JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
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 commonly used to denote canine hyperadrenocorticism-associated dermal mineralization, commonly 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
• The overlying skin is usually freely movable
• May or may not have erythema, swelling, and secondary pyoderma

 

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
• Cartilagenous 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:

• Typical 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, and is found in context with the diagnostic features of these neoplasms
• Inflammatory lesions may have milder and 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
• 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
• Binturongs: Recent report describing severe hydroxyapatite deposition disease (synonymous with calcinosis circumscripta) causing mineralization of the footpads and tissues adjacent to multiple joints (Takehana, Vet Pathol, 2021)
• White rhinoceros: Calcinosis circumscripta has been reported in a white rhinoceros secondary to chronic trauma
• Birds: Unusual condition
• Primates: Associated with prior trauma and microchip implantation

 

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. Kumar V, Abbas AK, Aster JC. Cellular responses to stress and toxic insults: adaptation, injury and death. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015: 65-66.
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. 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, et all. Severe Hydroxyapatite Deposition Disease in Binturongs (Arctictis binturong). Vet Pathol. 2021: 58(6):1147-1151.
10. 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.

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