Complete Surgical Removal of a Very Enlarged Pituitary Corticotroph Adenoma in a Dog

Introduction

Pituitary adenomas in dogs can be classified, based on their size, as either nonenlarged pituitaries containing microadenomas or enlarged pituitaries, which are also called macroadenomas.¹ In the human literature, pituitary macroadenomas refer to adenomas with a diameter > 10 mm but this leads to confusion with veterinary literature because canine pituitary adenomas may be enlarged, but can still be < 10 mm. Therefore, the terminology enlarged and nonenlarged pituitary adenomas, as previously described, is more appropriate in dogs than the terminology micro- and macroadenomas, as has been advocated in large case series.^2–4 In humans, giant adenomas comprise a clinical/therapeutic subset of pituitary adenomas that pose a surgical challenge.⁵ Giant pituitary adenomas in humans are defined as tumors with a diameter > 50 mm.⁵

Transsphenoidal hypophysectomy is an effective therapy for pituitary corticotroph adenomas in dogs; however, the survival and disease-free fractions after surgery decrease with increasing tumor size.^3,4 In very enlarged pituitary adenomas, with a diameter > 15–20 mm and concurrent development of neurologic signs, the dog’s owner is informed that the aim of pituitary surgery is a debulking pituitary surgery. This debulking surgery is considered to be more palliative, removing as much pituitary tumor tissue as possible within the safe limits of this surgery and resulting in reduction of the mass effect. In those cases, surgery is usually not curative for hypercortisolism and medical treatment remains necessary to manage the disease.

This case report describes the successful surgical treatment of a dog with hypercortisolism and neurologic abnormalities due to a pituitary corticotroph adenoma. The adenoma measured > 20 mm.

Case Report

A 13 yr old castrated male vizsla weighing 21 kg was presented to the authors with a 2 mo history of polyuria, polydipsia, polyphagia, kyphosis, and weight loss. On physical examination, the dog was thin and cardiac auscultation revealed a soft systolic murmur (grade 2/6) over the mitral area. Hematology showed lymphopenia and eosinopenia, and serum biochemical analysis revealed elevated concentrations of alkaline phosphatase (27.49 μkat/L; reference range, 0.70–3.01 μkat/L), alanine aminotransferase (1.65 μkat/; reference range, 0.33–0.92 μkat/L), and γ-glutamyl transferase (0.44 μkat/L; reference range, 0–0.1 μkat/L). Urinalysis showed a low specific gravity (1.008). Together, those findings supported a preliminary diagnosis of hypercortisolism. The diagnosis was confirmed with the adrenocorticotropic hormone (ACTH) stimulation test (using 0.25 mg tetracosactide esacetate^a IV) and the low-dose dexamethasone^b suppression test (0.01 mg/kg IV). The basal and postACTH plasma cortisol concentrations were 195 nmol/L (reference range, 27–132 nmol/L) and 872 nmol/L (reference range, 165–500 nmol/L), respectively. Both were consistent with hypercortisolism. There was no adequate suppression of plasma cortisol after a low dose of dexamethasone. Plasma cortisol concentration at 0 hr was 199 nmol/L (reference range, 27–132 nmol/L), 135 nmol/L at 4 hr (reference range, < 41 nmol/L), and 132 nmol/L at 8 hr (reference range, < 41 nmol/L). Abdominal ultrasonography revealed bilateral adrenal gland enlargement. The maximum diameter of the caudal pole of the left adrenal gland was 11 mm and that of the right was 10 mm (reference range for both adrenal glands, < 7.5 mm).

Treatment with trilostane^c (2.9 mg/kg per os [PO] q 24 hr) was started. After 15 days, the ACTH stimulation test was repeated 2 hr after trilostane administration. Plasma cortisol concentration was 52 nmol/L preACTH and 105 nmol/L postACTH. Those results were consistent with adequate control of the hypercortisolemic state, and the dosage of trilostane was not changed. At that time, the dog continued to have polyuria and polydipsia. After 2 mo, the dog developed neurologic signs. Neurologic examination showed an abnormal mental status with marked disorientation, a compulsive gait, and head pressing. The posture was normal. The gait was abnormal with pacing and circling. Postural reaction deficits were detected bilaterally following wheel barrowing, hopping, and tactile placing tests. Spinal reflexes were normal, and cranial nerve examination was normal. Based on the neurologic examination, the dog's signs were consistent with a lesion involving the cerebrum/thalamus.

