by Rachel Rivenburg, DVM*, Tina Jo Owen, DVM, DACVS, Linda G. Martin, DVM, MS, DACVECC, Annie V. Chen, DVM, MS, DACVIM (Neurology)
From WestVet Emergency and Specialty Center, Boise, Idaho (R.R.); and Department of Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington (T.J.O., L.G.M., A.V.C.).
Correspondence: tina.ow[email protected] (T.J.O.)
Accepted for publication: January 24, 2020.
ACTH (adrenocorticotropic hormone); CDI (central diabetes insipidus); CT (computed tomography); DM (diabetes mellitus); GH (growth hormone); HST (hypersomatotropism); IGF-1 (insulin-like growth factor 1); P/B (pituitary/brain); PD (polydipsia); PDH (pituitary-dependent hyperadrenocorticism); PU (polyuria); TSH (transsphenoidal hypophysectomy)
Medical management is currently the most common treatment for pituitary-dependent hyperadrenocorticism and hypersomatotropism/acromegaly in veterinary medicine. Medical management does not provide a cure for either disease process, and rarely is pituitary imaging a part of initial diagnostics. Early pituitary imaging in animals with clinically functional pituitary tumors provides a baseline assessment, allows monitoring of tumor changes, and permits radiation and surgical planning. Surgery is the only treatment for pituitary tumors that has curative intent and allows for a definitive diagnosis. Surgical removal of pituitary tumors via transsphenoidal hypophysectomy is an effective treatment for clinical pituitary tumors in patients exhibiting endocrine abnormalities associated with pituitary-dependent hyperadrenocorticism and hypersomatotropism. Surgery, however, is rarely pursued until patients have failed medical management, and often not until they are showing neurologic signs, making surgical success challenging. It is well documented that dogs surgically treated when the pituitary mass is small have a lower mortality, a lower recurrence rate, and a longer survival than those with larger pituitary masses. Providing owners with the option of early pituitary imaging in addition to medical, surgical, and radiation treatment options should be the standard of care for animals diagnosed with pituitary-dependent hyperadrenocorticism or hypersomatotropism.
Pituitary-dependent hyperadrenocorticism (PDH), which affects both dogs and cats, and hypersomatotropism (HST)/acromegaly, which primarily affects cats, are both caused by a pituitary tumor secreting excess hormone.1–5 Overproduction of adrenocorticotropic hormone (ACTH) is responsible for PDH and an overproduction of growth hormone (GH) causes acromegaly/HST. Acromegaly is the term used to describe the phenotypic characteristics that result from HST. In cats, these phenotypic characteristics include broad facial features, prognathism, and clubbed paws, among others.4,5
Hyperadrenocorticism is a common endocrine disorder in older dogs, with a reported incidence of 0.2%, or one to two cases per 1000 dogs per year; this translates to ~100,000 dogs afflicted annually in the United States.6,7 Of these cases, ~85% are PDH.1 PDH in the cat is rare. In a recent study, Niessen et al. reported that 25% of diabetic cats examined in the United Kingdom were ultimately diagnosed with HST.8 Diabetic cats were screened for HST by measuring insulin-like growth factor-1 (IGF-1), and 26% of them had elevated IGF-1. Of those cats, 20% underwent pituitary imaging, and 89% had a definable pituitary tumor on computed tomography (CT).8 These emerging data suggest that pituitary tumors resulting in HST are underdiagnosed in the diabetic cat population.
Currently, in the United States, the most common treatments for these pituitary tumors are medical management and radiation therapy; surgery is exceedingly rare compared with parts of Europe. Surgery (transsphenoidal hypophysectomy [TSH]) is the treatment of choice in the Netherlands and the United Kingdom for pituitary tumors in dogs and cats.9–12 The authors advocate for a shift in the standard treatment options in the United States for canine and feline pituitary tumors, with surgery included in the discussion with owners as TSH becomes more available in the United States.
