JPC SYSTEMIC PATHOLOGY
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, un-encapsulated moderately cellular neoplasm composed of spindle cells that form multiple blood-filled vascular spaces that are separated by variably thick bands of a fibrous connective tissue (collagen) matrix. Neoplastic cells have indistinct cell borders, small amounts of eosinophilic fibrillar cytoplasm, 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 10 HPFs. Multifocally vascular spaces are partially occluded by fibrin emboli along with small aggregates of dark granular pigment (hemosiderin). Multifocally there are low numbers of lymphocytes and plasma cells are scattered throughout the stroma as well as in the dermis surrounding adnexal structures. At the dermal-epidermal junction there are also multifocal melanin containing macrophages in the dermis (pigmentary incontinence). Apocrine glands and hair follicles are mildly ectatic and there is increased clear space with ectatic lymph vessels within the superficial dermis (edema).
MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Hemangioma, breed unspecified, canine.
Signalment (JPC #1945545): Unspecified breed and age, cat
HISTORY: A dermal mass on the paw
HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Effacing the deep dermis and subcutis and extending to deep and lateral borders is an un-encapsulated, infiltrative, densely cellular neoplasm composed of spindle cells which form variably sized blood-filled vascular spaces and often bulge into the lumen, occasionally wrap collagen bundles, and in more densely cellular areas are arranged in short, haphazard streams and bundles, all separated by a variable amounts of collagenous matrix. Neoplastic cells have indistinct borders, small to moderate amounts of eosinophilic fibrillar cytoplasm, irregularly round to oval nuclei with finely stippled chromatin, and one to two variably distinct nucleoli. There is moderate anisocytosis, anisokaryosis, and scattered single-cell necrosis, and the mitotic count is up to 5 per 10 HPFs. Multifocally throughout the neoplasm, there are variably sized areas of hemorrhage and necrosis, and low numbers of scattered lymphocytes, plasma cells, neutrophils and hemosiderin-laden macrophages. Within the superficial dermis there are scattered lymphocytes, plasma cells, and macrophages containing melanin (pigmentary incontinence) as well as ectatic lymph vessels (edema).
MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Hemangiosarcoma, breed unspecified, feline.
- Hemangiomas are benign tumors of vascular endothelium
- Common in dogs; rare in other domestic animals
- Dermal or subcutaneous tumors that occur anywhere on the body
- Slow growth; complete excision is curative
- Synonym: Angioma
- No breed or sex predilection in the dog; average age - 10 yrs
- Dogs: Most commonly visceral (involving the spleen, liver, lungs and/or right atrium)
- Visceral hemangiosarcoma: Highly aggressive; high metastatic potential, poor to grave prognosis
- Subcutaneous hemangiosarcoma: Moderately aggressive, moderate metastatic potential
- Cutaneous (dermal) hemangiosarcomas: Less aggressive; lower metastatic potential
- Synonyms: Angiosarcoma, malignant hemangioendothelioma
- At risk breeds include German shepherd dogs, golden retrievers, Bernese mountain dogs, boxers
- Average age: 10 yrs; males more often than females
- Cats: Rare in cats; cutaneous and subcutaneous more common than visceral or oral; common sites include head, distal limbs and paws 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
- Occurrence in dermis of thinly haired lightly pigmented skin suggests chronic solar irradiation may be a factor
- Some dermal hemangiosarcomas may be due to chronic solar irradiation; increased risk in greyhounds, whippets, American pit bulls (short hair, light skin)
- Serine protease urokinase plasminogen activator (uPA) and uPA membrane receptor (CD87) have been proven to play a role in the proliferation of canine HSA cells, regardless of primary location
- Splenic and non-splenic HSAs upregulate peroxyredoxin (PRDX) which may contribute to cancer cell survival in the face of oxidative stress by preventing tumor cell apoptosis; this is not seen in cutaneous HSAs
TYPICAL CLINICAL FINDINGS:
Hemangioma: Trauma induced bleeding may occur
Hemangiosarcoma (especially visceral)
- DIC may be associated (especially visceral, which often causes sudden death due to tumor rupture and hemorrhage)
- Thrombocytopenia, hypofibrinogenemia, prolonged activated partial thromboplastin time, prolonged one-stage prothrombin time, increased AST, anemia
- Schistocytes may be observed; acanthocytes, especially when liver is affected
TYPICAL GROSS FINDINGS:
- Subcutis: Moderately firm, well-circumscribed, reddish-black; alopecia and ulceration uncommon
- Dermis: Smaller and often sessile or pedunculated; alopecia, hemorrhage/ulceration common
- Usually solitary, may be multiple
- Dermal or subcutaneous lesions: Usually single, well-defined mass; red/brown to black; soft to firm; exudes blood when incised
- Alopecia, thickened skin, hemorrhage, or ulceration can be seen
- Solar induced lesions: Often multiple; tend to be dermal
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Two variants, based on size of vascular spaces
- Cavernous: Large spaces separated by fibrous connective tissue stroma
- Capillary: Little stroma; more cellular appearance
