Chapter 25 - Tumors of the Endocrine System Flashcards
What are the 3 classifications for endocrine tumors?
Non-neoplastic hyperplasias
Benign adenomas
Malignant carcinomas
How does non-neoplastic hyperplasia occur?
As a consequence of aberrant secretion of trophic hormones resulting in growth and increased function
Is hyperplasia reversible? Why is this controversial?
Not always even though the inciting cause is removed. Can be confused or difficult to differentiate from tumors as they grow independent of trophic factors
What are the general clinical manifestations of neuroendocrine tumors?
Result of growth, expansion, and metastasis of the tumor, producing traditional sequelae due to compression of normal tissue (adenoma), invasion and destruction of regional or systemic normal tissue function (carcinoma), and secretion of hormones or hormone-like substances
What is considered to be the classic theory of carcinogenesis in thyroid tissue? What has emerged recently?
Accumulation of somatic mutations leading to dedifferentiation from mature to anaplastic cells.
The theory of epithelial to mesenchymal transition which suggests the potential for cancer stem cells
What growth factors are known to play a role in the pathogenesis of endocrine neoplasia?
epidermal growth factor, insulin-like growth factors, growth hormone
Any single growth factor, however, cannot cause malignant transformation of a cell
From what cell types can pituitary tumors arise from (5)?
- corticotrophs
- somatotrophs
- thyrotrophs
- gonadotrophs
- lactotrophs
What are the different types of pituitary tumors? histologic types maybe?
Non invasive adenoma, invasive adenomas, adenocarcinomas (reserved for when mets are present)
Clinical size of pituitary tumors depend on what 2 big things?
Size and what they secrete
Which is the most clinically important pituitary tumor in the dog? What does it produce and with what clinical signs is it associated with?
Pituitary adenoma, corticotroph adenoma
Chronically excessive amounts of ACTH
Associated with clinical signs of hypercortisolism
Which is the most clinically important pituitary tumor in cats? With what clinical sings is it associated with?
GH-secreting somatotroph pituitary adenoma, occurs in the pars distalis
Causes acromegaly and insulin-resistant diabetes mellitus
When do non-functional pituitary tumors become clinically significant?
When they are large enough to cause neurologic signs - obtundation, stupor, behavioral changes, decreased apetite, etc
In a case series of 177 cases, what was the second most common type of brain tumor found and for what percentage did it account for?
Pituitary tumors
25%
Secondary intracranial neoplasia in the dog: 177 cases. JVIM, 2008.
What is another way pituitary tumors may present?
With loss of their function, resulting in hypothyroidism, hypocotisolism, gonadal atrophy, central diabetes insipidus
What is the most common cause of hypercortisolism in dogs? It accounts for ___% of cases.
Pituitary dependent Cushing’s disease = pituitary corticotroph adenoma
85%
What is the endocrinologic pathogenesis of pituitary corticotroph tumors?
Chronic excessive production of ACTH, which subsequently stimulates both of the adrenal glands to produce cortisol.
There is loss of negative feedback inhibition at the level of the pituitary gland and the hypothalamus can no longer control the production of ACTH as it does not matter if it produces CRH or not, pituitary gland will do what it wants. Feedback loops are not inhibited by the increased amount of cortisol.
What proteins and receptors are thought to be involved in pituitary corticotrophs?
leukemia inhibitory factor and its receptor are expressed but not mutated
Dopamine type 2 and somatostatin type 2 receptors are more prevalent in pituitary tumors when compared to normal pituitary tissues but expressed at low levels
What is the difference between a pituitary macroadenoma and a microadenoma?
This comes from human medicine
Micro <1cm in diameter
Macro >1cm in diameter
Controversial in human medicine
In a 2010 cross-sectional imaging study of 33 dogs with pituitary tumors, what percentage were found to be adenomas, invasive adenomas, and adenocarcinomas?
Adenomas - 61%
Invasive adenomas - 33%
Adenocarcinomas - 6%
Cross-sectional imaging characteristics of pituitary adenomas, invasive adenomas, and adenocarcinomas in dogs: 33 cases. JVIM, 2010.
What is the typical age, sex, and breed for dogs with PDH?
Older than 9 years
Females overrepresented
Dachshunds, terrier breeds, GSD, poodle breeds
What are the most common clinical signs of hypercortisolism?
PU, PD, polyphagia, abdominal enlargement, lethargy, panting, exercise intolerance, muscle weakness, alopecia, calcinosis cutis, thinning of the skin, reproductive abnormalities
Glucose intolerance and insulin resistance can develop in up to ___ of Cushing’s cases.
10%
What are the 4 effects of glucocorticoids that are responsible for the changes seen in dogs with HC or Cushings?
Glucocorticoid effects:
- Gluconeogenic effects
- Catabolic effects
- Immunosuppressive effects
- Antiinflammatory effects
The catabolic effects of glucocorticoids result in what?
