JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2022

I-N19

 

 

SLIDE A

Signalment (JPC #1961061): Unspecified breed and age, dog

 

HISTORY: A small dermal mass

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Expanding the dermis and subcutis, elevating the mildly hyperplastic epidermis, and compressing adnexa is a 5 X 10 mm, well-circumscribed, unencapsulated, moderately cellular neoplasm composed of spindle cells that form numerous blood-filled vascular channels separated by variably thick bands of mature collagenous matrix. Neoplastic cells have indistinct cell borders, small amounts of eosinophilic fibrillar cytoplasm, and oval to elongate nuclei with finely stippled chromatin and variably distinct nucleoli. Anisokaryosis and anisocytosis are mild and there is less than 1 mitotic figure per 2.37 mm². Multifocally, polymerized fibrin (thrombi) partially occlude vascular spaces. There are few scattered infiltrates of low numbers of lymphocytes and plasma cells within the neoplasm and surrounding adnexa in the overlying dermis. The superficial dermis contains increased numbers of small caliber blood vessels lined by hypertrophic endothelium (telangiectasia), few multifocal melanin-laden macrophages and free melanin pigment (pigmentary incontinence), increased clear space and ectatic lymphatics (edema). The overlying epidermis is diffusely and variably hyperplastic, with formation of short rete ridges, intracellular edema, acanthosis and orthokeratotic hyperkeratosis.

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Hemangioma, breed unspecified, canine.

 

SLIDE B

Signalment (JPC # 4090062-00): 8 year old, female spayed, Heeler mix

 

HISTORY: 1 month history of subcutaneous mass on right axilla/cranial thorax

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Effacing and expanding the dermis, elevating the focally ulcerated epidermis, and extending into the subcutis is an unencapsulated, infiltrative, densely cellular neoplasm composed of spindle cells arranged in haphazard streams and bundles on a variably dense collagenous matrix. Neoplastic cells are form variably sized blood-filled vascular channels, wrap around collagen bundles and have plump nuclei that bulge into vascular lumens. Neoplastic cells have indistinct borders, scant to moderate amounts of eosinophilic fibrillar cytoplasm, and irregularly oval to elongate nuclei with finely stippled chromatin and one to two variably distinct nucleoli. Anisocytosis and anisokaryosis are moderate and there are 5 mitotic figures per 2.37 mm². There is scattered single-cell necrosis. Multifocally, there is hemorrhage, fibrin, edema, and necrosis, and mild to moderate numbers of scattered lymphocytes, plasma cells, neutrophils, and hemosiderin-laden macrophages. The overlying epithelium is multifocally hyperplastic with acanthosis, intercellular edema (spongiosis), and multifocal parakeratotic hyperkeratosis. Focally, the epithelium is eroded and ulcerated and replaced with a serocellular crust. Adjacent to the neoplasm, the superficial dermal collagen is hypocellular and smudgy (solar fibrosis) with increased basophilia of wavy elastin fibers (solar elastosis).

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Hemangiosarcoma, mixed breed, canine.

 

SLIDE C

Signalment (JPC # 4083483-00): 15yo pony mare

 

HISTORY: Pony with swollen left eye, previous history of treatment of squamous cell carcinoma of the left third eyelid 8 years prior, section of left upper eyelid submitted.

 

HISTOPATHOLOGIC DESCRIPTION: Fibrovascular tissue, eyelid (per contributor): Expanding, effacing, and infiltrating the fibrovascular tissue is an unencapsulated, poorly circumscribed, densely cellular neoplasm composed of polygonal to spindloid cells arranged in indistinct nests, streams, and solidly cellular sheets, often forming variably sized vascular channels and occasionally wrapping collagen bundles on a collagenous stroma. Neoplastic cells are frequently plump, with nuclei that bulge into vascular lumens. Neoplastic cells have variably distinct cell borders, a moderate to abundant amount of eosinophilic cytoplasm that is occasionally vacuolated and rarely contains a single erythrocyte, with a round to pleomorphic nucleus with coarsely clumped chromatin and 1-3 prominent nucleoli. Anisocytosis and anisokaryosis are marked. There are 3 mitotic figures per 2.37 mm2, and mitotic figures are occasionally atypical. There is scattered single cell necrosis and multifocal areas of hemorrhage, fibrin, edema, and lytic necrosis characterized by loss of neoplastic cells with replacement by eosinophilic cellular and karyorrhectic debris. There are multifocal aggregates of moderate numbers of lymphocytes, plasma cells, macrophages, and viable and degenerate neutrophils admixed with necrotic cellular debris and scattered hemosiderin-laden macrophages.

