BACKGROUND.

As with most neoplastic conditions, the exact cause of thyroid neoplasia is not known. Studies have suggested an association between thyroid neoplasia and (1) iodine deficiency or excess, (2) chronic excesses in thyroid-stimulating hormone (TSH) secretion, (3) ionizing radiation, and (4) gene abnormalities and oncogene expression. In addition to these potential pathogenic mechanisms, in some older humans, a long-standing, slowly growing papillary carcinoma may begin to grow rapidly and “convert” to an undifferentiated or anaplastic carcinoma. This condition is usually recognized, because small thyroid masses can be easily detected in people and any sudden change in size can be easily monitored. There may be some similarity between this well-defined process in people and the poorly defined process in dogs. Some dogs will appear to have had a small thyroid mass that “suddenly” begins to expand, dramatically increasing in size. This “late anaplastic shift” is a potential cause of death from papillary carcinoma. Many of these papillary carcinomas secrete thyroglobulin, which can be used as a marker for recurrence or metastasis of the cancer (Greenspan, 2001).

IODINE DEFICIENCY OR EXCESS.

Early epidemiologic data suggested that thyroid cancer in people was more frequent in iodine-deficient areas, but others have contested these findings (Konig et al, 1981). In areas where iodine excess prevails, such as Iceland and Hawaii, a high incidence of thyroid cancer, particularly of the papillary type, has been reported in humans (Verschueren and Goslings, 1992). Experimental data and clinical experience in dogs have neither confirmed nor denied these trends.

THYROTROPIN, THYROID-STIMULATING HORMONE (TSH), AND THYROID GROWTH FACTORS.

The primary factor responsible for maintaining thyroid follicular cell function is TSH (Roger and Dumont, 1982). The role of TSH in thyroid growth is not as obvious, however. There are conflicting opinions regarding the importance of TSH in thyroid neoplasia in humans. In dogs, receptor affinity and concentration, as well as a functional response to TSH, are similar in both normal thyroids and thyroid carcinomas (Verschueren et al, 1992a). Thus some canine thyroid carcinomas appear to retain sensitivity to the growth-promoting effect of TSH, but poor correlation has been demonstrated between TSH binding and TSH dependence in humans (Darbre and King, 1987). Many tumors with TSH binding and adenylate cyclase response did not regress following suppression of serum TSH concentrations with L-thyroxine treatment (Saltiel et al, 1981).

IONIZING RADIATION.

The relationship between ionizing radiation and thyroid cancer has been recognized in humans since the late 1940s and early 1950s. The causative effect of radioiodine on thyroid cancer development was further supported by its high incidence in areas of radioactive fallout, such as the Marshall Islands (Conard, 1984). The short-lived isotopes (¹³²I and ¹³⁵I) are of greater concern than the more commonly used isotope, ¹³¹I (Verschueren, 1992a). Thyroid cancers resulting from radiation exposure are usually well-differentiated thyroid papillary or papillary-follicular carcinomas (Schneider, 1986). Irradiation has been demonstrated to be a cause of thyroid neoplasia in dogs (Verschueren, 1992a).

ONCOGENES.

Extensive studies have been conducted on the expression of oncogenes in human thyroid cancers. This research has revealed evidence of gene mutations in both benign and malignant thyroid neoplasms (Fig. 5-1). Activating mutations in the gsp oncogene or TSH-R in the thyroid follicular cell have been associated with increased growth and function. Aberrant DNA methylation, activation of the ras oncogene, and mutation of the MEN1 gene located at 11q13 are associated with benign follicular adenomas. Loss of the 3P suppressor gene may then result in the development of follicular carcinoma, and further loss of suppressor gene P53 may allow progression to an anaplastic carcinoma. Mutations in the ret and trk oncogenes are associated with the development of papillary carcinomas. Again, loss of the P53 suppressor gene may allow progression of this tumor to an anaplastic carcinoma. These hypotheses suggest progressions from benign to malignant tumors or from a “differentiated” carcinoma to an “undifferentiated” (and more lethal) carcinoma. Indeed, pathology specimens from older affected people that had long-standing goiters and recent rapid growth of the masses may demonstrate transition from papillary or follicular carcinoma to anaplastic carcinoma (Suarez et al, 1988; Bos, 1989; Lemoine et al, 1990; Wynford-Thomas, 1997; Komminoth, 1997; Schlumberger, 1998; Hanna et al, 1999; Greenspan, 2001). This phenomenon is referred to as “late anaplastic shift” and is mentioned in the introduction to this section. Similar studies have not yet been applied to canine thyroid neoplasia.