- Thinning of the skin
- Poor wound healing
- Muscle wasting
- Decreased bone density
The antiinflammatory and immunosuppressive properties of glucocorticoids are responsible for what?
Increased susceptibility to infection seen
What is the most common infection seen in dogs with HC?
UTI
In one study of dogs with HC, what percentage had UTIs?
46%
Hypertension and proteinuria are more serious disorders associated with canine HC. True or false?
True
Over 80% of dogs with Cushin’s were reported to be hypertensive in one case series.
PTE although uncommon, can also be seen.
Over ___% of dogs with canine Cushing’s were reported to be hypertensive in one case series.
80%
What are some labwork abnormalities seen in dogs with Cushing’s disease?
CBC: Neutrophilia, monocytosis, lymphopenia, eosinopenia, thrombocytosis
Chemisty: elevated ALP, ALT, cholesterol
UA: isosthenuria or hyposthenuria
What are some screening tests used for suspicion offor Cushing’s? How are their specificity and sensitivity?
- Urine cortisol:creatinine ratio
- Very sensitive but not specific, should not be used in ill patients
- Low-dose dexamethasone suppression test (LDDST)
- Highly sensitive (less likely to give false negatives)
- Able to distinguish between PDH and ADH in some cases
- ACTH stimulation test
- Lower sensitivity and higher specificity than the LDDST
Which tests are considered differentiation tests for Cushing’s disease?
- HDDST
- Endogenous ACTH levels
- Dogs with ADH, these should be low
- Dogs with PDH, theese should be high
- Advanced imaging
Approximately what percentage of dogs with HC have PDH?
80 to 85%
Neuro clinical signs is not common
In an 1996 study of 13 dogs that underwent MRI evaluation of the brain at the time of PDH diagnosis, how many dogs had a visible pituitary mass and how many had neurologic clinical signs from the disease? How many dogs had neuro signs at the 1 year follow up?
8
None
2
___ to ___ % of dogs with PDH have tumors that are not visible on MRI and ___ to ___ are at risk for the development of neurologic clinical signs. If clinical signs develop, they develop ___ to ___ months from the diagnosis.
40-50% - these are unlikely to develop neurologic clinical signs
15 to 25% of dogs with PDH are at risk for development of neurologic clinical signs due to the presence of an enlarging tumor
6 to 18 months
Canine hyperadrenocorticism (Cushing’s syndrome). Canine and feline endocrinology and reproduction, 2004.
Transphenoidal hypophysectomy has an overall success rate of ___.
65% - not done commonly, only in a place in Europe
Complications: central diabetes insipidus,
In a 1990 study of 6 dogs with functional pituitary macrotumors that were treated with 10 4Gy fractions (total of 40Gy), what was the MST? What happened with the neurologic clinical signs and ACTH levels?
MST 743
Neuro CS resolved in all dogs
ACTH levels remained high for at least 1 year after therapy
In one study, megavoltage irradiation on pituitary tumors in 24 dogs with neurologic CS, ___ dogs achieved a complete remission of the neurologic CS and ___ achieved a partial remission. What correlation between what 2 things was noted in this sutudy?
10 and 10
Tumor size and CS
Early treatment is better for these
Megavoltage irradiation of pituitary macrotumors in dogs with neurologic clinical sings. JAVMA, 1998.
In a 2007 study comparing the neurologic response and prognostic factors in dogs with pituitary masses treated with radiation therapy versus untreated dogs, the MST in the treated group was ___ days compared to ___ days in the untreated group. What were the 1, 2, and 3 year estimated survival rates for the trated vs the untreated group?
Treated group:
- MST 1405 days
- 1-yr survival rate 93%
- 2-yr survival rate 87%
- 3-yr survival rate 55%
Untreated group:
- MST 551 days
- 1-yr survival rate 45%
- 2-yr survival rate 32%
- 3-yr survival rate 25%
Treated dogs with smaller tumors lived longer than those with large, again suggesting that early treatment is better
Survival, neurologic response, and prognostic factors in dogs with pituitary masses treated with radiation therapy and untreated dogs. JVIM 2007.
What is the endocrinologic in dogs with PDH treated with RT?
Hard to predict, ACTH does not always normalize alhtough neuro CS do tend to resolve. If ACTH normalizes, it is in the minority and it is long after treatment was received.
Approximately what percentage of cats with HC are due to pituitary disease?
80 to 85%
Feline HC is often associated with what other endocrinologic condition?
Insulin-resistant diabetes
What are some clinical signs of cats with HC?
PU/PD, polyphagia, weight loss, pot-bellied appearance due to hepatomegaly, muscle weakness, thin fragile skin that tears and bruises easily, generalized muscle atrophy, unkempt haircoat, alopexia
What are treatment options for cats with PDH?
Surgical bilateral adrenalectomy was the treatment of choice for some time. Also reported hypophysectome and RT. Medical treatment with trilostane - could be use as sole treatment or in preparation for surgery or RT.
They are poor surgical candidates because of poor healing.
What is feline acromegaly?