 

MORPHOLOGIC DIAGNOSIS: Fibrovascular tissue, eyelid (per contributor): Epithelioid hemangiosarcoma, breed unspecified, equine.

 

GENERAL DISCUSSION:

• Hemangioma: Benign tumors of vascular endothelium
• Hemangiosarcoma (HSA): Malignant tumor of vascular endothelium; may arise in any tissue; cutaneous and subcutaneous HSAs may be primary or metastatic from primary visceral tumor
• Cutaneous neoplasms are common in dogs (mostly benign), occur occasionally in cats (mostly malignant) and horses (mostly benign), less common in other species
• Visceral HSA (C-N02, P-N07): Most common form of HSA in the dog; involves the spleen, liver, lungs and/or right atrium; highly aggressive; high metastatic potential, poor to grave prognosis

 

PATHOGENESIS:

• Generally unknown
• Chronic solar irradiation may cause transformation of normal resident endothelial cells; evidenced by occurrence dermis of thinly haired, lightly pigmented skin and conjunctiva and increased risk in whippets and other short haired lightly pigmented breeds; UV radiation can be both a tumor initiator and promoter
• May arise from circulating stem cells from bone marrow or sites of EMH (Schlein 2022)
• Mutations of P53 and PTEN identified in canine HSA (Schlein 2022)
• Congenital hemangiomas documented in many species (may be called vascular nevus or hamartoma)

 

TYPICAL CLINICAL FINDINGS:

• Hemangioma: slow growing; excision curative
  1. Common in older dogs. No breed or sex predilection; occur in sparsely haired and lightly pigmented skin, often on sun exposed abdomen/flank; can arise on non-pigmented conjunctiva
• Hemangiosarcoma:
  1. Cutaneous (dermal) HSAs: less aggressive, lower metastatic potential, may be cured by wide surgical excision
  2. Subcutaneous HSAs: moderately aggressive with moderate metastatic potential; commonly recurs following excision; higher risk in whippets and other lightly pigmented thin-coated breeds; subcutaneous location suggests increased likelihood of a primary visceral HSA
  3. Conjunctival HSA: temporal bulbar conjunctiva or leading edge of third eyelid most common; higher prevalence with increased sunlight; post-operative recurrence is common, but minimal to no metastasis
  4. Intramuscular HSA (dogs, horses): high metastatic potential
  5. Horses: HSA uncommon but conjunctival vascular tumors in horses are most often HSA and can be aggressive, infiltrative, and metastatic
  6. Thrombocytopenia, hypofibrinogenemia, prolonged aPTT/PT, increased AST, anemia; schistocytes (fragmented RBCs) and acanthocytes (spiculated RBCs) 

 

TYPICAL GROSS FINDINGS:

• If solar induced, often multiple, tend to be dermal
• Hemangioma:
  1. Dermis: red to dark red well circumscribed mass in non-pigmented, sparsely haired skin; may be sessile or pedunculated; hemorrhage/ulceration common
  2. Subcutis: Moderately firm, well-circumscribed, reddish-black; alopecia and ulceration uncommon

• Hemangiosarcoma: Dermal or subcutaneous; well-defined mass; red/brown to black; soft to firm; exudes blood when incised; may be hemorrhagic; overlying skin may be thickened, alopecic, or ulcerated seen

