Introduction

Disorders associated with canine hypercalcemia, often discovered serendipitously during serum biochemical analysis, include paraneoplastic hypercalcemia (lymphoma, anal sac apocrine gland adenocarcinoma, and uncommonly, in association with malignancies of lung, mammary gland, nasal, pancreas, thymus, thyroid, ovarian, and testicular epithelial and melanocyte origin), renal failure (acute and chronic), hypoadrenocorticism, primary hyperparathyroidism, vitamin D toxicosis, or in association with some granulomatous inflammatory disorders (blastomycosis, histoplasmosis, or schistosomiasis). Hypercalcemia of malignancy (HCM) is one of the most commonly recognized systemic manifestations of cancer in veterinary medicine, most frequently associated with lymphoid neoplasia of T-lymphocyte immunophenotype, including multicentric, mediastinal, and polyostotic forms of lymphoma.^1,2 Recognition of HCM can aid in the search for metastatic disease beyond the primary tumor site, the assessment of the therapeutic response, and in monitoring for possible tumor reocurrence.^3–5 Leiomyoma is a common smooth-muscle neoplasm of both the human and canine female genital system. In women, tumors are most frequently located in the uterus, followed by the cervical, round, and inguinal ligament. Human vaginal leiomyoma is reported as rare with ∼300 cases reported.⁶ Leiomyoma is the most common tumor of the tubular genitalia of the bitch, involving the uterus, cervix, and vagina, and may be solitary or multiple.⁷ Cytomorphologic features, including pleomorphism, rate of mitoses, and presence/extent of invasiveness, are the criteria used to differentiate leiomyoma from malignant leiomyosarcoma.⁷ Humoral hypercalcemia of benignancy associated with human uterine leiomyoma as a consequence of tumor-produced parathyroid-hormone-related protein (PTHrP) is a well-described entity, with several published case reports.^8–13 A similar correlation between uterine or vaginal leiomyoma and hypercalcemia of benignancy in the dog has not been reported. There is a single published report of hypercalcemia in a canine patient with esophageal leiomyoma; however, it was not reported if this patient reverted to normocalcemic status after successful surgical removal of the tumor.¹⁴ In this case report, we describe a canine patient diagnosed with a vaginal mass and documented hypercalcemia. Histopathologic analysis of the tumor following resection identified a benign leiomyoma. The patient reverted to normocalcemic status following surgical removal of the neoplasm.

Case Report

An 8 yr old intact female Lhasa apso mixed-breed dog presented with a chief complaint of a perivulvar mass of >1 yr duration. The mass was described as “initially internal, but now was external,” and it was reported that the mass had grown significantly over the past year. The client also perceived the patient as drinking excessive amounts of water. Physical examination revealed a pedunculated and irregular mass in the left perivulvar region 8 cm in diameter, extending from the left labium and extending cranially and laterally. No significant anal sac lesions were identified on digital rectal examination. The patient had a body condition score of 5/9 and weighed 19.7 lbs. The differential diagnoses for the perivulvar mass lesion included benign or malignant neoplasia, granulomatous inflammation, benign cyst, and focal abscess. Complete blood count, serum chemistry, and urinalysis were performed. Significant findings included hypercalcemia (12.6 mg/dL, reference interval [RI] 8.4–11.8 mg/dL), hyperglycemia (120 mg/dL, RI 63–114 mg/dL), and hypophosphatemia (2.4 mg/dL, RI 2.5–6.1 mg/dL). All other parameters were within the RIs, including serum albumin (3.2 g/dL, RI 2.2–3.9 g/dL). A granulomatous inflammatory process was ruled out based on physical examination findings, clinical pathology, and survey radiography. Considerations for the hypercalcemia and hypophosphatemia included hypercalcemia of malignancy (paraneoplastic hypercalcemia) and primary hyperparathyroidism. Additional patient testing, including an assessment of ionized calcium, parathyroid-hormone, and PTHrP, was initiated, but was not completed because of sample transport and logistical complications. Repeat patient sampling and testing was subsequently recommended but was declined by the owner. Presurgical staging to include radiographic and ultrasonographic imaging and surgical excision of the mass (with histopathological analysis) with ovariohysterectomy was recommended but was delayed because of owner financial constraints. At a recheck examination performed 20 wk after the initial presentation, patient serum calcium and albumin levels revealed persistent hypercalcemia (14.2 mg/dL) and normalbuminemia (3.2 g/dL). Serum phosphorus was not rechecked at that time. No significant intrathoracic or intra-abdominal abnormalities were identified on survey thoracic and abdominal radiographs. An 8 cm mass lesion was identified on radiography, arising from the left distal vagina and extending cranially and laterally (Figure 1). Ultrasonographic evaluation was declined for financial reasons. The mass was surgically resected and ovariohysterectomy was performed at the time of the mass removal. Patient recovery was uneventful. The mass was fixed in formalin and submitted for histopathological evaluation, which identified a neoplasm composed of well-differentiated smooth muscle myocytes with a mitotic index of 3 mitotic figures per 10 high-power (400×) fields (Figure 2). Histologic features were consistent with a microscopic interpretation of benign leiomyoma. Two additional veterinary pathologists reviewed the biopsy and favored an interpretation of benign leiomyoma. Serum calcium was rechecked 2 wk after surgical excision of the mass, and the patient was found to be normocalcemic (9.5 mg/dL). The patient’s serum albumin and phosphorus levels were not reevaluated at that time. Immunohistochemistry was performed on the leiomyoma using antibodies directed against PTHrP^a. Occasional-to-moderate numbers of neoplastic smooth-muscle myocytes demonstrated positive cytoplasmic immunoreactivity, with areas of confluent cellular immunoreactivity, interspersed with regions of fewer, randomly distributed PTHrP-positive myocytes (Figure 3).

