Pituitary Pathology

Question 1

Overview of sellar region masses

*Know this for tests

Answer 1

a. 85%+ of sellar region masses are pituitary adenomas, which although not formally graded, are equivalent to WHO grade I; almost all the other non‐pituitary
adenoma sellar region masses are also WHO grade I and treated by surgical
resection except in instances where medical therapies are available
i. These Pituitary adenomas are the most common, and they are usually benign (WHO Grade 1 equivalent)
ii. TX with surgery

b. Some pituitary adenomas are hyperfunctioning and produce physiologically‐ unregulated excess of endocrine hormone(s); many are clinically non functioning and produce mass effect or visual disturbances due to compression of critical nearby anatomical structures
i. usually benign (may have mass effect), sometimes will produce high amount of hormone

c. Most uncommon (Rathke cleft cyst), or rare, sellar region masses (pituicytoma,
spindle cell oncocytoma, hypophysitis) closely mimic pituitary adenomas on
neuroimaging and clinically mimic clinically non functioning pituitary adenomas in
that they present with mass effects or visual disturbance

d. All except craniopharyngioma predominantly affect middle age adults;
craniopharyngioma has two age peaks, pediatric (5‐15 yrs) and middle age (45‐60
yrs) adults

Question 2

Development of the pituitary gland

Answer 2

a. The hypophysis is an amalgam of two tissues.

b. Early in gestation a finger of ectoderm grows upward from the roof of the mouth.
i. This protrusion is called Rathke’s pouch and will develop into the anterior pituitary or adenohypophysis.

c. At the same time that Rathke’s pouch is developing, another finger of ectodermal tissue evaginates ventrally from the diencephalon of the developing brain.
i. This extension of the ventral brain will become the posterior pituitary or neurohypophysis.

d. Ultimately, the two tissues grow into one another and become tightly apposed, but their structure remains distinctly different, reflecting their differing embryological origins.

Question 3

Anterior and posterior pituitary gland
12 weeks (left)
Adult posterior gland (right)

Answer 3

a. TTF-1 is a transcription factor that is found in the posterior pituitary
i. use antibody for this transcription factor after 12 weeks

Question 4

Pituitary gland at 22 weeks gestation

Answer 4

a. The pituitary hormones will begin secreting at 8 weeks of gestation
b. Every few weeks, new types of hormones are secreted

Question 5

Microadenoma

Answer 5

a. By definition, a microadenoma (seen in the image below) is a tumor less than 10 mm in diameter.
b. Pituitary adenomas may secrete hormones, but most are clinically inactive.
c. Many pituitary lesions are discovered while investigating other neurologic problems; these lesions are called incidentalomas.
d. With the use of MRI increasing, the discovery of such incidental microadenomas will become more of a clinical problem

Question 6

macroadenoma

Answer 6

The sellar region is a site of various types of tumors. Pituitary adenomas are the most common. They arise from epithelial pituitary cells and account for 10-15% of all intracranial tumors. Tumors exceeding 10 mm are defined as macroadenomas, and those smaller than 10 mm are termed microadenomas. Most pituitary adenomas are microadenomas.

Question 7

Invasive

macroadenoma

Answer 7

a. May not invade blood vessels… But it can invade:
bone,
sphenoid sinus,
dura

b. Can compress against nerves in cavernous sinus
i. Can compress CN 4,5 and 6

Question 8

Key Points

Answer 8

a. Less than 5% of pituitary tumors are familial; the rest are sporadic
b. Identifications of inherited pituitary syndromes is important because of the associated pathologies; pituitary tumors might be the presenting feature in these syndromes and important implications exist for family members
c. Four genes have so far been identified as associated with familial pituitary tumors syndromes: MEN1, CDK1B, PRKAR1A, and AIP
d. Up to 20% of patients with clinical features of multiple endocrine neoplasia type 1 do not have a mutation in MEN1; these patients might have mutation CDK1B or other genes not yet identified
e. AIP has been identified as a mutated gene in patients with familial isolated pituitary adenomas, particularly thosewho have adenomas that secrete growth hormone
f. Features that suggest an inherited pituitary tumor syndrome include parathyroid tumors, pancreatic endocrine tumotrs, atrial myxomas, lentigines Schwann-cell tumors (Carney complex), family history and young age at onset