Contrast-enhanced computed tomography (CT) with IV administration of contrast medium^d (640 mg/kg) produced an inhomogeneous enhancement of a pituitary mass (precontrast density was 55 Hounsfield units [HU] ± 5.58 HU and postcontrast density was 118.2 HU ± 5.46 HU) as shown in Figure 1. The pituitary mass measured 15 mm in height, 21.4 mm in width, and 18.3 mm in length. The pituitary height/brain area ratio (P/B) was .98 (reference range for nonenlarged pituitaries, < 0.31).² The tumor expanded rostrally toward the tuberculum sellae, caudally over the dorsum sellae, and dorsally beyond the sella turcica and into the third ventricle. The ovoid mass had distinct margins that separated it from the surrounding brain tissue. The owner was informed about the therapeutic options, such as medical treatment, irradiation, and palliative treatment. Euthanasia was also considered because a 13 yr old vizsla is a geriatric patient and at its normal life expectancy. The owner elected surgical treatment.

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Transsphenoidal hypophysectomy was performed according to a microsurgical technique described previously.^6,7 The mass was removed in multiple large fragments (Figure 2), and hypophysectomy was considered complete when the infundibular recess at the ventral aspect of the hypothalamus was visualized. Plasma ACTH concentrations within the 2 hr period before surgery were 9.24 pmol/L and 8.80 pmol/L. Those levels decreased to 3.30 pmol/L, 2.42 pmol/L, 2.20 pmol/L, 2.42 pmol/L, and 2.20 pmol/L at 1 hr, 2 hr, 3 hr, 4, hr, and 5 hr after surgery, respectively. Histopathology and immunohistochemistry of the surgical specimens revealed a pituitary corticotroph adenoma. Hematoxylin and eosin staining of the neoplastic cells revealed a basophilic granular cytoplasm with round to ovoid nuclei with prominent nucleoli and rare mitotic figures. Immunohistochemistry of the adenoma using a previously described routine staining protocol, with the addition of appropriate canine positive and negative controls, showed strong staining for ACTH, weak staining for α-melanocyte-stimulating hormone, and no staining for growth hormone.⁸

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Immediately following debulking of the tumor, treatment was started with 0.01% desmopressin^e 1 drop (≈  5 μg) q 8 hr in the conjunctival sac, and hydrocortisone^f 1 mg/kg q 8 hr IV was administered 5 hr after surgery. The dog was kept sedated for 24 hr with continuous IV administration of propofol^g. The dog was subsequently awakened by slowly decreasing then stopping the propofol administration. Recovery was complicated by cough and tachypnea. Auscultation of the lungs revealed harsh sounds, and thoracic radiographs showed a focal left-sided alveolar infiltrate suggestive of aspiration pneumonia. The dog was empirically and successfully treated with amoxicillin trihydrate/clavulanate potassium^h (12.5 mg/kg PO q 12 hr for 2 wk) and enrofloxacinⁱ (2.5 mg/kg PO q 24 hr). After discharge, medication consisted of desmopressin (1 drop [5 μg] q 8 hr in the conjunctival sac), cortisone acetate^j (0.3 mg q 12 hr PO for life), and l-thyroxine^k (15 μg/kg q 12 hr PO for life).