Long-term survival and endocrine remission with TSH are good.6,9–11,13,14 TSH addresses the underlying cause, the pituitary tumor, while also directly addressing the mass effect of the tumor and the endocrine dysfunction. Remission or improvement with TSH is more immediate, whereas medical management and/or radiation therapy may take several months.15–28
Although medical management remains the most common treatment for PDH and radiation therapy the most common for HST in the United States, both diseases can be successfully treated with TSH.6,9–11,14 Indeed, Feldman and Nelson state that TSH is the treatment of choice for dogs with PDH, a treatment limited only by the availability of an experienced surgical team.29
Importantly, TSH is the only treatment that offers the potential for a cure when complete removal of the pituitary tumor is achieved and can be a treatment option at all stages of PDH and HST. It is well documented that dogs treated early with TSH when the pituitary mass is small have a lower mortality, a lower recurrence rate, and a longer survival than those with larger pituitary masses.10 TSH allows for rapid improvement of endocrine signs and the opportunity to determine tumor type in dogs and cats with larger tumors. TSH also allows for decompression of the brain and rapid improvement of neurologic signs. Early pituitary imaging in patients diagnosed with PDH or HST is an important component of a complete diagnostic workup and will provide crucial information in deciding if a patient is a surgical candidate.
This paper is written with the intent of providing general practitioners and specialists information about the diagnosis, treatment (medical management, radiation therapy, and surgery), and surgical case selection for patients diagnosed with PDH or HST/ acromegaly.
Confirmation of PDH or HST must be made before considering treatment options. It is reported that between 20 and 100% of dogs with PDH have a histologically confirmed pituitary adenomawith the others having pituitary hyperplasia.1 The majority of dogs presenting with PDH are >9 yr of age with no definitive data suggesting a sexrelated prevalence.1 PDH tends to affect smaller dogs, with 75% of dogs weighing <20 kg.1 The most common presenting clinical signs for canine PDH include polyuria (PU), polydipsia (PD), polyphagia, panting, abdominal distension, endocrine alopecia, and musculoskeletal changes, among others.1 Neurologic signs, such as altered mentation and behavior, seizures (although rare), or poor appetite, may also be seen with PDH.1 A recent study by Menchetti et al. described neurologic signs, including abnormal mentation and behavior as well as gait and postural reaction abnormalities, in dogs with an enlarged pituitary gland.30 Dogs in this study also frequently had cervical hyperesthesia, potentially reflecting pain due to the mass effect and brain compression. Neurologic signs were positively associated with the size of the pituitary mass.30
Hyperadrenocorticism is rare in cats with PDH, accounting for 75–80% of cats diagnosed with Cushing’s disease; 80% of cats with PDH will have concurrent diabetes mellitus (DM).2 Clinical signs beyond those associated with DM may be subtle but can include abdominal enlargement, unkempt or thinning hair coat, muscle weakness, changes in mental status, and worsening neurologic status.2 Skin fragility is often seen secondary to hypercortisolism in cats.2
HST/acromegaly is most commonly diagnosed in diabetic cats >7 yr of age, of whom the majority are male domestic shorthairs and domestic longhairs, weighing 5–7 kg.3 The most common early clinical signs include PU/PD and polyphagia, as well as ataxia, weakness, and plantigrade stance caused by diabetic neuropathy.3 Weight loss can be seen in cats with both DM and HST; however, cats with HST often have a robust body condition or may even gain body mass in the face of unregulated blood glucose levels.3 Increased secretion of GH leading to insulin resistance is the suspected cause of DM.3
Many effects of GH are mediated by IGF-1.3 IGF-1 secretion predominantly occurs in the liver under direct stimulation by pituitary-derived GH. Normally, GH secretion is suppressed by negative feedback mechanisms; however, when there is overproduction of GH secondary to a pituitary adenoma, negative feedback mechanisms fail, and GH secretion continues unchecked, resulting in constant stimulation of hepatic IGF-1 secretion.8,31 GH antagonizes the peripheral action of insulin and has a direct action on pancreatic islets to increase β-cell secretory capacity potentially causing β-cell hyperplasia.32 Prolonged GH hypersecretion leads to DM because insulin secretory capacity is exceeded.32
