Multifocal osteoma cutis in a golden retriever

Abstract

Résumé

A 10-year-old, spayed female, obese golden retriever was presented to the Veterinary Teaching Hospital at the Ontario Veterinary College for a history of an acute onset of thrombocytopenia. After ruling out underlying infectious or neoplastic disease, the patient was diagnosed presumptively with immune-mediated thrombocytopenia. Treatment with vincristine (Vincristine Sulfate; Mayne Pharma [Canada], Montreal, Quebec), 0.02 mg/kg bodyweight (BW), IV, once, and prednisone (Apo-Prednisone; Apotex, Toronto, Ontario), 2 mg/kg BW, PO, q24h on a tapering dose, was initiated. At a reevaluation 2 wk later, the thrombocytopenia had resolved. However, the patient exhibited clinical and biochemical evidence of iatrogenic hyperglucocorticoidism, including muscle wasting and weakness, severe polyuria, polydypsia, polyphagia, and panting, as well as markedly elevated alkaline phosphatase (AP) (16390 U/L; reference range, 22 to 143U/L), gamma-glutamytransferase (191 U/L; reference range, 0 to 7 U/L), and alanine aminotransferase (ALT) (513 U/L; reference range, 19 to 107 U/L). Additionally, the patient was reported to have decreased energy and to spend the majority of the day sleeping. Reduction of the prednisone dose to 1 mg/kg BW, PO, q24 h led to significant improvement in the clinical signs. The dose of prednisone was subsequently reduced gradually, allowing discontinuation of all therapy 10 wk later.

The patient was presented again 6 mo after the original diagnosis, at which time physical examination revealed dermatologic lesions, including excessive shedding of the hair; generalized mild scaling of the skin; a firm mass in the upper lip at the site of a documented previous laceration; and multiple, firm, well-circumscribed, plaque-like cutaneous masses over bony prominences subject to trauma when the dog was recumbent (“pressure points”). The largest masses were located bilaterally over the elbows; however, masses were also present over the stifle, tuber calcanei, ischiatic tuberosity, and anconeal process, bilaterally. Popliteal lymph nodes were slightly firm, bilaterally.

Values on a complete blood cell count were within normal limits. A serum biochemical profile revealed a mild elevation in urea (11.7 mmol/L; reference range, 3.5 to 9.0 mmol/L), as well as mild elevations in AP (212 U/L) and ALT (341 U/L). The elevated AP and ALT activities were suspected to reflect a residual mild hepatopathy due to the corticosteroid treatment. Differential diagnoses considered for the elevated urea included a high protein diet, early renal insufficiency, or mild gastrointestinal hemorrhage. A fecal occult blood test was negative. Urine specific gravity was 1.013, which may have reflected normal daily variation with water intake, polyuria, or early renal insufficiency. Results for a thyroid panel consisting of a total thyroxine (T4) and thyroid stimulating hormone (TSH) were within normal limits. An abdominal ultrasonograph revealed a diffusely hyperechoic liver, consistent with hepatopathy, and normal appearing adrenal glands and abdominal lymph nodes. Fine needle aspirates of the popliteal lymph nodes revealed a reactive left lymph node with eosinophilic inflammation, and a reactive right lymph node with eosinophilic and mild plasma cell hyperplasia, attributable to mild skin inflammation. Thoracic radiographs provided no evidence of metastasis. Radiographs of the right hindlimb and left forelimb revealed superficial, irregularly shaped, poorly demarcated, masses with the opacity of mineral over the lateral aspect of the stifle and lateral aspect of the elbow. The masses did not appear to involve the adjacent joints or bony structures. Histologic examination of full-thickness skin biopsies of lesions over the right and left scapulae and left stifle revealed well-circumscribed nodules of differentiated cortical bone within the deep dermis, surrounded by mature fibrous connective tissue. Calcium deposition was not identified along collagen fibers. The superficial dermis exhibited evidence of edema and eosinophilic inflammation. The histologic diagnosis was multifocal osseous metaplasia (osteoma cutis) of the deep dermis. Although the lesion in the upper lip was not sampled grossly, it was similar to the areas evaluated, so it was suspected to represent an additional osteoma cutis lesion. Although the history would support a diagnosis of calcinosis cutis, the absence of dystrophic mineralization of collagen fibers and the presence of mature fibrous connective tissue surrounding the multiple foci of cortical bone were most consistent with osteoma cutis, which has been described most extensively in the human literature.

