Transsphenoidal hypophysectomy for the treatment of hypersomatotropism secondary to a pituitary somatotroph adenoma in a dog

Abstract Pituitary‐dependent hypersomatotropism is rarely diagnosed in dogs and surgical treatment is not reported. A 6‐year‐10‐month male neutered Patterdale Terrier presented with polyuria, polydipsia, progressive pharyngeal stertor, excessive hair growth and widened facial features and paws. Serum insulin‐like growth factor‐1 concentration via radioimmunoassay was consistent with hypersomatotropism (1783 ng/mL). A pituitary mass was identified on magnetic resonance and computed tomography imaging. Six weeks later, glucosuria, starved hyperglycemia and serum fructosamine above the reference range (467.6 μmol/L, RI 177‐314) were documented, consistent with diabetes mellitus. Transsphenoidal hypophysectomy was performed under general anesthesia without complications. Pituitary histopathology identified an acidophil neoplasm, with positive immunostaining for growth hormone. Postoperatively, there was rapid resolution of clinical, biochemical and morphologic changes of hypersomatotropism with persistence of diabetes mellitus. This case demonstrates successful resolution of hypersomatotropism with ongoing diabetes mellitus in a dog after surgical treatment by transsphenoidal hypophysectomy.

Hospital) with a 3-month history of polyuria and polydipsia (PUPD), weight gain, lethargy, increased coat length and progressive inspiratory stertor.Physical examination revealed broad facial features, widened paws and increased facial hair length (Figure 1).Interdental spaces were wide and there was a mild prognathia inferior (Figure 1).
A mild pharyngeal stertor was evident.No other abnormalities were detected on physical examination.
Hematology and serum biochemistry findings at presentation are documented in Supplemental Tables 1 and 2. Urinalysis did not reveal abnormalities with no glucosuria present.Urine protein: creatinine ratio was 0.56 (RI < 0.5).Thyroid hormone tests were consistent with euthyroidism as serum total thyroxine (TT4) was 1.42 μg/dL Magnetic resonance imaging (Ingenia Ambition 1.5 Tesla, Phillips, Amsterdam, Netherlands) of the head revealed a moderately enlarged pituitary gland (maximum height 6.4 mm), predominantly hypo-to isointense to surrounding gray matter on T2-weighted images with no evidence of mass effect on the surrounding brain parenchyma  Transsphenoidal hypophysectomy was performed largely as previously described, with the additional use of a surgical head clamp (Brainsight, Rogue Research, Canada) as reported in cats for rigid head positioning. 5,6The entirety of the grossly visible cream colored pituitary gland was extirpated using a combination of neurosurgical forceps, probes and gentle suction.The pituitary fossa was inspected after pituitary gland removal using a 2.7 mm rigid endoscope (Hopkins Forward-Oblique Telescope 30 , Karl-Stortz, Slough, UK) to confirm that there were no macroscopically visible remnants.Closure was performed as previously described (Supplemental Information).Postoperative CT imaging of the head revealed a 5.2 mm Â 8.9 mm defect in the basisphenoid bone, with an air-filled cavity within the pituitary fossa occupying the region of the excised pituitary gland (Figure 2).were discontinued 12 hours postoperatively and oral hormone supplementation was instituted (0. Histopathology of the excised pituitary gland was consistent with a pituitary acidophil neoplasm.Sections from the pituitary gland were immunostained using a rabbit antiporcine GH antibody, as previously described. 7Sections from a formalin-fixed normal pituitary gland from a dog were used as controls.The pituitary tissue was infiltrated with a uniform population of polygonal acidophilic cells which were positively immunostaining for growth hormone and associated with loss of normal reticulin pattern.These findings were consistent with a growth hormone producing pituitary neuroendocrine neoplasm/ somatotroph adenoma (Figure 3; full protocol in Supplemental Information).
The dog was discharged 4 days postoperatively, at which time serum IGF-1 concentration had decreased to 396 ng/mL (Figure 4), then returned 11 weeks later for a follow up appointment.Soon after discharge the dog was persistently hyperglycemic and insulin lente therapy was restarted and gradually increased to 0.3 U/kg twice daily.
PUPD had resolved and there were morphological signs of acromegaly resolution, with a return to normal hair length and head appearance (Figure 1), and no inspiratory stertor.There was normalization of the previous mild anemia and serum biochemistry also revealed no abnormalities other than mild hypoglycemia and increased fructosamine (see Supplemental Tables 1 and 2).Serum IGF-1 concentration was 49 ng/mL, consistent with biochemical remission of hypersomatotropism (Figure 4), and TT4 was 1.32 μg/dL (RI 0.39-3.42μg/dL; 17 nmol/L; RI 13-51 nmol/L).The owners reported that the dog was mildly lethargic and was displaying heat-seeking behavior.These clinical signs subsequently resolved after an increase of oral levothyroxine dosing to 30 μg/kg once daily.Conjunctival desmopressin was substituted for oral desmopressin acetate (0.1 mg total BID; Aspire Pharma Limited, UK) because of concerns regarding iatrogenic conjunctivitis with the use of desmopressin drops.Six months after surgery serum IGF-1 concentration was 35 ng/mL (Figure 4).
At 12-month follow-up after surgery, the dog was reported to have normal energy levels with no recurrence of previous clinical signs of hypersomatotropism and had normal water intake.The dog was receiving the postoperative medications described above and 0.25 U/kg of subcutaneous insulin lente every 12 hours.