GH assays have historically not been widely available in the United States, and GH measurement may not be an ideal diagnostic test because GH secretion can be pulsatile in nature and has an extremely short half-life.31,33 IGF-1 has a much longer half-life than GH as well as greater stability.32,33 Other than DM, most clinical features of acromegaly (i.e., overgrowth of soft tissue, bony enlargement, organomegaly) are the result of an indirect anabolic effect of GH excess mediated by IGF-1 secretion.31 Therefore, circulating IGF-1 concentrations serve as a biomarker for GH hypersecretion.31
The United States reports IGF-1 in SI units of nmol/L, whereas the United Kingdom and the Netherlands report in ng/mL and mg/L, respectively.34 It is important to note the units of measurement to avoid errors. Cats with DM and clinical signs suspicious of HST/ acromegaly typically have an IGF-1 level >131 nmol/L (SI units) or >1000 ng/mL.4,5
Although HST is becoming an increasingly recognized cause of insulin resistance, a large proportion of cats with HST remain undiagnosed because of a lack of phenotypic expression of HST/acromegaly.8 Phenotypic signs include enlargement of the head, abdomen, and paws (50–83%), prognathia inferior (35–71%), and hepatomegaly and/or renomegaly (26–100%), among others.3 It is also possible for cats to be acromegalic but not develop DM.35 Because some acromegalic cats may not develop insulin resistance and others may not have phenotypic expression of HST, advanced imaging of the pituitary gland is recommended as an early diagnostic tool in the assessment of the diabetic or acromegalic cat following documentation of elevated IGF-1 concentrations.3,8
Diagnosis of PDH or HST/acromegaly is made using history, signalment, physical exam findings, endocrine testing, and advanced imaging of the pituitary gland. It is beyond the scope of this paper to provide an in-depth discussion of endocrine diagnosis; readers should consult other sources for more details.1,3,13,36,37 MRI and CT imaging are the primary modalities used for diagnosing pituitary masses. MRI is preferred for soft tissue and intracranial structures, although CT imaging is less expensive, may not require anesthesia, and is a more readily available diagnostic screening tool for pituitary tumors.13,38
The 2012 American College of Veterinary Internal Medicine consensus statement on spontaneous canine hyperadrenocorticism recommends that pituitary imaging be considered for all dogs diagnosed with PDH and considers imaging essential for those exhibiting neurologic signs.37 We suggest adoption of a similar early pituitary imaging protocol for cats diagnosed with HST because radiation and TSH are more effective when treating small pituitary tumors in patients not exhibiting neurologic signs.10
Pituitary imaging is recommended before implementing medical management and essential for treatment planning before TSH or pituitary irradiation.37,39,40 Two related papers followed dogs newly diagnosed with PDH for 1 yr. Bertoy et al. in 1995 evaluated 21 dogs diagnosed with PDH. These dogs did not have neurologic signs at the time of initial diagnosis and had not received any treatment at the time of the initial MRI. On MRI, 11 of 21 dogs (52%) had a visible mass measuring between 3 and 12 mm at the greatest vertical height.39 In 1996, Bertoy et al. reported results of repeat MRI 1 yr later in 13 dogs from the original paper. Of these 13 dogs, 12 had been treated with mitotane.40 Five of the 13 dogs had a normal MR image 1 yr before; however, 1 yr later 3 dogs had a normal MR image whereas 2 had a visible pituitary mass.40 Eight dogs diagnosed 1 yr before with a mass also had a visible mass on follow-up, with 4 of the 8 having an increase in vertical height of the original mass and 2 dogs developing neurologic signs.40 Five of the original 21 dogs had a pituitary mass measuring >10 mm; 4 of the 5 developed neurologic signs. None of the dogs with a mass <10 mm developed neurologic signs.40 Ten of 13 dogs diagnosed with PDH either initially or at 1 yr follow-up had a visible pituitary mass. Bertoy et al. concluded that drugs such as mitotane that are directed at the adrenal glands may contribute to growth of pituitary masses.39,40 Furthermore, a study by Teshima et al. in 21 healthy dogs assessed by MRI revealed significant pituitary enlargement over a 16 wk course of trilostane administration, adding additional support to the possibility of medical treatment accelerating the growth of pituitary adenomas and the onset of neurologic signs due to pituitary gland enlargement.41