FIGURE 5-1 Molecular defects associated with development and progression of human thyroid neoplasms. The hypothetical role of specific mutational events in thyroid tumorigenesis is inferred from their prevalence in the various thyroid tumor phenotypes.

(Reproduced with permission from Greenspan, 2001)

PATHOLOGIC VERSUS CLINICAL SURVEYS.

The percentages of malignant and benign canine thyroid tumors identified at necropsy are approximately equal. Malignant thyroid tumors occur with a greater frequency in the dog than in other species. Furthermore, the relatively frequent finding of benign tumors in the dog from pathology reports exceeds clinical experience. Benign thyroid tumors in the dog are usually unrecognized antemortem, because they are nonfunctional, quite small, and cause no clinical signs. In contrast, malignant thyroid tumors are relatively large, cause clinical signs that can be recognized by owners, and are easily palpated by veterinarians. As discussed earlier in this chapter, with the increased use of cervical ultrasonography as a diagnostic aid for dogs with a variety of conditions, it can be safely assumed that the diagnosis of “incidentally discovered” thyroid tumors will escalate. Therefore clinical identification of benign thyroid tumors, as well as “small” malignant thyroid tumors, will increase.

RECOGNITION OF MALIGNANT VERSUS BENIGN THYROID.

As is typical of most endocrine tumors, pathologists sometimes have difficulty distinguishing benign from malignant thyroid tumors. Criteria such as cellular atypia and mitotic activity are not consistently reliable markers in discriminating between these two forms of neoplasia. Well-differentiated follicular carcinoma, in some cases, may be histologically distinguished from the benign condition only by demonstration of vascular or capsular invasion (Hedinger et al, 1988; Verschueren and Goslings, 1992). Owing to the recognized prevalence of malignant tumors seen by veterinary practitioners, most pathologists tend to identify thyroid masses that have been biopsied or surgically removed as “malignant until proven otherwise.”

PHYSICAL APPEARANCE AND CLINICAL FEATURES.

The majority of benign canine thyroid tumors (adenomas) are small, solid, focal lesions that are not usually detected during life. The frequency with which these tumors are identified will be greatly enhanced by the increased use of cervical ultrasonography as a diagnostic tool. It is not understood why small, benign thyroid tumors in the cat tend to be functioning tumors that result in clinical hyperthyroidism whereas similar tumors in the dog are more commonly nonfunctioning or normally functioning. If a dog is diagnosed with a benign, nonpalpable thyroid tumor in our hospital, the most common reason is simple identification of an incidentally discovered mass with cervical ultrasonography. Much less commonly, a dog with a benign tumor may have the same clinical signs associated with any cervical mass: owner observation of the mass, respiratory signs, or difficulty swallowing (Loar, 1986; Lawrence et al, 1991).

Canine thyroid adenomas are often solitary, distinct, slightly soft masses. A well-delineated capsule is seldom noted. Solid adenomas are round or ovoid and measure a few millimeters to several centimeters in diameter. They are usually cream to reddish brown in color and may compress adjacent normal thyroid tissue. Large cystic adenomas can be turgid and filled with an amber or blood-tinged fluid (Belshaw, 1983; Capen, 1985). The central cavities of cystic adenomas have either a smooth or an irregular lining. The physical appearance of canine thyroid adenomas is distinct from the “adenomatous hyperplasia” typically identified in hyperthyroid cats. Although small focal masses similar to those seen in dogs are recognized in cats, the most frequently recognized feline hyperfunctioning thyroid resembles a compressed cluster of grapes involving the entire gland that may be cystic or cavitary upon cutting through the tissue.

HISTOLOGY.

In dogs, most small solid thyroid adenomas are characterized as having follicles that are irregular and either small or large, microscopically. The cystic structures noted in some tumors are lined by dense fibrous tissues from which project fronds of uniform cells arranged in follicular and/or compact cellular patterns. Because cysts are seen in some small adenomas, it is likely that growth is inhibited occasionally by degenerative episodes and these patterns of development are responsible for the final gross and microscopic appearance of these tumors (Belshaw, 1983; Capen, 1985). Although canine thyroid adenomas are well recognized and thoroughly described in the literature, thyroid tumors observed by clinicians should be assumed to be malignant until proven otherwise. Some thyroid tumors may be benign, but the incidence of malignancy and the aggressive nature of these tumors dictate rapid action on the part of the veterinarian. This approach can assure the owners that their pet is being given the best chance for a cure.