| DISCUSSION
This is a case of a diabetic dog with acromegaly because of a pituitary somatotroph adenoma treated with transsphenoidal hypophysectomy.
The reported clinical signs associated with hypersomatotropism, ing and pituitary histology.Pituitary histopathology from acromegalic dogs has rarely been described. 3,8Acidophil proliferation accompanied by positive immunostaining for GH in previous cases was similar to our dog and is 1 criteria for the diagnosis of pituitary somatotroph adenomas/neuroendocrine tumor in humans. 9In humans with acromegaly, various histologic tumor subtypes have been described and may have some relevance to prognosis in human acromegaly treatment. 10Subclassification of tumor types is based on histopathological, immunohistochemical and electron microscopy findings that are currently not utilized in veterinary practice.Pituitary acidophil neoplasms can secrete only GH or prolactin (PRL) concurrently, with the latter being less common and sometimes clinically silent. 10Around 30% of humans with acromegaly will have mixed GH and PRL-secreting pituitary tumors.2][13] PRL staining was not performed in this case and might have been useful to exclude a mixed GH and PRL-secreting tumor although the clinical relevance of such a classification is unknown in dogs.Alongside the pituitary mass, CT imaging also revealed thickened cortices of several limb bones.While this is a subjective finding and should be treated with caution, it could be consistent with thickened bones that have been described in the skull of cats with acromegaly. 14tuitary surgery is the preferred treatment option in human medicine, because of high and rapidly achieved remission rates. 15Transsphenoidal hypophysectomy was elected in this dog because of the potential for achieving biochemical and clinical remission of hypersomatotropism, based on findings in humans and cats.Recently, transsphenoidal hypophysectomy has been shown to be an effective treatment option for hypersomatotropism-induced diabetes mellitus in cats with high rates of diabetic remission (71%-92%) and median survival times of 853-1347 days reported. 6,16,17[20] Treatment modalities reported for acromegaly resulting from pituitary tumors in dogs are limited to 2 previous case reports, treated with conventional radiation therapy and medical management. 2,4Following radiation therapy in these dogs, both cases had persistent clinical signs of hypersomatotropism and increased serum IGF-1 concentration, although this subsequently resolved in 1 dog after treatment with pasireotide.There was improvement in glycemic control in both cases, and 1 dog achieved diabetic remission.While newer techniques, such as stereotactic radiation therapy, have been reported for the treatment of hypersomatotropism and diabetes mellitus in cats, diabetic remission rates are not as high as those reported with surgical management, and little information is available regarding changes in serum IGF-1 concentration following treatment. 21,22rum IGF-1 concentration in our dog decreased rapidly to normal following surgery (396 ng/mL) and was persistently decreased at 11 weeks postoperatively (49 ng/mL), demonstrating the effectiveness of this procedure in achieving biochemical remission of acromegaly in this dog.As a result, surgical treatment by transsphenoidal hypophysectomy was effective in achieving remission of acromegaly in this dog and can be considered as a first-line treatment for dogs with pituitary adenoma-associated growth hormone excess.While there is evidence of treatment benefit associated with medical management, [23][24][25][26][27] transsphenoidal hypophysectomy provides the additional potential for a curative treatment by removing the hormone-producing pituitary tumor.
A notable postoperative complication in this case was the development of transient hypernatremia, likely associated with iatrogenic central diabetes insipidus because of the sudden loss of antidiuretic hormone secretion following removal of the posterior pituitary gland. 19Increases in serum sodium are documented in dogs and cats after hypophysectomy and careful monitoring of sodium status is an important postoperative consideration. 6,17,28Clinicians should be aware of the need for frequent monitoring of fluid and electrolyte balance, supplementation with synthetic desmopressin, provision of adequate oral free water and the use of appropriate intravenous fluid therapy.
A feature of this case was the absence of overt diabetes mellitus at the time of initial diagnosis, its subsequent development and then persistence after hypophysectomy and resolution of hypersomatotropism.This is in contrast to the situation in most cats, where almost all cases of acromegaly are diagnosed as a result of having insulinresistant diabetes mellitus. 298,30 PUPD was present before overt diabetes mellitus developed in this dog, although markedly worsened after the onset of DM.PUPD and polyphagia without DM has been noted in 1 dog with pituitary-dependent acromegaly, although this case was shown to have impaired glucose tolerance. 12It is unclear if this was also the case for the dog described in this report.

