Hypercalcemia of Malignancy in a Cat With Bronchogenic Adenocarcinoma

Case Report

A 16-year-old, neutered male, domestic shorthaired cat was presented with a 2-week history of progressive lethargy and decreased appetite. On initial evaluation, the cat was estimated to be 5% dehydrated with a decrease in skin turgor and a body condition score of 6/9. The remainder of the physical examination was within normal limits.

Serum biochemical analysis revealed an amylase of 1154 U/L (reference range 300 to 1100 U/L), a blood urea nitrogen (BUN) of 34 mg/dL (reference range 10 to 30 mg/dL), and a creatinine of 1.5 mg/dL (reference range 0.3 to 2.1 mg/dL). A decreased platelet estimate of 168 × 10³/μL (reference range 200 to 500 × 10³/μL) and a lymphopenia of 1 × 10³/μL (reference range 1.8 to 7 × 10³/μL) were apparent on a complete blood count. Additional testing revealed a hypercalcemia with a total calcium of 13 mg/dL (reference range 8 to 11.8 mg/dL) and an ionized calcium of 1.73 mmol/L (reference range 1.16 to 1.34 mmol/L). Parathyroid hormone (PTH) was normal at <5 pg/mL (reference range 0 to 36 pg/mL). Serum thyroxine was also within normal limits. Parathyroid hormone-related protein (PTH-rp) levels were not obtained during initial evaluation because of inappropriate sample submission.

Thoracic radiographs showed an irregularly marginated soft-tissue and gas opacity mass seen in the left caudal lung lobe, with irregularly thickened wall margins. A mild bronchial pattern was also seen that was consistent with aging. The heart and pulmonary vasculature were unremarkable. Thoracic computed tomography (CT) was performed the following day. After the cat was sedated and following a bolus intravenous (IV) administration of 400 mg iodine/lb (MD-76),^a 3-mm contiguous slices of the thorax were obtained in a spiral fashion. An irregularly marginated cavitary mass measuring 2 cm in diameter was identified in the left caudal lung field. The mass had patchy, nonuniform contrast enhancement. No evidence of pulmonary metastatic neoplasia or thoracic lymph-node enlargement was noted. On the edge of the CT scan, an irregularly marginated, lucent, 2.17-cm mass was seen in the right cranial dorsal liver, near the dorsal aspect of the gallbladder. Ultrasound examination of this region was performed, and an ultrasound-guided, fine-needle aspirate of a slightly hypoechoic, 2-cm mass lesion was obtained. Cytological evaluation of this liver mass was most consistent with nodular hyperplasia, and no evidence of neoplasia was seen.

Because of the radiology findings of a pulmonary mass as well as laboratory findings of hypercalcemia, the most likely differential diagnosis was a primary pulmonary malignant neoplasm. Surgical excision and biopsy were recommended; however, the owner chose to delay surgical excision of the pulmonary mass by 18 days. To medically treat the hypercalcemia during this time, a single, 1.5-mg/kg dose of pamidronate disodium^b was given IV over 3 hours prior to discharge. The cat’s ionized calcium concentration 2 days before surgery (16 days after pamidronate administration) was 1.39 mmol/L (reference range 1.2 to 1.32 mmol/L).

A thoracotomy was performed at the left fifth intercostal space. A single, 2-cm, raised, white mass was observed on the left caudal lung lobe. The tracheobronchial lymph nodes were within normal limits. The left caudal lung lobe’s associated vessels and bronchus were ligated, and the lobe was excised. The cat recovered routinely. Histopathology demonstrated a broad, irregularly expanding, and infiltrative multilobar mass consistent with papillary adenocarcinoma of a bronchoalveolar cell origin.

Postoperative serum calcium levels were measured 68 days after pamidronate treatment to obtain values unaltered by the action of pamidronate. The ionized calcium was 1.3 mmol/L, total calcium was 9.7 mg/dL, PTH was 10.3 pg/mL, and BUN was 27 mg/dL. Postoperative PTH-rp was 0 pmol/L. Given the histopathological evaluation of the excised mass and the normalization of calcium after lung mass resection, a diagnosis of hypercalcemia caused by bronchogenic adenocarcinoma was made. Six months after surgery, at the time of this writing, the cat continued to thrive with no signs of hypercalcemia or tumor recurrence.

Discussion

Primary lung tumors in cats are relatively uncommon.¹ Cats affected with these tumors can have clinical signs that include lethargy, weight loss, wheezing, coughing, dyspnea, anorexia, vomiting, diarrhea, tachypnea, ataxia, hemoptysis, and lameness. Primary lung tumors can be categorized as bronchial, bronchiolar-alveolar, or unknown in origin. The bronchial tumors are bronchial adenomas, bronchial adenocarcinomas, adenosquamous carcinoma, squamous carcinoma, and bronchial gland adenocarcinomas. The bronchiolar-alveolar tumors consist of bronchioalveolar carcinomas, while primary tumors of unknown origin are anaplastic carcinomas.²

Median survival time in cats with primary lung tumors has been statistically related only to histological morphology of the tumor. In cats with moderately differentiated tumors, the median survival time with complete surgical resection is 698 days; in cats with poorly differentiated tumors, the median survival time is 75 days. The size of tracheobronchial lymph nodes is believed to be of prognostic importance in dogs¹ but has yet to be proven in cats. One study showed median survival times of 412 days for cats without tracheobronchial lymph node enlargement and 73 days for cats with lymph-node enlargement; however, this difference was not statistically significant.¹

