Pituitary adenoma/Pituitary neuroendocrine tumour

General

Pituitary adenoma
Pituitary neuroendocrine tumour (PitNET)

Members of the International Pituitary Pathology Club proposed the use of the term “neuroendocrine tumor” rather than “adenoma” to define tumors of adenohypophyseal cells

A clonal neoplastic proliferation of anterior pituitary hormone-producing cells.

These lesions represent tumours derived from endocrine cells of the anterior pituitary gland.

Definition

Essential criteria

The tumour must be located in the sellar or suprasellar region.
Histopathological features should match those of a low-grade neuroendocrine tumour that displays destruction of the normal anterior gland acinar structure.
Subclassification is determined based on the immunoreactivity for pituitary hormones and/or lineage-specific transcription factors.

Desirable criteria

Reticulin fibre disruption should be demonstrated, as it distinguishes tumours from hyperplasia where acini are expanded but intact.
The use of low-molecular-weight cytokeratins is helpful for identifying specific subtypes, particularly somatotroph and corticotroph tumours.
Tumour proliferation should be indicated by either mitotic count or Ki-67 expression.

Numbers

30-40yrs old

Equal Sex

Functioning pituitary adenomas are the most common

65% of adenomas secrete an active hormone

48% Prolactin
10% GH
6% ACTH
1% TSH

35% Non-functioning

Pituitary adenomas are identified incidentally in up to 20% of the general population.

Clinically diagnosed tumours have a reported prevalence of 78–116 cases per 100,000 population.

They account for approximately 16.5% of brain tumours reported in the United States.

Incidence rates increase with age, and approximately 5% of cases are diagnosed in patients under 20 years of age.

Certain subtypes show a sex predilection; for example,

Cushing disease is more common in female patients,
Lactotroph tumours are more frequently resected in male patients.

Grading

There is no formal WHO grading system for pituitary adenomas

Instead, the classification emphasises high-risk subtypes that show an increased propensity for early recurrence and resistance to treatment.

Histopathology

Macroscopic

These range from small pale nodules within the pituitary gland to large cohesive hyperaemic masses with pushing borders.

Tumours frequently extend into the suprasellar space or invade adjacent structures such as the sphenoid sinus, cavernous sinus, and bone.

Haemorrhagic necrosis is often present in cases of pituitary apoplexy.

Microscopic

Tumours are generally monomorphic and can exhibit diffuse, papillary, or trabecular growth patterns.

Neoplastic cells may be acidophilic, basophilic, or chromophobic, and they typically possess bland nuclei with regular chromatin.

Mitotic activity is typically low.

Immunophenotype

Subclassification is based on derivation from specific cell lineages using hormones and transcription factors.

PIT1-lineage tumours include somatotroph (GH), lactotroph (PRL), and thyrotroph (TSH) subtypes.

TPIT-lineage tumours comprise corticotroph subtypes that express TPIT and ACTH.

SF1-lineage tumours include gonadotroph subtypes expressing SF1 and variable gonadotropins.

Null cell tumours lack all pituitary transcription factors and hormones.

Genetic features

Most tumours occur sporadically and show monoclonality.

Somatic mutations in GNAS are found in as many as 40% of somatotroph tumours, while USP8 or USP48 mutations are common in corticotroph tumours.

Inherited susceptibility is linked to syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex, and McCune-Albright syndrome.

Other associations include DICER1 syndrome, neurofibromatosis type 1, and Lynch syndrome.

Localisation

Most tumours arise in the sellar region, often extending into the suprasellar area.

Ectopic occurrences have been documented in the sphenoid sinus, clivus, and within teratomas.

