Management of Endocrine Neoplasia
Steven Withrow United States
Managing common endocrine tumors constitutes significant effort in companion animal practice. The diagnosis of pituitary, thyroid and adrenal tumors in dogs and cats is often straightforward. Treatment, however, involves complex or controversial decisions and extensive post-treatment monitoring.
Pituitary-dependent hyperadrenocorticism (PDH) accounts for 80�85% of clinical hyperadrenocorticism (HAC) in dogs and cats and is due to a micro- or macroadenoma. Adrenal-dependent hyperadrenocorticism (AH) is due to a primary tumor of the adrenal cortex and is discussed below. The hypophyseal-pituitary-adrenal axis is systemically linked by long and short feedback mechanisms and therefore clinical, diagnostic, and therapeutic management of HAC is likewise intricately linked between these endocrine organs.
The clinical presentation, diagnosis, and differentiation of PDH from AH has been thoroughly detailed in recent reviews and the clinical evaluation of companion animals with HAC has become a common skill of veterinarians. The predominant features in both dogs and cats include polyuria/polydipsia, alopecia, polyphagia, and nonspecific signs of lethargy and exercise intolerance. Most cats are also hyperglycemic and managed for insulin-resistant diabetes mellitus. Following effective management of HAC, insulin requirements often decline and a minority of cats with diabetes may no longer require insulin. Cats without concurrent diabetes mellitus still present with polyuria/polydipsia. Cats may have dermatologic involvement including fragile skin, recurrent pyoderma, and seborrhea.
The diagnosis and differentiation of HAC is straightforward when clinical signs, abdominal ultrasonographic data, screening tests, and provocative endocrine testing are considered together. Care should be used in the diagnosis of hyperadrenocorticism, however, in animals that do not concurrently exhibit classic signs of hyperadrenocorticism, since non-adrenal illness may significantly affect endocrine evaluation of the pituitary-adrenal axis. Management of HAC must be put in context with any other medical problems the dog may have. Few dogs with HAC require urgent correction of cortisol levels and in some situations immediate treatment of the condition may not be in the best interest of the patient. Management of other disorders may take priority. However, ultimate control of HAC in dogs is needed when more urgent conditions have been controlled, in order to prevent the catabolic and immunosuppressive effects of hypercortisolemia from further debilitating the patient or compromising successful treatment of concurrent disease.
Conventional therapy of PDH in dogs involves administration of o,p' �DDD. Bioavailablity is poor and administration with meals is recommended. Pulverizing tablets should be avoided in order to reduce potential exposure of this carcinogenic substance to the owners. The goal of therapy with o,p' -DDD is to induce sub-total adrenal lysis such that the post ACTH stimulation cortisol value is < 5 ug/dl. The standard protocol involves a loading dose interval followed by a maintenance-dosing period. An initial dose of 30�50 mg/kg PO per day for 10 days is suggested. Medium or large size dogs may require dividing the dose in order to reduce vomiting. Supplying the owners with prednisone or prednisolone (0.15�0.25 mg/kg/d) should be standard protocol as well since the loading phase of treatment may induce an adrenocortical crisis. ACTH stimulation tests should be used to monitor response if clinical signs of adreno-cortical suppression are observed or following the 10 days of o,p' -DDD loading. Approximately 50% of dogs will relapse within the first year. Re-treatment with a loading period of o,p' -DDD at the doses above and an increase in the maintenance dose by 50% is recommended.
Other treatment options exist for dogs with PDH if o,p' -DDD is not effective or if the dog is not able to tolerate the drug. Ketoconozole reduces cortisol levels rapidly but is relatively expensive and requires continuous daily dosing. Irradiation of the pituitary gland has resulted in significant reduction of CNS clinical signs in dogs with pituitary macroadenomas. Tumor size, severity of neurologic signs, and endocrine activity influence response to radiation therapy in dogs with pituitary macroadenomas. The median progression free survival following irradiation was 20 months in dogs with favorable clinical parameters (i.e., seizures and/or mild neurologic signs only, functional macroadenoma and small relative tumor size). Dogs with more severe neurologic signs due to large, nonfunctional tumors had a poorer prognosis. No conclusions regarding normalization of endocrine function following irradiation could be made due to concurrent o,p' -DDD treatment in some dogs. However, the two year control rate of hyperadrenocorticism was 32% in the 12 dogs not treated with o,p' -DDD following irradiation. Additional prospective studies are warranted to extend these observations on the use of radiation therapy for PDH. The benefit of radiation therapy for dogs with PDH without neurologic signs is unknown. Trans-sphenoidal hypophysectomy has been described.
