Pituitary Tumor
BACKGROUND
What is the % of pituitary tumors in relation to all primary brain tumors?
~10%–15% of all diagnosed primary brain tumors are of pituitary origin with up to 25% seen on autopsy series.
What % of pituitary tumors are functional vs. nonfunctional?
75% of pituitary tumors are functional, while 25% are nonfunctional.
What are the sex and age predilection for pituitary tumors with symptomatic presentations?
Symptomatic pituitary tumors occur mostly in females. 70% occur from 30–50 yrs.
What are some heritable syndromes that predispose to pituitary tumors, and what is the inheritance pattern?
MEN-1
(3 “Ps”: pituitary, parathyroid, pancreas), 11q13 mutant/menin. Autosomal dominant inheritance.
What is Nelson syndrome?
Nelson syndrome is ACTH-secreting adenoma that develops after adrenalectomy (pts can develop hyperpigmentation of the skin due to a melanocyte-stimulating hormone).
What are the embryonic derivatives of the ant pituitary vs. post pituitary?
Anterior: Rathke pouch (oral ectoderm)
Posterior: extension of the 3rd ventricle (neuroectoderm)
What is the name for the bony structure that houses the pituitary?
The sella turcica houses the pituitary.
What are the boundaries of the sella?
Tuberculum sellae anteriorly, dorsum sellae posteriorly, sphenoid sinus inferiorly, dural folds superiorly, and posterior clinoid processes laterally.
What CN deficit is most commonly caused by pituitary adenoma?
CN II. Pituitary adenomas are the most common cause of optic chiasm compression. Less commonly, CN III, CN IV, and CN VI deficits can cause ocular motility symptoms.
What hormones are secreted by lobes of the pituitary?
Anterior: prolactin (PL), GH, ACTH, TSH, LH, FSH
Intermediate: melanocyte-stimulating hormone (MSH)
Posterior: ADH, oxytocin
What is the histopathologic description of the cells of nonfunctional tumors?
Histopathologically, the cells of nonfunctional tumors are chromophobic.
What hormones are secreted by basophilic cells? Acidophilic cells?
Basophilic: ACTH, TSH, LH, FSH
Acidophilic: GH, PL
What is the most common functional pituitary tumor? 2nd most common? 3rd most common?
Prolactinoma (30%) > GH (25%) > ACTH (∼15%)
Which pituitary tumors are more common in males and the elderly? Which are more common in females?
Males and the elderly: nonfunctioning or GH
Females: PL and ACTH secreting
Which are the more common pituitary tumors: micro- or macroadenomas?
Macroadenomas (≥1 cm) are the more common pituitary tumors.
Which are the most common pituitary tumors in females?
Microadenomas (<1 cm) are the most common pituitary tumors in females, particularly those that are PL secreting.
What is the most common cause of pituitary dysfunction in adults? Children?
Adults: pituitary adenoma
Children: craniopharyngioma
What histologic features are prominent in prolactinomas?
Calcifications and amyloid deposits are prominent in prolactinomas.
What immunohistochemical stains are positive in pituitary adenomas?
Synaptophysin, chromogranin, and hormone-specific stains
WORKUP/STAGING
With what signs/Sx do pts with a nonsecretory pituitary tumors present?
Bitemporal hemianopsia (optic chiasm compression), HA (↑ICP), oculomotor deficits: CNs III–IV, VI, V1–V2 (cavernous sinus compression), hydrocephalus (3rd ventricle compression), hyperprolactinemia (disruption of PL suppression from hypothalamus due to compression of pituitary stalk), or panhypopituitarism (from general glandular disruption).
With what signs/Sx do pts with secretory pituitary tumors present?
PL secreting (50%): galactorrhea, amenorrhea, infertility, and vaginal dryness for women, loss of libido, erectile dysfunction and infertility for men
GH secreting (25%): acromegaly
ACTH secreting (20%): Cushing disease
TSH secreting (≤1%): hyperthyroid symptoms
What is the DDx of a pt with a pituitary mass?
Pituitary tumor, craniopharyngioma, meningioma, glioma, suprasellar germ cell, mets, and benign lesions (cyst, aneurysm, empty sella syndrome)
What is the workup of a pt with a pituitary tumor?