INTRODUCTION.

Carcinomas of the canine thyroid are usually large solid masses. Their malignant nature is often grossly evident at the time of surgery or necropsy as a result of invasion into adjacent structures. Extension of malignant thyroid tumors into or around the esophagus, trachea, cervical musculature, nerves, and thyroidal vessels is fairly common. However, invasion into the lumen of structures, such as the esophagus or trachea, is extremely unusual. Distant metastasis is quite common. It has been estimated that 40% to 60% of affected dogs have detectable distant metastases at time of clinical admission (Jeglum and Whereat, 1983; Harari et al, 1986; Withrow and MacEwen, 2001). Distant metastases are most likely identified in the pulmonary parenchyma or in regional lymph nodes. By contrast, results of necropsy studies suggest that 60% to 80% of thyroid carcinomas had spread (Capen, 1985; Verschueren et al, 1992b). Of course, the typical necropsy takes place a significant amount of time after the average time of diagnosis. Thus the higher incidence of distant tumor spread is to be expected. In addition, metastases too small to be detected with radiographs, ultrasonography, or other diagnostic aids may be noted histologically.

DEMONSTRATION OF METASTASIS.

Metastasis occurs most commonly to the lungs, retropharyngeal lymph nodes, and liver (Lurye and Behrend, 2001). Lymphatic drainage of the thyroid gland is primarily in the cranial direction, so lymph node enlargement is most likely to be detected cranial and medial to the primary tumor. Occasionally, both ipsilateral and contralateral cervical lymph nodes may be involved. Metastasis to other locations is also possible, including the adrenal gland, kidneys, liver, heart base, spleen, bone and bone marrow, prostate, brain, skeleton, and spinal cord (Harmelin et al, 1993; Verschueren et al, 1992b; Lurye and Behrend, 2001). The differentiation between benign and malignant thyroid neoplasia depends on the answers to two questions: (1) Is there evidence of similar tissue in regional lymph nodes, lungs, or other locations, as well as evidence of local invasion into surrounding structures? (2) What is the microscopic appearance of the tissue? Rarely, small malignant tumors may resemble adenomas. Histologic evaluation is imperative on any thyroid tumor removed by a veterinarian.

HISTOLOGY.

Cellular pleomorphism may suggest malignant potential, but the diagnosis of carcinoma is dependent primarily on evidence of capsular and vascular invasion. These features may be subtle, and diagnosis of malignancy should not be assumed to be solely the job of the pathologist. Good communication between clinician (who can inform the pathologist regarding gross tissue invasion by the tumor, vascularity of the mass, and other pertinent clinical information) and pathologist can be quite helpful in gaining a full and complete understanding of the microscopic findings of submitted tissue.

Thyroid tumors of follicular cell origin are usually further subclassified as follicular, compact (solid), papillary, compact-follicular, or undifferentiated (anaplastic), depending on their pattern of growth (Table 5-2). In addition, veterinary oncologists use a clinical staging classification system initially developed by the World Health Organization (Table 5-3). The largest percentage of canine thyroid carcinomas contain both follicular and compact cellular patterns and are classified as “mixed-cellular,” “compact-follicular,” or “solid-follicular” carcinomas. Slightly less common are the pure follicular carcinomas. A smaller percentage of thyroid tumors are pure compact carcinomas. Undifferentiated (anaplastic) tumors are uncommon but recognized in about 10% of dogs with thyroid tumors. Papillary carcinomas are rare in the dog. Thyroid carcinomas may also arise from parafollicular cells (C-cells, medullary carcinomas), but this cell type is uncommon in dogs. As discussed in the next section, medullary thyroid carcinoma has probably been underdiagnosed in the past, and the prevalence of this histologic type of tumor will increase with appropriate use of immunocytochemical stains. The least common thyroid tumors recognized by veterinary clinicians are benign tumors (adenoma). However, as previously discussed, it is anticipated that the prevalence of benign thyroid tumors will rise as cervical ultrasonography provides evidence of incidentally discovered cervical masses. Electron microscopy and immunohistochemistry may be helpful and/or necessary in defining the cell of origin.