Aetiology

Multiple endocrine adenomatosis or neoplasia(MEA or MEN) type I:

Autosomal dominant inheritance
High penetrance
Also involves

Pancreatic islet cell tumors (which may produce gastrin and hence Zollinger-Ellison syndrome)
Parathyroids (hyperparathyroidism), and
Pituitary tumors (nonsecretory)

Pituitary and Sellar Tumour types

Anterior pituitary

Pituitary adenomas

Most benign

Origin

Anterior pituitary

Various ways of classification

By invasiveness of disease

Invasive

Anatomic classification of pituitary adenoma (modified Hardy system)

Extension

Suprasellar extension

0: none
A: expanding into suprasellar cistern
B: anterior recesses of 3rd ventricle obliterated
C: floor of 3rd ventricle grossly displaced

Parasellar extension

Dᵃ: intracranial (intradural)

ᵃ specify: 1) anterior, 2) middle, or 3) posterior fossa

E: into or beneath cavernous sinus (extradural)

Invasion/Spread

Floor of sella intact

I: sella normal or focally expanded; tumor <10 mm
II: sella enlarged; tumor ≥10 mm

Sphenoid extension

III: localized perforation of sellar floor
IV: diffuse destruction of sellar floor

Distant spread

V: spread via CSF or blood-borne

5% become locally invasive
Genetically they are different from the non-invasive ones but histologically they are the same
Malignancy course more in larger tumours
Investigation

Sometimes hard to tell if it is invading the cavernous sinus

I.e. tumour can be pushing on the Dura rather than actually invading
Most definitive sign of cavernous sinus invasion is carotid encasement

Invasive prolactinomas often present with hyperprolactinemia (prolactin levels >1000ng/ml)

Caution: giant invasive adenomas with very high PRL production may have a falsely low PRL level due to “hook effect”

Presentation

Visual acuity reduction

Most present
Due to compression of the optic apparatus
Produce gradual visual deficit, rare but sudden vision loss can occur too

Ophthalmoplegia

Cavernous sinus invasion
Usually develop after visual loss

Exophthalmos

Orbital invasion due to compromise of orbital venous drainage

Hydrocephalus

Suprasellar extension may obstruct one or both foramen of Monro

Nasal obstruction.

Invasion of the skull base may lead
CSF rhinorrhea may occur by tumor shrinkage in response to dopamine agonists (e.g. bromocriptine).

This carries the risk of ascending meningitis.

Noninvasive

By endocrine function (aided by immunostaining)

Functional-Hormone secreting (70%)

Prolactinoma (Not surgical tumour)

Most common secretory adenoma
Some can secrete both GH and prolactin
Origin: anterior Pituitary lactotrophs
Clinical presentation

Females present earlier as they have more symptoms

Amenorrhea-galactorrhoea syndrome (AKA Forbes-Albright syndrome, AKA Ahumadadel Castillo syndrome).

Variants: oligomenorrhea, irregular menstrual cycles.

5% of women with primary amenorrhea will be found to have a PRL-secreting pituitary tumour.

Remember: pregnancy is the most common cause of secondary amenorrhea in females of reproductive potential.

The galactorrhea may be spontaneous or expressive (only on squeezing the nipples)

Males presents later

Impotence, decreased libido

Galactorrhoea is rare (oestrogen is also usually required)

Gynecomastia is rare

Prepubertal prolactinomas may result in small testicles and feminine body habitus

Either sex

Infertility is common

Due to suppression of GnRH secretion by prolactin

Bone loss

Osteoporosis in women, and both cortical and trabecular osteopenia in men
Due to a oestrogen suppression from hyperprolactinaemia, not due to the elevated prolactin itself

ACTH-secreting pituitary adenoma (Cushing disease) → See below

Thyrotropin (TSH)-secreting adenomas

Rare: 1% of pituitary tumours
Central/secondary hyperthyroidism → inc. T3/4, elevated or normal TSH
33% are non-secretory
Most are aggressive and invasive
60% of cases are due to lack of recognition that the thyroid symptoms are not due to primary hyperthyroidism. These patients after undergoing thyroid ablation → lack of T3/4 negative feedback to tumour → sudden increase in size of TSH secreting adenoma → mass effect symptoms
Clinical presentation

Anxiety
Palpitation (a fib)
Heat intolerance
Hyperhidrosis
Wt loss despite inc intake
Hyperactivity
Lid lag
Not present here only present in graves (auto-ab to TSH receptor, have abs that cause the following