Pituitary tumor workup: H&P (physical: CNs, visual field, endocrinopathy), labs, including hormone levels, thin-slice MRI through the base of skull, and tissue Dx (transsphenoidal resection)
What lab findings are suggestive of a prolactinoma?
Normal prolactin is ~2–25. If >100–200, prolactinoma is suspected, particularly in the setting of a pituitary mass.
What are other causes of elevated PL?
Pregnancy, lactation, polycystic ovary syndrome, hypothyroidism (thyroid-releasing hormone from hypothalamus stimulates PL secretion), seizures, and cirrhosis.
What lab findings are suggestive of a GH adenoma?
GH >10 (not suppressed by glucose) and elevated IGF-1 are findings that suggest GH adenoma.
What lab abnormalities are noted in Cushing Dz?
High cortisol not suppressed by low-dose dexamethasone and normal or ↑ACTH
What is Cushing syndrome?
Cushing syndrome is elevated cortisol due to a variety of causes (e.g., adrenal production, exogenous use). Pts have low ACTH, unlike in Cushing Dz.
What primary malignancies most commonly metastasize to the pituitary?
Breast and lung cancer. Usually in the setting of diffuse metastatic disease with >4 other sites.
TREATMENT/PROGNOSIS
What are the Tx paradigms of choice for the management of pituitary adenomas?
1. Observation if small, nonsecreting microadenomas or prolactinomas
2. Medical management with bromocriptine or cabergoline for a microadenoma prolactinoma not causing local symptoms. However, 30% cannot tolerate bromocriptine due to nausea, HA, and fatigue.
3. Surgical resection if hypersecreting or symptomatic (due to mass effect for nonsecreting tumors) → observation or postop radiation if fail to suppress biochemically.
Can also consider external radiation therapy alone for definitive local treatment with either stereotactic radiosurgery or fractionated radiation.
How long does it take for normalization of the PL level to occur after initiating pharmacologic suppression?
Normalization of the PL level takes 1–2 mos following the initiation of pharmacologic suppression.
What pharmacologic agents are used for GH-secreting pituitary adenomas?
Somatostatin, octreotide, and pegvisomant (GH receptor antagonist)
What pharmacologic agents are used for ACTH-secreting pituitary adenomas?
Ketoconazole (best), cyproheptadine (inhibits ACTH secretion), mitotane (↓ cortisol synthesis), RU-486 (blocks glucocorticoid receptor), and metyrapone
What is the hormone normalization rate after surgery for a hyperfunctioning pituitary tumor?
Hormone levels normalize in 80%–90% of those with microadenoma and ∼65% of those with macroadenoma.
What types of surgical resection are used for pituitary tumors, and what are the indications?
Transsphenoidal microsurgery: for microadenomas, decompression, debulking of large tumors, reducing hyperfunctioning tumors
Frontal craniotomy: for large tumors with invasion into cavernous sinus, frontal/temporal lobes
Where is the scar located after transsphenoidal resection?
There is no visible scar. Transsphenoidal resection is done through the nose or alternatively from behind the upper lip.
What are the LC rates after transsphenoidal resection? Are they better for macroadenomas or microadenomas?
95%. LC rates are better for microadenomas after surgical resection.
What are some poor prognostic factors after transsphenoidal resection of prolactinoma?
Size >2 cm, high preop PL level, ↑age, and longer duration of amenorrhea
What are some poor prognostic factors after surgical resection of GH-secreting tumors?
High preop GH and somatomedin-C levels, tumors >1 cm, and extrasellar extension
Which pituitary tumors have a high recurrence rate after resection?
TSH-secreting tumors (risk factors: Hx of thyroid ablation, Hashimoto thyroiditis, prior RT/surgery)
What are the indications for radiotherapy in the Tx of pituitary tumors?
Pituitary tumor indications for radiotherapy:
1. Medically inoperable or otherwise not felt to be good surgical candidate due to proximity to vessels or cavernous sinus.
2. Persistence of hormone defect after surgery
3. Macroadenoma with STR or decompression
4. Recurrent tumor after surgery
What are the long-term control rates for hormone-secreting tumors after RT?