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hemangioma: Well circumscribed mass with variably sized, blood-filled vascular spaces lined by a single layer of well-differentiated flattened endothelial cells
  1. Mitotic figures rare
  2. Often have thrombi, hemosiderosis
  3. +/- solar-induced changes 
  4. Variants
     • Capillary: highly cellular, composed of capillaries with single layer of endothelial cells; minimal to moderate stroma which may contain mast cells
     • Cavernous: large vascular channels with single layer of endothelial cells
     • Angiokeratoma: raised dermal hemangioma; accompanied by prominent epidermal hyperplasia which extends into neoplasm and surrounds vascular channels
     • Others: Inflammatory lobular capillary hemangioma (granulation-tissue type hemangioma, follows trauma), mixed capillary-cavernous, spindle cell; epithelioid hemangioma (rare in dogs, cattle, dogs) (Roccabianca)
• Hemangiosarcoma: Pleomorphic plump endothelial cells in single or multiple layers lining and wrapping collagen to form irregular vascular channels or solidly cellular areas with indistinct vascular channels
  1. Nuclei prominent (bulging), hyperchromatic
  2. Mitotic figures frequent
  3. Often have thrombi, hemorrhage, necrosis, hemosiderosis/hematoidin
  4. +/- solar-induced changes
  5. Variants: Conventional (well differentiated, cavernous or capillary), kaposiform (spindle cell), epithelioid variants
  6. Epithelioid HSA: reported in horses and one dog; composed of large epithelioid cells with little or no histologic evidence of vascular origin; cytokeratin negative; reported in horses in peri-ocular tissues (e.g. eyelid) and one report in the kidney (Hughes Jour Vet Diagn Invest 2018); single case report of cutaneous epithelioid HSA in a dog; see P-N07 for visceral epithelioid HSA in a dog
• Hemangioendothelioma: intermediate vascular tumor; less well demarcated than a hemangioma, plump nuclei, some mitotic activity; epithelioid and retiform variants reported (Roccabianca)
• Solar-induced change: may be present in adjacent skin if UV-induced neoplasm
  1. Sunburn cells (acute): Individual or bands of apoptotic keratinocytes in the outer stratum spinosum; apoptosis is likely p53-mediated
  2. Solar elastosis (chronic): Degeneration of superficial dermal collagen with replacement by thick, wavy basophilic degenerate elastic fibers; hallmark of chronic UV exposure in humans but rare in animals; documented in dogs, cats, sheep, and horses
  3. Solar fibrosis (chronic): Pale, hypocellular, “smudgy” collagen, begins superficially and extends deeply, rarely replaces hair follicles
  4. Solar dermatitis (sunburn): In chronic stages, hallmark is a narrow pale hypocellular band of collagen at dermo-epidermal junction; also features acanthosis, apocrine gland ectasia, follicular keratosis (+/- cyst formation, furunculosis), peri-follicular fibrosis; perivascular to lichenoid inflammation; plasma cells and lymphocytes predominate admixed with varying numbers of neutrophils, macrophages, and occasional eosinophils; +/- pigmentary incontinence, +/- solar elastosis
  5. Telangiectasia: Proliferative dermal vessels with plump, “crowded” endothelium
  6. Actinic (solar) keratosis: Hyperplastic (early) epidermal lesions with spongiosis, dermatitis, necrotic keratinocytes; dysplastic (chronic) epidermal lesions feature orthokeratotic and parakeratotic hyperkeratosis, perivascular mononuclear infiltrates, scarring; solar elastosis rare; frequently progresses to squamous cell carcinoma (I-N04); documented in dogs, cats, horses

 

ULTRASTRUCTURAL FINDINGS:

• Weibel-Palade bodies: Specific cytoplasmic marker for endothelial cells
• Continuous basement membranes

 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry: Immunoreactive for Factor VIII-related antigen, vimentin, CD31 (PECAM), type IV collagen, laminin; CD34 has the highest labeling intensity in neoplastic cells, but lacks specificity
• A recent study also illustrated that canine splenic HSA cells express CD14 (myeloid marker) and p53 +/- CD117 and CD133 (both hematopoietic stem cell markers) (Kakiuchi-Kiyota 2020)
• Cytology: aspirates often bloody and paucicellular; neoplastic endothelial cells exfoliate individually or in sheets and are irregular to spindle to epithelioid; high N:C ratio, multiple nucleoli; evidence of acute or chronic hemorrhage present; may have extramedullary hematopoiesis; organizing hematomas can produce reactive spindle cells that mimic pleomorphic endothelial cells from hemangiosarcoma

 

DIFFERENTIAL DIAGNOSIS:

• Lymphangioma, lymphangiosarcoma:
  1. Rare tumors of lymphatic endothelium; Usually in subcutis along ventral midline and limbs; poorly demarcated masses that tend to ooze; neoplastic cells grow directly on bundles of dermal collagen forming numerous clefts and channels devoid of erythrocytes
  2. Poorly differentiated varieties difficult to differentiate from hemangiosarcomas; sometimes just called angiosarcomas
  3. IHC: positive for lymphatic vessel endothelial receptor-1 (LYVE-1), podoplanin (D2-40), vascular endothelial growth factors receptor-3 (VEGFR-3); also positive for factor VIII-related antigen and CD31 like hemangiomas/HSAs
  4. EM: discontinuous or absent basement membranes and numerous pinocytotic vesicles (HSAs have a continuous basement membrane)

• Feline ventral abdominal angiosarcoma: Rare, infiltrative but rarely metastatic, characteristic lesion with indistinct borders on caudoventral abdomen which oozes serum and appears bruised; LYVE-1 positive indicating lymphatic origin
• Scrotal hamartoma (I-N20): Rare, proliferative vascular lesion seen in older dogs with pigmented scrotal skin; not a true neoplasm; vascular hamartomas can occur anywhere in the skin (though the scrotum is the more common location)
• Cutaneous angiomatosis: Vascular endothelial proliferative disorder; irregular capillaries in dermis and subcutis; most common in cattle and horses; one case in an immunosuppressed dog caused by Bartonella (bacillary angiomatosis); multisystemic progressive angiomatosis described in one dog affecting  GI tract, skin, and peritoneal surface

