Pituitary tumors: Pathology review

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Case Study0:00–1:03

While doing your rounds, you see a 6 year-old named Alex who presents with severe headaches and vision impairment which began six months ago.
More specifically, he has some difficulty seeing things on the periphery, what he describes as tunnel vision. Examination reveals bitemporal hemianopia and a much taller stature than expected for his age, with disproportionately long arms and legs.
Soon after, you see Maria, who says she has been unsuccessfully trying to have a baby for the last two years. She also mentions that she hasn’t had her menstruation in 3 months, but had milky nipple discharge.
Hormone serum measurements were performed in both, showing an increase in insulin-like growth factor-1 levels in Alex and an increase in prolactin levels in Maria.Now, both seem to have a disease affecting the pituitary.

Physiology1:03–3:06

But first, a bit of physiology. The pituitary is a small gland situated in a tiny bony space called the sella turcica.
It is linked to the hypothalamus by the pituitary stalk, and it is divided into the anterior pituitary and the posterior pituitary.
The posterior pituitary is not glandular; thus it doesn’t make its own hormones. Instead, it stores and secretes oxytocin and antidiuretic hormone which are produced in the hypothalamus.
By contrast, the anterior pituitary has five types of hormone producing cells. First, lactotrophs secrete prolactin, which stimulates breast milk production and inhibits ovulation and spermatogenesis.
Second, somatotrophs secrete growth hormone, or GH. GH acts directly on target tissues to stimulate growth and development.
Then, corticotrophs secrete adrenocorticotropic hormone, or ACTH for short. ACTH makes the adrenal glands secrete cortisol.
Cortisol is in charge of the stress response and keeping blood pressure and blood sugar in the normal range. Fourth, thyrotrophs secrete thyroid stimulating hormone, or TSH.
TSH makes the thyroid gland release thyroid hormones, T3 and T4. Thyroid hormones speed up the basal metabolic rate in all cells, so it keeps cellular processes going at an optimal rate.
And finally, gonadotroph cells secrete luteinizing hormone, or LH, and follicle-stimulating hormone, or FSH, that stimulate ovarian or testicular production of sex cells and sex hormones.Now, most pituitary tumors are adenomas, which are benign tumors.

Adenomas3:06–5:24

These tumors could arise spontaneously, but may also be associated with certain disorders like multiple endocrine neoplasia type 1, or MEN1 where tumors also develop in the parathyroid glands and the pancreas.
Okay, so when a pituitary adenoma is under one centimeter across, it is called a microadenoma. Because these tumors are small, they rarely cause any symptoms and are usually incidental findings on brain imaging.
If the tumor is larger than one centimeter across, it’s called a macroadenoma. As they grow, macroadenomas can press on the normal parts of the pituitary and cause severe headaches and hypopituitarism, which is when one or all of the anterior pituitary hormones are decreased.
If the tumor grows superiorly, it can compress the nearby optic chiasm, which is where the optic nerves partially cross.
This leads to visual abnormalities like bitemporal hemianopia, or narrowing of the vision field, a very high yield fact to remember!
If it extends laterally, it can invade the cavernous sinus, a structure made of venous channels located on both sides of the sella turcica, and press on the nerves that pass through it.
This causes cavernous sinus syndrome. The syndrome consists of ophthalmoplegia, which is weakness or paralysis of the muscles involved in eye movement due to compression of CN III, IV, and VI; decreased corneal and maxillary sensations due to compression of CN V; and Horner syndrome due to compression of the sympathetic plexus within the sinus.
Remember that Horner syndrome is a combination of miosis, decreased pupil size; ptosis, a drooping eyelid; and anhidrosis or decreased sweating.Both micro and macroadenomas can be non-functional or functional.

