Volume 11 | Issue 10 | December 2019 Clinical Consults What’s Your Diagnosis?

PATIENT HISTORY RECTAL EXAMINATION— SIGNALMENT: “Chelsea” is a 7.5-year-old female spayed Labradoodle. Weight Important In Every Sick and Well Patient! 70 lb/34 kg.

PERTINENT PAST HISTORY: “Chelsea” has been a very healthy dog. She has experienced historical intermittent urinary Donna J. Spector , DVM, DACVIM, Internal Medicine tract infections (UTIs) but no other major systemic issues. She eats dry adult commercial dog food. She is current on recommended vaccinations and takes monthly preventatives as recommended by TABLE 1. her primary care veterinarian. “CHELSEA’S” BLOODWORK CURRENT HISTORY: “Chelsea” had recently Calcium (ref. range 8.4-11.8 mg/dL) 18.9 mg/dL begun experiencing an increase of urination Phosphorus (ref. range 2.5-6.1 mg/dL) 2.9 mg/dL and urinary accidents in the house. The owner initially did not describe an BUN (ref. range 9-31 mg/dL) 42 mg/dL accompanying increase of water drinking. (ref. range 0.5-1.5 mg/dL) 1.6 mg/dL The owner brought in a free-catch urine Creatinine sample for analysis which revealed pyuria ALKP (ref. range 5-160 U/L) 177 U/L (20-30 WBC/hpf) and rare bacteria. “Chelsea” was prescribed amoxicillin 500 mg USG 1.012 PO BID for 7 days to treat a presumptive UTI. The owner reported the amoxicillin helped Chelsea” was diagnosed with severe hypercalcemia and mild renal failure likely secondary to the with the clinical signs for a short period but severe hypercalcemia. An Internal Medicine consultation was recommended ASAP. “Chelsea” became polydipsic and polyuric fairly soon after stopping and within one month she began experiencing mild INTERNAL MEDICINE EVALUATION stranguria. She was rechecked at this time The owners reported “Chelsea” to have a picky appetite and she had lost a total of 10 pounds in the and physical examination was reportedly previous 12 months. She had experienced a mild amount of vomiting but was still having normal stool unremarkable. Amoxicillin was refilled for 14 quality. The owner felt she was quite lethargic and drinking and urinating excessively. The owners days. When her clinical signs of pu/pd and were still reporting some degree of stranguria and mild tenesmus. Upon physical examination, “Chelsea” stranguria were persistent, “Chelsea” was bright, alert and responsive, and well hydrated with normal thoracic and cardiac auscultation. Her returned for bloodwork 10 days later. A abdomen palpated normally. She had normal external genitalia. When her tail was lifted you could see lateral abdominal radiograph revealed no an asymmetric bulge in the left perianal region. On rectal examination, she had a very large stones (see Figure 1). See Table 1 for her (>6cm) irregular anal gland mass. Palpable sublumbar lymphadenopathy was also be noted on rectal bloodwork abnormalities. exam. The concern was for anal gland adenocarcinoma with associated paraneoplastic hypercalcemia. FIGURE 1. FIGURE 2. and other carcinomas also cause hypercalcemia of malignancy. Idiopathic hypercalcemia is a common differential for hypercalcemia in cats – but not dogs.

Clinical Signs Dogs with hypercalcemia may be asymptomatic or they may have clinical signs of lethargy, vomiting, constipation, diarrhea, polyuria, polydipsia, weakness, twitching and/or seizures. Many patients with hypercalcemia (especially related to primary hyperparathyroidism) suffer from uroliths and may have associated pollakiuria, hematuria and/or stranguria.