Exophthalmos
Pretibial myxoedema

Non-functional (15-30% of pituitary adenomas)

Non-secretory

Null-cell adenoma
Oncocytoma

Secrete products that do not cause endocrinological symptoms

Gonadotropin-secreting adenoma (acromegaly/gigantism)
Silent corticotropin-secreting adenoma
Glycoprotein-secreting adenoma

By light microscopy with routine histological staining (obsolete)

Chromophobe:

Most common (ratio of chromophobe to acidophil is 4‑20:1).
Originally considered “non-secretory,” in actuality may produce prolactin, GH, or TSH

Acidophil (eosinophilic):

Produce prolactin, TSH, or GH

Basophil

Gonadotropins, β-lipotropin, or usually ACTH → Cushing’s disease

By electron microscopic appearance

By Size

Microadenoma:

Tumour<1cm diameter.
Currently, 50% of pituitary tumours are < 5mm at time of diagnosis.

These may be difficult to find at the time of surgery.

Macroadenomas: >1cm diameter.

Giant >4cm

By Knosp score

Grade

Description

Invasion (%)

Gross total resection (%)

Endocrinological remission (%)

Medial to medial tangent

Surgical: 0

Histological: 0

Tumour extends to space between the medial tangent and the intercarotid line

Surgical: 1.5

Histological: 0

Tumour extends to space between the intercarotid line and the lateral tangent

Surgical: 9.9

Histological: 88

Tumour extends lateral to the lateral tangent

3A = above the intracavernous ICA into the superior cavernous sinus compartment

3B = below the intracavernous ICA into the inferior cavernous sinus compartment

3A
Surgical: 26.5

Histological: 86
3B

Surgical: 70.6

Histological: 86

Complete encasement of intracavernous ICA

Surgical: 100

Histological: 100

Pituitary carcinomas

Rare (<140 reports)

Invasive

Secretory

ACTH
PRL

Can metastasize

Poor prognosis:

66% @1 yr mortality
Little improvement with surgery, radio-/chemo-therapy

Posterior pituitary and Sellar (Neurohypophyseal tumours)

Origin: posterior pituitary

See tumour of the sellar region

Craniopharyngioma
Granular cell Tumour of the Sellar
Pituicytoma
Spindle cell oncocytoma

Differential

Rathkle cleft cyst

TS meningioma

Differential meningioma vs macroadenoma

Tail

Check clivus, incisura

Meningioma invades the orbital apex
Meningioma narrows carotid

Craniopharyngioma's

Mets

ICA aneurysm

Germ cell tumours: tumour markers

Clinical presentation for anterior pituitary tumours

General

Visual deficit

Bedside confrontational testing to rule out visual field deficit (classically bitemporal hemianopsia)

Deficits of cranial nerves within cavernous sinus

III, IV, VI: disorder of pupil and extraocular muscles
V1, V2: reduced sensation in forehead, nose, upper lip, and cheek

Functional tumours tend to present earlier

Symptoms caused by physiologic effects of excess hormones

This applies less e.g. to prolactinomas in males since the symptoms may be mild or unrecognized

Endocrine syndromes

Hormone over-secretion (secretory tumour)

Prolactin (PRL)

Females

Amenorrhea-galactorrhea syndrome

Males

Impotence

Aetiologies:

Prolactinoma: neoplasia of pituitary lactotrophs
Stalk effect:

Pressure on the pituitary stalk → reduce the inhibitory control over PRL secretion causing a modest increase in serum prolactin → galactorrhoea
Overcome by serial dilution

Growth hormone (GH)

Aetiology

Pituitary adenoma

Presentation

Adults: acromegaly (>95%)

Large hand and feet
Frontal bossing
Large jaw
Change in ring size or shoe size or coarsening of facial features,

Prepubertal children (before epiphyseal plate closure): produces pituitary gigantism (very rare)

Investigations

Glucose tolerance test

Normally GH will drop with glucose
In Acromegaly, Giving glucose will not result in a drop in GH

