Pathology in Practice

Michelle C. Woodward Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Ingeborg M. Langohr Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Elizabeth Bamberger Public Utility District No. 1 of Douglas County, 1151 Valley Mall Pkwy, East Wenatchee, WA 98802.

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Aubrey L. Hirsch Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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History

A 6-year-old 29-kg (63.8-lb) spayed female Boxer had a 6-month history of immune-mediated hemolytic anemia that was initially managed with oral administration of prednisone (1.7 mg/kg [0.77 mg/lb], q 12 h) and mycophenolate (8.6 m/kg [3.9 mg/lb], q 12 h). Owing to a lack of response, cyclosporine (3.4 mg/kg [1.5 mg/lb], PO, q 12 h) was added to the treatment regimen after 1 month. After 3.5 months of treatment, the dog continued to receive mycophenolate and cyclosporine, and the prednisone dosage was tapered until the dosage was 1.1 mg/kg (0.5 mg/lb), every 24 hours. Approximately 4 months after starting treatment, the dog developed erythematous to yellow to white papules coalescing into plaques in the inguinal region. These lesions were firm and sparsely eroded. At this time, prednisone administration was tapered and discontinued and application of dimethyl sulfoxide daily to the lesions was instituted. Two months later, the dog was referred to a dermatologist for evaluation of multiple new, firm intradermal and subcutaneous masses.

Clinical and Gross Findings

At the dermatologic consultation evaluation, the dog was bright, alert, and responsive; heart rate, respiratory rate, and rectal temperature were within reference limits. A static grade 3/6 heart murmur was detected via cardiac auscultation. Multiple hard, well-circumscribed, individual to irregularly lobulated subcutaneous to intradermal masses were evident throughout the body, including (but not limited to) tissue over both anconeal processes, the ventral aspect of the thorax, and both scapulae (Figure 1). These masses were variable in maximum length (1.5 to 5 cm) and depth (0.5 to 3 cm). On palpation, several masses appeared to be attached to underlying tissue and were not movable. Firm, haired (approx 0.5 × 2 × 4-cm) plaques were noted bilaterally over the ischiatic tuberosities. The inguinal region was alopecic and had multifocal erythematous to hyperpigmented, firm, raised plaques with areas of erosion. There was also an area of thin hair with firm papules along the dorsal midline at the level of the pelvic limbs.

Figure 1—
Figure 1—

Photograph of a 2.5 × 5-cm irregular hard mass located over the right scapula in a 6-year-old Boxer that had a 6-month history of glucocorticoid treatment for immune-mediated hemolytic anemia. The mass was irregularly lobulated and mildly alopecic in focal areas; it could not be separated from underlying tissue or muscle when manipulated. The shape and size of the mass could not be altered, even with considerable digital pressure. Multiple similar masses were distributed in a bilaterally symmetric pattern throughout the dog's skin.

Citation: Journal of the American Veterinary Medical Association 253, 9; 10.2460/javma.253.9.1125

Punch biopsy samples were collected from lesions on the caudal aspect of the left thigh, dorsal midline, inguinal region, and left shoulder region for histologic examination. Full-thickness samples were not obtained from all affected locations. The biopsy samples from the shoulder and caudal left thigh regions were difficult to obtain, requiring considerable force to penetrate the tissue with the biopsy instrument. At these sites, following removal of the biopsy sample core, the remaining surrounding tissue was hard and pale pink to white and did not move to fill the empty space created by sample removal.

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page

Histopathologic Findings

Sections from all 4 biopsy sites contained deep dermal and subcutaneous islands of immature woven bone surrounded by variably thick bands of fibrous connective tissue, separating and compressing epidermal adnexa (osteoma cutis). The islands of ectopic bone had smooth margins lined by a single layer of osteoblasts and occasional hyaline cartilage, with 1 or 2 chondrocytes/lacuna delimited by homogeneous basophilic extracellular matrix (Figure 2). Within the biopsy sample from the inguinal region and to a lesser extent within the biopsy sample from the dorsal midline, there were also scattered deeply basophilic fragmented mineral deposits in the superficial to mid-dermis (calcinosis cutis). These deposits appeared to be primarily within follicular infundibula and were in part surrounded by fibroblasts, epithelioid macrophages, multinucleate giant cells, and neutrophils (Figure 3). In the remaining dermis, scattered perivascular and periadnexal plasma cells and lymphocytes were evident, as were few neutrophils and mast cells. There was also mild to moderate follicular and epidermal epithelial hyperplasia, characterized by acanthosis and orthokeratotic hyperkeratosis.

Figure 2—
Figure 2—

Photomicrographs of a section of the skin biopsy sample obtained from one of the hard masses over the ischiatic tuberosities of the dog in Figure 1. A—The deep dermis is expanded by a well-demarcated, large area of ossification encircled by fibrosis (arrows). The overlying haired skin is unremarkable. H&E stain; bar = 2 mm. B—Higher-magnification view of the area of deep dermal ossification in panel A. It is lined in part by osteoblasts (arrows) and in part by hyaline cartilage (asterisks). H&E stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 253, 9; 10.2460/javma.253.9.1125