Best outcomes with RT for GH-secreting tumors (80%) > ACTH (50%–80%) > PL (30%–40%)
What should be done with medical/pharmacologic Tx before initiating RT for pituitary adenomas?
Medical Tx needs to be D/C b/c of lower RT sensitivity with concurrent medical Tx. (Landolt AM et al., J Clin Endocrinol Metab 2000)
What is the typical LC rate with RT for pituitary tumors?
The LC after RT is >90% for most pituitary tumors (Loeffler JS et al., J Clin Endocrinol Metab 2011).
What are the typical RT volumes and doses used for pituitary tumors?
With IMRT or proton beam therapy: Treat operative bed + gross disease + 0.3 – 0.5 cm PTV; 45–50.4 Gy in 1.8 Gy/fx if postop with no gross Dz, 54 Gy for gross Dz.
How long does it typically take for hormone stabilization to occur after Tx with RT?
It takes yrs for hormone stabilization after Tx with RT (GH: 50% normalize at 2–5 yrs, 70% after 10 yrs).
What evidence supports at least 45 Gy as the min effective RT dose for pituitary tumor control?
Older Florida data (McCollough WM et al., IJROBP 1991): 10-yr LC was 95%.
What are the indications for and the benefits of SRS in the Tx of pituitary adenomas?
SRS is used for microadenomas and yields better control of hormone secretion (same LC as fractionated and is more convenient).
What are the typical SRS doses used for functional vs. nonfunctional tumors?
Functional SRS dose: ~20 Gy
Nonfunctional SRS dose: ~14–18 Gy
What are the differences between LINAC-based and Gamma Knife (GK)-based SRS for pituitary tumors?
With GK, there is less homogeneous dose to the tumor, more precise setup, and slightly less normal tissue treated (similar outcomes/conformality can be achieved with LINAC-based SRS, however).
When is FSR preferred instead of SRS for pituitary adenomas?
FSR is preferred when the pituitary lesion is >3 cm and/or the lesion is <2 mm from the chiasm.
What RT doses are used with fractionated EBRT? When is EBRT typically used?
45–50 Gy (nonfunctioning), 50–54 Gy (functioning). Fractionated EBRT is typically used for large adenomas and/or lesion is < 2 mm from chiasm or optic nerves.
What form of radiation can be used to reduce dose to normal tissues with fractionated EBRT?
Proton therapy. The Loma Linda experience showed it to be effective (Ronson BB et al., IJROBP 2006). However, long-term results needed to determine clinical results from normal tissue sparing.
TOXICITY
What is the most common toxicity of pituitary irradiation?
Hypopituitarism. Risk is ∼20% at 10 yrs posttreatment (Brada et al., Clin Endocrinol 2002) with fractionated radiation or SRS (Sheehan et al.,J Neurosurg 2013).
What is the RT TD 5/5 tolerance dose threshold for developing hypopituitarism?
The TD 5/5 is 40–45 Gy. GH levels ↓ 1st, then LH/FSH → TSH/ACTH.
What is the tolerance of the optic nerves/chiasm with the use of conventional RT?
With conventional RT, 50–54 Gy is the tolerance of the optic nerves/chiasm.
What is the TD of the optic nerve to single-fx SRS?
8 Gy is the TD of the optic nerve with single-fx SRS.
What are the main benefits of using SRS for pituitary adenomas?
Benefits of SRS include ↓ neurocognitive sequelae and possible preservation of normal pituitary function by reducing the dose to the hypothalamus (↑ risk of damage to the optic nerve/chiasm).
What is the best way to assess the response to RT in GH-secreting tumors?
The response to RT can be assessed by monitoring IGF-1 levels.
What hormone is the 1st to respond/decrease after RT?
GH is the 1st hormone to respond/decrease after RT.
What is the operative mortality/complication rate after surgery?
Mortality: 1%–2%
Complication rate: 15%–20%
What are the most common surgical complications after resection of pituitary tumors?
Diabetes insipidus (6%) → hyponatremia and CSF leak
Which pituitary pts/tumor types are prone to increased rates of 2nd malignancies after Tx with RT?
Men with GH-secreting pituitary adenomas have increased rates of 2nd malignancies after RT. (Norberg L et al., Clin Endocrinol 2007)
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