Canine Thyroid Neoplasia
Tumors of the canine thyroid gland constitute 1.2�4% of all tumors in dogs. The median age at diagnosis is nine to ten years and there is no consistent gender predisposition. Boxers are predisposed to both benign adenomas and malignant thyroid tumors. In addition, beagles and golden retrievers have been identified as breeds at increased risk of thyroid cancer. The etiology of thyroid carcinoma in the dog is unknown although thyroid tumors in all species may be induced following sufficient radiation exposure. The majority of dogs with thyroid carcinoma are euthyroid while 20% may be hyperfunctional with or without accompanying signs of hyperthyroidism. Hypothyroidism may also result because of tumor destruction of normal thyroid tissue. Approximately 33% of dogs with thyroid carcinoma have documented metastasis at the time of diagnosis most likely evident in the pulmonary parenchyma or in regional lymph nodes. Lymphatic drainage is cranial towards the submandibular and retropharyngeal lymph nodes in the region of the thyroid gland in dogs. During the natural course of the disease in dogs, approximately 65�90% of dogs with untreated thyroid carcinoma will develop metastasis to a wide variety of tissues. Ectopic thyroid tissue may give rise to carcinoma without involvement of the thyroid gland itself and may be distributed along vestigial nodules of the ventral neck and into the mediastinum.
Routine staging of thyroid carcinoma in dogs involves survey radiographs of the thorax for pulmonary metastasis, general health assessment by means of hematologic screening, and additional evaluations of ancillary tumor sites or suspicious metastatic sites. Ultrasound evaluation or a computed tomographic scan with contrast enhancement of the neck is valuable when a large, fixed mass is present. The scan can determine the extent of soft-tissue invasion and likelihood of surgical excision and will be helpful for radiation therapy planning.
Treatment of canine thyroid carcinomas is dictated by the size of the mass, extent of invasion, symptoms of hyperthyroid disease in other organs, and the available treatment options. Surgery of the thyroid nodule provides the best outcome with the least morbidity when tumors are freely moveable without deep tissue invasion. Mobility is best determined when the dog is anesthetized since attachment to deep structures is often not appreciated when the dog is awake. The surgical approach is through a midline incision. It is possible to sacrifice the jugular vein, carotid artery and vagosympathetic trunk unilaterally with acceptable morbidity (unilateral Horner�s syndrome). Bilateral resection may result in laryngeal paralysis and possibly megaesophagus. Dogs with fixed and bilateral lesions are poor operative candidates. Surgery is potentially complicated due to local tissue invasion and excessive hemorrhage or regional coagulation abnormalities becoming systemic coagulopathies following surgical manipulation. Such complications should be anticipated prior to the excision.
External beam radiation therapy is currently being evaluated in dogs with unresectable thyroid masses. The preliminary data suggest radiation may be used for primary therapy or to downstage large, invasive thyroid tumors. Surgical removal of the residual tumor burden following irradiation may provide further benefit since primary tumor recurrence accounts for significant mortality. Surgical resection of irradiated tissue in this region should be accomplished with the understanding that long term fibrosis and contracture may result in constriction of vital regional respiratory structures.
Thirty-fifty percent of dogs treated with either doxorubicin or cisplatin may demonstrate a partial response (> 50% reduction in volume). Such response rates of thyroid carcinoma to chemotherapy suggest a role for chemotherapy in the management of thyroid tumors although increased survival times for a majority of dogs with thyroid carcinoma treated with chemotherapy has not been confirmed.