CT can be useful for identifying a pituitary adenoma. Dynamic contrast-enhanced CT can identify a so-called pituitary flush: the arterial blood supply of the neurohypophysis seen slightly earlier than the enhancement of the adenohypophysis through the portal blood supply. Displacement, distortion, reduction, or disappearance of the pituitary flush in the early phase of dynamic contrast-enhanced CT can be used to identify microadenomas or nonenlarged pituitary tumors.42,43
Medical Management of PDH in Dogs
Administration of mitotane, trilostane, ketoconazole, or selegiline can improve the quality and length of life for many patients.16–19 Medical management, however, fails to address the underlying pituitary tumor and requires lifelong administration of medications by owners with regular monitoring.13 In addition, mitotane and trilostane have well-documented side effects.17,19 Reported remission rates of some clinical signs in dogs treated with trilostane are between 70 and 86%.19,44 This high rate of remission may reflect the fact that these studies included dogs who had improvement of PU/ PD alone but not other clinical signs. Published mean survival times of dogs with PDH treated twice daily with trilostane is 930 days (2.55 yr).19 Complete disease remission, however, is rarely achieved with medical management of PDH, although remission of certain clinical signs such as PU/PD, alopecia, and diabetes can occur.19
Medical Management of Acromegaly/HST in Cats
Most cats with HST develop insulin-resistant DM secondary to the antagonistic effects of elevated GH at the level of the insulin receptor.3,45 Insulin resistance and persistent clinical signs of DM are common problems that require frequent escalation of the insulin dose, increased veterinary monitoring, and added costs that can make treatment financially unrealistic and create owner frustrations with the long-term medical management of such cats.45
Pasireotide decreases IGF-1 concentrations and improves insulin sensitivity.46 In the study by Gostelow et al. evaluating monthly pasireotide treatment in cats with HST, 3 of 14 cats in the trial went into diabetic remission ~90 days after the initiation of treatment, and, with monthly injections of pasireotide, 2 of 3 cats remained in remission until death; the third cat was alive at 1420 days at the time of writing of the article. There were significant decreases in IGF-1 concentration, q 12 hr insulin dose, and Insulin Resistance Index over the 6 mo trial period.46 Eleven of 14 cats experienced adverse effects, the most common being diarrhea, occurring in 76% of the cats and prompting withdrawal of 2 cats from the study. Other adverse events were hypoglycemia in 5 cats, polyphagia in 2 cats, transient injection site reaction in 1 cat, and delayed hair growth in 1 cat.46 It is unknown whether pasireotide has any effect on decreasing the size of the pituitary mass, and no information was provided on improvement of clinical signs related to acromegaly.46 Statistics for long-term survival time for cats with HST treated with pasireotide are not currently available given the expense and difficulty in obtaining the medication and lack of more long-term studies.
Although medical management (insulin and/or pasireotide) treats clinical signs and is, in general, a safe option for HST, it does not address the space-occupying effects, compression and destruction of adjacent brain tissue with subsequent neurologic signs, or the growing pituitary tumor. Remission of HST is rarely achieved with medical management.
Radiation protocols for the treatment of PDH and HSTare still being researched and vary in the literature; treatment options include conventionally fractionated, coarse-fractionated, single-fraction radiotherapy, and stereotactic radiation therapy.20–27 Marcinowska et al. found significantly longer mean survival times with 10 fractions versus the same total dose divided over 5 fractions. However, the authors state that further studies are needed to establish the optimum radiotherapy protocol for the treatment of canine pituitary tumors.20
In 14 of 19 dogs with PDH and pituitary tumors treated with radiation using a 4 MV linear accelerator delivering sixteen 3 Gy (48 Gy) fractions on a Monday-through-Friday schedule, there was 93% survival at 1 yr with a mean survival of 1405 days (3.85 yr).27 However, clinical signs and results of endocrine testing did not improve in 6 of 14 of these dogs.27 Radiation therapy in dogs with severe neurologic signs such as stupor and being nonambulatory was associated with a 6.6-fold greater risk of death due to their pituitary tumor than that in dogs who presented with less severe neurologic signs.28 These findings again highlight the importance of early diagnosis with pituitary imaging and intervention.