- Variably sized, blood-filled vascular spaces lined by a single layer of well‑differentiated endothelial cells
- Often see organized thrombi and foci of hemosiderosis
- Well-circumscribed with rare mitotic figures
- Irregular vascular clefts or channels lined by pleomorphic spindle cells (endothelial cells)
- Nuclei of cells lining clefts may be prominent, bulging, pleomorphic, and hyperchromatic
- Neoplastic cells often wrap hyalinized collagen bundles
- May have solid areas of closely packed pleomorphic spindled cells with only vague, small vascular channels
- Mitotic figures are frequent; hemorrhage and necrosis occur commonly
- Solar induced change may be an associated finding:
- Solar elastosis and fibrosis:
- In dogs,
- Dermis may contain perivascular to lichenoid inflammation; plasma cells and lymphocytes predominate admixed with varying numbers of neutrophils, macrophages, and occasional eosinophils; pigmentary incontinence may also be present
- Laminar alteration of collagen, begins superficially and extends deeply, replacing hair follicles (rare); pale, hypocellular, “smudgy” collagen; degeneration of superficial dermal with replacement by thick, wavy basophilic fibers of elastotic material
- In cats,
- Lichenoid dermatitis is generally not observed; inflammation is mild and perivascular
- True laminar fibrosis is sometimes seen (looks more like scar tissue, vs. the pale, altered collagen in dogs)
- In dogs,
- Actinic keratosis:
- Solar induced hyperplasic and dysplastic epidermal lesions that occur in dogs and cats
- Develop in non-pigmented and lightly haired skin exposed to repetitively excessive UV light (e.g. sunbathers)
- May progress to invasive squamous cell carcinoma
- Main histologic features:
- Epidermal hyperplasia with dysplasia without invasion through the basement membrane (infiltration of the dermis signifies SCC)
- Parakeratosis is in parallel layers in the dog (“stacked parakeratosis”)
- Proliferative dermal vessels with plump, “crowded” endothelium
- Dog – dermal inflammation is perivascular to lichenoid, may be accompanied by solar elastosis and laminar fibrosis; pigmentary incontinence may be present
- Cat – lichenoid dermatitis is generally not present; inflammation is mild and perivascular; may have more intense dermal inflammation with fibrosis
- Solar elastosis and fibrosis:
- Weibel-Palade bodies: Specific cytoplasmic marker for endothelial cells
ADDITIONAL DIAGNOSTIC TESTS:
- Immunohistochemistry: Neoplastic cells are positive for Factor VIII-related antigen (variable), vimentin, CD31(PECAM), type IV collagen and laminin; CD34 has the highest labeling intensity in neoplastic cells, but lacks specificity for hemagiosarcoma.
Lymphangioma, lymphangiosarcoma: Tumors of lymphatic endothelium; rare in all species
- Usually in subcutis along ventral midline and limbs; poorly demarcated dermal masses
- Neoplastic cells grow directly on bundles of dermal collagen, dissecting them and forming numerous clefts and channels devoid of erythrocytes
- Recurrence is common; metastasis is rare
- Stain with lymphatic vessel endothelial receptor-1 (LYVE-1), podoplanin, and vascular endothelial growth factors receptor-3 (VEGFR-3)
- Lymphangioma/sarcoma has been reported to be positive for Factor VIII-related antigen and CD31, so these stains will not necessarily help differentiate from hemangioma/sarcoma
- Pooly differentiated varieties are difficult to differentiate from hemangiosarcomas; sometimes just called angiosarcomas
- Generally well differentiated located n the dermis and subcutis
- Vascular structures dissect between collagen, adipocytes, and facial planes, creating ragged tumor margins
- Tumor cells may resemble HSA cells and bulge into the lumen of the vascular channel with pleomorphic, oval nuclei, and frequent mitotic figures
- When located on the caudal abdomen, may incorporate and infiltrate inguinal lymph nodes.
- The presence of pleomorphic lymphatic endothelial cells lining vascular channels, focal lack of endothelial cells, blindly ending trabeculae, and infiltrative growth, separates lymphangiosarcoma from lymphangiomatosis
- EM – lymphangiosarcomas have a discontinuous or absent basement membranes and numerous pinocytotic vesicles; HSAs have a continuous basement membrane
Feline ventral abdominal angiosarcoma
- Blood vessel or lymphatic origin: Controversial
- Rare; seen only in cat; distinctive lesion on caudoventral abdominal wall which oozes serum
- Diffuse bruised appearance: No distinct mass
- Subcutis: Neoplastic endothelial cells form clefts and channels which contain few erythrocytes; edema, hemorrhage
- Neoplastic cells are closely associated with collagen bundles
- Infiltrative; frequent recurrences; metastasis is rare
- EM - lack a basement membrane; consistently express CD31 and factor VIII if of blood vessel origin
Scrotal hamartoma: 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)
Angiomatosus: Secondary to lymphedema; there is marked hypoplasia of the deep lymphatic vessels with an increase in extracellular matrix and inflammation; prominent vascular proliferation (neovascularization) in clusters; on EM proliferating vascular structures have a continuous basement membrane
- IHC is needed to differentiate vascular from lymphatic proliferations; CD44 and podocalyxin (vascular endothelial cells) versus lymphatic vessel endothelial receptor-1 (LYVE-1), podoplanin, and vascular endothelial growth factors receptor-3 (VEGFR-3) (lymphatic endothelial cells).