Sleep studies

Sleep apnea

Coronary angiography and echo

Most common cause of death is cardiovacular death

Colonoscopy

Bowel cancer

Thyroid ultrasound

Thyroid hyperplasia

Corticotropin AKA adrenocorticotropic hormone (ACTH)

Screening test

Adrenal axis screening; see tests to assess cortisol reserve

Hypocortisolism

8 AM cortisol level:

Better for detecting hypocortisolism.
Cortisol levels normally peak between 7–8 AM. AM cortisol may normally be elevated slightly above the reference range.
Normal: 6–18 mcg/100 ml (165-500nmol/L)

Interpretation:

8 AM cortisol < 6 mcg/100 ml: suggestive of adrenal insufficiency
8 AM cortisol 6–14 mcg/100 ml: nondiagnostic
8 AM cortisol > 14 mcg/100 ml: adrenal insufficiency is unlikely

Hypercortisolism

24-hour urine free cortisol (UFC):

Do 2-3 collections
One advantage with UFC over DST is that overall cortisol production is independent of

Corticosteroid binding globulin changes
Dexamethasone compliance.

Variability can come from

Patient collection of urine issues
Sex
BMI
Age
Very high or low urinary volume

As urine volume and glomerular filtration rate strongly predict UFC, other screening tests such as LNSC may be preferred for patients with

Renal impairment (CrCl <60mL/min) OR
Significant polyuria (>5 L/24 h)

Sodium intake

More accurate for hypercortisolism

Almost 100% sensitive and specific, false negative rare except in stress or chronic alcoholism
If not elevated several times above normal, at least 2 additional test should be made

11 PM salivary cortisol:

Late night salivary cortisol (LNSC)

Based on the assumption that patients with CS lose the normal circadian nadir of cortisol secretion
Technique

Do at least 2 or 3 test
Sampling saliva at usual bedtime rather than at midnight could decrease false positive results, as cortisol nadir is tightly entrained to sleep onset

This is the time of the usual cortisol nadir (lowest).

Accuracy

High sensitivity >90%

Is as good as low-dose DMZ suppression test

Specificity is the highest of all test
Test must be run at NIH approved lab.

Should not be performed in patients with disruption of the normal day/night cycle, such as night-shift workers → use UFC

Cushing’s disease

Endogenous hypercortisolism due to hypersecretion of ACTH by an ACTH-secreting pituitary adenoma

Is just one cause of Cushing syndrome: a collection of symptoms due to hypercortisolism

Cushing’s syndrome

Prolonged exposure to high levels of cortisol secondary to exo or endogenous sources.

Nelson syndrome

A rare condition

Follows 10–30% of total bilateral adrenalectomies (TBA) performed for Cushing’s disease

1-4 yrs following TBA

Mechanisms

TBA → reduction in cortisol levels → no inhibition of CRH → CRH and then ACTH rises

Rise in CRH → growth in Corticotroph adenomas → mass effect/(rare) malignant transformation
Rise in ACTH production and secretion →

Hyperpigmentation: Linea nigra, scars, gingivae, and areolae.

Increased proopiomelanocortin production → increased MSH levels
ACTH cross reactivity to increase MSH levels

Hypertrophy of adrenal tissue rests → painful testicular enlargement and oligospermia.

Aberrant adrenal rests represent collections of cells that have become trapped within the developing gonad during foetal development

Classic triad:

Hyperpigmentation (skin & mucus membranes),
Abnormal ↑ ACTH, and
Progression of pituitary tumours (the last criteria is now controversial)

Treatment options:

Surgery (transsphenoidal or transcranial),
XRT,
Medication

Cooke cell adenoma

Aggressive ACTH secreting tumour

Investigation for ACTH dependent cushing syndrome

Differentiating ectopic (bronchial Ca) vs pituitary cause (Cushing disease)

High does dexamethasone Suppression test

Will suppress pituitary adenoma ACTH but not ectopic
Don’t use this anymore as it can make patient feel unwell and high dose 8mg of dex sometimes can not necessarily suppress cortisol even in pituitary causes of Cushing syndrome.