Radiation can decrease tumor size by 25–50% and lower the insulin requirement in acromegalic cats; however, radiation alone is unlikely to completely resolve all clinical signs related to a functional pituitary tumor.21,24–26,47 In cats with pituitary tumors undergoing a variety of radiotherapy protocols, 60–90% no longer needed insulin or had improved insulin response and a partial or complete remission of neurologic signs.21,25,26
A recent study by Wormhoudt et al. showed a median survival time of 1072 days (2.94 yr) for acromegalic cats who underwent stereotactic radiation therapy.21 Ninety-five percent (39 of 41) of cats experienced a decrease in their required insulin dose, with 32% (13 of 41) achieving diabetic remission. Diabetic remission was permanent (until death or lost to follow-up) in 62% (8 of 13) and temporary in 38% (5 of 13).21 Mean survival time in studies evaluating conventionally fractionated, coarse-fractionated, and singlefraction radiation treatment of acromegalic cats ranged from 508 to 840 days (1.39–2.30 yr).21,24–26,47
Although radiation may help alleviate neurologic signs associated with a tumor’s space-occupying effects, medical treatment is often still used in conjunction to treat endocrine-related effects of a functional tumor.15,47 In a study by Sawada et al., radiation therapy reduced neurologic signs in the majority of patients (eight of nine dogs) but had no effect on plasma ACTH and serum cortisol concentrations; the majority of dogs were maintained on trilostane following radiation therapy.15 In addition, four of eight dogs with improved neurologic signs later developed recurrence of neurologic signs due to pituitary hemorrhage suspected secondary to the radiation.15 As with medical treatment, radiation does not completely resolve the pituitary tumor.
TSH is the current technique for pituitary surgery in the dog and cat. TSH is the only treatment that offers decompression, rapid resolution of both endocrine and neurologic signs, a definitive diagnosis, and intent to cure. TSH has been previously described, and readers are encouraged to consult these sources regarding the surgical procedure as well as a more thorough explanation of postoperative monitoring and complications.6,9,13,14
Although TSH is currently only available at a few institutions worldwide (Netherlands, United Kingdom, Japan, and United States), the literature indicates that surgery is the best treatment for endocrine remission of PDH and HST and the reduction of neurologic signs caused by a growing pituitary tumor. In dogs with PDH, remission rates (defined as the resolution of both clinical signs and endocrine dysfunction) following TSH are 86–95% with a recurrence rate of 25% and a mortality rate, defined as death by any cause within 4 wk of surgery, of 10–12%.6,10 In cats with PDH, remission rates following TSH are 70%, with a recurrence rate of 20%.14
Long-term estimated survival rates for dogs with PDH following TSH at 1, 2, 3, and 4 yr were 86, 79, 74, and 72%, respectively.10 In a study by van Rijn et al. of 306 dogs with PDH undergoing TSH, the median survival time of 300 dogs for whom follow-up information was available was 781 days (2.14 yr). The median disease-free remission interval was 951 days (2.61 yr) for 257 dogs with confirmed remission of hypercortisolism after surgery. Over time, 69 of 257 (27%) of the dogs with confirmed remission developed recurrence of hypercortisolism after a median period of 555 days (1.52 yr).10
The van Rijn study revealed that the larger the pituitary mass, the worse the prognosis.10 The pituitary/brain (P/B) ratio (height of the pituitary [mm] / area of the brain [cm2]) is an attempt to standardize the size of the pituitary with respect to patient size, because dogs vary greatly in body and brain size.48 A normal P/B ratio is ≤0.31. A pituitary tumor is considered enlarged when the P/ B ratio is >0.31.48 Dogs with a presurgical P/B ratio >0.31 and undergoing TSH had a significantly shorter survival time and a shorter disease-free interval than those with a P/B ratio of ≤0.31.10 Dogs who died within 4 wk of surgery had a significantly higher P/B ratio.10 Over the course of the 20 yr van Rijn study, there was also an overall increase in dogs with large pituitary tumors at the time of surgery, likely due to the implementation of medical therapy leading to a delay in pursuing surgery.10 This again highlights the importance of early pituitary imaging as well as the need to consider TSH in patients with smaller tumors that would likely have better endocrine control, less neurologic dysfunction, and lower mortality rates.