Several prognostic factors have been identified that may help determine treatment decisions in dogs with thyroid carcinoma. As previously mentioned, attachment or invasion of the mass into surrounding tissue is an unfavorable factor. When evaluating a freely mobile mass, the size of the nodule appears to be a prognostic predictor of metastasis in dogs with thyroid carcinoma.
Feline Thyroid Neoplasia
Hyperthyroidism is the most common endocrine disorder in cats and has been extensively reviewed. The etiology and pathogenesis of such a significant health issue in cats is still not known. Although the primary demographic features of feline hyperthyroidism have not changed significantly over the preceding 15 years, the clinical manifestations of the disorder have changed. Most cats with hyperthyroidism now present with mild rather than severe weight loss, a palpable thyroid nodule, and a heart murmur. Polyuria/polydipsia and polyphagia are much reduced in incidence compared to 10�15 years ago.
The diagnosis of hyperthyroidism is routinely based on elevated serum T4 value although fluctuation of serum thyroid hormones is now recognized and cats with 'occult' hyperthyroidism may have T4 values within the upper half of the normal reference range.
Following the diagnosis of hyperthyroidism a thorough evaluation of other systems should be conducted. Tachycardia and an elevated R-wave on ECG remain the most frequent cardiac abnormalities in hyperthyroid cats. Thoracic radiographs and a cardiac ultrasonographic evaluation are prerequisites to therapy. Azotemia or overt renal failure is a significant sequelae following control of hyperthyroidism. Thyroid hormone overproduction increases glomerular filtration rate (GFR) and may mask underlying renal disease. It is unclear how to determine which cats may be at risk of developing renal complications without accurate determination of GFR, although a concentrated urine specific gravity prior to treatment may be helpful.
Radionuclide imaging with technetium pertechnetate is indicated to confirm the anatomic extent of functional thyroid tissue. Approximately 70�80% of cats with hyperthyroidism have bilateral lobe involvement and often the nodules may not be individually discernible on physical exam. Only 10% of these cats have bilaterally symmetrical nodules. More often, one lobe is large and the other is small which may make diagnosis of bilateral disease confusing. Occasionally, functional thyroid gland nodules exist in combination with functional ectopic thyroid tissue in the mediastinum and rarely cats may have ectopic functional thyroid tissue within the mediastinum without a palpable thyroid nodule. Without specific knowledge of this additional tissue, surgical removal of the thyroid nodule would not result in resolution of the disease. The location of thyroid tissue obviously determines the type and extent of therapy and therefore thyroid scanning is recommended if available. It is particularly important if surgical resection of the thyroid nodule(s) is the treatment of choice. A radionuclide scan to locate potential ectopic thyroid tissue is not as critical if radioiodine or medical management is to be considered.
Treatment of Feline Hyperthyroidism
A trial therapeutic period with gradually increasing doses of methimazole is recommended prior to definitive treatment to determine the extent of occult renal disease. If the renal disease is mild, marginal but acceptable hyperthyroidism may be maintained with methimazole, or definitive treatment may be completed and thyroid hormone supplementation administered to increase GFR and reduce azotemia. Owners must be informed of the need for thyroid replacement prior to definitive therapy. Prolonged methimazole therapy is not routinely recommended since it is associated with anorexia, vomiting, and bone marrow dyscrasias in approximately 20% of cats. However, in some situations and with adequate monitoring, methimazole may be tolerated for prolonged periods (> 2�3 months).