Seven days after surgery, neurologic signs, except for the postural reaction deficits, disappeared. The dog’s water consumption and appetite normalized, and in the following mo, the body weight increased and activity improved. Remission of hypercortisolism was monitored 4 wk, 6 mo, and 1 yr after surgery by measuring basal urinary corticoid/creatinine ratio (UCCR) in two urine samples collected at home (i.e., stress-free). The UCCRs after hypophysectomy were 1 × 10⁻⁶ at 4 wk, 0.8 × 10⁻⁶ at 6 mo, and 1 × 10⁻⁶ at 1 yr (reference range, < 8.3 × 10⁻⁶), consistent with a complete and persistent remission of hypercortisolism.⁹ Contrast-enhanced CT of the hypophyseal fossa was repeated 3 mo after surgery, and no residual pituitary tissue was evident (Figure 3). Eight mo after surgery, the dog suddenly developed a severe head tilt to the left and a tendency to fall to the left side. Neurologic examination showed a normal mental status, vestibular ataxia, and mild bilateral postural deficits following tactile placing tests. Mild bilateral postural reaction deficits in the posterior limbs had been detected in several previous physical examinations of the dog. Spinal reflexes were normal, and a spontaneous horizontal nystagmus with the fast phase to the right side was present. Positional ventrolateral strabismus of the left eye was detected, and a menace response was normal. Based on the neurologic examination, the dog's signs were most consistent with a peripheral vestibular disease. CT of the head was unchanged from the previous postoperative study (Figure 3). The origin of the vestibular dysfunction was not identified, and geriatric vestibular disease was considered the most likely diagnosis. After a few days, the clinical condition improved markedly, and after 1 mo the only abnormality was a mild head tilt.

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Thirteen mo after surgery, the dog developed weakness, inappetence, then anorexia with weight loss. The dog showed acute severe respiratory distress and collapsed and died before arriving at the clinic.

A complete postmortem examination was performed. Macroscopic examination of the skull revealed no evidence of pituitary tissue remnants in either the hypophyseal fossa at the surgical site or at the base of the brain at the opening to the third ventricle (Figure 4A). At the microscopic level, no pituitary tumor remnants could be detected in either location. Macroscopic examination of the adrenal glands revealed a 3 cm × 2 cm × 2 cm right adrenal gland and a focally distended wall of the caudal vena cava (Figure 4B). No abnormalities were found in other endocrine tissues. Histologic examination of the right adrenal gland showed a solid neoplasm arranged in lobules that were separated by abundant fibrovascular stroma (Figure 4C). Neoplastic cells varied from round to polygonal, containing ample slightly granular eosinophilic cytoplasm with a round to oval nucleus that was often eccentrically placed. Immunohistochemistry was performed using a streptavidin/biotin complex method and diaminobenzidine as the chromogen. The panel included the primary antibodies (antichromogranin A^l, synaptophysin^m, neuron-specific enolaseⁿ, S100 protein^o, keratin AE1/AE3^p) as described in another case.¹⁰ The cytoplasm of neoplastic adrenal cells displayed a strong, diffuse immunoreactivity to chromogranin A and neuron-specific enolase (Figure 4D), confirming the histologic diagnosis of pheochromocytoma.

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Discussion

Clinical signs exhibited by dogs with very enlarged pituitary tumors may reflect endocrine and space occupying effects. The endocrine manifestations are those typical of Cushing’s syndrome. The first neurologic signs are almost always subtle. Common initial signs include dullness, listlessness, and decreased appetite. Those signs may progress to anorexia, restlessness, loss of interest in normal activities, delayed response to stimuli, and episodes of disorientation. Signs exhibited by dogs with very enlarged pituitary tumors include obtundation, stupor, ataxia, tetraparesis, and aimless pacing.¹¹ Less frequently observed problems include nystagmus, circling, head pressing, behavior changes, blindness, seizures, and coma.¹¹

