CASE REPORTS
Complete Surgical Removal of a Very Enlarged Pituitary Corticotroph Adenoma in a Dog Federico Fracassi, PhD, DVM, DECVIM-CA, Luciana Mandrioli, PhD, DVM, Dardan Shehdula, PhD, DVM, Alessia Diana, PhD, DVM, Guy C.M. Grinwis, PhD, DVM, Bjo¨rn P. Meij, PhD, DVM, DECVS
ABSTRACT A 13 yr old castrated male vizsla was referred to the authors’ institute because of polyuria, polydipsia, polyphagia, and weight loss. Pituitary-dependent hypercortisolism (PDH) was diagnosed by hormone testing and adrenal and pituitary imaging. Computed tomography (CT) revealed a pituitary mass measuring 21 mm in width. Medical therapy was initiated with trilostane. Despite adequate control of the hypercortisolemia, the polyuria and polydipsia persisted and the dog developed neurologic signs due to the pituitary mass effect. Pituitary transsphenoidal debulking surgery was performed and immunocytochemistry confirmed a corticotroph adenoma. The dog survived for 13 mo after surgery. Postmortem examination revealed an empty fossa without pituitary remnants and the presence of a malignant pheochromocytoma in the right adrenal gland. This case report demonstrates, for the first time, that a large pituitary adenoma in the dog may be treated successfully by pituitary surgery. (J Am Anim Hosp Assoc 2014; 50:---–---. DOI 10.5326/JAAHA-MS-5987)
Introduction
tumor size.3,4 In very enlarged pituitary adenomas, with a diame-
Pituitary adenomas in dogs can be classified, based on their size,
ter . 15–20 mm and concurrent development of neurologic
as either nonenlarged pituitaries containing microadenomas
signs, the dog’s owner is informed that the aim of pituitary sur-
1
or enlarged pituitaries, which are also called macroadenomas.
gery is a debulking pituitary surgery. This debulking surgery is
In the human literature, pituitary macroadenomas refer to ade-
considered to be more palliative, removing as much pituitary
nomas with a diameter . 10 mm but this leads to confusion with
tumor tissue as possible within the safe limits of this surgery and
veterinary literature because canine pituitary adenomas may be
resulting in reduction of the mass effect. In those cases, surgery is
enlarged, but can still be , 10 mm. Therefore, the terminology
usually not curative for hypercortisolism and medical treatment
enlarged and nonenlarged pituitary adenomas, as previously
remains necessary to manage the disease.
described, is more appropriate in dogs than the terminology
This case report describes the successful surgical treatment
micro- and macroadenomas, as has been advocated in large
of a dog with hypercortisolism and neurologic abnormalities due
case series.2–4 In humans, giant adenomas comprise a clinical/
to a pituitary corticotroph adenoma. The adenoma measured
therapeutic subset of pituitary adenomas that pose a surgical
. 20 mm.
challenge.5 Giant pituitary adenomas in humans are defined as tumors with a diameter . 50 mm.5
Case Report
Transsphenoidal hypophysectomy is an effective therapy for
A 13 yr old castrated male vizsla weighing 21 kg was presented
pituitary corticotroph adenomas in dogs; however, the survival
to the authors with a 2 mo history of polyuria, polydipsia, poly-
and disease-free fractions after surgery decrease with increasing
phagia, kyphosis, and weight loss. On physical examination, the
From the Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy (F.F., L.M., D.S., A.D.); and Department of Pathobiology, Faculty of Veterinary Medicine (G.G.) and Department of Clinical Sciences of Companion Animals (B.M.), Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
ACTH adrenocorticotropic hormone; CT computed tomography; HU Hounsfield units; P/B pituitary height/brain area ratio; PDH pituitary-dependent hypercortisolism; PO per os; UCCR urinary corticoid/creatinine ratio
Correspondence:
[email protected] (F.F.)