TABLE 5-2 HISTOLOGIC DIAGNOSIS OF THYROID TUMORS IN 237 DOGS RECOGNIZED AS HAVING A THYROID MASS ANTEMORTEM

TABLE 5-3 CLINICAL STAGING OF CANINE THYROID TUMORS

IMMUNOHISTOCHEMISTRY.

Immunochemical techniques have refined the pathologic diagnoses of virtually all neoplasms, including those of thyroid origin. Immunohistochemical analysis of thyroid neoplasms for thyroglobulin, calcitonin, calcitonin gene–related peptide (CGRP), and neuron-specific enolase has been studied in dogs and has been demonstrated to contribute to the diagnosis of medullary carcinoma (Moore et al, 1984; Holscher et al, 1986; Leblanc et al, 1991). Studies of these C-cell complexes have demonstrated four different cell types: those that stained for thyroglobulin, calcitonin and CGRP, somatostatin, or no marker. These data suggest the possibility of a common cell lineage for the follicular cell and the parafollicular cell. This finding concurs with the occurrence of mixed follicular and parafollicular tumors in humans, bulls, and horses, but not in dogs (Ljungberg et al, 1983; Ljungberg and Nilsson, 1985; Tateyama et al, 1988; Leblanc et al, 1990; 1991).

It has been accepted that medullary carcinoma may be difficult to distinguish from other thyroid tumors by light microscopy alone. This has probably resulted in a prevalence of underestimation regarding medullary carcinoma among dogs with thyroid malignancy. The incidence was thought to be <5% (Patnaik and Lieberman, 1991; Leblanc et al, 1991); however, when specific immunocytochemical stains were applied to thyroid tumors from dogs, the incidence of medullary thyroid carcinoma was 36%. This is obviously a much higher incidence than previously suggested (Carver et al, 1995). Furthermore, it was thought that histologic classification was not a useful prognostic factor (Brodey and Kelly, 1968; Mitchell et al, 1979; Harari et al, 1986; Klein et al, 1988; Ogilvie, 1996). The long-term prognosis may be better for dogs with medullary carcinoma of the thyroid compared with that in dogs with thyroid carcinomas of follicular origin. Medullary carcinomas have a lower rate of distant metastases, they are well encapsulated versus the incomplete encapsulation typical of follicular carcinomas, and they appear to be easier to surgically remove (83% successful removal of medullary carcinoma versus 52% successful removal of follicular carcinoma; Carver et al, 1995).

INCIDENCE.

Several reports agree that thyroid tumors account for 1% to 4% of all tumors found in dogs. It is also understood that some thyroid tumors are not recognized by clinicians and are found only at necropsy, because they are too small to be palpated and do not cause clinical signs. Thyroid tumors may represent an isolated neoplastic “event,” or they may occur in conjunction with the development of other tumors. The identification of more than one tumor in an individual dog is usually considered simply a coincidental finding.

MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES.

Veterinary medicine has derived benefit, historically, from the experience of physicians in human medicine and from using human beings as our “animal model” of disease. Physicians often have the ability to track family histories relative to disease states and to determine the likelihood that an individual may or may not have certain problems based on “familial” tendencies. This is certainly true of thyroid disease and thyroid neoplasia. Therefore attempts to draw analogies from the human experience and to apply that information to veterinary patients may be helpful. About 80% of people with medullary carcinoma of the thyroid, for example, have “sporadic” disease. By contrast, 20% of those patients have a tumor that can be traced back as a “familial disorder,” that is, one in which their genetic background predisposed them to this condition. Four familial patterns of disease occur with respect to medullary carcinoma of the thyroid. These familial conditions in people should be used to remind veterinary clinicians that a thorough evaluation of any dog is warranted, even after diagnosis of thyroid cancer. This is true because some dogs may have more than one problem. Before investing time, money, and emotion into treating one problem, we should attempt to ensure that a dog does not have other serious disease.