The most common treatment in dogs with pituitary-dependent hypercortisolism (PDH) has been the medical therapy with either mitotane or with a competitive inhibitor of adrenal 3β-hydroxysteroid dehydrogenase (trilostane).^11,12 Although effective, those treatments are not directed at the elimination of the primary pituitary lesion. Early diagnosis, pituitary imaging, and treatment at the pituitary level should be the hallmarks of a diagnostic and treatment protocol for canine PDH.² Surgery, medication, and radiotherapy are used to treat various types of pituitary adenomas in humans.¹³ Selective pituitary adenomectomy is still considered the first line of treatment of Cushing’s disease in humans. Radiotherapy is also an option for treatment of pituitary corticotroph adenomas in humans and companion animals.^14–19 It can be used as either a secondary treatment after unsuccessful pituitary surgery or as a primary treatment in patients when surgery is contraindicated (i.e., invasive macroadenoma) or in the presence of a more aggressive malignant tumor (adenocarcinoma).^15,18,20 In one study, 24 dogs with enlarged pituitary tumors (diameter ≥ 10 mm) were irradiated and had mean and median overall survival times of 15.7 mo ± 2.9 mo and 11.7 mo ± 5.9 mo, respectively. The authors of that study concluded that radiation therapy is effective in dogs with mild to moderate neurologic signs, but did not improve survival in dogs with severe neurologic signs.¹⁷ In a more recent study, 19 dogs with pituitary masses (median height, 13 mm; range, 7–21 mm) were irradiated. Mean survival time was 46.8 mo (95% confidence interval, 35.1–58.4 mo) and the tumor size was identified as a negative prognostic factor for survival.¹⁹ In dogs with PDH, pituitary irradiation was more effective in delaying tumor growth than in controlling ACTH secretion.^15,17,18

An extended follow-up of 181 dogs treated with PDH over a 12 yr period proved the effectiveness of transsphenoidal hypophysectomy for canine PDH.^3,4,7 In one of these studies, prognostic factors for the outcome after transsphenoidal hypophysectomy were determined.⁴ The results of that study showed that, among others factors, pituitary size negatively affects survival and remission of disease after hypophysectomy in dogs with PDH. In the present case, remission of hypercortisolism was confirmed by repeated measurements of UCCRs and postoperative CT scanning. That finding was surprising because the primary aim of surgery was debulking of the pituitary mass to alleviate the neurologic signs. Postoperative UCCRs can be used to monitor surgical outcome and recurrence of hypercortisolism in the case of Cushing’s disease and, indirectly, pituitary tumor regrowth.⁴ In the case reported herein, complete tumor removal was monitored with postoperative UCCRs and complemented with periodic CT scans of the pituitary region and ultimately confirmed by an empty fossa on postmortem examination. This case shows, for the first time, that even in the case of a pituitary adenoma > 20 mm in width, complete tumor removal and remission of hypercortisolism are possible.

In humans, giant pituitary tumors are defined by some authors based on extension on the local structures.²¹ A recent study in dogs demonstrated that pituitary masses with a vertical height > 19 mm were more likely to be invasive adenomas; however, in the case reported herein, the authors did not detect any evidence of invasive behavior of the adenoma.²²

There are no detailed studies on outcome after transsphenoidal hypophysectomy in dogs with pituitary adenomas with a diameter > 20 mm. In a large study including 181 dogs that underwent hypophysectomy, there was only 1 dog with a pituitary tumor with a P/B of 1.1 and a diameter of 18 mm that was successfully removed, which was comparable to the case reported here.⁴ However, in the latter case, no detailed follow-up information was available except that there was remission of disease. In two recent case series of dogs with PDH treated with transsphenoidal hypophysectomy, the dimensions of the pituitary adenomas were not reported; however, the biggest pituitary adenomas had a P/B of .69 and .70, respectively.^23,24

Pheochromocytoma is a tumor of the chromaffin cells of the adrenal medulla or sympathetic paraganglia.¹ A variety of vague and nonspecific clinical signs attributed to excessive secretion of catecholamines has been reported in dogs with pheochromocytoma, and antemortem diagnosis is difficult.²⁵ Similarly, in the case reported herein, the pheochromocytoma was only discovered at necropsy.

Excessive panting, acute respiratory distress, weakness, and clinical deterioration are commonly reported clinical signs of pheochromocytoma.²⁵ Those signs were present in this dog and could be explained by the presence of a functional pheochromocytoma.

Previous reports of the coexistence of PDH and pheochromocytoma suggest that the combination is not rare in dogs and, therefore, should not be regarded as an incidental finding.^25–28 In humans, the occurrence of those tumors in the same patients has been speculated to be related to aberrant neural crest development.²⁹

Conclusion

This case report demonstrates, for the first time, that an enlarged pituitary adenoma > 20 mm, causing neurologic deficits due to the mass effect, may be treated successfully by transsphenoidal hypophysectomy.