- Equine: Very young horses; usually on distal limbs; can be congenital (AKA lobular capillary hemangioma or vascular nevus) may acquire a plaque-like, warty appearance and be termed a “verrucous hemangioma”
- Swine: Rare; when present, usually in scrotum of Yorkshire and Berkshire boars; can be congenital
- Equine and swine: Verrucous variant; less well-demarcated, multinodular, associated with epidermal hyperkeratosis
- Avian: Sporadic and of unknown etiology; subject to trauma and profuse bleeding at site of tumor; in chickens may be related to retroviral infection
- Cattle: occur in adult and older animals; congenital has been reported as well
Hemangiosarcomas: Reported less commonly in the cow (may be associated with bracken fern), horse, pig, goat, chicken and sheep
- Equine: Epithelioid hemangiosarcomas in ocular tissues (e.g. eyelid); primarily composed of large epithelioid cells with little or no histologic evidence of vascular origin; vimentin, CD31, factor VIII positive; cytokeratin negative
- Animal model: Canine hemangiosarcoma resembles human angiosarcoma; used as a model of primitive angiogenic endothelium
- Hemangiosarcoma one of the most common spontaneous tumors in RasH2 mice
- Peroxisomeproliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists (used in the treatment of type 2 diabetes mellitus and hyperlipidemias) induced hemangiomas and hemangiosarcomas in treated mice
Single case reports:
- Cheetah: Non-FeLV associated multicentric T-cell lymphoma and cutanous HSA
- Snake: Cardiac hemangiosarcoma
- Anwar S, Yanai T, Sakai H. Immunohistochemical detection of urokinase plasminogen activator and urokinase plasminogen activator receptor in canine vascular endothelial tumours. J Comp Pathol. 2015;153:278-282.
- Anwar S, Yanai T, Sakai H. Overexpression of peroxiredoxin 6 protects neoplastic cells against apoptosis in canine haemangiosarcoma. J Comp Pathol. 2016;155:29-39.
- Arenas-Gamboa AM, Mansell J. Epithelioid haemangiosarcoma in the ocular tissue of horses. J Comp Pathol. 2011;144:328-333.
- Cole PA. Association of canine splenic hemangiosarcomas and hematomas with nodular lymphoid hyperplasia or siderotic nodules. J Vet Diag Invest. 2012;24(7);759-762.
- Goldschmidt MH, Hendrick MJ. Tumors of the skin and soft tissues. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002: 99-101.
- Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog & Cat. 2nd ed. Ames, IA: Blackwell; 2005:148-15, 399-401, 741-753.
- Gruntzig K, Graf R, Boo G, et al. Swiss canine cancer registry 1955-2008: Occurrence of the most common tumour diagnoses and influence of age, breed, body size, sex and neutering status on tumour development. J Comp Pathol. 2016;155:156-170.
- Jennings RN, Miller MA, Ramos-Vara JA. Comparison of CD34, CD31, and factor VIII-related antigen immunohistochemical expression in feline vascular neoplasms and CD34 expression in feline nonvascular neoplasms. Vet Pathol. 2012;49(3);532-537.
- Kakiuchi-Kiyota S, Arnold LL, Yokohira M, Koza-Taylor P, Suzuki S, Varney M, Pennington KL, Cohen SM. Evaluation of direct and indirect effects of the PPARγ agonist troglitazone on mouse endothelial cell proliferation. Toxicol Pathol. 2011;39(7):1032-45
- Kakiuchi-Kiyota S, Crabbs A, Arnold LA, Pennington KL, Cook JC, Malarkey DE, Cohen SM. Evaluation of expression profiles of hematopoetic stem cell, endothelial cell, and myeloid cell antigens in spontaneous and chemically induce hemangiosarcomas and hemangiomas in mice. Toxicol Pathol. 2013;41;709-721.
- Lindemann DM, Carpenter JW, Nietfeld JC, Gonzalez E, Hallman M, Hause BM. Multicentric T-cell lymphoma and cutaneous hemangiosarcoma in a captive cheetah (Acinonyx jubatus). J Zoo Wildl Med. 2015;46(4):961-966.
- 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: 726-727.
- Muller G, Scott D, Miller W, Griffin C. Veterinary Dermatology. 6th ed. Philadelphia, PA: W.B. Saunders; 2001:1297-1301.
- Nambiar PR, Turnquist SE, Morton D. Spontaneous tumor incidence in rasH2 mice: review of internal data and published literature. Toxicol Pathol. 2012;40(4):614-23.
- Perez-Ecija A, Estepa JC, Barranco I, Rodriguez-Gomez IM, Mendoza FJ, Gomez-Laguna J. Verrucous hemangioma with pseudoepitheliomatous epidermal hyperplasia in an adult horse. Vet Pathol. 2014;51(5):992-995.
- Shoemaker M, Barrie M, Holman H, et al. Pathology in practice. J Am Vet Med Assoc. 2015; 248(2):153-155.