Physical Examination A thorough physical examination is an Clinical Note: “Chelsea’s” examination returned one week later at which time her absolute necessity in the workup of demonstrates the importance of performing a ionized calcium was 1.86 mmol/L – hypercalcemia and must involve palpation of thorough rectal examination on every patient improved but still moderately to markedly long bones, mammary glands, lymph nodes, presented for urinary complaints. “Chelsea’s” elevated. Surgery was performed to remove prostate, all organs, anal sacs, etc. A retinal anal gland mass must have been present for the the anal gland mass and her sublumbar examination must be included to evaluate preceding several months and could have been lymph nodes. Surgery was relatively thoroughly for fungal disease. identified at an earlier stage in the disease uneventful and histopathology confirmed process. All patients presenting for urinary and apocrine gland adenocarcinoma with Laboratory Abnormalities gastrointestinal complaints but also EVERY metastasis to the sublumbar lymph node. Marked lipemia, hemolysis, hemoconcentration healthy patient at an annual examination should Her hypercalcemia resolved immediately and hyperproteinemia can falsely elevate total be undergoing rectal examination! post-operatively. serum calcium. It is always prudent to obtain a second sample on a fasted (non-lipemic), Review of the abdominal radiographs (see DIAGNOSIS non-hemolyzed sample prior to pursuing Figure 1) revealed ventral deviation of the additional diagnostics for hypercalcemia. colon which was concerning for sublumbar Apocrine gland adenocarcinoma Clinical Note: All abnormalities in serum total lymphadenopathy. An abdominal ultrasound – left calcium always warrant further investigation! and three-view thoracic radiographs were The CBC usually has non-specific changes. recommended for further staging of this disease. Sublumbar lymph node metastasis The chemistry panel will reveal hypercalcemia Paraneoplastic hypercalcemia and the phosphorus concentration may give Abdominal ultrasound revealed markedly enlarged sublumbar lymph nodes (7.5 cm long x 3.5 cm wide) with a diffusely infiltrated DISCUSSION TABLE 2. appearance (see Figure 2). There was no A detailed discussion of hypercalcemia and MOST COMMON CAUSES OF HYPERCALCEMIA other lymphadenopathy or ascites noted. A apocrine gland adenocarcinoma is beyond fine needle aspirate of the enlarged lymph the scope of this article and the reader is Hypercalcemia of malignancy – lymphoma, nodes was obtained and revealed metastatic directed to the listed references. multiple myeloma, anal gland adenocarcinoma, adenocarcinoma. The thoracic radiographs other carcinomas revealed no cardiac or pulmonary abnormalities. Hypercalcemia Hypoadrenocorticism Etiology Primary hyperparathyroidism There are many causes of hypercalcemia in An ionized calcium was performed and was Nutritional secondary hyperparathyroidism markedly elevated at 2.44 mmol/L (ref. range dogs (see Table 2). The most common 1.12-1.4 mmol/L). “Chelsea” was admitted etiology in dogs is hypercalcemia of Osteolytic disease to the hospital for intravenous saline diuresis. malignancy. Neoplasia will be diagnosed in Acute or chronic renal failure Once her azotemia resolved, an injectable approximately 2/3 of dogs with hypercalcemia. Vitamin D toxicosis dosage of zoledronic acid was administered Lymphoma is an extremely important Granulomatous disease (blastomycosis, to help control her hypercalcemia and make differential, although anal gland histoplasmosis, etc.) her a more stable surgical candidate. She adenocarcinoma (AGAA), multiple myeloma clues as to etiology. Low to normal phosphorus Clinical Note: I find it helpful to pull ionized Treatment of Hypercalcemia levels are generally consistent with calcium and serum PTH levels at the same Treatment is aimed at identifying and then hypercalcemia of malignancy or primary time so they are matched samples. I submit treating the underlying cause. However, hyperparathyroidism. If