Abstract
A well-circumscribed, expansile, and nonencapsulated cardiac rhabdomyoma composed of tightly arranged, large, variably sized, ovoid to irregular, swollen myocytes with deeply eosinophilic cytoplasm and varying degrees of cytoplasmic vacuolation was detected in an eight- to nine-month-old female beagle dog in a routine toxicology study. By histochemistry, the neoplasm was periodic acid-Schiff positive. By immunohistochemistry (IHC), neoplastic cells were positive for desmin and myoglobin and negative for vimentin and smooth muscle actin. Spontaneous lesions in the heart of young beagle dogs are rare in drug safety studies. On the basis of histopathology, histochemistry, and IHC findings, a diagnosis of cardiac rhabdomyoma was made. Cardiac rhabdomyoma is one of the most frequently occuring primary tumors of the heart and, by far, the most common neoplasm in human infants and children. To our knowledge, this is the first report of the canine cardiac rhabdomyoma.
Rhabdomyomas are benign solitary or multiple neoplasms that originate from striated muscles (Meuten 2002). Rhabdomyomas can occur in the myocardium, skeletal muscles of the larynx, and in the head region in both humans and animals (Meuten 2002; Radi 2006). In humans, cardiac rhabdomyomas are one of the most frequently occuring primary tumors of the heart and, by far, the most common in infants and children (Fletcher 2000). The tumor occurs mostly in the left or right ventricle with lesser involvement of the atria. The clinical profile depends on the tumor size and can vary from cardiomegaly, congestive heart failure, cardiac arrhythmia, and sudden death to perinatal death (Fletcher 2000). In laboratory animals, cardiac rhabdomyoma rarely occurs in guinea pigs (Hoch-Ligeti et al. 1986). A mouse model of cardiac rhabdomyoma has been generated and is associated with loss of the TSC-1 gene in ventricular myocytes. These mice had a median survival of six months and developed dilated cardiomyopathy (Meikle et al. 2005). In domestic animals, cardiac rhabdomyoma has been reported most frequently in swine and rarely in cattle, sheep, and deer (Bradley et al. 1980; Kolly et al. 2004; Meuten 2002; Tanimoto and Ohtsuki 1995). These tumors are usually seen at slaughter and are deemed to be incidental lesions (Meuten 2002). A breed predisposition of cardiac rhabdomyoma was reported in red wattle and red wattle crossbred swine (McEwen 1994).
In dogs, hemangiosarcoma is the most common cardiac tumor (Ware and Hopper 1999). Most cardiac tumors usually have a malignant behavior, and they most often (excluding lymphoma) occur in dogs between the ages of seven and fifteen years (Ware and Hopper 1999). A case of intra-atrial rhabdomyoma causing chylopericardium and right-sided congestive heart failure was reported in a six-year-old Staffordshire bull terrier that had a four-week history of progressive lethargy, ascites, and exercise intolerance (Mansfield et al. 2000). Here we report a spontaneous case of cardiac rhabdomyoma in a young dog with histopathologic, histochemical, and immunohistochemical features similar to that seen in children.
The dog was an eight- to nine-month old female beagle from a two-week oral toxicity study. The dog was individually housed in a stainless steel cage and fed daily with Purina Certified Canine Diet (PMI Nutritional International Inc., Dexter, MI.) with free access to water. Clinical and physical examinations, body weights, electrocardiograms, blood pressure, clinical hematology/biochemistry, and urinalysis were periodically performed throughout the conduct of the study. At study termination, the animal was sacrificed by exanguination after intravenous barbiturate anesthesia and necropsied. Various representative tissue samples, including the heart, were collected, fixed in 10% buffered formalin, routinely processed to prepare hematoxylin and eosin (H&E) slides, and evaluated by microscopic examination. The heart had a focal expansile and nonencapsulated neoplasm consistent with cardiac rhabdomyoma. To further characterize this cardiac neoplasm, histochemical (periodic acid-Schiff [PAS]) and immunohistochemical (desmin, smooth muscle actin [SMA], myoglobin, and vimentin) stains were applied to sections of heart.