 

COMPARATIVE PATHOLOGY:

• Horses: Lobular capillary hemangioma (vascular nevus or hamartoma); multiple discrete densely cellular dermal lobules composed of haphazardly arranged small caliber vascular structures lined by plump endothelial cells, low mitotic rate; congenital or occurs at < 1 year of age; usually on distal limbs; nodular, cauliflower or plaque-like
• Pet birds: Hemangiomas and hemangiosarcomas occasionally occur and are most common in skin/subcutis; hemangiomas are more common in budgies; pet birds can also have vascular hamartomas in dermis/subcutis; other sites for hemangiomas/hemangiosarcomas include heart, spleen, liver, metacarpus, diaphysis of long bones; metastasis has been documented in kidney (Schmidt)
• Chickens: Hemangiomas/hemangiosarcomas induced by avian hemangioma virus (retrovirus) (Schmidt)
• Mice: Hemangiomas/hemangiosarcomas somewhat common primary neoplasms of liver; also occur in ovary/uterus (Percy)
• Swine: Hemangiomas are rare; when present, usually in scrotum of Yorkshire and Berkshire boars; probably congenital hamartomas (I-N20)
• Cattle: Cutaneous hemangiomas occur in adult and older animals; congenital has been reported as well; hemangioma/HSA has been reported in urinary bladder following bracken fern ingestion (Roccabianca)
• Cats: Hemangiosarcomas rare; cutaneous and subcutaneous more common than visceral or oral; common sites include white haired areas (face/pinna) for cutaneous masses, and trunk for subcutaneous masses; metastasis of cutaneous and subcutaneous hemangiosarcoma has been reported, often to the lung; visceral hemangiosarcoma found in spleen, liver and lungs, though rarely in the heart.

 

REFERENCES:

1. Bolfa P, DellaGrotte L, Weronko T, et al. Cutaneous epithelioid hemangiosarcoma with granular cell differentiation in a dog: a case report and review of the literature. J Vet Diagn Invest. 2018;30(6):951-954.
2. Del Aguila G, Torres CG, Carvallo FR, Conzalez CM, Cifuentes FF. Oral Masses in African pygmy hedgehogs. J Vet Diagn Invest. 2019: 31(6):864-867.
3. Fisher DJ. Cutaneous and subcutaneous lesions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 98-99. 
4. Hughes K, Scott HL, Blanck M, Barnett TP, Spanner Kirstiansen J, Foote AK. Equine renal hemangiosarcoma: clinical presentation, pathologic features, and pSTAT3 expression. J Vet Diagn Invest. 2018;30(2):268-274.
5. Kakiuchi-Kiyota S, Obert L, Crowell DM, et al. Expression of Hematopoietic Stem and Endothelial Cell Markers in Canine Hemangiosarcoma. Toxicol Pathol. 2020; 48(3):481-483.
6. Mauldin GA, Kennedy JP. Integumentary system. In: Maxie MG ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed., Philadelphia, PA: Elsevier Saunders; 2016: 575-577, 726-727, 736.
7. Nóbrega DF, Sehaber VF, Madureira R, et al. Canine Cutaneous Haemangiosarcoma: Biomarkers and Survival. J Comp Pathol. 2019 Jan;166:87-96.
8. Percy DH, Barthold SW. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:114-115.
9. Raskin RE, Conrado FO. Integumentary system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 93-95.
10. Roccabianca P, Schulman FY, Avallone G, Foster RA, Scruggs JL, Dittmer K, Kiupel M. Surgical Pathology of Domestic Animals. Vol 3: Tumors of Soft Tissue. Gurnee, IL: Davis Thompson DVM Foundation. 149-179.
11. Schlein LJ, Thamm DH. Review: NK-kB activation in canine cancer. Vet Pathol. 2022: 59(5):724-732.
12. Schmidt RE, Reavill DR, Phalen DRn. Pathology of Pet and Aviary Birds. 2^nd ed. Ames, IO: 2015; 12,17,120,191,195,256.
13. Stockham SL, Scott MA. Thyroid function. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Blackwell Publishing; 2008: 143-149, 172, 234, 240, 243, 308, 678, 859.
14. Valentine BA. Skeletal Muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1015-1016.
15. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1210-1218.
16. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed., Philadelphia, PA: Elsevier Saunders; 2016: 481-482

 

 

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