A five-point MRI classification system based on tumor extension has been developed, with grade 1 having no extension and grade 5 having the most extension. Cases were then classified as type A if there was no arterial circle of Willis or cavernous sinus involvement and type B if these blood vessels were involved. Dogs with grade 1–3, type A classifications had better prognosis following TSH.13,49
Fenn reported on a group of ~60 cats from the United Kingdom suffering from HST who were treated by TSH.12 Ninety percent of cats survived surgery, with ~70% of the surviving cats experiencing remission of DM and the majority of remaining cats displaying a decrease in their insulin requirement.12 Ninety-two percent of the cats had normalization of IGF-1 by 4 wk after the operation, and those who achieved diabetic remission remained so long term with only 4 cases of recurrence with follow-up ranging from 1 to 5.8 yr.12 Overall median survival for this group of cats was 2.3 yr, with the majority of recorded deaths attributed to unrelated comorbidities.12 It is interesting to note that cats with hypertrophic cardiomyopathy secondary to HST who underwent hypophysectomy, and normalization of IGF-1 concentrations, had reversal of most of the echocardiographic changes seen with the cardiomyopathy.50
TSH permits a histopathologic diagnosis that can provide important information in developing a treatment plan and prognosis. Once a histologic diagnosis has been made, and if gross tumor is still present after TSH, the addition of adjunctive therapies such as chemotherapy and/or radiation can be implemented to potentially increase survival.
Miller et al. developed a protocol to characterize the histochemical and immunohistochemical features of canine pituitary adenomas and are conducting ongoing studies to evaluate pituitary tissue removed via TSH.51,52 This protocol is designed to determine definitive tumor type and identify those tumors that may behave in a more aggressive manner.51 The tissue is initially evaluated by hematoxylin and eosin stain to distinguish pituitary adenoma from hyperplasia, then by periodic acid-Schiff and immunohistochemistry to identify hormones to classify the adenoma as a corticotroph, melanotroph, or a different plurihormonal adenoma. A Ki-67 proliferation index, also included as part of the protocol, shows promise that an index >3% may be predictive of a shorter post- TSH survival.51
Importantly, TSH has the potential to be curative. Although there is no definition of cure in the veterinary literature, in human medicine, a patient 5 yr out from surgical treatment who remains disease free is considered cured. This time frame is impractical for veterinary patients because they have a much shorter lifespan and a higher likelihood of dying from causes other than the pituitary tumor. The possibility of complete tumor removal and cessation of all clinical signs, both neurologic and endocrine, for the animal’s remaining lifetime aids an owner’s decision in choosing surgery as the treatment of choice.
Patients currently considered for TSH include the following:
- Dogs diagnosed with PDH with a normal size pituitary gland;
- Dogs diagnosed with PDH who have failed medical management and have either a normal-sized or enlarged pituitary gland;
- Dogs diagnosed with PDH who have an enlarged pituitary tumor with or without neurologic signs;
- Cats with HST and a normal or enlarged pituitary gland; and
- Cats with DM exhibiting insulin resistance secondary to HST.
Surgery is the first line of treatment in humans with clinical pituitary masses and could be considered the first line of treatment in animals. In the United States, however, medical management is typically the first treatment, and animals are recommended for surgery only if medical management has failed or they have a large pituitary tumor.We would like to see a shift in this paradigmto earlier surgical treatment. As family veterinarians becomemore familiar with the success of TSH, and access to a skilled pituitary surgery team and facility becomes more widely available, surgery will emerge as an important option offered as a component of the initial treatment plan, along with medical and radiation therapy. As noted earlier, it will be crucial to consider TSH in dogs with PDH with nonenlarged pituitary tumors (P/B ratio ≤0.31) in order to have the best long-term outcome.
Patients being considered for TSH must have a complete workup by their family veterinarian and associated specialists and have a thorough discussion with the pituitary surgery team. Before committing to TSH, the owner must be advised of all available treatment options and potential benefits, risks, and complications associated with each.