Figure 3—
Figure 3—

Photomicrographs of a section of the skin biopsy sample obtained from the hyperpigmented, firm, raised plaques in the inguinal region of the dog in Figure 1. A—The dermis is obscured by marked fibrosis and focal superficial deposition of dark purple, partially fragmented mineral (asterisk). Several small, discrete islands of bone (osteoma cutis) are deeper within the dermis (arrows). The overlying epidermis is moderately acanthotic. H&E stain; bar = 2 mm. B—Higher-magnification view of the area of mineralization in panel A. It is lined in part by evident inflammation (asterisks) and appears to be within a disrupted follicular infundibulum (arrows), an unusual and likely late-stage alteration of calcinosis cutis. H&E stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 253, 9; 10.2460/javma.253.9.1125

Additional Findings

Thoracic radiography, performed subsequent to histologic examination of the biopsy samples, revealed multifocal, irregularly marginated, small mineral opacities within the superficial soft tissues of the dorsum, ventrum, and thoracic limbs (consistent with the gross physical findings in the skin). Multifocal, well-defined, variably sized, pinpoint mineral opacities in all lung lobes were identified (unchanged from previous radiographic findings 6 months prior). There was an ill-defined, small, round (0.5-cm-diameter) nodule with soft tissue appearance in the right caudodorsal lung field. Results of recheck thoracic radiography 2 months later were similar. Blood ionized calcium concentration was 5.6 mg/dL (reference range, 5.0 to 6.5 mg/dL).

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: multifocal osteoma cutis and calcinosis cutis in haired skin and subcutis of a dog.

Comments

Osteoma cutis, namely heterotopic ossification of the dermal or subcutaneous tissues, is rarely diagnosed in human and veterinary medicine. It is classified as primary or secondary on the basis of the underlying pathogenesis of bone formation. Primary osteoma cutis develops without evidence of underlying trauma or disease. In humans, primary ossification is rare, but some well-described syndromes include fibrodysplasia ossificans progressiva, Albright hereditary osteodystrophy, progressive osseous heteroplasia, and plate-like osteoma cutis.1 These syndromes are associated with genetic inheritance in humans. In contrast, secondary osteoma cutis develops in damaged skin and is often associated with underlying inflammatory disease, neoplasia, or tissue trauma. Secondary osteoma cutis has been more commonly reported in the veterinary medical literature,2–4 with primary osteoma cutis rarely described for dogs and reptiles.5,6 In the case described in the present report, lesions were located in areas associated with chronic rubbing or wear in recumbent or sitting dogs. The dog had received long-term treatment with a glucocorticoid, which is consistent with other reported cases of secondary osteoma cutis in dogs.2,3

There are various causes of calcium salt deposition in the skin, including dystrophic, metastatic, iatrogenic, and idiopathic calcification. Dystrophic calcification occurs in the face of normal serum calcium and phosphate concentrations and is localized to areas of tissue damage.7 Most cases of calcinosis cutis in veterinary medicine are classified as dystrophic.7,8 Metastatic calcification is the deposition of calcium salts in otherwise normal tissue and is rare in veterinary medicine.8 It is associated with hypercalcemia, hyperphosphatemia, or both.7 In the case described in the present report, the dog's circulating ionized calcium concentration was within reference range, supporting dystrophic calcification. Iatrogenic calcification is rarely reported, but is associated with skin exposure to calcium-containing compounds such as calcium chloride deicing products9 or landscaping products.10

Calcinosis cutis is the general term for the deposition of calcium salts in the dermis, epidermis, or subutis.8 It is uncommon in dogs but is often associated with long-term glucocorticoid administration or naturally occurring hyperadrenocorticism and is considered a form of dystrophic calcification.7,8 The pathogenesis of this process is not understood.8 In cases of calcinosis cutis associated with glucocorticoid treatment, lesions typically regress after discontinuation of drug administration (although this may take months).8 Osteoma cutis, although rare, often develops in dogs in conjunction with calcinosis cutis and may be a progressive form of calcinosis cutis.4,8 In the dog of the present report, the lesions in the inguinal region were most consistent with calcinosis cutis and developed approximately 2 to 3 months prior to biopsy. The hard masses (osteoma cutis) were initially noted near the time of prednisone treatment cessation. Lesions did not continue to worsen after diagnosis, and no new lesions had developed 16 months after diagnosis.

There is little information available in the veterinary medical literature regarding the treatment of osteoma cutis. Surgical removal of primary osteoma cutis lesions may be curative with no recurrence.5,6 The same treatment could be applied to cases of secondary osteoma cutis; however, if the underlying cause is not addressed, additional lesions can potentially develop. In humans, superficial lesions (miliary osteoma cutis) have been reported to improve with administration of retinoids.11,12 Unfortunately, such treatment is topical and was unlikely to have helped improve the large, thick masses in the dog of the present report. Initial evidence suggests that treatment with bisphosphonates does not resolve existing bone formation but may decrease the development of new lesions.13 There is no published information regarding the use of either bisphosphonates or retinoids for treatment of osteoma cutis in veterinary patients, to our knowledge. Topical application of dimethyl sulfoxide may hasten the resolution of calcinosis cutis,14 but primary treatment should address the underlying cause if possible. The lesions that were most consistent with calcinosis cutis (erythematous, crusted papules and plaques in the inguinal region) in the dog of the present report were treated with dimethyl sulfoxide topically once daily. Surgical removal of osteoma cutis masses was declined by the owner because the patient was doing well clinically.

Acknowledgments

The authors thank Dr. Amy Grooters for photographic assistance.

References

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