Non-functional adenomas5:24–7:01

Now, most non-functional adenomas grow for a really long time without causing any trouble, until reaching the size of a macroadenoma.
Macroadenomas present with compression symptoms, especially headache, bitemporal hemianopia, and double vision. Sometimes, hypopituitarism features, like impaired growth, sexual dysfunction, and intolerance to cold might also develop.
Another possible consequence is pituitary apoplexy, occurring when the blood vessels of the adenoma rupture and cause a hemorrhage that compresses the blood vessels of the pituitary itself.
Symptoms are similar to those caused by compression like bitemporal hemianopia and severe headaches, but meningeal signs like neck stiffness can also be present.
Because blood supply to the pituitary is obstructed, this leads to pituitary ischemia, necrosis, and loss of pituitary function.
Non-functional adenomas are usually diagnosed by brain MRI, while pituitary hormone screening might also show a decrease in hormone levels in those with hypopituitarism.
Treatment of symptomatic individuals consists of transsphenoidal surgery. Asymptomatic adenomas smaller than 2 centimeters, however, can be monitored with an MRI, visual field testing, and screening for hormone hypo- or hypersecretion.Functional adenomas, on the other hand, often lead to an excess of hormones.

Functional Adenomas7:01–7:47

First, lactotroph adenomas, or prolactinomas, are the most common type. Now, what you need to know is that, normally, prolactin secretion is controlled by the hypothalamus, which inhibits its production by releasing dopamine via the tuberoinfundibular pathway, and stimulates its production via thyrotropin releasing hormone or TRH.
Prolactin also causes negative feedback by inhibiting its own secretion since it causes dopamine release from the hypothalamus.
However, when there’s too much prolactin, dopamine inhibition is lost, and the hypothalamus can’t regulate prolactin production anymore.
Now, a macroadenoma can also obstruct the flow of dopamine from the hypothalamus, but compared to prolactinomas, the elevation in prolactin is usually mild and under 100 ng/ml.

Prolactinoma7:47–9:51

In premenopausal females, the main symptom of hyperprolactinemia is galactorrhea, or a milky nipple discharge outside of breastfeeding or pregnancy.
Now, another high-yield consequence is that excess prolactin suppresses hypothalamic production of gonadotropin-releasing hormone or GnRH, which leads to the pituitary secreting less LH and FSH.
And without gonadotropin stimulation, gonads can’t secrete sex hormones like estrogen and progesterone, causing hypogonadism.
Hypogonadism symptoms can include infertility, amenorrhea, which is absent menstruation, and vaginal dryness. Osteoporosis is another consequence that’s frequently tested, which can occur due to loss of bone density secondary to decreased estrogen levels.
And as a result, these female individuals tend to suffer fragility fractures. Males typically develop decreased libido, impotence, infertility, gynecomastia, and, rarely, galactorrhea.
Most individuals can also present with compression symptoms like bitemporal hemianopia and headaches as well. A brain MRI scan showing the tumor's size and extent and a blood test showing high serum prolactin levels confirm the diagnosis.
Treatment relies on dopamine agonists like cabergoline or bromocriptine that inhibit prolactin secretion just like dopamine would.
If the tumor is large, transsphenoidal resection could be attempted. Somatotroph adenomas make growth hormone and are the second most common type of pituitary adenoma.

Somatotroph adenoma9:51–12:21

Excess growth hormone causes different symptoms in children versus adults. In children, it causes gigantism, which is an increase in body size and height with disproportionately long arms and legs.
Something to remember is that these kids can get really tall because, unlike other causes of gigantism, GH doesn’t accelerate epiphyseal closure of the bone, which is responsible for linear growth.
In adults, it causes acromegaly, where there’s enlargement of the bones of the skull, hands, and feet. Other possible features of acromegaly include a large tongue with deep furrows, deep voice, diaphoresis, which is excessive sweating, impaired glucose tolerance, and increased risk of colorectal polyps and cancer.
In both gigantism and acromegaly, there can also be enlargement of visceral organs, like the heart. Screening for a somatotroph adenoma is actually a high-yield topic.
It’s done by measuring insulin-like growth factor 1, or IGF-1 levels, which is a liver-produced hormone through which GH stimulates long bone growth.
This is because daily GH secretion is pulsatile but it stimulates the liver to release a constant amount of IGF-1 throughout the day.
If high levels are detected, an oral glucose tolerance test is performed, where serum GH is measured before and after glucose administration.
This is because, in healthy people, a higher blood glucose level usually causes the body to stop producing GH. If GH levels stay the same, growth hormone hypersecretion can be diagnosed.
Brain MRI might also be required to assess the location and size of the tumor. Treatment consists of transsphenoidal resection.
If surgery is unsuccessful, medical therapy is done with dopamine agonists like cabergoline or a GH receptor antagonist like pegvisomant.
Some cases might also require radiotherapy.Corticotroph adenomas secrete excess ACTH, causing Cushing disease. Cushing disease is different from Cushing syndrome.