CRH stimultaion test

Ectopic doesn't response
Check for ACTH and Cortisol rise over time

Dynamic MRI

IPSS petrosal sampling

CRH given IV → measure central and peripheral ACTH

Central ACTH is 2x of peripheral
As long as ACTH rise 2x more
The central ACTH rise is greater than peripheral

Thyrotropin (TSH): secondary (central) hyperthyroidism

Heat intolerance

Gonadotropins (luteinizing hormone (LH) and/or follicle stimulating hormone (FSH)):

Usually does not produce a clinical syndrome

80–90% of “silent” are gonadotroph adenomas.

FSH: may produce ovarian hyperstimulation in reproductive age women causing amenorrhea & galactorrhoea (as with prolactin) along with ovarian cysts.

LH: these tumours are even more rare

Underproduction of pituitary hormones

Mech: compression of the normal pituitary by large tumours.
More common with nonsecretory tumours than with secretory tumours.
Highest to lowest sensitivity to compression: (mnemonic: Go Look For The Adenoma Please).

GH (61–100%) Growth Hormone deficiency
Gonadotropins (LH & FSH) (36–96%) gonadotropin deficiency (hypogonadotrophic hypogonadism) with anosmia is part of Kallmann syndrome
TSH (8–81%) hypothyroidism:

Cold intolerance, myxedema, entrapment neuropathies (e.g. carpal tunnel syndrome), weight gain, memory disturbance, integumentary changes (dry skin, coarse hair, brittle nails), constipation, increased sleep demand

ACTH (17–62%) hypoadrenalism:

Orthostatic hypotension, easy fatigability

Prolactin

Chronic deficiency of all pituitary hormones (panhypopituitarism) may produce pituitary cachexia (AKA Simmonds’ cachexia).
Selective reduction of a single pituitary hormone is very atypical with pituitary adenomas.

May occur with autoimmune hypophysitis, which most commonly involves ACTH or ADH (causing diabetes insipidus)
Deficiency of specific hormones:

Diabetes insipidus

Almost never seen preoperatively with pituitary tumors (except possibly with pituitary apoplexy).

If DI is present, other aetiologies should be sought, including:

Autoimmune hypophysitis

Other diff: IgG4 disease

Hypothalamic glioma
Suprasellar germ cell tumor

Pituitary incidentalomas

Discovered on imaging performed for some other indication

10-12%

Non-functional tumours present late

Tumours need to be large enough to cause neurologic deficits by mass effect

Mass effect (other than compression of the pituitary)

More common with nonfunctioning tumors.

Of functional tumors,

Prolactinoma is the most likely to become large enough to cause mass effect (especially in males or non-menstruating females)
ACTH tumor is least likely

Nonspecific symptoms include headaches

Pain due to compression of diaphragm that can go away if tumour grows beyond it.
V1 distribution h/a

Seizures are rarely attributable to pituitary adenomas and other etiologies should be sought.
Mass effect may occur suddenly as a result of expansion with pituitary apoplexy
Structures are commonly compressed and their manifestations include:

Optic chiasm:

Tumour grows superiorly through the diaphragma sella → produces bitemporal hemianopsia (non-congruous) +/- decreasing visual acuity

3rd ventricle compression → obstructive hydrocephalus
Cavernous sinus compression

Pressure on cranial nerves contained within (III, IV, V1, V2, VI): ptosis, facial pain, diplopia
Occlusion of the cavernous sinus: proptosis, chemosis
Encasement of the carotid artery by tumour:

May cause slight narrowing, but complete occlusion is rare

Macroadenomas may produce H/A possibly via increased intrasellar pressure

Invasive adenomas (mainly prolactinomas)

Infrequently present with CSF rhinorrhoea;

With invasive prolactinomas this may be precipitated by shrinkage resulting from medical treatment

Investigation

Careful medical history, previous growth pattern and physical examination

Current height, weight, surface area, pubertal staging and bone age

Accurate fluid intake and output record

Paired early morning plasma and urine osmolalities

Serum urea, creatinine, electrolytes and glucose

Thyroid function (thyroxine and thyrotropin)

