DOG - Pituitary macroadenoma with associated edema

Neurology Report - www.vetlabs.no

Reporting Neurologist Chris Levine, DVM, DACVIM

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What I see from your history is that he is a 7 year old Norwegian Elkhound who has inappropriate drinking and urination. Urine is hyposthenuric and is sterile. Cortisol is greater than 55mmol/L.?

With these clinical signs, hyperadrenocorticism is considered highest on my list and with a normal abdominal ultrasound, a pituitary tumor would be the greatest consideration. An MRI of the brain is indicated, just as you performed.?

FINDINGS: There is a large, heterogeneous mass that is avidly contrast enhancing arising from the sella turcica. The mass is 1.4cm tall and is causing mild mass effect with flattening of the rostral vermis of the cerebellum. Also, within the right external ear canal, there is a T2 hyper intense region. The remainder of the head is unremarkable.?

CONCLUSION: Pituitary Macroadenoma with perilesional edema

RECOMMENDATIONS: The pituitary mass is the cause for the clinical signs present. There are a few considerations for therapy including surgical debulking or radiation therapy. Also, medical therapies like Vetoryl, Selegiline, or Lysodren can be used to reduce the cortisone production in the body. Consulting an internal medicine specialist, radiation oncologist, or neurosurgeon who has performed pituitary resections is indicated for further care.?

I want to comment on pituitary tumors and radiation therapy below.?

Comments on Pituitary Tumors: The pituitary gland is an endocrine gland located at the base of the brain. Endocrine glands produce specialized chemicals called hormones, which regulate and integrate many activities to maintain internal stability of the body. The hormones pass directly into the blood to affect target cells elsewhere. The distinct endocrine glands are the adrenals, thyroid, parathyroids, pituitary gland and islets in the pancreas, although hormones are produced by many cells in other tissues. The pituitary links to other glands through its hormones and regulates hormone production by the adrenal, thyroid and sexual organs as well as growth and day-to-day cycles of activity (diurnal rhythm).

Most pituitary tumors are benign (and a few are non-cancerous cysts) but because of their location, they still produce serious adverse effects as they enlarge and they are rarely curable. Many produce hormones that have effects on the glands normally targeted by pituitary hormones, which also have effects on the targets of the hormones of these glands. The most common hormone produced by pituitary tumors stimulates the adrenal cortex leading to clinical signs associated with overstimulation of these glands (hyperadrenocorticism or Cushing's disease).

The reason why a particular pet may develop this, or any cancer, is not straightforward. Cancer is essentially the result of non-lethal genetic damage to cells with "external" contributory factors that may include radiation, chemicals, hormones and infections. The mutated cells upset the normal regulation of cell death and replacement. They do this by activating growth-promoting oncogenes (cancer genes), inactivating suppressor genes and altering the genes that regulate normal, programmed cell death (apoptosis).

Non-cancerous cysts of the pituitary glands may be genetic or due to malformation of the area in early life. We know little about the causes of pituitary cancers.

Cancer induction is a multistep process called tumor progression. Some cancers never progress past the first stages so remain benign. Others progress rapidly. Some animals have a greater tendency (genetic susceptibility) to cancer.

Some breeds have far more cancers than others, often of specific types. Boxers, Boston Terriers and Dachshunds have the highest incidence of pituitary tumors causing adrenal cortical hyperactivity.

Cysts around and in the pituitary gland are common in some breeds. Developmental cysts of one type cause breathing difficulties in short-nosed dogs. Another type causes growth failure and is a genetic problem, mainly in German Shepherd dogs.

Tumors of the pituitary exert pressure on the surrounding tissues. Not only does this affect the function of the gland but it may also affect the adjacent brain. Clinical signs associated with compression of adjacent structures may include difficulty seeing and 'diabetes insipidus' (excessive drinking and urination due to an inability to concentrate urine). Clinical signs associated with decreased output of the pituitary include slowing of the body's functions, low blood sugar and loss of sexual libido and performance.

Most pituitary tumors produce hormones. The most common hormone is adrenocorticotrophic hormone (ACTH), excess of which leads to increased size and activity of the adrenal cortex and over-production of adrenal hormones. The second most common type of pituitary tumor is not functional in dogs, but in cats, secondary effects include diabetes mellitus, degenerative arthritis and kidney disease.

The clinical signs of primary pituitary tumors that secondarily affect the adrenal glands are the same as those of primary adrenocortical tumors. They include increased appetite and thirst, loss of hair, dry skin and "blackheads" on the belly, hard (calcium) masses in the skin on the neck and back (these masses may ulcerate and become infected), and a pendulous or sagging abdomen caused by redistribution of body fat and weakening of muscles. Some dogs are also diabetic. The immune system is damaged so infections persist.

