JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2025

I-M13

Signalment (JPC #2020707): Dog

HISTORY: None

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis, footpad: Extensively expanding the dermis and subcutis, widely separating and compressing adjacent adnexa, and elevating the overlying moderately hyperplastic epidermis are multiple, up to 2 mm diameter, granulomas composed of central deposits of basophilic, granular to fragmented crystalline material (mineral) admixed with few erythrocytes, foamy macrophages, lymphocytes, and rare neutrophils. Mineral deposits are surrounded by epithelioid macrophages, multinucleated giant cells, fibroblasts, and few lymphocytes and plasma cells. Granulomas are separated by dense fibrous connective tissue and hypertrophied fibroblasts (fibrosis). There are increased numbers of small caliber blood vessels throughout the superficial dermis (neovascularization). Multifocally within the dermis are low numbers of periadnexal and perivascular lymphocytes, plasma cells, and mast cells. Apocrine glands and dermal lymphatics are mildly ectatic and there is increased clear space in the superficial dermis (edema). The epidermis is mildly hyperplastic, with acanthosis and rete pegs with intercellular edema (spongiosis). There is moderate diffuse epidermal and multifocal follicular orthokeratotic hyperkeratosis.

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis, footpad: Granulomas, calcareous, multiple, with epidermal hyperplasia and orthokeratotic hyperkeratosis, breed unspecified, canine.

CONDITION: Calcinosis circumscripta

SYNONYMS: Tumoral calcinosis

GENERAL DISCUSSION:

• Pathologic calcification occurs in two forms:
  • Dystrophic: Occurs in normocalcemic animals, often in areas of necrosis
  • Metastatic: Occurs in hypercalcemic animals with a predilection for tissues that have an internal alkaline compartment (gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins)
    • Associated with Vitamin D toxicity, hypercalcemia of malignancy, primary hyperparathyroidism, uremia
    • Occurs when calcium-phosphate solubility product P >60
• Calcinosis cutis is a general term for deposition of calcium and phosphate ions in the dermis, epidermis, and subcutis and refers to all forms of cutaneous dystrophic and metastatic calcification, regardless of the cause (metabolic, traumatic, or unknown)
  • This term is most used to denote canine hyperadrenocorticism-associated dermal mineralization, also seen with iatrogenic hyperglucocorticoidism
  • Calcinosis universalis: Widespread areas of calcinosis cutis
• Calcinosis circumscripta is a subgroup of calcinosis cutis referring to tumor-like deep dermal and subcutaneous nodules of deposited calcium salts
  • Occurs most frequently in young (< 2 years), rapidly growing, large breed dogs (especially German shepherds) and in brachycephalic dogs (boxers, Boston terriers)
  • Most often occurs at sites of previous trauma (bite wounds, ear crops), over bony prominences and pressure points (footpad), within paravertebral soft tissue, and in the tongue; also associated with choke collars and sites of subcutaneous injections, progestational compounds, and polydioxanone sutures (PDS)
    • Calcinosis circumscripta of the footpad is strongly associated with renal failure

PATHOGENESIS:

• The cause of calcinosis circumscripta is unknown but is most likely dystrophic
• Mechanism of dystrophic calcification: Initiation occurs with accumulation of calcium in mitochondria or in association with extracellular phospholipid vesicles of degenerate and necrotic cells > phosphate groups bind calcium > microcrystals occur with rearrangement of calcium and phosphate groups > propagation of microcrystal formation
• Tongue lesions may be due to degeneration of heterotopic salivary glands

TYPICAL GROSS FINDINGS:

• Usually solitary, firm to fluctuant, well-circumscribed, domed, subcutaneous nodules over pressure points, sites of previous injury, or tongue (young, large breed males); larger lesions may be ulcerated
• Gritty, chalky, or pasty material may extrude from ulcerated lesions
• Overlying skin is usually freely movable; +/- erythema, swelling, and secondary pyoderma
• May occur anywhere; common sites are over dorsal cervical region, groin, and axillae
• Metastatic mineralization more common on paw pads

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Large, irregular, coalescing lakes of basophilic mineral surrounded by zones of epithelioid macrophages and multinucleate giant cells admixed with lymphocytes, plasma cells, and neutrophils and separated by fibrosis (i.e. granulomas)
• The epidermis or mucosa is often hyperplastic or ulcerated
• Extrusion of mineral through the epidermis in chronic lesions
• Cartilaginous and/or osseous metaplasia may occur