Hypothyroidism: hypothyroid patients should have > 4 weeks of replacement to reverse hypothyroidism but most patients tolerate surgery even with hypothyrodism; however:

Do not replace thyroid hormone until the adrenal axis is assessed;

Giving thyroid replacement to a patient with hypoadrenalism can precipitate adrenal crisis.
If hypoadrenal, begin cortisol replacement first, may begin thyroid hormone replacement after 24 hours of cortisol

Cortisol at 9 a.m. (if patient is not receiving steroids)

Prolactin (to exclude prolactinoma)

α-Fetoprotein and β-hCG (to exclude secreting germinoma)

Insulin-like growth factor-1

Radiological features

MRI with gadolinium is the primary tool used to identify sellar masses.

Most tumours are hypointense on T1-weighted images with variable contrast enhancement.

T2-weighted signal intensity varies by subtype; densely granulated tumours tend to be hypointense, while sparsely granulated tumours are hyperintense.

Management

Endocrine

Prolactinoma is the only pituitary tumour for which medical therapy (dopamine agonist) is the primary treatment modality

If it is not causing symptoms do not treat. Treat the patient not the scan

If you tx asymptomatic ones (With dopamine agonist) it can shrink tumour → causing CSF leak/pneumocephalus → meningitis

Hormone Replacement Therapy (HRT)

Indication

For patients with endocrine deficits
Post op in cases where pituitary function is not normal

Corticosteroids

Indication: inadequate cortisol reserve as demonstrated by failing a cosyntropin stimulation test
May start cortisol immediately after cosyntropin stimulation test is done (do not need to wait for test results) then, when test results are available, continue or stop therapy based on test results
Physiologic replacement dose:

Cortisol 20mg PO q AM and 10mg PO q 4 PM
Stress doses may be needed

In patients without Cushing’s disease

9 am cortisol	Treatment
> 550 nmol/L	No requirement for hydrocortisone
400-550 nmol/L	Hydrocortisone only during severe illness or stress
< 400 nmol/L	Start regular oral hydrocortisone

If preoperative steroid reserve deficient:

In patients with proven cortisol deficiency before surgery, continue hydrocortisone and consider changing over to maintenance dosage when stable.
These patients will need further assessment at 4-8 weeks with anterior hormone profile and short synacthen test to determine whether they will need long-term steroids;

From GGC handbook

To diagnose adrenal insufficiency:

In stable patients in whom hypothalamic-pituitary-adrenal failure is suspected, perform a Short Synacthen® (Tetracosactide acetate, ACTH) test (SST):
Synacthen® 250 micrograms IM or IV

Sample cortisol at baseline and 30 minutes after Synacthen® (if unsure how to interpret results, seek specialist endocrine advice).
Take a paired ACTH sample at baseline.

Contact the Endocrine Team to arrange education, a Medic information bracelet and an emergency information card.

Additional fludrocortisone is likely to be required in primary hypoadrenalism.

Equivalent dose to Prednisolone 5mg is approximately equivalent to:

Hydrocortisone 20mg
Dexamethasone 750micrograms
Methylprednisolone 4mg
N.B. An equivalent dose is not always appropriate. When converting between different corticosteroids, consider whether a dose increase (e.g. to cover intercurrent illness, as above) or a dose decrease (when tapering dose down) is appropriate.

Thyroid hormone replacement

Thyroid replacement can precipitate adrenal crisis if started before cortisol in a patient with adrenal insufficiency (as may occur in panhypopituitarism)

Do a cosyntropin stimulation test and start cortisol
Thyroid replacement may be initiated after 1 full day of cortisol. ℞: start with Synthroid 125 mcg/d

Most hypothyroid patients frequently undergo surgery before then with no untoward effect

Testosterone replacement:

May increase intertumoral levels of oestradiol, which may promote tumour growth → wait for stabilization of tumour before starting

GH replacement

Safety with long-term use and the cost effectiveness of GHRT have not been clearly determined in past studies.