Definitive therapy currently consists of either surgical excision of the thyroid tissue or radio-iodide ablation of the thyroid with 131I. Surgical excision is generally considered when the cat is diagnosed with unilateral thyroid disease by radionuclide imaging. 131I radioiodine is the treatment of choice when bilateral thyroid disease exists or when ectopic thyroid tissue is identified, since fewer complications occur than following surgery and post-treatment hormone supplementation is often avoided. 131I may also be used to treat cats with thyroid carcinoma.(50) Higher doses may be necessary to effectively ablate the tumor in these circumstances
Recently, ethanol injection of thyroid nodules under ultrasound guidance was reported. Four cats with unilateral thyroid nodules received one injection. Resolution of clinical signs occurred within one week. No toxicity was evident except for mild voice change in two cats. Six cats with bilateral thyroid nodules were also injected. Injection of ethanol into both lobes resulted in death of the first cat and the remaining five cats had only one thyroid nodule injected. Relapse occurred in one cat with subsequent safe injection of ethanol in the contralateral nodule. Transient recurrent laryngeal nerve irritation occurred in two out of five cats resulting in voice change, Horner�s syndrome (vagosympathetic nerve), and gagging. Additional data from cats treated with ethanol injection will be eagerly anticipated.
Adrenal Gland Neoplasia
A recent compilation of adrenal lesions from several pathologic and clinical databases provides useful estimates of the prevalence of benign and malignant adrenal gland tumors in dogs and cats. Approximately 35-40% of geriatric beagles from research colonies had histopathologic evidence of nodular hyperplasia following a complete necropsy. Primary adrenal tumors (cortical and medullary) were reported in 5�19% of these dogs. Surprisingly, 33% of histopathologic adrenal lesions in research beagles were metastases from other malignant tumor sites. The most common tumors identified with adrenal metastases were lymphoma, hemangiosarcoma and melanoma. In contrast, primary adrenal tumors were reported in approximately 0.17�0.76% of pet dogs (1�2 % of all canine tumors) and 0.03% of cats (0.2% of feline tumors) from the Veterinary Medical Database. It is interesting that only 3�5 % of canine adrenal lesions in this database were metastases. These data, summarizing different endpoints, suggest the adrenal gland is affected with neoplasia more often than is clinically appreciated. The apparent discrepancy between clinical and histologic evidence of adrenal gland neoplasia is likely due to: 1) insensitive methods to noninvasively identify and characterize adrenal lesions antemortem; 2) difficulty obtaining tissue for biopsy due to the size, vascularity and location of the adrenal gland; and 3) some adrenal tumors may remain assymptomatic or occult.
Increased use of abdominal ultrasonography has enhanced our ability to identify clinical and subclinical adrenal abnormalities. Unexpected adrenal masses are identified in approximately 1% of abdominal ultrasound evaluations. However, discovery of adrenal lesions increases in dogs undergoing a complete abdominal ultrasound evaluation for a non-specific illness. For instance, in a recent retrospective review, 20 of 40 dogs later confirmed to have pheochromocytomas had suspect adrenal lesions despite the absence of clinical signs specifically related to that disorder. Those pheochromocytomas not identified on ultrasound were < 1 cm in diameter. Thus, increased attention to adrenal glands during ultrasound examination should increase the discovery of adrenal-specific lesions.
More sensitive methods of adrenal imaging will also aid in the characterization of lesions. In humans, carcinomas are generally larger than adenomas, invade into surrounding structures, and have different imaging qualities on CT or MR. Pheochromocytomas likewise have different imaging characteristics. Preliminary evidence in dogs supports this finding as well. Adenomas of the adrenal gland were generally < 2 cm in diameter and carcinomas were of any size, often > 2 cm. Calcification does not appear to be predictive for either adenoma or carcinoma although pheochromocytomas do not calcify. Expanded use of imaging modalities such as CT and MR in dogs and cats will likely provide additional data on the characteristics of specific adrenal lesions for use in diagnosis and treatment planning.
Incidental adrenal lesions should be investigated clinically if they are diagnosed. Non-neoplastic adrenal lesions such as cysts or granulomas are very rare in dogs or cats and the high incidence of metastatic lesions justifies a thorough endocrinologic screening and evaluation for non-adrenal neoplasms. Incidental adrenal masses may appear to be nonfunctional at the time of diagnosis although it seems likely that they are actually subclinically functional. The diagnosis and management of functional adrenal tumors are discussed below but identification of a nonfunctional, incidental adrenal mass creates a management dilemma. The diagnosis may be pursued aggressively with a surgical biopsy or may be more conservatively managed (frequent imaging, endocrine testing, blood pressure screening, etc.). However, management of neoplasia before it has become clinically apparent is clearly the best time to intervene.