Currently, owners elect surgery because their pet cannot tolerate the medication, they are unable to give medication or tire of doing so, their pet becomes refractory to the medication, medication cannot be obtained (as with pasireotide), the clinical signs associated with endocrine dysfunction cannot be controlled (such as insulin resistance), or the pituitary mass has expanded to the point at which neurologic impairment occurs. Although neurologic patients may not be the best surgical candidates, surgery is the only option that allows for rapid resolution of neurologic signs. Owners of these pets are warned of the risks associated with surgery, and surgery is often the last option for many of these patients.
Complications Associated with Surgical Therapy
TSH complications can be procedural, neurologic, and metabolic/ endocrine in origin. Procedural complications can include intraoperative hemorrhage, aspiration pneumonia (more common in dogs with PDH), congestive heart failure/fluid overload (more common in cats with HST), soft palate dehiscence, and keratoconjunctivitis sicca.6,9,10,12–14 Postoperative neurologic complications, which are surprisingly infrequently associated with TSH, can include decreased mental status, increased intracranial pressure, and blindness.6,9,13 Decreased mental status is generally limited to transient dullness after surgery and resolves within the first week following surgery.13 Blindness is most often transient.6 Somnolent or comatose state upon anesthetic recovery is often associated with a poor outcome.6,10 Postsurgical metabolic and endocrine signs most often seen are electrolyte disturbances and development of central diabetes insipidus (CDI) secondary to removal of the pituitary gland and the loss of antidiuretic hormone.13 CDI is typically transient, resolving within a few days to months (median of 4 mo) after surgery.9,53 Although precise prognostic factors contributing to the development of transient versus persistent CDI have not been determined, findings suggest a correlation between larger pituitary size and permanent CDI.13,53
Pituitary size is the most influential prognostic factor associated with TSH.10 In addition to pituitary size, advanced age and a high preoperative plasma ACTH level may predispose dogs with PDH to a higher mortality rate.54
Cats with HST and hypertrophic cardiomyopathy are prone to congestive heart failure secondary to overzealous fluid supplementation. Kenny et al. reported that, following surgery, 4 of 19 cats (21%) developed congestive heart failure due to fluid overload, although it was treated successfully with medical management.11
TSH is a challenging surgery with a steep learning curve that requires a cohesive team of surgeons and criticalists to both execute the procedure and manage postoperative complications. Initial outcomes with respect to complications and mortality can be quite high in the early stages of learning. Intense training and appropriate resources are crucial to ensure the best outcome for patients.
Although there can be significant risks associated with TSH, the mortality rate for smaller tumors is ~10%.10,12 Typically, the entire pituitary gland is removed at surgery; therefore, patients will require lifelong physiologic doses of corticosteroids and thyroid hormone, another aspect that owners should understand.13
Surgery is the only treatment modality that achieves a definitive diagnosis, decompression of the brain, and rapid resolution of neurologic and endocrine signs while providing curative intent.
Medical management may result in the remission of some clinical signs but necessitates long-termmedication administration and patient monitoring to control endocrine dysfunction. Further, it may allow or even potentiate continued growth of the pituitary tumor. Radiation can shrink the tumor and achieve decompression, but neurologic and endocrine improvement may come more slowly. Most patients who receive radiation experience persistent endocrine signs and remain on medical management during and typically after radiation therapy. Tumor regrowth as well as hemorrhage leading to the return of neurologic signs are not uncommon after radiation therapy.
Surgery is the only method that allows for histologic diagnosis of tumor type. Obtaining a histologic diagnosis may allow determination of prognosis, long-term survival, and the development of a more individualized treatment plan.
The consensus statement on canine hyperadrenocorticism by Behrend et al. states that pituitary imaging should be “considered for all dogs at the time of PDH diagnosis.”37 Eighty-nine percent of diabetic cats with elevated IGF-1 concentrations who underwent pituitary imaging had an identifiable pituitary mass.8 A similar recommendation of early pituitary imaging should therefore be made for cats with HST, making early pituitary imaging an integral component of the management of PDH and HST. Pituitary imaging assists in decision making, provides a baseline from which continued monitoring can document tumor growth, and is essential for treatment planning for either pituitary irradiation or TSH. Advanced pituitary imaging at the time of the diagnosis of PDH and HST will help identify pituitary tumors earlier when they are presumably smaller and easier to remove with fewer complications, thereby improving mortality rates and long-term survival.10
TSH, in addition to adjunct medical management and radiation therapy, should be included as a treatment option discussed with owners at the time of diagnosis. Radiation therapy after TSH has been done in a limited number of cases; however, long-term disease-free interval and survival have yet to be determined.