Of the four familial patterns associated with medullary carcinoma of the thyroid in humans, one or more may have analogous conditions in dogs. The four patterns recognized in people are (1) familial medullary thyroid carcinoma without associated endocrine disease (FMTC); (2) multiple endocrine neoplasia syndrome 2A (MEN 2A), consisting of medullary carcinoma, pheochromocytoma, and hyperparathyroidism; (3) multiple endocrine neoplasia syndrome 2B (MEN 2B), consisting of medullary carcinoma, pheochromocytoma, and multiple mucosal neuromas; and (4) MEN 2, consisting of MEN syndrome together with cutaneous lichen amyloidosis, a pruritic skin condition. The genes responsible for these familial syndromes have been mapped to the centromeric region of chromosome 10, which is the location of the ret proto-oncogene (a receptor-like tyrosine kinase gene), and mutations in exon 10, 11, or 16 of this location have been demonstrated in patients with these syndromes (Greenspan, 2001). If medullary carcinoma is diagnosed in a person, it is recommended that family members be screened for that tumor and that the patient and family members be screened for any of the other conditions found in MEN 2. In addition to tests designed to detect abnormalities suggestive of medullary carcinoma, gene mutations can be demonstrated in DNA from peripheral white blood cells by using polymerase chain reaction (PCR), restriction fragment-length polymorphism (RFLP), and family unit linkage analysis to identify gene carriers. In this manner, families can be screened for the carrier state, as well as for early diagnosis and treatment of serious disease states.

Dogs occasionally have tumors in several different endocrine organs (including the thyroid) simultaneously (Table 5-4). The answer as to whether these dogs have familial disorders analogous to the well-defined MEN syndromes in human beings awaits genetic study. It is suspected that many of these dogs simply have coincidental multiple problems. However, it is interesting to note that we have diagnosed seven dogs with concurrent medullary carcinoma of the thyroid, pheochromocytoma, and primary hyperparathyroidism due to a parathyroid adenoma. This does fit the criteria for MEN 2A. Also, a number of other dogs with thyroid tumors in our series have shown evidence of other glandular neoplasias (see Table 5-4). These 63 dogs include 27 different breeds. Multiple endocrine tumors do exist in dogs and cats, emphasizing the value of complete diagnostic evaluations even when a tumor, such as a thyroid mass, is palpable and recognized easily.

TABLE 5-4 HISTOLOGIC EVIDENCE OF MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROME IN 63 DOGS WITH THYROID TUMORS

SIGNALMENT.

Thyroid tumors in the dog typically develop in middle-aged and older animals. The average age for dogs with thyroid tumors, benign or malignant, is approximately 10 years. The age range is quite wide, but almost all dogs with thyroid tumors are 5 years of age or older (Fig. 5-2). One study conducted within a small colony of Beagles demonstrated an age-specific incidence of thyroid tumors of 1.1% per year in dogs 8 to 12 years of age and 4.0% per year in dogs 12 to 15 years of age (Haley et al, 1989).

FIGURE 5-2 The ages of 69 dogs with thyroid neoplasia at the time of diagnosis. The average age is approximately 10 years.

There is no obvious gender predilection for thyroid neoplasia in the dog (Harari et al, 1986). By contrast, the incidence of human thyroid cancer is about four times greater in women than in men at most ages (Greenspan, 2001). The breeds thought to be at increased risk appear to include Boxers, Beagles, and Golden Retrievers (Harari et al, 1986; Verschueren, 1992), although our experience is slightly different, with mixed-breed dogs and Labrador Retrievers being most commonly afflicted. As seen in Table 5-5, Beagles, Boxers, and Golden Retrievers were among the 42 breeds represented in our series. Breed incidence in dogs with thyroid tumors, in our experience, tends to correlate with breed popularity.

TABLE 5-5 BREED DISTRIBUTION OF 237 DOGS WITH THYROID TUMORS

CLINICAL SIGNS.

Dogs with nontoxic (not hyperthyroid) thyroid tumors are usually brought to veterinarians because the owners have seen or felt a mass in the neck or because the mass is causing clinical signs. The signs reported by different authors vary slightly. Without doubt the most frequent owner concern is feeling or sometimes seeing a midcervical or ventrocervical mass. Owners, while petting and scratching their dogs, may simply note the presence of a “swelling” in the throat area (Fig. 5-3). The mass may be unilateral or bilateral in location. Most thyroid tumors are felt to be just below the area of the larynx, but larger tumors may extend (common) or descend (uncommon) closer to the thoracic inlet.

