JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2019

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 multiple 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 10 HPFs. Multifocally vascular spaces are partially occluded by fibrin emboli and contain few aggregates of dark granular pigment (acid hematin, artifact). Multifocally there are low numbers of lymphocytes and plasma cells scattered throughout the neoplasm stroma and in the dermis surrounding compressed overlying adnexal structures. The superficial dermis contains increased numbers of small caliber blood vessels lined by hypertrophic endothelium (telangiectasia) and contains multifocal melanomacrophages (pigmentary incontinence). Apocrine glands and hair follicles are mildly ectatic and there is increased clear space and ectatic lymphatics within the superficial dermis (edema).

 

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 overlying focally ulcerated epidermis, and extending into the subcutis is an unencapsulated, infiltrative, densely cellular neoplasm composed of spindle cells forming variably sized blood-filled vascular channels or more solidly cellular areas arranged in short, haphazard streams and bundles separated by variable amounts of collagenous matrix. Neoplastic cells often bulge into the vascular channel lumens and often wrap collagen bundles. Neoplastic cells have indistinct borders, small to moderate amounts of eosinophilic fibrillar cytoplasm, and irregularly oval to elongate nuclei with finely stippled chromatin and one to two variably distinct nucleoli. There is moderate to marked anisocytosis, anisokaryosis, and scattered single-cell necrosis, and mitotic figures average up to 5 per 10 HPFs. Multifocally throughout the neoplasm there are variably sized areas of hemorrhage, fibrin, edema, and necrosis, and mild to mild numbers of scattered lymphocytes, plasma cells, neutrophils, and hemosiderin-laden macrophages. Adjacent to the neoplasm, the superficial dermal collagen is hypocellular and smudgy (solar fibrosis) with increased basophilia of wavy elastin fibers (solar elastosis). The overlying epithelium is multifocally hyperplastic with acanthosis, intercellular edema (spongiosis), and multifocal parakeratotic hyperkeratosis; there is focal erosion and ulceration with replacement with a serocellular crust. Within the superficial dermis there are low numbers of often perivascular lymphocytes, plasma cells, and few macrophages containing melanin (pigmentary incontinence) as well as ectatic lymph vessels (edema).

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Hemangiosarcoma, Heeler mix, 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 throughout the fibrovascular tissue is an unencapsulated, poorly circumscribed, densely cellular neoplasm composed of polygonal to spindloid cells arranged in indistinct nests, streams, solidly cellular sheets, occasionally wrapping collagen, and often forming variably sized vascular channels. Neoplastic cells are separated and supported by a fibrovascular matrix. Neoplastic cells have variably distinct cell borders, an abundant amount of eosinophilic to vacuolated cytoplasm that rarely contains a single erythrocyte, and a round to pleomorphic, vesiculate nucleus that often bulges into vascular lumens and has coarsely clumped chromatin and 1-3 prominent nucleoli. Anisocytosis and anisokaryosis are marked and there is frequent single cell necrosis. Mitotic figures average 3 per HPF and include bizarre mitoses. There are 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

      Hemangiomas are benign tumors of vascular endothelium

      Common in dogs; rare in other domestic animals

      Dog: No breed or sex predilection; average age is 10 yrs; dermal or subcutaneous tumors that occur in sparsely haired and lightly pigmented skin and often on sun exposed abdomen and flank areas; can arise on non-pigmented conjunctiva

      Equine: Common in horses less than 1 year of age; usually on distal limbs as nodular, cauliflower or plaque-like; can be congenital (AKA lobular capillary hemangioma or vascular nevus); may be too extensive for excision

 

Hemangiosarcoma (HSA)

·      Dogs:

·      Cutaneous (dermal) HSA: Less aggressive; lower metastatic potential

·      Variant: single case report of cutaneous epithelioid HSA (Bolfa Jour Vet Diagn Invest 2018); may display histologic and ultrastructural features similar to granular cell tumors (GCTs)

·      Subcutaneous HSA: Moderately aggressive, moderate metastatic potential; higher risk in whippets and other lightly pigmented thin-coated breeds

·      Conjunctival: 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

·      Visceral HSA (C-N02): Most common form; involves the spleen, liver, lungs and/or right atrium; highly aggressive; high metastatic potential, poor to grave prognosis; predisposed breeds include German shepherd dogs, golden retrievers, Bernese mountain dogs, boxers

·      Equine:

·      HSA is uncommon in horses

·      Conjunctival vascular tumors in horses are most often HSA; aggressive with local infiltration and distant metastasis

·      Epithelioid hemangiosarcomas are reported in ocular tissues (e.g. eyelid) and one case report in the kidney (Hughes Jour Vet Diagn Invest 2018); primarily composed of large epithelioid cells with little or no histologic evidence of vascular origin; vimentin, CD31, factor VIII positive; cytokeratin negative

 

PATHOGENESIS:

Hemangioma

      Occurrence in dermis of thinly haired lightly pigmented skin suggests chronic solar irradiation may be a factor; UV radiation can be both a tumor initiator and promoter