ADDITIONAL DIAGNOSTIC TESTS:

• von Kossa stains mineral blue
• Alizarin Red stains calcium bright red
• Mineralized material is usually strongly PAS- and Alcian blue-positive
• Cytologically, aspirates contain variable numbers of inflammatory cells including macrophages, neutrophils, and multinucleated giant cells with numerous clear, refractile crystals

DIFFERENTIAL DIAGNOSIS:

For histologic findings:

• Calcinosis circumscripta is histologically distinctive
• Pseudogout: Rare; deposition of calcium pyrophosphate dihydrate in periarticular tissues of old dogs; requires mineral analysis to differentiate
• Follicular neoplasms: Mineralization is common in pilomatricomas and rare in trichoepitheliomas
• Inflammatory lesions may have mild, less organized dystrophic mineralization

Other Forms of Cutaneous Calcification:

• Dystrophic calcinosis cutis:
  • Widespread calcinosis cutis: Associated with canine hyperadrenocorticism (hyperglucocorticism) most commonly occurring on the dorsum, axillae, and groin; lesions are frequently ulcerated papules and plaques composed of variably mineralized dermal collagen and basement membrane surrounded by granulomatous inflammation and with extrusion of mineral through the epidermis or into hair follicles
  • Direct absorption of calcium salts from calcium chloride-containing landscaping products; usually occurs on ventrum
  • Dermal perifollicular mineralization: Older toy poodles
  • Cutaneous mineralization secondary to severe chronic inflammation: Foreign body reaction, otitis externa, interdigital pyoderma, demodicosis, or neoplasia
• Metastatic calcinosis cutis: Rare; in the dog and cat always associated with chronic renal failure and occurs in footpads and interdigital skin – secondary HADD
  • Hydroxyapatite deposition disease (HADD) in humans is synonymous with calcinosis circumscripta – HADD is often primary, presenting in the young as an inherited autosomal recessive condition with failed renal excretion of phosphorus and excessive vitD synthesis = hydroxyapatite deposition in major joints (a form of metastatic mineralization) (Takehana, Vet Pathol., 2021).
• Idiopathic calcinosis cutis: Widespread cutaneous mineralization in young dogs (<1 year) that spontaneously regresses; reported in bulldogs, Doberman pinschers, dachshunds, Labrador retrievers, and Rottweilers

COMPARATIVE PATHOLOGY:

• Horse: Occurs most often near joints in young horses (1.5-4 years), often over the lateral stifle and is occasionally bilateral and usually asymptomatic; 50% cases reported are Standardbred
• Cat: Rare; recent report of oral calcinosis circumscripta associated with a wasp sting (Santos, J Comp Path, 2022)
• Tadpole: Calcinosis circumscripta due to endocrine disrupting chemicals and/or cholecalciferol containing plants has been described
• Frogs: the Eberth-Kastschenko (EK) layer is a deposition of calcium phosphate, proteoglycans, and glycoaminoglycans sudjacent to the epidermis in the dermis that shouldn’t be mistaken for dystrophic mineralization
• White rhinoceros: Calcinosis circumscripta has been reported in a white rhinoceros secondary to chronic trauma
• Birds: Uncommon; classic presentation
• Primates: Associated with prior trauma and microchip implantation (foreign body)
• Binturongs: Hydroxyapatite deposition disease (HADD) - One paper discussed a possible primary familial condition or a secondary to diet or renal causes (Takehana, Vet Pathol., 2021).

References:

1. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018:443.
2. 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; 2020:100.
3. Kramer JA, Bielitzki J. Integumentary system diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. London, UK: Academic Press; 2012:579.
4. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. Vol 1. St. Louis, MO: Elsevier; 2016: 562-564.
5. Pessier, AP. Amphibia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018:923.
6. Raskin RE, Meyer DJ, Boes KM. Skin and subcutaneous tissues. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023 86-87.
7. Santos, BBN, Pires APC, Tondo, LAS, et al. Oral Calcinosis Circumscripta Associated with Wasp (Hymenoptera vespidae) Sting in a Cat. J Comp Pathol. 2022; 196:16-20.
8. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Avian Birds. Ames, IA: John Wiley & Sons, Inc; 2015:253.
9. Takehana K, Moresco A, Johnson JG 3rd, Kasahara M, Kasahara N, Han S. Severe Hydroxyapatite Deposition Disease in Binturongs (Arctictis binturong). Vet Pathol. 2021;58(6):1147-1151.
10. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1134, 1251-1252.

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