serum phosphorus is the ionized calcium to the laboratory for emergency medical management is often elevated, renal disease, vitamin D toxicosis and evaluation and freeze the time-matched PTH required while diagnostic tests are being hypoadrenocorticism may be more likely. sample. If the ionized calcium returns as performed. Dogs typically show adverse elevated, I will then add-on/submit the PTH clinical signs at serum calcium concentrations Advanced Diagnostic Testing sample. This avoids the patient having to >15 mg/dL. Patients with serum calcium An ionized calcium should always be come back for another sampling and helps concentrations >18 mg/dL are usually quite ill performed in the evaluation of a total serum avoid the expense of another ionized calcium and require intervention. calcium elevation. Total serum calcium exists as it is imperative that the PTH be analyzed in three fractions: 1) protein bound, 2) at the same time as the ionized calcium. Dehydration exacerbates hypercalcemia by complexed or chelated to a variety of increasing renal tubular absorption of calcium, substances such as citrate, lactate, carbonate Parathyroid hormone-related Protein (PTHrP) decreasing renal calcium excretion through and 3) ionized. The ionized calcium, which assay is a humoral factor made by some reduced GFR and by hemoconcentration. makes up about 50% of total serum calcium, neoplastic cells. It has a structure and Correction of dehydration with intravenous fluid is the biologically active form of calcium. The function similar to PTH so is capable of therapy helps reduce the severity of protein bound calcium serves as a storage pool causing hypercalcemia. PTHrP is hypercalcemia. After dehydration is corrected, for the ionized form. Clinical Note: If the autonomously secreted by cancer cells and is diuresis with physiologic saline promotes ionized calcium is within normal limits, the not suppressed by serum calcium levels. continued renal excretion of calcium. hypercalcemia is not pathologic and does not Absence of PTHrP DOES NOT rule out require further workup. neoplasia as the cause of hypercalcemia as Diuretics such as furosemide can be there are other mechanisms by which cancer administered in adequately hydrated patients. Most often after a thorough history, physical can cause hypercalcemia. Some tumors Furosemide inhibits renal calcium examination and diagnostic imaging, the metastasize to bone and elaborate local reabsorption. Glucocorticoids lower serum source of hypercalcemia is apparent. factors to cause bone resorption. calcium by reducing bone reabsorption of However, if a hypercalcemic dog has no Hematopoietic bone marrow malignancies calcium, decreasing intestinal calcium masses or enlarged lymph nodes (peripheral, may cause hypercalcemia due to local absorption and increasing renal calcium thoracic, or abdominal) to aspirate or biopsy, osteolytic effects of the tumor on adjacent excretion. Clinical Note: Glucocorticoids and if there are no hemogram changes that bone. Some tumor cells, such as multiple can interfere with diagnostic testing aimed would suggest the need for bone marrow myeloma secrete osteoclast-activating factors. at determining the underlying cause of aspirate or biopsy, then PTH and PTH-rP hypercalcemia; therefore, it is imperative to determinations can be done to further define Vitamin D levels may be indicated based on the establish a definitive diagnosis prior to the cause of the hypercalcemia. Clinical patient’s history and if vitamin D toxicosis is starting glucocorticoids. Note: The major disadvantages to these suspected. additional tests include costs, specialized Bisphosphonates may be utilized effectively in sample handling and shipping ACTH stimulation testing may be indicated if dogs with moderate to severe hypercalcemia. requirements, and a slow turn-around time hypoadrenocorticism is suspected as an etiology Bisphosphonates, such as pamidronate and (5-14 days in most cases). of the hypercalcemia. Typically, there would be zoledronic