ª 2014 by American Animal Hospital Association
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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 mkat/L; reference range, 0.70–3.01 mkat/L), alanine aminotransferase (1.65 mkat/; reference range, 0.33–0.92 mkat/L), and g-glutamyl transferase (0.44 mkat/L; reference range, 0–0.1 mkat/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 esacetatea IV) and the low-dose dexamethasoneb 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
FIGURE 1 Transverse contrast-enhanced computed tomography
(CT) scan of the skull of a 13 yr old castrated male vizsla with pituitary-dependent hypercortisolism. Note the enlarged pituitary adenoma (*) measuring 21.4 mm in width.
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 ad-
and 18.3 mm in length. The pituitary height/brain area ratio
renal glands, , 7.5 mm).
(P/B) was .98 (reference range for nonenlarged pituitaries,
Treatment with trilostanec (2.9 mg/kg per os [PO] q 24 hr)
, 0.31).2 The tumor expanded rostrally toward the tuberculum
was started. After 15 days, the ACTH stimulation test was re-
sellae, caudally over the dorsum sellae, and dorsally beyond the
peated 2 hr after trilostane administration. Plasma cortisol con-
sella turcica and into the third ventricle. The ovoid mass had
centration was 52 nmol/L preACTH and 105 nmol/L postACTH.
distinct margins that separated it from the surrounding brain
Those results were consistent with adequate control of the
tissue. The owner was informed about the therapeutic options,
hypercortisolemic state, and the dosage of trilostane was not
such as medical treatment, irradiation, and palliative treatment.
changed. At that time, the dog continued to have polyuria and
Euthanasia was also considered because a 13 yr old vizsla is a
polydipsia. After 2 mo, the dog developed neurologic signs.
geriatric patient and at its normal life expectancy. The owner
Neurologic examination showed an abnormal mental status with
elected surgical treatment.
marked disorientation, a compulsive gait, and head pressing. The
Transsphenoidal hypophysectomy was performed according
posture was normal. The gait was abnormal with pacing and
to a microsurgical technique described previously.6,7 The mass
circling. Postural reaction deficits were detected bilaterally fol-
was removed in multiple large fragments (Figure 2), and hy-
lowing wheel barrowing, hopping, and tactile placing tests. Spinal
pophysectomy was considered complete when the infundibular
reflexes were normal, and cranial nerve examination was normal.
recess at the ventral aspect of the hypothalamus was visualized.
Based on the neurologic examination, the dog’s signs were con-
Plasma ACTH concentrations within the 2 hr period before sur-
sistent with a lesion involving the cerebrum/thalamus.
gery were 9.24 pmol/L and 8.80 pmol/L. Those levels decreased
Contrast-enhanced computed tomography (CT) with IV
to 3.30 pmol/L, 2.42 pmol/L, 2.20 pmol/L, 2.42 pmol/L, and
administration of contrast mediumd (640 mg/kg) produced an
2.20 pmol/L at 1 hr, 2 hr, 3 hr, 4, hr, and 5 hr after surgery, re-
inhomogeneous enhancement of a pituitary mass (precontrast
spectively. Histopathology and immunohistochemistry of the
density was 55 Hounsfield units [HU] 6 5.58 HU and post-
surgical specimens revealed a pituitary corticotroph adenoma.
contrast density was 118.2 HU 6 5.46 HU) as shown in Figure 1.
Hematoxylin and eosin staining of the neoplastic cells revealed
The pituitary mass measured 15 mm in height, 21.4 mm in width,
a basophilic granular cytoplasm with round to ovoid nuclei with
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Surgical Removal of a Pituitary Adenoma
(2.5 mg/kg PO q 24 hr). After discharge, medication consisted of desmopressin (1 drop [5 mg] q 8 hr in the conjunctival sac), cortisone acetate j (0.3 mg q 12 hr PO for life), and L-thyroxinek (15 mg/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., stressfree). The UCCRs after hypophysectomy were 1 3 1026 at 4 wk, 0.8 3 1026 at 6 mo, and 1 3 1026 at 1 yr (reference range, , 8.3 3 1026), 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 FIGURE 2 Intraoperative frontal view during transsphenoidal
detected in several previous physical examinations of the dog. Spinal reflexes were normal, and a spontaneous horizontal nys-
pituitary debulking surgery. Pituitary adenoma fragments are
tagmus with the fast phase to the right side was present. Positional
extracted with a grasping forceps through the dural incision (top).