Management of nonfunctioning pituitary adenoma (NFPA)

Consist of

Non-secreting and secreting tumour but with no clinical symptoms

Literature

Observation/Natural history

Only 2 reports of management with observation

40–50% tumour progression
21–28% required surgery

Observation only is not recommended for symptomatic NFPAs

Surgery

see surgical techniques
Surgery is recommended as the primary treatment modality for symptomatic NFPAs
Not enough data to support surgery for asymptomatic NFPA

Medical

Tumour response rates using

Dopamine agonists (e.g. Bromocriptine) in 0–60%
Somatostatin analogues (e.g. Octreotide) in 12–40%
Combination therapy in 60%.

Not recommended as primary treatment due to lack of a significant and consistent response

XRT:

As primary treatment: XRT not been shown to be equal or better than surgical management
As adjunctive therapy: XRT effective for residual tumour or recurrence

Follow up

Asymptomatic microadenomas (< 1cm)

Follow up pituitary MRI at years 1, 2, 5 and ± 10 (can stop follow up after 10 and possibly 5 years if no growth).

Asymptomatic macroadenomas (> 1 cm)

Check visual fields,
Pituitary bloodwork (to R/O pituitary insufficiency)
Pituitary MRI at years 0.5, 1, 2 & 5, and any time symptoms develop.

Surgical indications for nonfunctioning pituitary macroadenomas

Tumours causing symptoms by mass effect:

Visual field deficit (classically: bitemporal hemianopsia, panhypopituitarism)
Elevation of chiasm without endocrine abnormalities or visual field deficit: because of the possibility of injury to the optic apparatus

Invasive pituitary macroadenomas

Young patients
Old patients with deteriorating neurology

Acute and rapid visual or other neurologic deterioration.

Mech

Ischemia of the chiasm,
Pituitary apoplexy

Mainly from blindness

Hypopituitarism: can be treated with replacement therapy

Visual loss usually requires emergent decompression.

Biopsy for pathological diagnosis in questionable cases
Nelson’s syndrome

Surgery (transsphenoidal or transcranial): the primary treatment.
The aggressiveness of the tumour sometimes requires total hypophysectomy
XRT (possibly SRS) is used following subtotal excision
Medical therapy is usually ineffective.

Agents that could be considered include: dopamine agonists, valproic acid, somatostatin analogues, rosiglitazone, and serotonin agonists

Special cases

For invasive disease

Elderly patient:

Expectant management → intervention for signs of progression (radiographic or neurologic)

Central tumour or elderly patient with progression:

Transsphenoidal tumour debulking and/or XRT

Might leave residual tumour in the region of the cavernous sinus, mostly show little or no change over several years, and there is less systemic risk as there are nonfunctional secretion product)

Parasellar tumour and/or young age:

Radical surgery (often not curative)

Management of functioning pituitary adenomas

Prolactinomas

Dopamine agonist unless there is unstable deficit
Surgery only for

Patients not responding to DA and then try DA again
Have unstable deficits

ACTH secreting hormones (Cushing disease)

Gonadotropin-secreting tumours

Rarely, a non-functional tumour may secrete gonadotropins (FSH, LH).
No clinical syndrome.
Treatment w/ Long acting GnRH agonist or GnRH agonist

Mech for agonist: by down regulating GnRH receptors on normal and neoplastic pituitary gonadotrophs
This does not significantly reduce tumour size.

Thyrotropin (TSH) secreting adenomas

Transsphenoidal surgery: first-line treatment

These tumours may be fibrous and difficult to remove
If incomplete resection:

Post-op XRT

If hyperthyroidism persists:

Medical therapy
+ octreotide, bromocriptine (more effective for tumours that co-secrete PRL) + oral cholecystographic agents (which inhibit conversion of T4 to T3) e.g. iopanoic acid

Medical therapy

Normal and neoplastic anterior hypophyseal thyrotroph cells possess somatostatin receptors → respond to octreotide
Additional drugs may be required:

Beta-blockers or
Low-dose antithyroid drugs (e.g. Tapazole® (methimazole) ≈ 5mg PO TID for adults)

Octreotide

Dose less than with acromegaly.