Corticotroph adenoma12:21–14:50

Cushing syndrome refers to all the symptoms caused by high cortisol levels which can be caused not only by Cushing disease but many other conditions, including ACTH-secreting ectopic tumors or adrenal tumors.
Ok so, possible symptoms include a change in fat distribution, causing-moon facies, a round, full moon shaped face, buffalo hump, which is a fatty deposit on the upper back, and truncal obesity where fat accumulates around the abdomen and trunk rather than in the limbs.
Cushing disease can also result in skin hyperpigmentation. This is due to increased levels of melanocyte-stimulating hormone or MSH, which signals melanocytes to produce a lot of melanin, turning the skin darker than normal.
This occurs because ACTH shares a common precursor with MSH, called pro-opiomelanocortin, so when ACTH production increases, more MSH is also produced.
Ok, so diagnosis is based on elevated serum ACTH and elevated 24 hour urinary cortisol levels. However, keep in mind that a high-dose dexamethasone suppression test is also needed to distinguish between a pituitary or an ectopic secretion of ACTH.
Dexamethasone is a synthetic corticosteroid that provides negative feedback to the pituitary gland, resulting in suppression of ACTH production.
So, if after the test, ACTH and cortisol levels drop, it means the elevation was caused by a pituitary tumor. If the levels stay the same, it means there’s an ectopic source of ACTH.
Treatment is also transsphenoidal resection, but if the entire tumor can’t be removed, then radiation therapy can be used.
Therapy with drugs that block the adrenal synthesis of cortisol, like metyrapone can also be initiated to control the symptoms.
If medications aren’t sufficient to block the cortisol effects, a last resort is to surgically remove both adrenal glands.
Gonadotropin and thyrotropin-secreting pituitary tumors are extremely rare and usually cause compression symptoms. Gonadotropin-releasing tumors cause excess FSH and LH leading to gonadal hyperstimulation and, consequently, to high levels of sex hormones.

Gonadotropin and thyrotropin-secreting pituitary tumors14:50–15:49

Thyrotropin-secreting tumors cause excess TSH, which leads to hyperthyroidism, and as a result, excess T3 and T4. Diagnosis is based on elevated serum levels of FSH, LH, and sex hormones for gonadotropin-secreting tumors, and of TSH and T4 in thyrotropin-secreting tumors.
First-line treatment consists of transsphenoidal resection followed by radiotherapy in the case of surgical failure. Another benign tumor of the pituitary that you might come across is craniopharyngioma.
It is the most common childhood supratentorial tumor, which is an area located above the tentorium cerebelli. The tumor originates from the residual anterior pituitary embryonic tissue, called Rathke's pouch.
Symptoms depend on the tumor’s location. If it involves the area of the pituitary gland itself, the tumor can cause partial or complete pituitary hormone deficiency, leading to hypopituitarism.