ventrolateral strabismus of the left eye was detected, and a menace
Top is rostral, the surgeon’s view is frontal, perpendicular to the skull base. 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 a-melanocyte-stimulating hormone, and no staining for growth hormone.8 Immediately following debulking of the tumor, treatment was started with 0.01% desmopressine 1 drop (z 5 mg) q 8 hr in the conjunctival sac, and hydrocortisonef 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 propofolg. 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
FIGURE 3
potassiumh (12.5 mg/kg PO q 12 hr for 2 wk) and enrofloxacini
CT showed no pituitary remnants.
Three mo after hypophysectomy, contrast-enhanced
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response was normal. Based on the neurologic examination, the
abundant fibrovascular stroma (Figure 4C). Neoplastic cells var-
dog’s signs were most consistent with a peripheral vestibular
ied from round to polygonal, containing ample slightly granular
disease. CT of the head was unchanged from the previous
eosinophilic cytoplasm with a round to oval nucleus that was
postoperative study (Figure 3). The origin of the vestibular
often eccentrically placed. Immunohistochemistry was per-
dysfunction was not identified, and geriatric vestibular disease
formed using a streptavidin/biotin complex method and dia-
was considered the most likely diagnosis. After a few days, the
minobenzidine as the chromogen. The panel included the
clinical condition improved markedly, and after 1 mo the only
primary antibodies (antichromogranin Al, synaptophysinm, neuron-
abnormality was a mild head tilt.
specific enolasen, S100 proteino, keratin AE1/AE3p) as described
Thirteen mo after surgery, the dog developed weakness, in-
in another case.10 The cytoplasm of neoplastic adrenal cells
appetence, then anorexia with weight loss. The dog showed acute
displayed a strong, diffuse immunoreactivity to chromogranin A
severe respiratory distress and collapsed and died before arriving
and neuron-specific enolase (Figure 4D), confirming the his-
at the clinic.
tologic diagnosis of pheochromocytoma.
A complete postmortem examination was performed. Macroscopic examination of the skull revealed no evidence of pituitary
Discussion
tissue remnants in either the hypophyseal fossa at the surgical site
Clinical signs exhibited by dogs with very enlarged pituitary tumors
or at the base of the brain at the opening to the third ventricle
may reflect endocrine and space occupying effects. The endocrine
(Figure 4A). At the microscopic level, no pituitary tumor rem-
manifestations are those typical of Cushing’s syndrome. The first
nants could be detected in either location. Macroscopic exami-
neurologic signs are almost always subtle. Common initial signs
nation of the adrenal glands revealed a 3 cm 3 2 cm 3 2 cm right
include dullness, listlessness, and decreased appetite. Those signs
adrenal gland and a focally distended wall of the caudal vena cava
may progress to anorexia, restlessness, loss of interest in normal
(Figure 4B). No abnormalities were found in other endocrine
activities, delayed response to stimuli, and episodes of disori-
tissues. Histologic examination of the right adrenal gland showed
entation. Signs exhibited by dogs with very enlarged pituitary
a solid neoplasm arranged in lobules that were separated by
tumors include obtundation, stupor, ataxia, tetraparesis, and
FIGURE 4
A: Postmortem sagittal midline view of the brain. There are no pituitary tissue remnants ventral to the hypothalamic region
(arrow). B: The right adrenal gland is uniformly enlarged and bosselated (arrow). A concurrent marked distension of caudal vena cava is evident (arrowhead). C: The right adrenal gland has a pheochromocytoma. The neoplastic tissue is arranged in lobules separated by abundant fibrovascular stroma. Hematoxylin and eosin staining, bar ¼ 50mm. D: Neoplastic cells of the pheochromocytoma display a strong, diffuse cytoplasmic immunoreactivity to neuron-specific enolase. Diaminobenzidine chromogen and hematoxylin counterstaining, bar ¼ 50mm.
4
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Surgical Removal of a Pituitary Adenoma
aimless pacing.11 Less frequently observed problems include
pituitary tumor regrowth.4 In the case reported herein, complete
nystagmus, circling, head pressing, behavior changes, blindness,
tumor removal was monitored with postoperative UCCRs and
seizures, and coma.