Question 9

tuitary blastoma related to DICER1 mutation, almost always
ACTH IHC(+)

Answer 9

a. Pediatric/young adults occasionally get
pituitary adenomas and this population
is enriched for syndromic examples;
very rare infantile pituitary masses are
a different entity: pituitary blastoma

b. Almost all other pituitary adenomas SPORADIC
i. Incidental pituitary adenomas very
common at autopsy— and on neuroimaging

Question 10

Work up of pituitary adenoma

Answer 10

Find subtypes of pituitary adenoma
*all sorts of staining, don’t need to know

H&E
Reticulin
CAM5.2
Synaptophysin
Prolactin (PRL)
Growth hormone (GH)
Adrenocorticotrophic hormone (ACTH)

Follicle stimulating hormone (FSH)
(alpha subunit, luteinizing hormone (LH), ER (estrogen receptor)

Also helpful: neurofilament protein (NFP), TTF‐1 for identifying posterior gland or pituicytomas,
anti‐mitochondrial antibody

Question 11

Transcription factors delineate lineage

Answer 11

Different Adenoma by transcription factor family

1. Pit-1
2. SF-1
3. Tpit
4. Transcription Factor negative/unknown
5. Plurihormonal adenoma

*85% of usual ACTH adenomas are microadenomas, most prolactinomas in premenopausal women are microadenomas

Question 12

Pituitary adenoma type by transcription factor family

Answer 12

a. Pit‐1 (pituitary transcription factor)
i. Densely granulated somatotroph (growth hormone) adenoma
ii. Intermediate/mixed/transitional growth hormone adenoma (behaves like densely granulated growth hormone adenoma
iii. Sparsely granulated growth hormone adenoma
iv. Mixed growth hormone‐prolactinoma
v. Mammosomatotroph adenoma
vi. Sparsely granulated prolactin secreting (lactotroph) adenoma
viii. Densely granulated prolactin secreting (lactotroph) adenoma
viii. Acidophil stem cell adenoma
ix. Thyrotroph (TSH) adenoma
x. Silent subtype 3 adenoma (all with Pit‐1, variable GH/PRL/TSH)

b. SF‐1 (steroidogenic factor)
i. Gonadotroph adenoma, with or without IHC(+) for FSH, LH*
(*presence of SF‐1 defines gonadotroph adenoma even if hormone negative)

c. Tpit
i. Densely granulated ACTH (corticotroph) adenoma
ii. Sparsely granulated ACTH (corticotroph) adenoma
iii. Crooke cell adenoma
iv. Clinically silent ACTH adenoma (either densely granulated, i.e. subtype I, or sparsely granulated, i.e., subtype II)

d. Transcription factor negative/unknown
i. Null cell adenoma*
(*increasingly defined as SF‐1, Pit‐1, ACTH IHC negative [Tpit IHC not as widely available])

e. Plurihormonal adenomas
i. Uncertain lineage
7.

Question 13

Subtyping by hormonal status does matter

Answer 13

85% of usual ACTH adenomas are microadenomas,

most prolactinomas in premenopausal women are microadenomas

Question 14

Pituitary Adenomas

Non Secretors/weak secretors - Generally present with symptoms of mass effects

Answer 14

a. Headaches
b. Visual Field Deficits

c. Cranial Nerve Palsies
– Ptosis (eyelid droop)
– Diplopia (double vision)

d. Pituitary Hormone Deficits
(Panhypopituitarism)

e. Rarely
– Seizures
– Stroke
– CSF Leak

Question 15

Classic visual deficit for Pituitary Adenoma

Answer 15

a. Bilateral temporal hemianopsia is classic visual deficit

b. Will lose sight of the lateral visual fields that hit the nasal portion of the eye
i. Crossing fibers at optic chiasm are compressed

Question 16

Gonadotroph adenoma

Answer 16

a. Most common type of clinically non functioning adenoma

b. most common adenoma type to come to surgery

Question 17

Hormone negative adenoma

Answer 17

Hormone negative adenomas are clinically non functioning AND show no IHC(+) for
GH, PRL, FSH, LH, TSH, ACTH; most of these are SF‐1 (+), indicating gonadotroph lineage

Question 18

Excess growth hormone secretion

results in pituitary gigantism;

Answer 18

man at left is 5’ 7”
and patient at right is over 8’ tall.