FIGURE 5-3 A, Photograph of the shaved ventral cervical area of a dog with a large, obvious goiter (arrows). (Photograph courtesy of Dr. Jane Turrel.) B, Lateral view of the dog with a large thyroid tumor. The mass is delineated ventrally by the leash. C, Large thyroid tumor, at surgery, displacing the trachea. D, The thyroid tumor following excision.

Because most affected dogs remain healthy for some time, the swelling in the neck caused by tumor growth is often noted to develop slowly. In more than 75% of our dogs that were diagnosed antemortem as having a thyroid tumor, either the swelling was the only reason for seeking veterinary care or the swelling was pointed out by a veterinarian during an examination for some other problem (Table 5-6). Other clinical signs include coughing, rapid breathing (especially at times of rest), respiratory distress, difficulty in swallowing (dysphagia), alteration in the sound of a normal bark (dysphonia), weight loss, listlessness/depression, vomiting, regurgitation, anorexia or an obvious decrease in appetite, polydipsia, polyuria, hyperactivity, diarrhea, increased appetite, facial edema, and apparent pain or discomfort (see Table 5-6). Not surprisingly, the length of time between owner observation of the mass or clinical sign(s) and presentation of the dog for veterinary care is highly variable. In our series, some dogs were seen as quickly as the same day a mass was discovered, whereas others were not seen until as long as 36 months later. The average length of time was within 2 to 6 weeks.

TABLE 5-6 OWNER-OBSERVED SIGNS IN 237 DOGS WITH THYROID TUMORS

A surprising percentage of owners fail to notice any clinical signs in their dogs with thyroid tumors. As stated previously, there has been a dramatic increase in the use of cervical ultrasonography as a diagnostic aid. For the most part, we had been using this tool for dogs suspected to have laryngeal paralysis and those suspected as having primary hyperparathyroidism. As we began to bring “healthy” middle-aged and older dogs (>5 years of age) to our hospital for cervical ultrasonography to serve as controls, a number of “incidentally discovered” thyroid masses were identified. Added to this group of “healthy dogs” were the dogs with primary hyperparathyroidism that had hypercalcemia identified as a serendipitous finding on routine screening blood work. These dogs had blood taken as part of a geriatric assessment and, like our apparently healthy controls, had no clinical signs and were thought to be well. These healthy control dogs and the dogs with primary hyperparathyroidism account for almost all the dogs in our series with thyroid tumors but no clinical signs.

PHYSICAL EXAMINATION.

Most dogs with thyroid tumors have nontoxic thyroid malignancies. Nontoxic, in this context, means that the tumor is not functional and that the dog is not hyperthyroid. Physical examination reveals few abnormalities other than those problems noted by the owner. Many dogs are remarkably healthy, especially when compared with hyperthyroid cats. Two important aspects of a physical examination are emphasized: (1) The veterinarian should be certain that a complete physical examination is performed before making any recommendations to an owner regarding diagnosis, treatment, and prognosis. (2) The veterinarian must attempt to appreciate the size and invasive nature of the thyroid mass. If possible, the veterinarian should answer this question: Is this cervical mass (presumably thyroid until proven otherwise) freely movable?

Most thyroid masses are firm, asymmetrical, irregular in shape, and nonpainful. If both thyroid lobes are affected, the masses tend to be irregular and asymmetrical. Most thyroid tumors are located close to the typical normal thyroid region (at and ventral to the laryngeal area) in the neck and are not as ventral in location or as freely movable in the subcutaneous space as those in cats (see Fig. 5-3). Usually, the thyroid mass is nonmovable and obviously well embedded into surrounding tissue. It is usually not possible to palpate the interior or medial surface of the mass because of local invasion. An irregular shape is not always diagnostic of carcinoma, but an immovable mass usually implies local invasion and should raise a strong suspicion for malignancy at the time of examination.

Inspiratory and expiratory dyspnea has been identified in several dogs. Only a few dogs have been obviously cachectic (Fig. 5-4), depressed, or dehydrated. The noncachectic dogs are usually alert and active and have good mucous membrane color, normal capillary refill time, and no fever. A dry, lusterless hair coat is common, but alopecia is rare. Heart sounds are normal, and examination of the mouth, eyes, ears, and abdomen is unremarkable. Submandibular lymph nodes may be enlarged as a result of tumor spread or lymphatic obstruction.