11
complemented with periodic CT scans of the pituitary region and
The most common treatment in dogs with pituitary-
ultimately confirmed by an empty fossa on postmortem exami-
dependent hypercortisolism (PDH) has been the medical ther-
nation. This case shows, for the first time, that even in the case of
apy with either mitotane or with a competitive inhibitor of adrenal
a pituitary adenoma . 20 mm in width, complete tumor removal
3b-hydroxysteroid dehydrogenase (trilostane).
11,12
Although ef-
and remission of hypercortisolism are possible.
fective, those treatments are not directed at the elimination of the
In humans, giant pituitary tumors are defined by some
primary pituitary lesion. Early diagnosis, pituitary imaging, and
authors based on extension on the local structures.21 A recent study
treatment at the pituitary level should be the hallmarks of a di-
in dogs demonstrated that pituitary masses with a vertical height
agnostic and treatment protocol for canine PDH. Surgery,
. 19 mm were more likely to be invasive adenomas; however, in
medication, and radiotherapy are used to treat various types of
the case reported herein, the authors did not detect any evidence
2
pituitary adenomas in humans.
13
Selective pituitary adenomec-
of invasive behavior of the adenoma.22
tomy is still considered the first line of treatment of Cushing’s
There are no detailed studies on outcome after trans-
disease in humans. Radiotherapy is also an option for treatment
sphenoidal hypophysectomy in dogs with pituitary adenomas
of pituitary corticotroph adenomas in humans and companion
with a diameter . 20 mm. In a large study including 181 dogs
animals.
14–19
It can be used as either a secondary treatment after
that underwent hypophysectomy, there was only 1 dog with
unsuccessful pituitary surgery or as a primary treatment in
a pituitary tumor with a P/B of 1.1 and a diameter of 18 mm that
patients when surgery is contraindicated (i.e., invasive macro-
was successfully removed, which was comparable to the case
adenoma) or in the presence of a more aggressive malignant tu-
reported here.4 However, in the latter case, no detailed follow-up
mor (adenocarcinoma).15,18,20 In one study, 24 dogs with enlarged
information was available except that there was remission of
pituitary tumors (diameter $ 10 mm) were irradiated and had
disease. In two recent case series of dogs with PDH treated with
mean and median overall survival times of 15.7 mo 6 2.9 mo and
transsphenoidal hypophysectomy, the dimensions of the pitui-
11.7 mo 6 5.9 mo, respectively. The authors of that study con-
tary adenomas were not reported; however, the biggest pituitary
cluded that radiation therapy is effective in dogs with mild to
adenomas had a P/B of .69 and .70, respectively.23,24
moderate neurologic signs, but did not improve survival in dogs 17
Pheochromocytoma is a tumor of the chromaffin cells of the
In a more recent study, 19 dogs
adrenal medulla or sympathetic paraganglia.1 A variety of vague
with pituitary masses (median height, 13 mm; range, 7–21 mm)
and nonspecific clinical signs attributed to excessive secretion of
with severe neurologic signs.
were irradiated. Mean survival time was 46.8 mo (95% confidence
catecholamines has been reported in dogs with pheochromocy-
interval, 35.1–58.4 mo) and the tumor size was identified as
toma, and antemortem diagnosis is difficult.25 Similarly, in the
a negative prognostic factor for survival.19 In dogs with PDH,
case reported herein, the pheochromocytoma was only discovered
pituitary irradiation was more effective in delaying tumor growth
at necropsy.
15,17,18
than in controlling ACTH secretion.
Excessive panting, acute respiratory distress, weakness, and
An extended follow-up of 181 dogs treated with PDH
clinical deterioration are commonly reported clinical signs of
over a 12 yr period proved the effectiveness of transsphenoidal
pheochromocytoma.25 Those signs were present in this dog and
hypophysectomy for canine PDH.