Inset: note comparison in these two men’s
hand sizes ('acral megaly' = acromegaly)

Question 19

Densely granulated growth hormone adenoma

Answer 19

a. Densely granulated growth hormone cell adenoma shows a monotonous cell population (H&E)
b. Densely granulated growth hormone cell adenoma, with the monotony of the population underscored by (PAS‐orange G)

Question 20

Sparsely granulated growth hormone adenoma

Answer 20

A, Sparsely granulated growth hormone adenoma contains cells that lack the acidophilia of densely granulated tumors and may show more eccentrically placed nuclei and perinuclear clearing in the cytoplasm. (H&E)

B, Sparsely granulated growth hormone adenoma manifests have weaker growth hormone immunoreactivity. (Immunoperoxidase with hematoxylin counterstain)

C, Sparsely granulated growth hormone adenoma showing the signature feature of this adenoma type, widespread, ball-like, cytoplasmic ‘fibrous bodies’ on CAM5.2. (Immunoperoxidase with hematoxylin counterstain)

D, Sparsely granulated growth hormone adenoma on CAM5.2 parallels the accumulation of cytoplasmic filaments seen by EM, and obviates the need for the latter in diagnosis.

Question 21

Prolactinoma

Answer 21

a. Amenorrhea
b. Galactorrhea
c. Symptoms may be subtle, and presentation is often to the OB‐Gyn doctor for premenopausal women
d. Cause unknown but not related to use of birth control pills
e. Impotence in men (often longstanding, tumors almost always macroadenomas, sometimes giant adenomas >4 cm.)

Question 22

Acidophil stem cell adenoma

Answer 22

also Pit-1 driven, usually presents with prolactinemia but discordance between
Large size of adenoma and relatively modest serum PRL elevation

Question 23

ACTH (corticotroph) adenoma

Answer 23

Densely granulated type

Sparsely granulated type

Question 24

Pituitary Apoplexy

Answer 24

Bland infarction shown, may also present as hemorrhage or hemorrhagic necrosis

Question 25

Rathke Cleft Cyst

Answer 25

Wiki:

a. Rathke’s cleft cyst is a benign growth found on the pituitary gland in the brain, specifically a fluid-filled cyst in the posterior portion of the anterior pituitary gland
i. It occurs when the Rathke’s pouch does not develop properly and ranges in size from 2 to 40mm in diameter.

b. Asymptomatic cysts are commonly detected during autopsies in 2 to 26 percent of individuals who have died of unrelated causes.
i. Females are twice as likely as males to develop a cyst.
ii. If a cyst adds pressure to the optic chiasm, it may cause visual disturbances, pituitary dysfunction, and headaches.
iii. The majority of pituitary patients with chronic headaches have Rathke’s Cleft Cysts. This is believed to be caused by the constant change in volume and the drastic changes in vasopressure from fluctuations in gonadotrophs and ADH.

c. Symptoms vary greatly between individuals. RCCs can be non-functioning, functioning, or both.
i. Besides headaches, neurocognitive deficits are almost always present, but have high rate of immediate reversal if cyst is properly treated by being drained. They will eventually rupture if not addressed.
ii. Patients report attacks of violent headache radiating down the back of their neck. Cortisol will drop due to impact of ACTH production form apoplexy.

d, The treatment of choice for symptomatic cysts is drainage and taking a biopsy.
i. Radical excision is more dangerous because of the potential of damaging the patient’s pituitary function e.g. ADH storage and lowering growth hormone production.