A diagnosis is typically made using a combination of clinical suspicion, changes on routine blood work (increased alkaline phosphatase), and more definitive endocrine diagnostic testing (low dose dexamethasone suppression test/ACTH stimulation test/Endocrine panel sent to the University of Tennessee). If hyperadrenocorticism is presumed, then we try to differentiate between adrenal origin and pituitary origin. This can be done by performing an abdominal ultrasound to rule out an adrenal tumor. If there is bilateral enlargement of the adrenals and no specific mass present, then we can assume a pituitary origin. An MRI or CT scan are the only way to make a definitive diagnosis of a pituitary mass.

Once a pituitary tumor is diagnosed, we have to discuss the different ways to treat. There are surgical procedures, radiation therapy, and even chemotherapies that can help to reduce the size of a pituitary mass.

Historically, medical therapies had been the only method used at controlling pituitary masses, using Mitotane (op-DDD). In these patients, 52% had a relapse in clinical signs despite treatment within 1-2 years. 17% of patients succumbed to their disease within 6 months.

In human medicine, endoscopic transsphenoidal tumor resection is the treatment of choice. For our veterinary patients, this is also the gold standard method to remove pituitary masses, although there are very few locations that perform this procedure. In the USA, VCA West Los Angeles is the only hospital to my knowledge that performs this surgery. Alternately, Utrecht University in the Netherlands also performed (and actually first developed) the procedure for dogs. For our patients, 70% of dogs are disease free 4 years after surgery (Study of 181 dogs at Utrecht). Similar findings were presented by a group out of Japan, with 80% survival at 4 years post-surgery.

The last method of treating a pituitary tumor is by radiation therapy. The use of ionizing radiation (usually photons or electrons) in treating disease is called radiation therapy.? Ionizing radiation deposits large amounts of energy in a localized area.? The energy that is deposited disrupts atomic structures which in turn damages biological structures (DNA most commonly).? Radiation therapy is based on the principal that ionizing radiation may kill proliferating (rapidly dividing) cells by damaging DNA.? When the DNA is damaged, in many cases it interferes with the cell's ability to divide and the cell dies.? Tumor cells are rapidly proliferating and are thus sensitive to radiation.? Unfortunately, proliferating cells of normal tissues are also sensitive to radiation and may be damaged by radiation.? Therefore, the total radiation dose that can be given is determined by the most radiosensitive normal tissue in the treatment volume.

In veterinary medicine, there are two basic types of radiation therapy; traditional radiation (cobalt or traditional linear accelerator) and radiosurgery.? Radiosurgery may be performed using a surgically implanted stereotactic headframe, or with some machines, may be performed without any frame.? Radiosurgery can be performed with a gantry-based machine or with a Cyberknife machine.? Cyberknife radiosurgery uses an image-guided, robot-mounted linear accelerator (non-gantry based, no head-frame required).? Traditional radiation is by far the most common type of radiation in veterinary medicine.? Radiosurgery is performed only at only a few veterinary centers including Animal Specialty Center, University of Florida, and Colorado State University.? The only veterinary Cyberknife radiosurgery machine in the world is at the Animal Specialty Center.

Comments on Radiation Therapy: The use of ionizing radiation (usually photons or electrons) in treating disease is called radiation therapy.? Ionizing radiation deposits large amounts of energy in a localized area.? The energy that is deposited disrupts atomic structures which in turn damages biological structures (DNA most commonly).? Radiation therapy is based on the principal that ionizing radiation may kill proliferating (rapidly dividing) cells by damaging DNA.? When the DNA is damaged, in many cases it interferes with the cell's ability to divide and the cell dies.? Tumor cells are rapidly proliferating and are thus sensitive to radiation.? Unfortunately, proliferating cells of normal tissues are also sensitive to radiation and may be damaged by radiation.? Therefore, the total radiation dose that can be given is determined by the most radiosensitive normal tissue in the treatment volume.

In many, but not all cases, radiation therapy shrinks the tumor.? Radiation therapy does not kill cells immediately; it does not zap the tumor cells and cause immediate death.? Rather, radiation therapy damages DNA.? When DNA is damaged, one of three things can occur within the cell.?

First, the tumor cell may try to divide despite the DNA damage.? If this occurs, the cell should die (mitotic death) resulting in regression (shrinkage) of the tumor.? This mitotic death only occurs when the cell tries to divide.? Thus, if the tumor cells are dividing very rapidly, the tumor may regress very quickly whereas if the tumor cells are dividing more slowly, the tumor may regress more slowly.? Shrinkage may occur over weeks to months (or even years).? This is why radiation is not necessarily recommended for dogs that are not neurologically stable.

Second, the tumor cells may go into a quiescent state (ie a "dormant" state where the cells do not try to divide.? If the tumor cells become quiescent, the tumor may not grow, but it may not shrink either.? A quiescent state results in tumor stabilization.? Generally, we are happy with either shrinkage or stabilization of the tumor.

