When the history, physical examination, standard imaging (thoracic radiography, abdominal ultrasonography), and CBC and serum
chemistry profile results fail to identify a potential cause, further tests can be considered, such as PTH and PTH-related
peptide (PTHrP) concentration measurement and an ultrasonographic examination of the ventral cervical area, ideally by an
experienced radiologist. Generally, as with other disorders, the most common conditions are ruled out first by using the least
invasive techniques initially.
1A & 1B. A ventrodorsal radiograph of the right humerus (1A) and a right lateral radiograph of the lumbar spine (1B) of an
11-year-old female spayed mixed-breed dog presenting with signs of pain. Hypercalcemia, hypoalbuminemia, and hyperglobulinemia
were noted on the serum chemistry profile. Multifocal purely lytic lesions are seen. Bone marrow cytology and protein electrophoresis
confirmed a diagnosis of multiple myeloma.
Routine tests to detect tumors ("tumor hunting") or complete staging procedures are recommended to better determine the histologic
origin and extent of malignancy. Bone survey, via plain radiographs of the long bones and spine (Figures 1A & 1B), or bone scan, via nuclear scintigraphy (Figures 2A & 2B) generally with technetium 99m-ethylenediamine-tetramethylenephosphonic acid (99-Tc-EDTMP), may provide diagnostic clues
in cases of occult or unexplained hypercalcemia.
2A & 2B. Bone scintigraphy (99-Tc-EDTMP) in a 12-year-old male neutered mixed-breed dog (the dogs head is to the left) with
prostate carcinoma-a tumor type not reported to be associated with hypercalcemia in this species. Increased uptake represents
abnormal bone turnover and can be observed in many ribs (2A-open arrows) , in the sternum (2A-solid arrow), in the thoracic
spine (2A-arrowhead), and in the femoral diaphysis and ischium (2B-open arrows). Nonspecific uptake is also observed in the
coxofemoral and stifle joints from osteoarthritis (2B-arrowheads). Cytologic examination confirmed that a target bone lesion
(femur) was metastatic.
HYPERCALCEMIA OF MALIGNANCY: PATHOGENESIS
Hypercalcemia of malignancy may arise through three main mechanisms. First, tumor cells may produce and liberate soluble mediators
capable of acting on bone and kidneys through endocrine and paracrine pathways, a mechanism referred to as humoral hypercalcemia of malignancy.3-5,7,8,15,19 Second, cancer cells may subvert the enzymatic activity of 1 alpha-hydroxylase, thereby causing the unregulated conversion
of calcidiol to active calcitriol, which enhances intestinal absorption of calcium.8,22-26 This mechanism is poorly described with tumors in companion animals. Finally, certain tumor histologies such as leukemias,
lymphomas, myeloma, and certain carcinomas may directly cause osteolysis when they invade or metastasize to bones, resulting
in the dissolution of hydroxyapatite crystals through an agonist effect on osteoclasts during tumor progression.9,27