Hemangiosarcoma

      Dermal and conjunctival hemangiosarcomas may be due to chronic solar irradiation; increased risk in whippets and other short haired lightly pigmented breeds

      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 (Anwar Jour Comp Pathol 2016)

 

TYPICAL CLINICAL FINDINGS:

Hemangioma:

      Slow growth; complete excision is curative

      Trauma-induced bleeding may occur

 

Hemangiosarcoma (especially visceral)

      DIC may be associated (especially visceral HSA, 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:

Hemangioma

      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

Hemangiosarcoma

      Dermal or subcutaneous lesions: Usually single (unless solar induced), 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:

Hemangioma

      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

      +/- various solar induced changes (see below) olar elastosis, sunburn cells, laminar dermal fibrosis)

      Equine lobular capillary hemangioma – Multiple discrete dermal lobules of densely, haphazardly arranged small caliber vascular structures lined by plump endothelial cells with low mitotic rate

Hemangiosarcoma

·      Pleomorphic spindle cells (endothelial cells) that form irregular vascular clefts/channels and/or solid areas of closely packed pleomorphic spindle cells that may form only indistinct, small vascular channels

·      Nuclei of cells lining clefts may be prominent, bulging, pleomorphic, and hyperchromatic

·      Neoplastic cells often wrap hyalinized collagen bundles

·      Epithelioid variant: polygonal cells in densely packed sheets; vascular channels may not be evident

·      Mitotic figures are frequent; hemorrhage and necrosis occur commonly

·      Solar induced change may be an associated finding (see below)

Solar induced change

·      Acute solar induced change

·      “sunburn cells”: Individual or bands of apoptotic keratinocytes in the outer stratum spinosum; characteristic feature of acute solar damageapoptosis is likely p53-mediated;

·      Chronic solar-induced change

·      Dermal changes:

·      Solar elastosis: Reported in dogs, cats, sheep, and horses; hallmark of chronic UV exposure in humans but rare in animals; degeneration of superficial dermal with replacement by thick, wavy basophilic fibers of elastotic material

·      Solar fibrosis: Laminar alteration of collagen, begins superficially and extends deeply, replacing hair follicles (rare); pale, hypocellular, “smudgy” collagen

·      Solar dermatitis: 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

·      Telangiectasia: Proliferative dermal vessels with plump, “crowded” endothelium

·      Adnexal changes: comedones, cysts, apocrine gland ectasia

·      Epidermal changes: Actinic keratosis

·      Solar induced hyperplasic and dysplastic epidermal lesions that occur in dogs and cats and may progress to invasive squamous cell carcinoma

·      Develop in non-pigmented and lightly haired skin exposed to repetitively excessive UV light (e.g. sunbathers)

·      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”)

·      May be associated with hemangioma, hemangiosarcoma, or squamous cell carcinoma

·      The degree and type of lesions vary between species and individuals, e.g.:

·      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

 

ULTRASTRUCTURAL FINDINGS:

      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.

 

DIFFERENTIAL DIAGNOSIS:

·      Lymphangioma, lymphangiosarcoma: Tumors of lymphatic endothelium; rare in all species

      Usually in subcutis along ventral midline and limbs; poorly demarcated dermal masses that tend to ooze

      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 (D2-40), 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

      Lymphangiosarcoma:

      Pooly differentiated varieties are difficult to differentiate from hemangiosarcomas; sometimes just called angiosarcomas

      Generally well differentiated located in 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 lymphangiosarcoma

      Lymphatic origin (LYVE-1 positive staining)

      Rare; seen only in cat; distinctive lesion on caudoventral abdominal wall which oozes serum and has a diffuse bruised appearance with swollen abdominal skin (no distinct mass)

      Infiltrative; frequent recurrences; metastasis is rare

      EM - lack a basement membrane; consistently express CD31 and factor VIII if of blood vessel 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: Occurs most commonly in cattle and horses

      A vascular endothelial proliferative disorder; irregular capillaries in dermis and subcutis

      Bacillary angiomatosis caused by infection with Bartonella spp and Multisystemic progressive angiomatosis have both been described in the dog.

 

COMPARATIVE PATHOLOGY:

Hemangiomas

      Swine: Rare vascular abnormalities; when present, usually in scrotum of Yorkshire and Berkshire boars; may be congenital hamartomas

      Cattle: occur in adult and older animals; congenital has been reported as well

Hemangiosarcomas:

      Cats: Rare in cats; cutaneous and subcutaneous more common than visceral or oral; common sites include white haired areas most often involving the head or 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.

      Also reported less commonly in the cow, pig, goat, chicken, and sheep

 

REFERENCES:

1.    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.

2.    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.

3.    Brockus CW. Erythrocytes. In: Latimer KS, ed. Duncan & Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Oxford, UK: Wiley-Blackwell; 2011:19-21.

4.    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.

5.    Hargis AM, Myers, S. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2016:1044, 1063, 1110.

6.    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.

7.    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.

8.    Nóbrega DF, Sehaber VF, Madureira R, et al. Canine Cutaneous Haemangiosarcoma: Biomarkers and Survival. J Comp Pathol. 2019 Jan;166:87-96.

9.    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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