Third, the tumor cells with DNA damage may try to fix the DNA damage.? If the cells are able to fix the DNA damage, they can divide without dying.? This results in progression of the tumor (continued growth or regrowth of the tumor).? The ability of the tumor cells to fix radiation damage over time is the reason that radiation is most often not curative; eventually the tumor cells fix the DNA damage and are able to repopulate the tumor.? This may occur at any time (weeks to months to years) after radiation is given.

It is also important to note that if your dog has seizures, radiation therapy, in and of itself, has no effect on the seizure activity; seizures often continue even if there is good response to radiation.? Seizures will need to continue to be medically managed.

In veterinary medicine, there are two basic types of radiation therapy; traditional radiation (cobalt or traditional linear accelerator) and radiosurgery.? Radiosurgery may be performed using a surgically implanted stereotactic headframe, or with some machines, may be performed without any frame.? Radiosurgery can be performed with a gantry-based machine or with a Cyberknife machine. Cyberknife radiosurgery uses an image-guided, robot-mounted linear accelerator (non-gantry based, no head-frame required). Traditional radiation is by far the most common type of radiation in veterinary medicine.? Radiosurgery is performed only at only a few veterinary centers including Veterinary Cyberknife Cancer Center, University of Florida, and Colorado State University. The only veterinary Cyberknife radiosurgery machine in the world is at the Veterinary Cyberknife Cancer Center in Malvern Pennsylvania.

A traditional linear accelerator produces packets of energy called photons which are directed at a localized region.? The energy that is deposited by the photon disrupts atomic structures and, in turn, damages biological structures such as DNA.? A traditional linear accelerator is on a gantry that rotates 360o around an axis.? As such, it can treat from any angle around that axis, but cannot treat from any other angles.? In veterinary medicine usually 2-4 ports (or beam angles) are used to treat tumors.? As such, for any given beam angle, the normal tissue surrounding the tumor will get 25-50% of the total dose.? If normal tissue were to receive 25-50% of the total dose in one treatment, life threatening side effects would occur.? In order to avoid these side effects using traditional linear accelerator radiation, it is necessary to divide the total dose into fractions.? In veterinary medicine, usually 15-20 fractions are given over a period of 3-4 weeks.? The animal is anesthetized for each treatment.?

Radiation injuries to normal tissues are classified as acute or late reactions.? Acute radiation reactions are primarily due to epithelial cell responses (i.e., skin, mucous membranes, lining of the gut, etc.) These cells are rapidly proliferating.? Injury manifests itself in skin reactions ranging from epilation (hair loss), erythema (reddening of skin), dry desquamation (flaky skin), moist desquamation (blistering), to skin necrosis.? Some degree of acute radiation side effects will be seen in 80% of cases.? The second type of injury, late reactions, generally reflects radiation damage to endothelial and connective tissues.? Injury manifests itself as necrosis (death of cells), strictures, fibrosis (scarring), and secondary tumors.? Only about 5% of animals will experience late effects.? In addition, if the eyes were in the treatment field, dry eyes and corneal ulcers can result following the end of radiation therapy, and one to two years after the radiation therapy, lens opacification (cataracts) will always occur.?

The Cyberknife machine is also a linear accelerator that produces photons.? The difference between a traditional linear accelerator and the Cyberknife is that the Cyberknife is mounted on a robotic arm that has 6 degrees of freedom on each of 5 "arm" joints.? This flexibility allows the tumor to be treated from virtually any angle.? In addition, with Cyberknife radiation, hundreds of ports (beam angles) are used.? As such, normal tissue in each beam path only receives 1/100 or even 1/200 of the total dose.? Because the normal tissue in each beam path receives such a small dose it is possible for us to use many fewer treatments with Cyberknife radiosurgery (1-3 total treatments) compared to traditional treatment (15-20 treatments).?

Cyberknife radiosurgery allows a more conformal and higher dose of radiation to the tumor.? Experience in human medicine with Cyberknife radiosurgery and limited experience in veterinary medicine with other types of radiosurgery (framed, stereotactic) show that, in many cases, response to treatment is more favorable with radiosurgery than with conventional radiation.? In addition, Cyberknife radiosurgery limits dose to normal tissue.? Cyberknife radiosurgery requires fewer trips to the hospital, fewer treatments and fewer anesthetic episodes.

Although Cyberknife radiosurgery limits dose to normal tissue, there are some risks and possible side effects associated with treatment.? First, animals must be anesthetized in order to receive Cyberknife radiosurgery.? Anytime an animal is put under anesthesia, there is a risk of death.? The risk is very small (usually less than 1%), but there is a risk.? Second, it is possible to see radiation-related side effects.? As with conventional radiation, both acute and late effects may occur.? Acute side effects are much less likely with Cyberknife radiosurgery than with convention radiation.? Late effects are also unlikely to occur, but may, in rare cases, be life threatening.? The type of side effect, chance of occurrence, and severity of the effect vary by tumor type and location.?