDL levels; they induce pancreatic acinar cell, testicular Leydig cell and possibly liver tumors in rats

·      PPAR-gamma agonists have antimitotic effects on preadipocyte proliferation, while PPAR-delta agonists stimulate proliferation of preadipocytes

·      PPAR-gamma agonists have been used in human liposarcoma therapy

·      A study of human lipomas and liposarcomas (Wagner J Pathol 2011) found that:

·      PPAR-delta is highly expressed in liposarcoma (versus lipoma) and inhibits leptin expression

·      Leptin (an adipose tissue secretory factor or adipokine) is downregulated and appears to inhibit proliferation and migration in liposarcoma compared to lipoma

 

TYPICAL GROSS FINDINGS:

Lipoma

·      Well-circumscribed, soft, white to yellow neoplasms not attached to adjacent tissue

Infiltrative Lipoma

·      Soft, poorly circumscribed, deep subcutaneous masses attached to the surrounding tissue; may cause pain or interfere with limb function

Liposarcoma

·      Poorly circumscribed, firm, gray-white neoplasms

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Necrosis, hemorrhage, and fibrosis can occur in any of these neoplasms especially if they are large or traumatized

Lipoma

·      Well-circumscribed proliferation of well-differentiated adipocytes

·      Indistinguishable from normal fat except for compression of adjacent tissue and a fine capsule which separates tumor from normal adipose tissue

·      Some contain cartilage, bone, collagen or blood vessels

Infiltrative lipoma

·      Well-differentiated adipocytes that invade muscle, fascia, and occasionally bone

Liposarcoma

·      Densely cellular, infiltrative; round to spindle cells with variably sized intracytoplasmic vacuoles and a central nucleus (lipoblasts) mixed with lipocytes

·      May display anisokaryosis, multinucleated cells, and mitoses

·      Three subtypes

·      Well-differentiated liposarcoma: Resemble normal adipocytes with a single clear fat vacuole and a peripheral nucleus admixed with lipoblasts

·      Pleomorphic liposarcoma: Anaplastic with large bizarre multinucleated cells; only a few cells contain fat vacuoles

·      Myxoid liposarcoma: Scattered lipoblasts with abundant stromal mucin

·      Round cell variant: Neoplastic cell morphology is more round with abundant binucleate to multinucleate cells, including populations of myxoid and round cells; analogous to high-grade myxoid liposarcoma in humans

 

ADDITIONAL DIAGNOSTIC TESTS:

·      Immunohistochemistry

·      Vimentin positive; may be S-100 positive

·      Liposarcoma: higher mitotic rate correlated with lower FGF2 and higher PDGFR-beta expression

·      Liposarcoma: Like in humans, in dogs MDM2 expression is inversely correlated with grade (high MDM2 expression in grade I tumors), and is expressed frequently in canine well-differentiated and dedifferentiated liposarcomas but rarely in myxoid or pleomorphic liposarcomas; unlike humans, CDK4 has shown no histotype or grade correlation.

·      Histochemistry: Stains for lipid on frozen tissue sections include Oil-red-O, osmium, and Sudan black

 

DIFFERENTIAL DIAGNOSIS:

Histologic and/or gross differentials:

·      Normal subcutaneous adipose tissue: Must consider if sample is from FNA

·      Hibernomas (I-N14): Soft, brown tumor of brown adipose tissue; neoplastic cells have tiny cytoplasmic lipid droplets; occurs most commonly in the subcutis of the dorsal thorax and the axilla of rodents and wild mammals

·      Myelolipoma: Adipocytes are combined with myeloid elements; primarily in the liver of domestic cats and wild cats such as cheetahs, spleen of dogs, and the adrenal gland of nonhuman primates and cattle

·      Myxosarcoma: Absence of lipid vacuoles aids in differentiating from liposarcoma; spindle to stellate neoplastic cells

 

Other Lipocytic tumors:

Lipomatosis

·      Multicentric proliferation of architecturally normal adipose tissue

·      Pendulous, fatty skin folds involving the neck and trunk (dog); caudal thighs (cat)

·      Light microscopic findings: Diffuse thickening of the subcutis by mature adipocytes with a small number of primitive mesenchymal cells and lipoblasts

Fibrolipoma

·      Characterized by the presence of sparse to moderate amounts of dissecting fibrous connective tissue within a lipoma

·      Differential: Fibrotic adipose tissues (end-stage reaction to trauma or severe inflammation)

Angiolipoma

·      Clusters of branching blood vessels within an otherwise typical lipoma

·      Differential: Infiltrative hemangioma

Angiofibrolipoma

·      Bands of collagen and branching vessels dissecting well-differentiated adipose tissue

Chondrolipoma

·      Scattered islands of well-differentiated cartilage within otherwise typical lipoma

Spindle cell lipoma (Avallone Vet Pathol. 2017)

·      Benign rare tumor in dogs, recognized in humans

·      Hip, elbow, ventral abdomen, inguinal region, mid-dorsal trunk, forehead

·      Well circumscribed, varying proportions of mature adipocytes and spindle cells

Atypical lipoma

·      Similar to lipoma, with subtle increased cellularity and small numbers of individual or clustered lipoblasts; cellular atypia; considered low-grade liposarcoma