A disease of older cats resulting from chronic excessive GH secretion, usually from a functional somatotroph adenoma of the pars distalis of the pituitary gland.
This is the most clinically significant pituitary tumor in cats
Is there a sex predisposition for pituitary somatotroph tumors in cats? What is the typical history in these cats?
Has been reported most commonly in male cats
History: Insulin-resistant diabetes mellitus, with affected cats requiring 10 to 20 units of insulin per dose or more, often with inadequate control of their diabetes.
Why does insulin resistance occur in cats with feline acromegaly due to a pituitary somatotroph tumor?
Due to a GH-induced post receptor defect in the action of insulin on target cells.
What are clincal signs seen in cats with feline acromegaly?
Weight gain, as opposed to weight loss seen in cats with poorly regulated diabetes mellitus - this is highly suggestive of feline acromegaly.
Also, PU/PD, polyphagia, enlarged feet, broadening of the face, protrusion of the mandible, increased spacing between the teeth, abdominal enlargement, noisy or stertorous breathing, respiratory stridor, enlarged abdominal organs, cardiac murmurs, arrhythmias, gallop rhythm
What is the differnece in weight in cats with feline acromegaly vs PDH?
Feline acromegaly - FAT
PDH - SKINNY
How are neurologic clinical signs in cats with feline acromegaly?
Generally uncommon
Is there a reliable assay for dx feline acromegaly in USA?
Nope.
In Europe, however, there is an ovine GH assay validated for the diagnosis of feline acromegaly
Can there be an overalp in cats with diabetes and cats with acromegaly?
yes
Why are physical changes seen in cats with feline acromegaly?
Due to the anabolic effects of GH, which are mediated by peripherally synthesized IGF-1.
Where is IGF-1 produced? Which is more sensitive for dx acromegaly? GH or IGF-1?
Produced in the liver, levels of it increases in the presence of chronically increased GH production. Because GH may be pulsatile, even in some acromegalics, and because it has a short half, life, IGF-1 is a more sensitive test for acromegaly because it may reflect GH over the preceding 24 hours.
What is the sensitivity and specificity of IGF-1? For what type of test is it used?
Sensitivity 84%
Specificity 92%
Screening test
One study reported no differnce in IGF-1 in well controlled diabetics, poorly controlled diabetics, and healthy cats. In cats with acromegaly, it is usually at least twice the upper reference range value. There is a test for IGF-1 in USA.
Which imaging modality is more sensitive in cats with acromegaly?
MRI
Can be normal on imaging
What is the most widely reported treatment modality for cats with feline acromegaly secondary to a pituitary tumor?
Conventional RT
CSU - SRT
Some owners can just do insulin - dose used should be the one that controls the diabetes. Ranges usually in between 10 to 20 per dose.
What drugs are used in humns with acromegaly? MOA?
Somatostatin analogs, dopamine agonists, GH-receptor antagonists
MOA:
Somatostatin analogs - bind to GH receptors suppressing GH release from the pituitary - response assessed by measurement of IGF-1, GH, tumor size
Octreotide - one study show it did not work, another study suppressed GH for 120 post injection - using short acting
What is the short term and long term prongosis for cats with acromegaly? What do they usually succumb to? What is the MST in once case series?
Short term - fair to good
Long term prognosis - poor
Cardiac or renal faolure, neurologic disease, complications od poorly regulated diabetes
MST 20.5 months
What is the overall prevalence of adrenal tumors in dogs and cats? From what zone do they most commonly arise? In on study going over 191 canine cases that underwent surgery, what % were cortical and what % were medullary? What % of the cortical were further classidied as carcinomas, adenomas, and hyperplasia?
- 17-0.76% of dogs (1-2% of all canine tumors)
- 03% of cats (0.2% of all feline tumors)
cortical more common than medullary;
In one study of 191 dog cases:
- 80% were cortical: 50% carcinomas, 43% adenomas, 6% hyperplasia
- 17% were medullary:
Probably underdiagnosed
When the data from several cases evaluating the outcome of adrenal surgery in 191 dogs is combined, excuding the large restrospective study at UC Davis, what % arised from the medulla and cortex? What % of the cortical tumors were carcinomas, adenomas, or hyperplasia?
- 80% were cortical: 50% carcinomas, 43% adenomas, 6% hyperplasia
- 17% were medullary
In one very large retrospective study performed over a 20-year period at UC davis of patients with adrenal tumors what % of tumors in both dogs and cats were cortical, medullary (pheochromocytoma), and metastatic? What was the most common metastatic neoplasm in both spp?
Dogs:
- 41% cortical (78% adenomas, 21% carcinomas)
- 32% medullary/pheochromocytoma
- 27% medullary
Cats:
- 30% adrenocortical
- 10% medullary/pheochromocytoma
- 60% metastatic
Lymphoma!!!
Metastatic tumors to the adrenal glands in domestic animals. Vet Pathol, 2005. All metastatic melanomas were found at the medulla.