Paraneoplastic syndrome is defined as an abnormal physiological state of the body resulting from the effects of a distant tumor.^3,4 The paraneoplastic syndromes reported in veterinary medicine include hypercalcemia, cachexia, anorexia, disseminated intravascular coagulation, erythrocytosis, glomerulonephritis, myasthenia gravis, fever, hypoglycemia, anemia, gastrointestinal ulceration, thrombocytopenia, neutrophilic leukocytosis, nephrotic syndrome, pemphigus vulgaris, peripheral neuropathy, and hypertrophic osteopathy.^3,4

The most common cause of hypercalcemia in cats is malignant neoplasia associated with lymphoma and squamous cell carcinoma.⁵ Osteosarcoma, fibrosarcoma, multiple myeloma, and bronchogenic carcinoma have all been identified as possible causes as well.^5,6 Hypercalcemia of malignancy can be caused by two main pathophysiological mechanisms. First, hormones (most commonly PTH-rp) are secreted by tumor cells, which then signal the body’s homeostatic mechanisms to raise blood calcium levels. The PTH-rp immunoradiometric assay can accurately detect humoral hypercalcemia of malignancy in cats. Conversely, the clinical utility of immunohistochemical staining for PTH-rp has remained equivocal, as one study found that all lung tumors—regardless of whether the cat was hypercalcemic—had some degree of stain uptake.⁷ Because of this lack of substantiated efficacy, no immunohistochemical staining was performed on the neoplastic lesion described in the cat of this report. The second hypothesized mechanism for hypercalcemia of malignancy is the metastatic spread of a neoplasm into bone, thereby causing osteolytic activity that subsequently raises blood calcium levels.^3,7,8 Other causes for hypercalcemia in the dog and cat include hyperparathyroidism, renal failure, Addison’s disease, hyperalbuminemia, ingestion of toxins containing cholecalciferol or calcipotriene, granulomatous disease, osteolysis, and idiopathic hypercalcemia.^4,9

Reported clinical signs secondary to hypercalcemia (depending on the tumor’s location and size) include polyuria, polydipsia, muscle weakness, muscle tremors, lethargy, depression, anorexia, vomiting, constipation, and cardiac arrhythmias. The most frequent clinical signs seen in the cat are anorexia and lethargy.⁸ While mineralization of the myocardium rarely occurs, it can lead to cardiac arrhythmias.⁸ Hypercalcemia can also lead to renal failure by decreasing the glomerular filtration rate and by causing mineralization of the tubular basement membranes.^3,8 Polyuria of hypercalcemia is first a result of decreased responsiveness to antidiuretic hormone, compounded by severe vasoconstriction leading to decreased glomerular filtration rate and renal blood flow. Mineralization of the renal basement membrane, degeneration, and interstitial fibrosis of the renal tubules worsen prerenal and renal azotemia.^3,8

Pamidronate is a bisphosphonate that inhibits bone resorption by either direct interference with hydroxyapatite crystal dissolution or by direct action at the osteoclast level.⁹ Treatment of hypercalcemia is aimed at removing the underlying cause for hypercalcemia; however, pamidronate can be safely and effectively used to treat hypercalcemia without specifically targeting the underlying cause. The role of pamidronate in the clinical setting is outlined in this case where treatment of the primary cause for hypercalcemia had to be delayed. A previous study regarding the treatment of hypercalcemia in seven dogs and two cats demonstrated that pamidronate at a dose of 1.05 to 1.70 mg/kg IV in dogs and 1.5 to 2 mg/kg IV in cats can be used with an onset of action within 48 hours of administration in most cases. A clinical duration of action for pamidronate was between 11 days and 9 weeks. Calcium levels for the cat in this case report were rechecked >9 weeks after treatment with pamidronate. The normalization of the cat’s ionized calcium was, therefore, likely because of tumor excision rather than from persistent pamidronate activity. Pamidronate has shown no effect on cytology, serology, PTH, or PTH-rp, and therefore has not been shown to hinder diagnosis.⁹ No adverse effects directly attributable to pamidronate were observed in this case or in the study previously mentioned.⁹

In a previous case study by Anderson,⁶ a presumed diagnosis of hypercalcemia of malignancy was made in a cat that was given a histopathological diagnosis of pulmonary adenocarcinoma from tissue collected at necropsy. The limitation of that study was that euthanasia prevented monitoring for subsequent return to normocalcemia after removal of the malignancy. In this study, pulmonary adenocarcinoma was the only identifiable cause for the cat to be hypercalcemic. The hypercalcemia of malignancy was further substantiated by the fact that when the malignancy was removed, the cat’s hypercalcemia resolved. While it is presumed that the cat had a preoperative elevation of PTH-rp caused by hormone production from the malignancy (which resolved on postoperative blood work), this could not be substantiated because of the inability to collect initial PTH-rp values. However, an elevated PTH-rp would have only served to offer further validation that bronchogenic adenocarcinoma in cats can cause paraneoplastic hypercalcemia.

Conclusion

A diagnosis of hypercalcemia of malignancy can be definitively proven by the diagnosis of hypercalcemia in a cat with a malignant tumor and no other causes for hypercalcemia. Resolution of the hypercalcemia after complete excision of the tumor was considered diagnostic for hypercalcemia of malignancy. Previous feline cases of presumed hypercalcemia from bronchogenic adenocarcinoma have been reported but could not be confirmed either because the cats were euthanized or the postoperative calcium levels could not be checked after diagnosis of a primary lung tumor.^5,6 To the authors’ knowledge, this is the first case confirming that primary bronchogenic adenocarcinoma in cats is capable of causing paraneoplastic hypercalcemia.