3,4,7
In one of these studies,
prognostic factors for the outcome after transsphenoidal hy-
could be explained by the presence of a functional pheochromocytoma.
pophysectomy were determined.4 The results of that study
Previous reports of the coexistence of PDH and pheochro-
showed that, among others factors, pituitary size negatively af-
mocytoma suggest that the combination is not rare in dogs and,
fects survival and remission of disease after hypophysectomy
therefore, should not be regarded as an incidental finding.25–28
in dogs with PDH. In the present case, remission of hyper-
In humans, the occurrence of those tumors in the same pa-
cortisolism was confirmed by repeated measurements of UCCRs
tients has been speculated to be related to aberrant neural crest
and postoperative CT scanning. That finding was surprising be-
development.29
cause the primary aim of surgery was debulking of the pituitary mass to alleviate the neurologic signs. Postoperative UCCRs can
Conclusion
be used to monitor surgical outcome and recurrence of hyper-
This case report demonstrates, for the first time, that an enlarged
cortisolism in the case of Cushing’s disease and, indirectly,
pituitary adenoma . 20 mm, causing neurologic deficits due to
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the mass effect, may be treated successfully by transsphenoidal hypophysectomy. FOOTNOTES a Synacthen; Novartis, Origgio, Italy b Dexadreson; Intervet, Peschiera Borromeo, Italy c Modrenal; Wanskerne, St. Austell, England d Visipaque320; Amersham Health AS, Cork, Ireland e Minrin; Ferring, Hoofddorp, The Netherlands f Solu-Cortef; Upjohn, Ede, The Netherlands g Propofol-Lipuro; Braun Medical Supplies, Melsungen, Germany h Synulox; Pfizer Animal Health, Capelle a/d IJssel, The Netherlands i Baytril; Bayer, Kiel, Germany j Cortisoni acetate; Genfarmam, Maarssen, The Netherlands k L-thyroxine; Aesculaap; Boxtel, The Netherlands l Chromogranin A; Dako Cytomation, Glostrup, Denmark m Synaptophysin; Dako Cytomation, Glostrup, Denmark n Neuron-specific enolase; Dako Cytomation, Glostrup, Denmark o S100; Dako Cytomation, Glostrup, Denmark p Cytokeratin clones AE1/AE3; Dako Cytomation, Glostrup, Denmark REFERENCES 1. Kiupel M, Capen C, Miller M, et al. Histological classification of tumors of the endocrine system of domestic animals. World Health Organization international histological classification of tumors of domestic animals, second series, vol. 12. Gurnee (IL):Charles Louis Davis DVM Foundation; 2008:17. 2. Kooistra HS, Voorhout G, Mol JA, et al. Correlation between impairment of glucocorticoid feedback and the size of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism. J Endocrinol 1997;152(3):387–94. 3. Hanson JM, van ’t HM, Voorhout G, et al. Efficacy of transsphenoidal hypophysectomy in treatment of dogs with pituitarydependent hyperadrenocorticism. J Vet Intern Med 2005;19(5): 687–94. 4. Hanson JM, Teske E, Voorhout G, et al. Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism. J Neurosurg 2007;107 (4):830–40. 5. Chacko G, Chacko AG, Lombardero M, et al. Clinicopathologic correlates of giant pituitary adenomas. J Clin Neurosci 2009;16(5): 660–5. 6. Meij BP, Voorhout G, Van den Ingh TSGAM, et al. Transsphenoidal hypophysectomy in beagle dogs: evaluation of a microsurgical technique. Vet Surg 1997;26(4):295–309. 7. Meij BP, Voorhout G, van den Ingh TSGAM, et al. Results of transsphenoidal hypophysectomy in 52 dogs with pituitarydependent hyperadrenocorticism. Vet Surg 1998;27(3):246–61. 8. Fracassi F, Mandrioli L, Diana A, et al. Pituitary macroadenoma in a cat with diabetes mellitus, hypercortisolism and neurological signs. J Vet Med A Physiol Pathol Clin Med 2007;54(7): 359–63. 9. van Vonderen IK, Kooistra HS, Rijnberk A. Influence of veterinary care on the urinary corticoid:creatinine ratio in dogs. J Vet Intern Med 1998;12(6):431–5.
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