How sensitive and specific has ultrasound been reported to be for the detection of invasion of adrenal tumors into the caudal vena cava? What about contrast enhanced CT?
US:
- Sensitivity 80-100%
- Specificity 90%
Contrast enhanced CT:
- Sensitivity 92%
- Specificity 100%
What % of functional cortisol-secreting tumors of the adrenal cortex are responsible for canine and feline cases of naturally occuring HC?
15 to 20%
Dogs with PDH accounts for 80 to 85% of cases
A review of functional adrenal tumors in dogs suggested that approximately ___% of them were ___.
60% carcinomas
Approximately what % of adrenocortical carcinomas invade the phrenicoabdominal vein? Extension into what veins can be seen?
20%
Renal vein and caudal vena cava
Metastasis in dogs with adrenocortical carcinomas has been identified in approximately ___% of cases. Where do they most commonly metastasize to?
50%
Liver and lungs
In an 1986 study evaluating the results of surgical treatment for hyperadrenocorticism caused by adrenal gland neoplasia in 25 dogs, the perioperative mortality was ___%. In more recent case series, the perioperative mortality ranges from ___ to ___ %.
60%
19 to 28%
MSTs reported for dogs undergoing adrenalectomy for both carcinomas and adenomas is?
MST carcinoma 230-778 days
MST adenoma
687.5 days
Using mitotane as a cytotoxic agent for dogs that cannot undergo surgery for the treatment of ADH reports a MST in 32 dogs of ___ months.
A recent study comparing mitotane vs trilostane for dogs with adrenal tumors reported a MST of ___ days and ___ days. This study confimred that the survival time is negatively affected by the presence of what?
16.4 months
Uses higher doses than that used in PDH
Mitotane MST: 102 days
Trilostane MST : 353 days
Metastatic disease
Recent study: JVIM 2011
What is the most common adrenocortical disorder in cats? What are the most common tumors associated with this?
What are some key features if this condition in cats?
Hyperaldosteronism
Aldosterone secreting arenocortical tumors; adenoma or carcinoma
Hypokalemia, hypertension (w or w/o ocular changes), concurrent renal disease
What cells in the adrenal medulla form part of the sympathetic system? These neoplastic cells give rise to what tumors? Predominantly, what do they secrete?
Chromaffin cells
Pheochromocytoma
Catecholamines
How common are pheochromocytomas in dogs and cats?
Uncommon in dogs, rare in cats
Pheochromocytomas are considered to be a ____ tumor. Metastasis from them is seen in ___ of cases. What are common metastatic sites? Vacular invasion has been reported in as many as ___% of cases.
Malignant tumors
40% met rate
Liver, spleen, lungs, regional LN, bone, and CNS
82% have vascular invasion
How is catecholamine release? What are some CS and PE findings associated with them?
Episodic - CS may be intermittent
Weakness, episodic collaps, panting, anxiety, restlessness, excercise intolerance, decreased eppetite, weight loss, PU/PD, hypertension, panting, tachypnea, tachycardia, cardiac arrhythmias, weakness, pallor
What IHC marker can distinguish pheochromocytoma from adrenocortical tumors?
Chromogranin A
What can be measured in urine and plasma of dogs with pheos?
Urinary catecholamine and metanephrine to creatinine ratios
{lasma free metanephrine and normetanephrines
What is the tx of choice for pheos? What are life threatening complications of this type of treatment?
Surgery
Intraoperative hypertension, hypotension, cardiac arrhythmias, hemorrhage
What can dogs get prior to surgery in order to reduce intraoperative mortality and complications? In one study, dogs that received this had a mortality rate of ___% when compared to dogs that did not receive this therapy which had a mortality rate of ___%
Phenoxybenzamine, an a-adrenergic antagonist
0.1-0.25mg/kg q 12 for 20 days (2 weeks really)
Mortality rate with therapy 13%, without 48%
Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma. JVIM 2008.
What therapy modalities have not been evaluated in dogs with pheos?
Chemo and RT
RT with ______ has been evaluated in 1 dog for the treatment of a pheochromocytoma.
Treatment of a malignant pheochromocytoma in a dog using I131-metaidobenzylguanidine. JAAHA, 2011.
What are 3 factors that can affect prognosis in dogs with pheos?
What is the MST in dogs that undergo surgery?
Tumor size, presence of mets, local invasion
374 days, some dogs may survive for 2 to 3 years
Evaluation of prognostic factors in the surgical treatment of adrenal gland tumors in dogs: 41 cases. JAVMA, 2008.
What is the overall perioperative mortality for dogs undergoing adrenalectomy for all adrenal tumors? MST?
10 to 20%
MST of 690to 953 days
Dogs that had emergency surgery for acute adrenal bleeding can experience a ___% mortality rate.
50
Dogs with adrenocortical tumors that have PDH have what major complications after surgery?
Adrenal insufficiency, PTE thromboembolism, pancreatitis, renal failure, wound dehisance
Steroids should be supplemented on a case by case basis
What should be done when an incidental adrenal mass is found?