Surgery may not be the treatment of choice for all patients and their owners; however, being well informed and aware of all options is important in deciding the best treatment plan for their pets. The increased survival rate and disease-free interval in dogs and cats with smaller tumors treated surgically supports the recommendation for early advanced imaging of patients presenting with functional pituitary tumors. It is important to note that TSH is a technically difficult surgery with a steep learning curve that requires a pituitary surgical team comprising a cohesive group of specialists. With experience and teamwork, the surgery and postoperative care can be exceptionally successful with excellent patient outcomes.
The authors would like to see a shift in the paradigm for the diagnosis and treatment of pituitary tumors in veterinary medicine in the United States. This paradigm shift would be to address patients with pituitary tumors with early brain imaging when tumors are small, giving rise to the option for earlier surgical intervention that will ultimately improve long-term success.
- Behrend EN. Canine hyperadernocorticism. In: Feldman EC, Nelson RW, Reusch CE, et al., eds. Canine and feline endocrinology. 4th ed. St. Louis: Elsevier Saunders; 2015:377–451.
- Graves TK. Hypercortisolism in cats (feline Cushing’s syndrome). In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 7th ed. St. Louis: Elsevier Saunders; 2010:1840–7.
- Reusch CE. Disorders of growth hormone. In: Feldman EC, Nelson RW, Reusch CE, et al., eds. Canine and feline endocrinology. 4th ed. St. Louis: Elsevier Saunders; 2015:37–76.
- Gunn-Moore D. Feline endocrinopathies. Vet Clin North Am Small Anim Pract 2005;35:171–210.
- Norman EJ, Mooney CT. Diagnosis and management of diabetes mellitus in five cats with somatotrophic abnormalities. J Feline Med Surg 2000;2:183–90.
- Mamelak AN, Owen TJ, Bruyette D. Transsphenoidal surgery using a high definition video telescope for pituitary adenomas in dogs with pituitary dependent hypercortisolism: methods and results. Vet Surg 2014;43:369–79.
- de Bruin C, Meij BP, Kooistra HS, et al. Cushing’s disease in dogs and humans. Horm Res 2009;71(suppl 1):140–3.
- Niessen SJ, Forcada Y, Mantis P, et al. Studying cat (Felis catus) diabetes: beware of the acromegalic imposter. PLOS One 2015;10:e0127794.
- Meij BP, Voorhout G, van den Ingh TS, et al. Results of transsphenoidal hypophysectomy in 52 dogs with pituitary-dependent hyperadrenocorticism. Vet Surg 1998;27:246–61.
- van Rijn SJ, Galac S, Tryfonidou MA, et al. The influence of pituitary size on outcome after transsphenoidal hypophysectomy in a large cohort of dogs with pituitary-dependent hypercortisolism. J Vet Intern Med 2016;30:989–95.
- Kenny P, Scudder C, Keyte S, et al. Treatment of feline hypersomatotropism. Efficacy, morbiditiy and mortality of hypophysectomy. J Vet Intern Med 2015;29:1271.
- Fenn J. Feline hypophysectomy for the treatment of hypersomatotropism: a review and update. In: Proceedings of the American College of Veterinary Internal Medicine Forum; June 14–16, 2018; Seattle, WA.
- Owen TJ, Martin LG, Chen AV. Transsphenoidal surgery for pituitary tumors and other sellar masses. Vet Clin North Am Small Anim Pract 2018;48:129–51.
- Meij BP, Voorhout G, van den Ingh TS, et al. Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats. Vet Surg 2001;30:72–86.
- Sawada H, Mori A, Lee P, et al. Pituitary size alteration and adverse effects of radiation therapy performed in 9 dogs with pituitary-dependent hypercortisolism. Res Vet Sci 2018;118:19–26.
- Bruyette DS, Ruehl WW, Entriken T, et al. Management of canine pituitary-dependent hyperadrenocorticism with l-deprenyl (Anipryl). Vet Clin North Am Small Anim Pract 1997;27:273–86.
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