Osteoma cutis is defined as the formation of bone in dermal or subcutaneous tissues and is usually classified as primary or secondary. Primary osteoma cutis occurs in normal skin with no evidence of underlying lesions, whereas secondary osteoma cutis occurs in damaged or disrupted skin, like that which occurs in humans with inflammatory disorders, such as acne vulgaris or solitary morphea profunda, or certain forms of neoplasia, like basal cell carcinoma (1,2). Primary and secondary forms may be further characterized, based on their distribution, into solitary or miliary osteoma cutis (2).

In the human literature, cutaneous ossification is uncommonly reported; a review of 20 000 skin biopsies by Burgdorf and Nasemann (1) yielded only 35 cases in which osteoma cutis lesions were identified. In veterinary medicine, osteoma cutis is extremely rare, although foci of osseous metaplasia have been reported in association with chronic calcinosis cutis and in lesions of calcinosis circumscripta (3). Frazier et al (4) have described 2 cases of osteoma cutis in large breed dogs with chronic skin disease and iatrogenic hyperglucocorticism. Similarities noted between the current case and those reported by Frazier et al (4) include markedly elevated AP activity, a history of iatrogenic hyperglucocorticoidism, and histologic ossification of the dermis. However, the previously reported cases differ in the lesion distribution and severity of preexisting skin disease. Specifically, both dogs in the prior report were presented with a lesion distribution more suggestive of calcinosis cutis. In addition, 1 dog had significant mixed inflammatory infiltrate, and the other dog exhibited mineralization of collagen and an inflammatory infiltrate, in addition to areas of dermal osseous metaplasia. Collagen mineralization and a significant perilesional inflammatory component were notably absent in the current case. To the authors’ knowledge, there have been no previous reports in the veterinary literature of multifocal osseous metaplasia over pressure points, as is described herein.

The pathogenesis of extraskeletal ossification has not been well elucidated. There are 2 proposed mechanisms for formation of lesions of osteoma cutis: 1) A disordered embryologic process in which normal mesenchymal cells that are destined to differentiate into osteoblasts are present in the wrong location (hamartoma); and 2), a metaplastic process, in which normal extraskeletal mesenchymal cells are stimulated to become osteoblasts by external factors (1,5,6).

Davis et al (2) have proposed that primary osteoma cutis may be mediated by regulatory factors similar to those involved in the formation of normal bone, including G (guanine nucleotide regulatory) proteins, c-fos oncogene, and bone morphogenic proteins (BMPs) and their receptors. If so, mutations or genetic alterations within genes regulating expression of these factors may predispose to ectopic bone proliferation, which subsequently can be triggered by trauma or other initiating stimuli. In human patients with primary osteoma cutis, formation of lesions at areas of known trauma or surgical intervention has been well described (2). In addition, extra osseous implantation of BMP has been reported to stimulate the formation of new bone in murine soft tissues (7). Normal bone production is also dependent on specific growth factors, many of which may be produced by inflammatory cells in the dermis. One of these factors, transforming growth factor B (TGF-B), has been identified in osteoblasts within osteoma cutis lesions in the skin of human patients (8).

High levels of AP activity, an enzyme produced by osteoblasts, have also been reported in lesions of osteoma cutis (5,8). It has been suggested that lesions of osteoma cutis do not expand outward from the edges, but progress via a high rate of internal remodeling, with bone resorption by AP as a key component of this process (9). In the case described in this report, dramatic induction of serum AP was demonstrated in association with corticosteroid administration; however, skin AP activity was never investigated.

Treatment options for osteoma cutis are quite limited. If an underlying disease, such as inflammation or neoplasia, can be identified, it should be specifically addressed. However, the ossified lesions are often permanent, and surgical excision is the treatment of choice (5). Other described therapies include administration of bisphosphonates (5,9), which inhibit bone resorption and therefore theoretically reduce progression of the lesion via remodeling; this therapy has shown minimal success in human patients. Other therapies that have been investigated, with varied success, include laser ablation, tretinoin gel, and curettage (2,10).

The patient described in this report represents a novel presentation of multifocal lesions of cutaneous ossification, suspected to represent secondary osteoma cutis with a multifactorial etiology. Microtrauma at pressure points due to obesity, underlying mild skin inflammation, and prolonged recumbence due to muscle weakness and obesity may have contributed to the dramatic lesions noted. A multifactorial etiology is supported by the paucity of reported cases of osteoma cutis in veterinary medicine despite widespread, high dose, long-term corticosteroid use. Due to the extent of the lesions, surgical excision was impractical in this patient. At this time, symptomatic therapy, including soft padded bedding and monitoring for growth and discomfort of the lesions has been elected, and corticosteroid use will be avoided in the future. CVJ

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