BP, fundic exam, endocrinologic testing to rule out a functional adrenal tumor, imaging of the thorax (to r/o met dz).
When should an adrenalectomy for an incidentaloma should be performed?
Functional masses, locally invasive, larger than 2.5cm in maximum dimension.
Masses smaller than 2cm with no evidence of humoral activity should be monitored with AUS 1 month after dx, 2,4 and 6m
Thyroid tumors account for what % of tumors in dogs?
In necropsy studies, it is estimated that ___ to ___% are benign adenomas. However, a recent Medical Database review reported that ___% of 545 canine thyroid cases were ____ or ____ and only ____ were _____.
1.1 to 3.8%
30 to 50% in necropsy studies
90% - carcinomas or adenocarcinomas
9.3% - adenomas
While most adenomas are ____, most carcinomas are ____.
Adenomas - silent
Carcinomas - malignant, funtional
What are the 2 main different histologic types of thyroid carcinomas? Which one is more common?
- Follicular
- Medullary, parafollicular or C-cell carcinomas - relatively uncommon
What are the different subgroups of follicular cell carcinomas? Which ones are most common in humans and in dogs? What IHC stain can be used to identify them all?
Papillary, follicular, compact (solid), anaplastic
IHC: thyroglobulin, thyroid transcription factor 1
Humans: papillary
Dogs: follicular and compact/solid
What IHC most accurately identifies parafollicular/C-cell/medullary carcinomas? What other IHC are also positive?
Calcitonin, calcitonin gene-related peptide, thyroid transcription factor, chromogranin A, and neurononspecific enolase.
What molecular pathogenesis has been described for papillary, follicular, and anaplastic carcinomas? What may play a role in carcinogenesis?
Papillary - activation of the tyrosine kinase receptor RET and TRK
Follicular - activating mutations in RAS
Anaplastic - inactivating mutations in p53
TSH or TSH receptor may play a role in carcinogenesis
TSH receptor in humans is frequently affected with what two alterations?
Hyperfunctioning or silencing mutations
What is the typical age for thyroid tumors in dogs?
Older, 9 to 11 yrs
Familial medullary thyroid carcinoma has been described in dogs with what breed influence?
Alaskan malamute
Which thyroid lobe is most commonly affected in dogs with thyroid carcinoma? What percentage od dogs have bilateral enlargement?
Right and left lobes equally affected
60% have bilateral involvement
What are some locations for ectopic thyroid tissue?
Anywhere from the base of the tongue up to the heart
Base of tongue, cervical ventral neck, cranial mediastinum, heart
What % of dogs with thyroid carcinoma have visible metastasis at the time of diagnosis and what % eventually develop mets?
35-40% at the time of dx
80% eventually develop mets
Metastatic potential increases when the primary tumor volume measures exceed ____cm3 and approaches 100% when the tumor volume is ___cm3. Bilateral tumors are ___ times more likely to met.
23
100
16x
What are the most common metastasic sites for thyroid tumors?
Regional LN (retropharyngeal, cranial cervical, mandibular) and lungs
Are the majority of thyroid carcinomas functional or non-functional?
Non functional
Based on clinical signs and T4 concentrations, what % of dogs are euthyroid, hypothyroid and hyperthyroid?
60% euthyroid
30% hypothyroid
10% hyperthyroid
What molecular compound is used for thyroid scintigraphy? When is nuclear scintigraphy indicated?
Tc-pertechnetate and much less commonly, radioactive iodine (I123, 131)
To identify metastatic disease, for RT planning, to identify residual disease after surgery, to identify ectopic thyroid tissue, to determine if therapy with I 131 will work
In order for it to work, they tumor must be able to trap the compound and in the case of iodine, organifying it
When tumors are freely movable and there is no evidence of metastatic disease, what is the tx of choice?
Surgery
What surgical complications may arise after surgery?
- Hypocalcemia due to hypoparathyroidism
- Hypothyroidism
- Damage to the recurrent laryngeal nerve
- Damage to the vagosympathetic trunk
If the thyroid carcinoma is freely movable, what is the MST after surgery? What about if it is not freely movable?
MST 3 yrs if freely movable
MST 6 to 12 months if invasive
What RT protocols have been described for thyroid carcinomas? What is the time to tumor reduction? MST?
Definitive:
- 48Gy delivered in 4Gy fractions (12 x 4Gy)
- Time to maximal tumor reduction 8 to 22 months
- 80% progression free survival rate at 1 year
- 72% progression free survival rate at 3 years
- MST > 2yrs
Palliative (when mets present):
- 36Gy delivered in 9Gy fractions (6 x 9Gy)
- Time to tumor reduction 11 to 24 months
- Overall MST 22 months
When is RT preferred over sx for thyroid carcinomas?
Invasive or metastatic tumors (palliative)
Metastasis in one study did not affect prognosis
In humans, what is done after surgery for thyroird carcinomas?