Craniopharyngioma15:49–17:24

If it compresses the pituitary stalk, a high-yield fact is that it can decrease the secretion of antidiuretic hormone from the posterior pituitary, leading to diabetes insipidus and symptoms like extreme thirst and increased urinary output and frequency.
A large craniopharyngioma can increase prolactin levels by interfering with hypothalamic dopamine release, causing galactorrhea, and also causing compression symptoms like headaches and bitemporal hemianopia.
Diagnosis is based on a contrast brain MRI, which can show calcified cysts with cholesterol crystals. Screening for pituitary hormone deficiencies should also be done since it can be associated with cortisol deficiency, and if that is the case, treatment with hydrocortisone should be initiated before the tumor is removed surgically.
Radiotherapy can be used when surgery is unsuccessful. There’s also Nelson syndrome, which is characterized by abnormal hormone secretion, enlargement of the pituitary gland, and the development of large and invasive adenomas.
It typically occurs after a few years in around one quarter of those who undergo surgical removal of the adrenal glands for Cushing disease.
Because the adrenal glands are removed, it leads to cortisol deficiency and this increases corticotropin-releasing hormone or CRH production within the hypothalamus.

Nelson syndrome17:24–18:34

As a result, the ACTH-secreting pituitary adenoma that caused Cushing disease in the first place gets even bigger. Symptoms associated with Nelson syndrome include abnormal skin hyperpigmentation, headaches, bitemporal hemianopia, and amenorrhoea.
Diagnosis is based on history, brain MRI, and increased ACTH serum levels. Treatment consists mostly of transsphenoidal resection and radiotherapy.And finally, malignant tumors like pituitary carcinomas are super rare.
Actually, pituitary carcinomas look like adenomas under a microscope and can lead to the same symptoms. The only way to tell them apart is when the tumor spreads to another part of the body.
Most often pituitary carcinoma spreads to the brain, spinal cord, meninges or the covering of the brain and spinal cord, or bone around the pituitary.

Malignant pituitary tumors18:34–19:08

Treatment is also similar to adenomas.Alright, as a quick recap. Non-functional adenomas present with compression symptoms, like headaches and visual impairment, hypopituitarism, and can cause pituitary apoplexy.
Functional pituitary adenomas can cause similar symptoms but also overproduce pituitary hormones. The most common type is prolactinomas.
In premenopausal females, symptoms consist of galactorrhea, amenorrhea, infertility, and osteoporosis. Males usually develop a decreased libido, impotence, infertility, and gynecomastia.
Next up is Growth-hormone secreting pituitary adenomas which cause gigantism in children and acromegaly in adults. ACTH-secreting pituitary adenomas cause Cushing disease and symptoms like a full-moon facies, buffalo hump, and truncal obesity.

Review19:08–21:03

For non adenoma tumors, we have craniopharyngioma which is the most common childhood supratentorial tumor and symptoms are caused by mass effect.
Nelson syndrome is characterized by abnormal hormone secretion, pituitary enlargement, and large and invasive adenomas following surgical removal of the adrenal glands for Cushing disease.
Symptoms associated with Nelson syndrome include abnormal skin hyperpigmentation, headaches, bitemporal hemianopia, and amenorrhoea.
Finally pituitary carcinomas are rare and cause the same mass effects as the other pituitary tumors. However they can metastasize to other parts of the brain, spinal cord, and bones.
Now back to our cases. Alex presents with a history of severe headaches and bitemporal hemianopia.
Examination reveals taller stature than expected for his age, with disproportionately long arms and legs. His clinical picture is highly suggestive of gigantism secondary to a growth hormone-secreting tumor.
Another clue was the increase in IGF-1 levels. Further testing should include a GH level after an oral glucose tolerance test and brain MRI to confirm the diagnosis.
Maria presents with a history of infertility and amenorrhea, and examination revealed galactorrhea. The presence of galactorrhea suggests hyperprolactinemia, which was actually confirmed by hormone serum measurements.

Summary21:03–21:58

The next step would be brain imaging to confirm the presence of a pituitary tumor. Another clue was the increase in i G F one levels Further testing should include a G H level after an oral glucose tolerance test and brain MRI To confirm the diagnosis Maria presents with the history of infertility and amenorrhea and examination revealed galactorrhea The presence of galactorrhea suggests hyperprolactinemia which was actually confirmed by hormone serum measurements The next step would be brain