Question 26

Frequency of sellar region masses

Answer 26

1. PITUITARY ADENOMAS
   
   • by far the most common
2. CRANIOPHARYNGIOMAS
   
   • 2nd most common
3. HYPOPHYSITIS
   
   • rare
4. PITUICYTOMAS
   
   • rare
5. SPINDLE CELL ONCOCYTOMAS
   - uber rare

Question 27

Summary of sellar region masses

Answer 27

a. 85%+ of sellar region masses are pituitary adenomas, which although not formally graded, are equivalent to WHO grade I; almost all the other non‐pituitary
adenoma sellar region masses are also WHO grade I and treated by surgical
resection except in instances where medical therapies are available

b. Some pituitary adenomas are hyperfunctioning and produce physiologically‐
i. unregulated excess of endocrine hormone(s); many are clinically non functioning and produce mass effect or visual disturbances due to compression of critical nearby anatomical structures

c. Most uncommon (Rathke cleft cyst), or rare, sellar region masses (pituicytoma,
spindle cell oncocytoma, hypophysitis) closely mimic pituitary adenomas on
neuroimaging and clinically mimic clinically non functioning pituitary adenomas in
that they present with mass effects or visual disturbance

d. All except craniopharyngioma predominantly affect middle age adults;
craniopharyngioma has two age peaks, pediatric (5‐15 yrs) and middle age (45‐60
yrs) adults

Question 28

Child with ACTH-secreting pituitary adenoma

Answer 28

Child at age 9 years prior to development of an ACTH-secreting pituitary adenoma. Same child as in Figure at left, now at age 11 years with severe Cushing’s disease, photographed just prior to surgical removal of his corticotroph adenoma. Note plethora and truncal obesity.

Question 29

Pituitary adenoma

Wiki Summary

Answer 29

a. Pituitary adenomas are tumors that occur in the pituitary gland. Pituitary adenomas are generally divided into three categories dependent upon their biological functioning: benign adenoma, invasive adenoma, and carcinomas.
i. Most adenomas are benign, approximately 35% are invasive and just 0.1% to 0.2 are carcinomas.
ii. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.

b. Non-invasive and non-secreting pituitary adenomas are considered to be benign in the literal as well as the clinical sense;

c. Adenomas which exceed 10 millimetres (0.39 in) in size are defined as macroadenomas, with those smaller than 10 mm referred to as microadenomas.
i. Most pituitary adenomas are microadenomas, and have an estimated prevalence of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies)
ii. A majority of pituitary microadenomas often remain undiagnosed and those that are diagnosed are often found as an incidental finding, and are referred to as incidentalomas.

d. Pituitary macroadenomas are the most common cause of hypopituitarism, and in the majority of cases they are non-secreting adenomas.
e. While Pituitary adenomas are common, affecting approximately one in 6 of the general population, clinically active pituitary adenomas that require surgical treatment are more rare, affecting approximately one in 1000 of the general population

Question 30

Risk factors for Pituitary adenoma

Wiki Summary

Answer 30

1. Multiple endocrine neoplasia
   Adenomas of the anterior pituitary gland are a major clinical feature of multiple endocrine neoplasia type 1 (MEN1), a rare inherited endocrine syndrome that affects 1 person in every 30,000. MEN causes various combinations of benign or malignant tumors in various glands in the endocrine system or may cause the glands to become enlarged without forming tumors. It often affects the parathyroid glands, pancreatic islet cells, and anterior lobe of the pituitary gland. MEN1 may also cause non-endocrine tumors such as facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas. Approximately 25 percent of patients with MEN1 develop pituitary adenomas.

2. Carney complex
 Carney complex (CNC), also known as LAMB syndrome and NAME syndrome is an autosomal dominant condition comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity and is distinct from Carney's triad. Patients with CNC develop growth hormone (GH)-producing pituitary tumors and in some instances these same tumors also secrete prolactin.

3. Familial isolated pituitary adenoma
   Familial isolated pituitary adenoma (FIPA) is a term that used to identify a condition that displays an autosomal dominant inheritance and is characterised by the presence of two or more related patients affected by adenomas of the pituitary gland only, with no other associated symptoms that occur in Multiple endocrine neoplasia Type 1 or Carney complex