I-131 to destroy occult microscopic or metastatic disease
When is I 131 indicated in dogs?
Advanced unresectable, metastatic, residual tumor
What are the stages for thyroid carcinoma?
Stage I -
Stage II - 2 to 5cm diameter, fixed or unfixed
Stage III - >5cm diameter, fixed or unfixed
Stage IV - metastatic?
What was the MST in over 80 dogs with stage II, III, and IV thyroid carcinoma that received I-131?
MST for stage II and III >2 yrs
MST for stage III 1yr
What are complications of RT and I-131 in thyroid carcinoma dogs?
RT: laryngitis, tracheitis, esophagitis - usually well tolerated
I-131 - myelosuppression, hypothyroidism (all require thyroid supplementation?
What is the maximum dose for I-131?
0.2Gbq/kg (5mCi/kg)
What is the response rate of thyroid carcinomas to doxorubicin or cisplatin? What other drugs have been used? For which dogs is chemo considered?
30 to 50% demonstrated a partial response
Mitoxantrone, actinomycin D, Palladia
Large non-resectable tumors, gross metastatic disease, lymphatic or vascular invasion seen on histopathology
What is the most common endocrine disorder in cats? By what is it caused?
Hyperthyroidism
Almost always, caused by a primary thyroid abnormality that results in the production and secretion of excessive thyroxine (T4) and triiodothyronine (T3).
What is the cause in the majority of the hyperthyroid cause? What percentage of cats have bilateral lobe involvement?
Multinodular adenomatous hyperplasia
70% to 90%
What percentage of cats have thyroid carcinoma? What is the metastatic rate?
1 to 3%
70% - regional LN and lungs
What mutation has been identified in hyperthyroid cats?
Mutation in the TSH receptor
Overexpression of RAS oncogenes
in the TSH receptor-G protein-cAMP system
What risk factors have been indentified in hyperthyroid cats?
Canned food, dlea control products, indoor residence, cat lotter, brominated flame retardant, iodine content of cat food
What is the most common signalment for hyperT cats? Which breeds are at decreased risk?
Older 12 to 15 yrs
Siamese and Himalayan are at decreased risk
Definitive diagnosis of hyperthyroidism in cats is made by what?
Elevate T4
What percentage of hyperthyroid cats have a total T4 within the normal reference range?
<10%
If you suspect hyperthroidism in a cat with a normal T4 what should you do?
Repeat it in 1 to 2 weeks, or request a free T4 (should never be interpreted alone)
What arethe treatment options for hyperthyroidism in cats?
Antithyroidal drugs, surgical thyroidectomy, radioactive iodine therapy
Antithyroidal drugs - Methimazole - widely used in USA, carbimazole, widely used in Europe
They inhibit thyroid hormone synthesis by interfering with oxidation of iodide, iodination of tyrosyl residues in thyroglobulin, and the coupling of iodotyrosines to iodothyronines
What should be done before surgery? What is the most common complication after surgery?
Thyroid scintigraphy
6 to 15% develop hypocalcemia due to transient hypoparathyroidism
Also, Horner’s syndrome, laryngeal paralysis
What is the treatment of choice for feline hyperthyroidism?
Radioactive iodine
What is the elimination half life of I-131? What type of radiation does it emit once the cat has received it? Which accounts for 80% of tissue damage?
8 days
beta and gamma radiation
beta accounts for 80% of the tissue damage
Using the standard dose, what percentage of cats remain hyperthyroid after treatment?
<5%
When this occurs, a second treatment is usually curative
What is the MST of cats with hyperthyroidism treated with I-131? Most common causes of death?
An old study says 2 yrs, a newer one says 4 yrs
Most common cause of death was renal disease or cancer
Approximately how long after tx of hyperthyroid cats does renal disease unmasks?
1 month
What can affect survival time of cats after treatment ofor hyperthyroidism?
Becoming hypothyroid
NOT becoming azotemic
How common are parathyroid tumors in dogs and cats?
Uncommon in dogs, rare in cats
Where do parathyroid tumors arise from?
Chief cells - autonomously secrete PTH leading to hypercalcemia due to primary hyperPTH
What are the effects of PTH in the body?
Direct effects on: bone and kidneys
Indirect effects on: intestines - mediated by vitamin D
Approximately ___ % of dogs and cats with primary hyperPTH have _____ parathyroid mass. What is the most common tumor? Less common?
90% have a single parathyroid mass
Adenoma - most common
Less common - cystadenoma, carcinoma, hyperplasia
What is the signalment for primary hyperPTH in dogs and cats? Is there a breed predisposition in dogs?
Olderdogs and cats
Keeshonden dogs - autosomal dominant mode of inheritance - affected gene has not been yet identified
Four hyperplastic PT masses should raise concern for what?
Secondary hyperPTH
What are the clinical signs seen in dogs with hyperPTH?