acid, inhibit osteoclast function, accompanying clinical signs of Addison’s disease which reduces calcium reabsorption from In patients without overt cancer and an as well as the classic laboratory findings of bones. They also help slow growth of some elevated ionized calcium, a matched PTH hyponatremia, hyperkalemia and hypoglycemia. tumors by inhibiting production of certain assay should be performed to evaluate for growth factor cytokines by osteoblasts. primary hyperparathyroidism. Clinical Note: Diagnostic imaging including thoracic and Most dogs affected by primary abdominal radiographs and/or ultrasonography hyperparathyroidism will have low to normal are utilized to identify abnormalities that would “CHELSEA’S” TREATMENT AND phosphorus serum concentrations. In the indicate hypercalcemia of malignancy. Cervical UPDATE normal patient, serum PTH levels are low or ultrasonography is often used to identify a “Chelsea’s” diagnosis did not pose the undetectable when serum calcium is parathyroid mass in patients suspected of having diagnostic dilemma like some cases of elevated. If PTH levels are within the primary hyperparathyroidism as an etiology of hypercalcemia and her surgical treatment was reference range or elevated in a their hypercalcemia. Diagnostic imaging also also relatively straightforward. She did, hypercalcemic patient, primary helps identify complications of hypercalcemia however, serve as a very good reminder of the hyperparathyroidism is most likely present. such as urolithiasis. importance of performing rectal examinations on every patient and as a reminder of the TABLE 3. benefits of early disease detection. STAGING SYSTEM FOR ANAL GLAND ADENOCARCINOMA IN DOGS

“Chelsea” recovered uneventfully from surgery STAGE PRIMARY TUMOR SIZE METASTASIS and had an oncology consultation post- STAGE 1 <2.5 cm maximum diameter No metastasis operatively. A clinical staging system for anal gland adenocarcinomas has been proposed STAGE 2 >2.5 cm maximum diameter No metastasis (see Table 3). Based on this system, Lymph node metastasis <4.5 cm maximum diameter “Chelsea” was a Stage 3b. STAGE 3a No distant metastasis Many methods of treatment have been Lymph node metastasis STAGE 3b >4.5 cm maximum diameter described for anal sac adenocarcinoma, No distant metastasis including surgery, radiation therapy, Any lymph node status chemotherapy, electrochemotherapy, and STAGE 4 Any primary tumor size various combinations of these treatments. Distant metastasis

In general, dogs affected by anal gland adenocarcinoma treated with surgery have Hypercalcemia increases the clinical signs treatment of the tumor bed to control local far better median survival times (MST) than associated with anal gland adenocarcinoma disease recurrence. dogs treated without surgery. Additionally, and is a negative prognostic indicator in some dogs with sublumbar lymph node metastasis studies. In one study, the MST was 256 days “Chelsea’s” owners declined radiation therapy have significantly better outcomes when both for dogs with hypercalcemia, compared to but did choose to use toceranib chemotherapy as the primary anal gland mass and the 584 days for normocalcemic dogs. a means to hopefully control the disease. metastatic lymph nodes are removed, “Chelsea” is just beginning this chemotherapy compared to dogs undergoing removal of Anal gland adenocarcinoma has a 20-50% protocol and will be monitored appropriately. She only the primary anal gland mass. MST has local recurrence rate with surgery alone. will begin routine rectal exams with standard local been reported as 1205 days for dogs with Hypofractionated radiation therapy has a disease recurrence checks and metastasis Stage 1 disease, 722 days for stage 2, 492 place in the treatment of anal gland screening every 3-6 months. Recurrence of days for stage 3a, 335 days for stage 3b, and adenocarcinoma and was offered to hypercalcemia will be an excellent way to monitor 71 days for stage 4. “Chelsea’s” owners as a post-surgical her for disease recurrence.