50–100 mcg S/c TDS → titrate to TSH, T4 and T3 levels.

Outcome

TSH levels decline by>50% in 88%, with 75% becoming normal
T4 and T3 levels decrease in 100%, with 75% becoming normal.
Tumor shrinkage: 33%.

Radiation therapy

Indication

Incompletely resected tumors
Recurrent disease

Who to treat

Clinical

Aggressive

Pathological factors

Biomarkers

Radiological

Invasion Knop 4

Progression

Touriss paper
Asioli 2019

Cons

Second tumour

Meningioma
Malignant astrocytoma

Cognition problems

The younger the patient is the more issues with this

Can use both SRS and External beam radiotherapy

Typically contraindicated for tumors within 3-5 mm of the optic chiasm,
Respecting a maximum dose constant of 10 Gy or less to the optic nerves and chiasm.
Local control using SRS is generally in excess of 90% for non-secretory tumors.

Fractionated radiotherapy

Indicated for tumors abutting optic nerve or chiasm and for diffuse or large tumors.
Conventional EBXRT usually consists of 40–50Gy administered over 4–6 weeks.

Radiation therapy should not be routinely used following surgical removal.

Follow patient with yearly MRI.
Treat recurrence with repeat operation unless it is for acromegaly
Consider radiation if recurrence cannot be removed and tumour continues to grow.

Sellar radiation therapy for specific pituitary adenoma types

Nonfunctioning pituitary tumours

Some benefit in reduce recurrence for post op tumour residue.
Doses of 40 or 45Gy in 20 or 25 fractions, respectively, is recommended.
Spindle cell oncocytoma more radioresistant than the nononcocytic undifferentiated cell adenoma

Functioning

SRS appears to result in a shorter time to hormone normalization than fractionated radiotherapy.
Though tumor control remains high, hormonal remission is seen in 25-75% of patients and depends on the tumor subtype (i.e., prolactinoma, Cushing’s disease, Nelson’s syndrome, or acromegaly).
Cytostatic medical management of secreting pituitary adenomas should be discontinued pre-radiotherapy if symptoms allow

Patients receiving octreotide or dopamine agonists show markedly inferior control rates in several series.

For treatment of Acromegaly

Not the preferred initial treatment.
Works better with lower initial GH levels.
Outcome

GH levels begin to fall during the first year after XRT,
GH levels drop in 50% at 2 yrs
Reaching ≤ 10ng/ml in 70% of patients at 10 years.
Reaching ≤ 5 ng/ml in 90% of patients at 20 years

During this latency period, patients are exposed to unacceptably high levels of GH (octreotide may be used while waiting).
Patients are also still at risk for radiation side effects mentioned above.

Options include: EBRT, stereotactic radiosurgery (about equally effective).
Recurrence rate of pituitary tumors removed transsphenoidallyᵃ

Extent of removal	Post-op XRT?	Reccurence rate
Subtotal	No	50%
Gross total	No	21%
Subtotal	Yes	10%
Gross total	Yes	0%

ᵃ 108 macroadenomas, 6 mos to 14 years follow up

For treatment of Cushing’s disease

Hypercortisolism in 20–40%, and produces some improvement in another 40%.
Improvement may not be seen for 1–2 yrs post treatment.

Based on the size and location, either SRS or conformal EBRT may be considered.

Side effects

Radiation injury to the

Radiation-induced hypopituitarism

Occurs in more than 50% of patients after 10 years
Is the most common late toxicity.
A mean pituitary dose of 15 Gy was found to pose little risk of subsequent thyrotropic, gonadotropic, or adrenocorticotropic function; but at 5 years half of patients had low gonadotropic and thyrotropic function at doses above 17 Gy and low adrenocorticotrophic function at doses above 20 Gy.
Dose to the pituitary stalk and hypothalamus may also contribute to hypopituitarism following SRS.

Optic nerve and chiasm: blindness

Lethargy
Memory disturbances
Cranial nerve palsies
Tumour necrosis with haemorrhage → apoplexy.