PU/PD, weakness, lethargy, decreased appetite, weight loss, muscle wasting, vomiting, trembling
What are the most common causes of hypercalcemia in dogs?
GOSH DARN IT
Granulomatous disease
Osteolytic diseases
Spurious
Hyperparathyroidism
Vitamin D toxicosis
Renal disease
Neoplasia - hyperCa of malignancy
Idiopathic
T
How is hyperparathyroidism diagnosed?
Elevated ionized calcium and high PTH
What percentage of dogs with hypercalcemia have a normal PTH value?
73%
This is abnormal because it should be suppressed and low - not normal. Indicates loss of negative feed back inhibition
What imaging modality can be used to dx parathyroid masses? Masses as small as what can be identified?
US
3mm
When does the risk of mineralization occur with hypercalcemia?
when Ca x Ph = > 70
What is the most common trreatment for primary hyperPTH?
Suergery
Ethanol abalation can also be done
How many PT glands can safely be removed?
3 out of 4
will not cause hypocalcemia
Why can hypocalcemia be seen after surgery?
Parathyroid gland atrophy of the one that was not cancerous
Is tetany seen with hypo or hyper Ca?
Hypo
When should hypoCa be treated? What is used?
If ionized concentration <0.8-0.9 or if total calcium is <8 to 9.
Ca gluconate for acute therapy - IV. SQ should be avoided, causes tissue irritation
Vitamin D (calcitriol) and oral Ca for chronic therapy
What is the prognosis for primary hyperPTH?
Very good with tx, metastatic dz is extremely rare and hypocalcemia can be managed
Short term prognosis may also be okay because it slowly progresses
What % of dogs and cats experience recurrence of primaryhyperPTH?
<10%
second surgery or abalation is curative
How common are pancreatic beta-cell tumors (insulinomas) in dogs?
Rare in humans and cats, uncommon in dogs
What is the problem with these tumors? What is the hallmark of this tumor?
neoplastic B cells fail to appropriately inhibit insulin secretion at lowl blood glucose concentrations
Normal or elevated blood insulin concentration in the presence of hypoglycemia
What hormones, besides insulin, do pancreatic B cells tumor secrete?
Glucagon, somatostatin, pancreatic polypeptide, GH, IGF-1, gastrin
In humans, what % of insulinomas are benign?
90%
What is the behavior of insulinomas in dogs? Metastasis is detected in approximately ___% of canine insulinomas. What are the most common metastatic sites?
They are malignant, regardless of being adenomas or carcinomas.
50%
regional LN and liver
pulmonary mets is rare
What are the stages of insulinoma according to WHO?
Stage I -only in pancreas
Stage II - pancreas + LN
Stage III - pancreas + distant mets
In a multivariate analysis, it was found that ____ was predictive of DFI time and that ____ was predictive for both DFI time and survival time.
Tumor size
Ki67 index
Where do the clinical signs of insulinoma result?
From neuroglycopenia - the effects of hypoglycemia on the CNS; weakness, ataxia, collapse, disorientation, behavioral changes, seizures
Catecholamine release from low blood glucose may also cause muscle tremors, shaking, anziety, and hunger
How can clinical signs be? By what can they be precipitated
Acute, episodic, precipitated by fasting, excitement, exercise, eating
Patients with chronic hypoglycemia have less pronounced clinical signs - these may behave normally
What has been described in patients with insulinoma?
Peripheral neuropathy - rare
How is insulinoma confirmed?
Hypoglycemia <60mg/dL and elevated or normal insulin levels
insulin glucose paired samples, NOT ratios
Abdominal US has been reported to be able to find a pancreatic mass in < than ___% of cases.
<50%
Cannot be used to rule in or out an insulinoma
In a study comparing CT, AUS, and CT (SPECT), which was found to be the most sensitive?
CT
What is the sensitivity of SPECT with In-DTPA-D-Pho-octreotide for detection of insulinomas?
50%
What does the acute treatment of insulinoma involve in general?
Dextrose bolus and CRI - with caution bec it can further stimulate secretion of insulin, glucagon for the hyperinsulinimic hypoglycimic crisis, exploratory laparotomy when patient is stable regardless of imaging findings
What is the chemotherapy drug of choice for patients with insulinoma that cannot undergo surgery? What is the MOA? Side effects?
What is the problem with choosing this modality of treatment over others?
Streptozocin, kilss B cells of the pancreas
Can cause nephrotoxicity but if you give it with diuresis this does not occur as commonly
Other SE: diabetes mellitus, hypoglycemia, mild hematologic changes
Does not significantly increase the duration of normoglycemia when compared to medical management or surgery
What medical therapies are used? Response rate of some?
- Prednisone
- Diazoxide - nondiuretic benzothiadiazine that suppresses insulin release from b-cells, stimulates hepatic gluconeogenesis and glycogenolysis, and inhibits cellular uptake of glucose, 70% response rate
- Octreotide- somatostatin receptor ligand that inhibits synthesis and secretion of insulin by pancreatic b cells - alleviates hypoglycemia in 50% of dogs
Avoid excitement
Diets high in fat, protein, and complec CHO should be fed in small frequent meals
Simple sugars avoided
What if the prognosis of dogs with insulinoma in the short and long term?