All the parameters assessed during the in-life portion of the study remained within the historical limits of normal. Body weight at terminal sacrifice was 7.9 kg. Absolute heart weight and ratios (heart:brain and heart:body weight) were comparable to other animals on study and were within the historical reference range. There were no gross pathology observations. Microscopic alterations were evident only in the myocardium of the left ventricle. The myocardium had a focal, well circumscribed, expansile, and nonencapsulated neoplasm. The neoplasm consisted of tightly arranged, large, variably sized, ovoid to irregular, swollen myocytes. The cells had variably distinct cell borders with a deeply eosinophilic cytoplasm and varying degrees of cytoplasmic vacuolation. The nuclei were single, oval to elongate, peripherally located, and contained stippled chromatin and occasionally one or two prominent nucleoli. No mitotic figures were seen (Figure 1). Histochemistry demonstrated that all neoplastic cells were PAS positive (Figure 2), consistent with cytoplasmic glycogen accumulation. Adjacent normal myocytes were PAS negative. Immunohistochemistry demonstrated that all neoplastic cells had a strong, diffuse cytoplasmic imunoreactivity for desmin (Figure 3) and myoglobin (Figure 4). Neoplastic cells did not demonstrate immunoreactivity to SMA (Figure 5) or vimentin (Figure 6).
In humans, cardiac rhabdomyomas occur in pediatric patients and are frequently associated with tuberous sclerosis, a hereditary autosomal-dominant syndrome related to TCS-1 and TSC-2 gene mutation (Vaughan et al. 2001), but they also can be seen in normal infants (Silverman et al. 1976). Whether cardiac rhabdomyoma is a true neoplasm or a hamartoma is still a controversial issue in the medical literature (Benvenuti et al. 2001). One of the most interesting aspects of these tumors is their tendency to undergo spontaneous regression (Vaughan et al. 2001). The dog in this study was less than one year old, did not exhibit signs of cardiac compromise, and the electrocardiogram was within normal limits. It has been suggested that the term cardiac rhabdomyoma is to be applied to intracardiac nodules that are composed of glycogen-filled, striated muscle cells with a spider-web appearance (Tanimoto and Ohtsuki 1995). The tumor in this case was PA*S positive, indicating that the cells contain polysaccharide/glycogen. Following routine histologic processing, loss of glycogen leads to the distinctive appearance referred to as spider cells owing to the radial arrangement of residual sarcoplasm extending out from the nucleus (Meikle et al. 2005). Desmin, a specific myocyte intermediate filament, was strongly and diffusely positive in the cytoplasm of neoplastic myocytes. No vimentin, an intermediate filament present in mesenchymal cells, staining was present in neoplastic cells. No SMA immunoreactivity was present in neoplastic cells. Neoplastic cells had strong immunoreactivity to myoglobin, which is a specific marker of rhabdomyoblastic differentiation. These results are in agreement with those seen in swine and human cardiac rhabdomyomas, where strong positive desmin staining and variable to negative vimentin staining can be seen (Basso et al. 1997; Tanimoto and Ohtsuki 1995). The age of this dog; location of the tumor; and microscopic, histochemical, and immunohistochemical features have similarities to swine and human pediatric rhabdomyoma.
The exact histogenesis of cardiac rhabdomyoma is uncertain. Ultrastructural studies of human cardiac rhabdomyomas demonstrated a spectrum of possible myofibril differentiation. The following features have been reported: (1) glycogen bodies, (2) numerous mitochondria with tubular cristae, (3) lipid deposits, (4) desmonsomal attachments suggestive of Purkinje-type fibers, (5) intercalated discs characteristic of myocardial fibers, and (6) peculiar striated structures resembling zebra bodies (Silverman et al. 1976). Based on this ultrastructural description, conducting fibers may be involved in the histogenesis. The following features have been reported in an ultrastructural study of cardiac rhabdomyomas in swine: (1) neoplastic cells contained myofibrils that frequently showed myofibrillar degeneration and produced large intracytoplasmic vacuoles, and these myofibrils often mingled with nemaline bodies and leptofibrils that continued to the Z bands; (2) T-systems; (3) sarcoplasmic reticulum; (4) intercalated discs; and (5) increase of glycogen and mitochondria and appearance of atrial-specific granules associated with the Golgi apparatus (Tanimoto and Ohtsuki 1995). These results suggest that cardiac rhabdomyomas can arise either from two types of fibers, or they have a pluripotent embryonic cell origin.
Among laboratory animal species, no reports of cardiac rhabdomyomas are available in beagle dogs. Spontaneous lesions in the heart of young beagle dogs are rare in drug safety studies. This report represents the first description of spontaneous cardiac rhabdomyoma in a beagle dog.