ACKNOWLEDGMENT
No funding was received for this study.The authors thank Dr Frederik Allan, MRCVS, for his help in facilitating growth-hormone staining of the pituitary gland in this case.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.
F I G U R E 4 Serum insulin like growth factor-1 (IGF-1) concentrations before and after transsphenoidal hypophysectomy.Dashed line indicates IGF-1 of 1000 ng/mL (reference values are derived from the reference laboratory guidelines: adults of large breeds >200 ng/mL, puppies >500 ng/mL, dwarfism <50 ng/mL, acromegaly >1000 ng/mL; Nationwide Specialist Laboratory Services Ltd, UK).

(Figure 2 )
. Computed tomography (CT; Aquilion Lightning 80, Canon Medical Systems, California, United States) of the head, thorax and abdomen demonstrated a moderately enlarged, uniformly contrastenhancing pituitary gland (Figure 2) as well as thickened soft palate/ pharyngeal tissue and thickened cortices of the humerus, femur and tibia.There was mild hepatomegaly, and the remainder of the CT study did not reveal further abnormalities.The owner elected for hypophysectomy.In the week before presentation for surgery the dog developed more marked PUPD, was F I G U R E 1 Photographs illustrating morphological changes in a 6-year-10-month male neutered Patterdale Terrier with acromegaly.(A) Normal hair length before diagnosis.(B) Increased hair length and large paws noted by the owners at the time of diagnosis.(C) Prognathism and widened interdental spaces seen preoperatively.(D) Normalization of hair length seen at 11-week postoperative reexamination.
Postoperatively the dog made a rapid recovery without complications or neurological deficits.Insulin and hydrocortisone infusions F I G U R E 2 Sagittal (A) and transverse (B) T2-weighted magnetic resonance imaging (MRI) image of the brain, showing a largely T2-weighted hypointense, moderate enlargement of the pituitary gland, with no significant mass effect (white arrows).Transverse computed tomography (CT) reconstructions of the pituitary mass at the time of diagnosis (C-post contrast) and 15 minutes postoperatively under the same general anesthetic (D), demonstrating the absence of the previously present contrast-enhancing pituitary mass.Postoperatively the surgical burr hole in the basisphenoid bone is evident, ventral to a radiolucent air-filled pituitary fossa, with a small volume of air present in the third ventricle.
including hair coat changes and inspiratory stertor, resolved by 11 weeks postoperatively.Biochemical remission of hypersomatotropism was achieved and persisted for the 12 months recorded postoperatively.Despite improvements in glycemic control, the dog remained diabetic.As a result, given the clinical and biochemical remission of hypersomatotropism, it is possible that diabetes mellitus developed independently from acromegaly in this dog or irreversible pancreatic beta cell dysfunction occurred secondary to the hypersomatotropism.Definitive diagnosis of hypersomatotropism was achieved through a combination of compatible clinical signs, increased serum IGF-1 concentration, evidence of a pituitary mass on advanced imag-

F I G U R E 3
Sections through the excised pituitary neoplasm.(A) H&E.Expanding the pars distalis and compressing the adjacent nonneoplastic parenchyma (arrow) is an unencapsulated poorly demarcated neuroendocrine neoplasm.(B) H&E.Higher magnification of the densely cellular acidophilic neuroendocrine neoplasm, which is composed of polygonal eosinophilic cells exhibiting moderate pleomorphism and occasional mitotic figures (inset; arrowhead).(C) Reticulin.Within the neoplasm there is diffuse loss of the preexisting pars distalis reticular framework compared to a control pituitary gland (inset).(D) Immunohistochemistry (IHC) with antibodies against multicytokeratin (AE1/AE3).There is negative immunostaining of the neoplastic cells.There is strong cytoplasmic immunostaining of the compressed nonneoplastic acidophils (topleft).(E-F) IHC with antibodies against growth hormone.(E) Control pars distalis.There is strong cytoplasmic immunostaining of nonneoplastic acidophils.(F) Neoplasm.There is diffuse moderate to strong cytoplasmic immunostaining of the neoplastic cells (inset).