Clinical Signs and Diagnosis:
Approximately 15% of dogs diagnosed with hyperadrenocorticism (HAC) are hypercortisolemic because of a primary adrenal cortical tumor (AH). The great majority of adreno-cortical tumors in dogs secrete glucocorticoids and clinical signs consistent with hypercortisolemia are the hallmark of functional tumors of the adrenal cortex. In addition to cortisol, mineralocorticoids and adrenal androgens may be inappropriately released by adrenocortical tumors. Aldosterone-secreting adrenal tumors without concurrent hypercortisolemia have been reported in cats and dogs.
Adrenal tumors occur in geriatric (mean age = 11 yrs.) dogs. Large breeds (Poodles, German Shepherds, retrievers and terriers) and females appear to be over-represented in the clinical reviews of adrenal tumors. Adrenal tumors in cats are rare and insufficient information exists to characterize this disease.
Clinical signs associated with hyperadrenocorticism, whether due to an adrenal mass or a pituitary mass are similar and have been thoroughly reviewed in the recent literature. Briefly, the diagnosis of hyperadrenocorticism is based on appropriate signs, laboratory abnormalities consistent with hypercortisolemia, and results of endocrinologic screening tests such as endogenous ACTH, the ACTH stimulation test, low-dose dexamethasone suppression (LDDS) test, high-dose dexamethasone suppression (HDDS) test, 24-hour urine cortisol excretion, or the urine cortisol: creatinine ratio. A recent summary of ultrasonographic features from dogs with hyperadrenocorticism concluded adrenal mass lesions, usually unilateral, were identifiable in dogs with AH and that dogs with PDH rarely produced discreet adrenal nodules or masses.
Treatment of Adrenal Cortical Tumors
The management of adrenal tumors requires consideration of the clinical status of the patient, the extent of tumor invasion into surrounding structures and the ability to support the patient post-operatively. The ideal surgical candidate is not compromised with sequelae due to hypercortisolemia and has a non-invasive, non-metastatic adrenal cortical adenoma. Most dogs, however, are compromised medically by hypercortisolemia and adrenal tumors are malignant in approximately half of the dogs. Dogs that survive the procedure and progress routinely through the post-operative management for compensatory hypoadrenalcorticism have a fair to good prognosis. The one and two year survival in dogs surviving resection of adrenal tumors is approximately 80�90%. Post-operative management requires close attention to electrolyte balance and administration of glucocorticoids. Dexamethasone is generally administered before and immediately after surgery. An ACTH stimulation test is accomplished 24�48 hrs post-operatively after which, prednisone may be substituted for dexamethasone and maintained with appropriate monitoring for two to three months.
o,p' -DDD or ketoconazole are effective at reducing cortisol secretion from adrenal tumors and should be recommended for dogs that are not surgical candidates or for pre-operative amelioration of signs. Higher doses of o,p' -DDD for longer periods are needed for dogs with adrenal tumors compared to dogs with PDH (50�75 mg/kg/day for 14 days is the recommended starting dose). Routine assessment of adrenal function as described for PDH is needed but continued induction dosing may be necessary or escalation of the dose (in 50 mg/kg/day increments per 14-day interval) may be required. Once controlled, maintenance of suppressed cortisol production may be accomplished with 50�75 mg/kg/week although relapses occur in approximately 50% of dogs. Adjusted maintenance doses may resolve these relapses temporarily. o,p' -DDD may also be initiated in dogs that have overt metastases in an attempt to palliate symptoms. Ketoconazole at the routine dose (10 mg/kg PO q12h) will result in reduced cortisol concentrations and attenuated clinical symptoms in approximately 50% of dogs with adrenal tumors. It is most often recommended for four to eight weeks as a prelude to surgical resection of the adrenal mass to normalize concurrent cortisol-induced disease that may affect the anesthetic or surgical procedure.
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