·      Differentials: Mildly inflamed lipoma, steatitis, fibrolipoma

Myxoid liposarcoma

·      Less common variant of liposarcoma characterized by mucinous/myxomatous/myxoid background

·      Differentials: Myxoid variants of other spindle cell malignancies

Pleomorphic liposarcoma

·      Tumor cells vary markedly in size and shape; multinucleated giant cells are common

·      Lipoblasts: Marked nuclear variability with hyperchromatism and prominent nucleoli

·      Differentials: Histiocytic sarcoma, anaplastic sarcoma with giant cells

Intracranial lipomatous hamartoma

·      Mature adipose tissue with varying amounts of intervening fibrous tissue or other mesenchymal elements

·      Uncommon, reported in human, dog, mice, rats, ducks, single report in horse, pig, humpback whale; generally asymptomatic unless compressing adjacent neuroparenchyma

 

COMPARATIVE PATHOLOGY:

·      Lipomas occur in all species

·      Bovine: Rare; Most often located in internal organs

·      Horse: Pedunculated lipomas develop in the mesentery and cause intestinal strangulation

·      Snakes: One report showed 8 of 33 soft tissue masses studied were lipoma; this study was the first report of lipoma in a ribbon snake, and of angiolipoma in a black-headed python and corn snakes (Deitz J Comp Pathol 2016)

·      Infiltrative lipoma: Rare reports in horses, cattle, and cats

·      Liposarcomas: Rare in all species

·      In cats, have been associated with vaccination sites and retrovirus infection

·      Renal liposarcomas in research rats

·      Case reports:

·      Well-differentiated liposarcoma with metastasis in a cat (Alvare J Vet Diagn Invest 2017)

·      Metastatic pleomorphic liposarcoma in a South African fur seal (Pervin J Comp Pathol 2016)

·      Lypocytic tumors/deposition:

·      Case reports:

·      Lingual chondrolipoma in a dog (Furumoto J Comp Pathol 2017)

·      Choroid plexus adipocytes in New Zealand White rabbits and Beagle dogs (Rudmann Tox Pathol 2019)

 

REFERENCES:

1.    Alvare E, Dreyfus J, Carlson T, Pinkerton ME, Shaffer K. Well-differentiated inflammatory liposarcoma with metastasis in a 6-y-old cat. J Vet Diagn Invest. 2017; 29(6): 896-899.

2.    Avallone G, Pellegrino V, Muscatello LV, Sarli G, Roccabianca P. Spindle cell lipoma in dogs. Vet Pathol. 2017; 54(5): 792-794.

3.    Avallone G, Pellegrino V, Roccabianca P, Lepri E, Crippa L, Beha G, De Tolla L, Sarli G. Tyrosine kinase receptor expression in canine liposarcoma. Vet Pathol. 2017; 54(2):212-217.

4.    Avallone G, Roccabianca P, Crippa L, Lepri E, Brunetti B, Bernardini C, Forni M, Olandese A, Sarli G. Histological classification and immunohistochemical evaluation of MDM2 and CDK4 expression in canine liposarcoma. Vet Pathol. 2016: 53(4)773-780.

5.    Deitz J, Heckers KO, Aupperle H, Pees M. Cutaneous and subcutaneous soft tissue tumours in snakes: A retrospective study. J Comp Pathol. 2016;155(1):76-87.

6.    Dennis MM, McSporran KD, Bacon NJ, Schulman FY, Foster RA, Powers BE. Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet Pathol. 2011;48(1):73-84.

7.    Furumoto R, Michishita M, Arai K, Soeta S, Takahashi K. Lingual chondrolipoma in a dog. J Comp Pathol. 2017; 157: 11-14.

8.    Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell; 2005: 766-777.

9.    Hard GC, Seely JC, Betz LJ. A survey of mesenchyme-related tumors of the rat kidney in the National Toxicology Program Archives, with particular reference to renal mesenchymal tumor. Tox Pathol. 2016; 44(6): 848-855.

10. Hendrick MJ. Mesenchymal Tumors of the Skin and Soft Tissues. In: Meuten DJ, ed. Tumors in Domestic Animals, 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017: 158-160.

11. 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.

12. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. New York, NY: Elsevier, Inc.; 2016:726.

13. Plumlee QD, et al., High-grade myxoid liposarcoma (round cell variant) in a dog, J Comp Pathol. 2016; 155:305-309.

14. Pervin M, Izawa T, Ito S, Kuwamura M, Yamate J. Metastatic liposarcoma in a South African fur seal (Arctocephalus pusillus). J Comp Pathol. 2016:155(1):72-75.

15. Rudmann D, Colleton C. Interstitial adipocytes in the Beagle dog and New Zealand White rabbit choroid plexus. Tox Pathol. 2019; 47(4): 553-555.

16. Scott DW, Miller WH, Griffin CE. Neoplastic and non-neoplastic tumors. In: Muller & Kirk's Small Animal Dermatology, 7th ed. St. Louis, MO: Saunders; 2013: 801-803.

17. Wagner KD, Benchetrit M, Bianchini L, Michiels JF, Wagner N. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is highly expressed in liposarcoma and promotes migration and proliferation. J Pathol. 2011;224(4):575-588.


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