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Discussion

Paraneoplastic HCM is the most common cause of hypercalcemia in the companion dog, followed by hypoadrenocorticism, primary hyperparathyroidism, and chronic renal failure.¹⁵ Neoplasms implicated in hypercalcemia of malignancy include lymphoma (15% of all forms), apocrine gland (anal sac) adenocarcinoma, and multiple myeloma.^1–3 There are published case reports of hypercalcemia of malignancy associated with cases of canine malignant melanoma, canine ovarian papillary adenocarcinoma, canine renal cell carcinoma, and canine complex mammary carcinoma.^16–19 The etiology of HCM involves one or a combination of two mechanisms. The most common mechanism involves the production of systemically active humoral factors that disrupt normal calcium homeostasis. The second mechanism involves direct effects on bone either through primary or metastatic invasion and induction of mediators involved in bone resorption.³ In HCM, the most commonly involved mediator is PTHrP. In nontumor bearing dogs, PTHrP has been demonstrated in multiple tissues, including mammary and endocrine glands, muscle, bone, brain tissue, and epithelial cells. In normal physiologic levels, PTHrP exerts biologic activity on the kidneys, intestines, and bone matrix, increasing renal distal tubular calcium resorption and excretion of phosphorus, promoting intestinal calcium and phosphorus absorption, and activating bone cells, including increasing osteoclast-mediated resorption of bone. In HCM associated with anal sac apocrine gland carcinoma, supraphysiologic levels of PTHrP are associated with progrowth, survival, and metastatic effects on the tumor itself.^20,21 Hypercalcemia of benignancy similarly involves the production of PTHrP by a neoplastic cell population; however, by definition, the tumor itself is benign. Human hypercalcemia of benignancy is rare, although individual cases have been described in the published literature.²² In one study, among a total of 138 cases of PTHrP-mediated hypercalcemia, solid-organ malignancies made up 82.6% (n = 114) of cases, whereas hematological malignancies and benign neoplasms each accounted for 8.7% (n = 12).²³ Published case reports of human hypercalcemia of benignancy include several cases of hypercalcemia associated with primiparous and gravid uterine leiomyomas.^8–13 Published reports of hypercalcemia of benignancy in dogs are rare and include benign mixed-mammary tumors and a dog with a benign renal angiomyxoma.^24,25 A recent case report described hypercalcemia associated with a benign esophageal leiomyoma, which was surgically removed; the case report, however, does not indicate if the patient returned to normocalcemic status after the surgical excision.¹⁴ Previously published studies have used immunohistochemical techniques to demonstrate a relationship between neoplastic cell-positive PTHrP immunoreactivity and patient hypercalcemia in cases of canine benign and malignant mammary mixed-tumors and in cases of canine apocrine gland adenocarcinoma of the anal sac.^20,24

Conclusion

In this case, a dog with a benign vaginal leiomyoma was found to have hypercalcemia. Although true hypercalcemia (based on ionized calcium measurement) could not be confirmed for logistical reasons, the hypercalcemia was documented on two occasions based on total calcium levels. A subsequent workup failed to demonstrate a primary malignant neoplastic process, evidence of a primary parathyroid tumor, or evidence of granulomatous inflammatory disease. Surgical removal of the leiomyoma resulted in subsequent conversion of the patient to normocalcemic status. Ideally, demonstration of elevated serum ionized calcium and serum/plasma PTHrP would have been useful to support the diagnosis of hypercalcemia of benignancy, but unfortunately, such testing was not performed because of owner financial constraints and testing logistical and physical limitations. However, immunohistochemistry performed using antibodies directed against PTHrP on formalin-fixed, paraffin-embedded sections of the resected leiomyoma demonstrated occasional-to-moderate positive cytoplasmic immunoreactivity among the population of neoplastic smooth muscle myocytes. This demonstrated PTHrP-positive immunoreactivity in conjunction with the patient’s conversion to normocalcemic status following the surgical resection of this tumor support an interpretation of hypercalcemia of benignancy. Although uncommon, hypercalcemia of benignancy should be considered on the list of differential diagnoses in a patient in whom hypercalcemia is identified.