Short - good
Long - poor
MST following partial pancreatectomy? What does it depend on?
What is the DFI of stage I, II and II?
MST of stage III?
12 to 14 months
Stage of the disease
50% of stage I dogs free of hypoglycemia at 14 months post op
<20% of stage II and II dogs free of hypoglycemia at this time
Stage III - 6 months
A retrospective stufdy performed in 2007 that evaluated 28 dogs with insulinoma reported a MST of ___ days for 19 dogs undergoing partial pancreatectomy, with a median DFI of ___ days. A subset of those dogs also received prednisolone and has a MST of ___ days. For 8 dogs that received medical therapy alone, the MST was ___ days. When all dogs that received medical therapy were considered as a group, the MST after institution of therapy was ___ days.
A retrospective stufdy performed in 2007 that evaluated 28 dogs with insulinoma reported a MST of 785 days for 19 dogs undergoing partial pancreatectomy, with a median DFI of 496 days. A subset of those dogs also received prednisolone and has a MST of 1316 days. For 8 dogs that received medical therapy alone, the MST was 196 days. When all dogs that received medical therapy were considered as a group, the MST after institution of therapy was 452 days.
Improved survival in a retrospective cohort of 28 dogs with insulinoma. JSAP, 2007.
What breed of cats may be overrepresented for insulinomas?
Siamese
Surgical management of cats with insulinoma reports a MST of ___ months.
1 to 32 months.
What are gastrinomas? By what cells is gastrin produced in pancreatic tumors? Where are gastrin producing cells located?
Neuroendocrine tumors that secrete an excessive amount of gastrin
They are located in the duodenum and gastric antrum, but not in the pancrease. The cell of origin for primary pancreatic gastrinomas is now known, but D cells - which secrete gastrin in the fetus and neonate, are the most likely caise.
What is Zollinger-Ellison syndrome?
Triad of a non-beta-cell neuroendocrine tumor in the pancreas, hypergastrinemia, and gastrointestinal ulceration.
How common are gastrinomas in dogs and cats? In what organ are the majority of these reported? What about in humans?
Uncommon in dogs, rare in cats
Pancreas in dogs and cats
Duodenum in humans
What is the biologic behavior of gastrinomas?
What % has mets at the time of diagnosis? Common met sites?
Highly metastatic
Lier, regional LNs, spleen, peritoneum, small intestine, omentum, or mesentery identified in 85% of dogs and cats at the time of diagnosis.
What are the most common clinical signs associated with gastrinomas?
Vomiting and weight loss
Also,melena, abdominal pain, anorexia, hematemesis, hematochexia, and diarrhea
What may abdominal imaging show you in patients with gastrinomas?
Ulcers
How can gastrinomas be dx?
Basal serum gastrin levels
Scintigraphy using radiolabeled pentetreotide
In which other cases may gastrin levels be elevated?
Renal, hepatic, gastric disease, after therapy with antacids
Long term medical management for gastrinomas?
Proton pump inhibitors, H2 receptor antagonists, sucralfate
Octreotide has been used in 2 dogs with success
MST for gastrinomas?
1 week to 26 months
How common are glucagonomas in dogs and cats?
Rare in dogs, never reported in cats
With which dermatitis are glucagonomas associated with?
superficial necrolytic dermatitis, diabetic dermatopathy, hepatocutaneous syndrome, necrolytic migratory erythema
What happens with blood glucose levels and glucagonomas?
What other conditons can you get?
Hyperglycemia
Overt diabetes mellitus, hypoaminoacidemia, increased liver enzyme values
What are lesionas associated with NME?
Hyperkeratosis, crusting, ulceration and erosions of the footpads, mucocutaneous junctions, external genitalia, distal extremities, pressure points, ventral abdomen
From what cells do glucagonomas arise from?
Alpha cells in the pancreas
Tx of choice for glucagonoma?
Sx
Is metastasis common at the time of diagnosis? Prognosis?
Yes
Prognosis is poor
When NME is suspected, what condition should be ruled out?
Liver disease because it is more common
Dermatologic lesions in patients with glucagonomas may respond to treatment with what?
Amino acid infusions, oral protein supplementation with protein powder or egg yolks, zinc, essential fatty acids
How common are intestinal carcinoids in dogs and cats? From which cells do they arise from? In what organs have they been reported?
Rare in dogs and cats
Enterochromaffin cells
GI tract, liver, gall bladder, pancreas
What do intestinal carcinoids release?
Tx of choice? What is the prognosis? Why?
Vasoactive substances
Surgery
Poor, mets present at dx
What chemotherapy has been tried against intestinal carcinoids?
Carboplatin
Adjuvant carboplatin for the treatment of intestinal carcinoid in a dog. In Vivo, 2008.