REFERENCES Henry, Carolyn J. Paraneoplastic Syndromes/Hypercalcemia of Malignancy. Chapter 333. In: Ettinger SE, Feldman EC: The Textbook of Veterinary Internal Medicine. 7th ed., Elsevier, St. Louis, 2019. Feldman, Edward C. Disorders of the Parathyroid Gland. Chapter 286. In: Ettinger SE, Feldman EC: The Textbook of Veterinary Internal Medicine. 7th ed., Elsevier, St. Louis, 2019. Craven, Melanie. Rectoanal Disease/Anal Sac and Perianal Neoplasia. Chapter 272. In: Ettinger SE, Feldman EC: The Textbook of Veterinary Internal Medicine. 7th ed., Elsevier, St. Louis, 2019. CLINICAL ASSESSMENT If the ionized calcium is 1.86 mmol/L (ref. Glucocorticoids are the treatment of 4 range 1.12 – 1.4 mmol/L) and the parathyroid 8 choice for hypercalcemia as they are well Which of the following are fractions of total hormone (PTH) level is 2.5 pmol/L (ref. range 0.5 tolerated and highly effective. True or False? serum calcium? – 5.8 pmol/L) the diagnosis is NOT compatible 1 with primary hyperparathyroidism. True or False? Bisphosphonates? a. Protein bound 9 a. Can be effective for moderate to b. Ionized If PTHrP is normal in a hypercalcemic severe hypercalcemia c. Chelated 5 dog, neoplasia CAN be ruled out as an etiology of the hypercalcemia. True or False? b. Must be administered as an d. All of the above intravenous infusion If total serum calcium is elevated and is Hypercalcemia is usually idiopathic in c. Are administered (depending on the 2 repeated on a second sample, an ionized 6 dogs. True or False? medication) q 2-4 weeks calcium does not need to be performed. True d. May be nephrotoxic or False? Which of the following is the most common e. All of the above 7 neoplasia causing hypercalcemia in dogs? The treatment of choice for anal gland If the total serum calcium is 13.5 mg/dL a. Hemangiosarcoma (ref. range 8.4 -11.8 mg/dL) and the ionized adenocarcinoma with metastasis to 3 b. Mast cell tumor 10 calcium is 1.2 mmol/L (ref. range 1.12 – 1.4 local sublumbar lymph nodes is surgery. mmol/L), further workup for hypercalcemia is c. Multiple myeloma True or False? not necessary. True or False? d. Melanoma CLINICAL ASSESSMENT ANSWERS: 1. D. All of the above. 2. False. An ionized calcium always needs to be performed to evaluate if the ionized calcium fraction is elevated and there is a true pathologic hypercalcemia. 3. True. In this situation, the total serum calcium is elevated at 13.5 mg/dL, but the ionized fraction is normal at 1.2 mmol/L. This patient may have had hyperlipidemia, hemolysis, renal disease or some other factor affecting the total serum calcium. This ionized calcium fraction is not pathologic and does not require further workup. 4. False. This concentration of PTH should be considered inappropriately elevated in comparison to the degree of ionized hypercalcemia present. Up to 50% of dogs with primary hyperparathyroidism will have PTH levels within the “normal” reference range. 5. False. Although cancer cells secrete this humoral factor with a structure and function similar to PTH and thus being capable of causing hypercalcemia, it is not the only mechanism by which cancer cells cause hypercalcemia. Some tumors metastasize to bone and elaborate local factors to cause bone resorption. Hematopoietic bone marrow malignancies may cause hypercalcemia due to local osteolytic effects of the tumor on adjacent bone. Some tumor cells, such as multiple myeloma secrete osteoclast-activating factors. 6. False. Hypercalcemia in dogs is usually paraneoplastic. Up to 2/3 of dogs with hypercalcemia will be diagnosed with neoplasia. 7. C. Multiple myeloma. The most common neoplasias in dogs to cause hypercalcemia include lymphoma, multiple myeloma, anal gland adenocarcinoma and various other carcinomas. 8. False. Although glucocorticoids lower serum calcium by reducing bone reabsorption of calcium, decreasing intestinal calcium absorption and increasing renal calcium excretion, their overall effective is somewhat mild to moderate. Additionally, glucocorticoids can interfere with diagnostic testing aimed at determining the underlying cause of hypercalcemia; therefore, it is imperative to establish a definitive diagnosis prior to starting glucocorticoids. There are other therapies, such as IV fluid diuresis and bisphosphonates that are preferential to glucocorticoids for this reason. 9. E. all of the above 10. True. In general, dogs affected by anal gland adenocarcinoma treated with surgery have far better median survival times than dogs treated without surgery. Additionally, dogs with sublumbar lymph node metastasis have a significantly better outcome when both the primary anal gland mass and the metastatic lymph nodes are removed, compared to dogs undergoing removal of only the primary anal gland mass.