Lab diagnosis of pituitary tumors

LAB DIAGNOSIS OF PITUITARY TUMORS

FROM -DR. GARGI TIGNATH GUIDED BY -DR. PURTI

AGRAWAL

INTRODUCTION

Pituitary gland is a small, bean-shaped structure ,lies at the base of the brain within the confines of the sella turcica.

Intimately related to the hypothalamus, connected by both a stalk, composed of axons extending from the hypothalamus & rich venous plexus constituting a portal circulation.

Along with hypothalamus, has a central role in the regulation of most of the other endocrine glands.

composed of two morphologically and functionally distinct components:1.Anterior lobe (adenohypophysis) 2.posterior lobe (neurohypophysis).

SYMPTOMS AND SIGNS OF PITUITARY DISEASE CAN BE GROUPED AS FOLLOWS:

Hyperpituitarism-related effects:

Hyperpituitarism arises from excessive secretion of trophic hormones.

Most often results from an anterior pituitary adenoma but also may be caused by other pituitary and extrapituitary Lesions.

Hypopituitarism-related effects:

Nonfunctional pituitary adenomas may encroach upon and destroy adjacent normal anterior pituitary parenchyma, causing hypopituitarism.

Local mass effects:

Radiographic abnormalities of the sella turcica, including sellar expansion, bony erosion, and disruption of the diaphragma sellae.

close proximity of the optic nerves and chiasm to the sella-

expanding pituitary lesions -compress decussating fibers in the optic chiasm.

Defects in the lateral (temporal) visual fields—-called bitemporal hemianopia.

Pituitary macroadenoma-Thinning and demineralization of the sellar floor, as well as suprasellar extension, are seen.

NORMAL HISTOLOGY OF PITUITARY GLAND

Normal anterior pituitary. Note the variation in cellular granularity. The staining ranges from acidophilic to chromophobic; several dark-staining basophils are also present.

Posterior pituitary- consists of the axonal processes and terminations of the vasopressin and oxytocin-producing supraoptic and paraventricular nuclei. In addition, endothelial cells and pituicytes, modified astrocytes, contribute to its cellularity

Normal anterior pituitary. Acini and cords of cells are demonstrated (reticulin stain).

Pituitary tumors

Account for 10-25 % of brain tumors

Medium age : between 20-50 years

Children rarely have pituitary adenomas.

Most tumor in children are craniopharyngiomas and are associated with growth failure and diabetes insipidus.

Most pituitary adenomas in children are prolactinomas

In women Prolactinomas, GH secreting adenomas and ACTH-secreting adenomas are more frequent.

In men GH secreting adenomas are more frequent.

HISTOGENESIS OF PITUITARY TUMORS

Two hit hypothesis:

Pituitary adenomas are monoclonal tumors

Polyclonal adenomas may result from excessive stimulation of pituitary by specific releasing hormones

Pituitary cells have a genetic protective factor against tumor proliferation.

Lost of one protective allelle - first hit is not associated with tumor transformation, a point mutation of the second allelle – second hit results in tumor proliferation .

Tumor occurs only if both protective factors are lost

PITUITARY TUMORS - CLASSIFICATION

According to their size:

Microadenomas: have <1 cm, do not modify the shape of sella turcica and do not produce pituitary tumor syndrome

Macroadenomas: have > 1 cm. and according to the direction they develop produce “the syndrome of pituitary tumors”

According to their degree of aggression

Benign adenomas

Invasive adenomas

Carcinomas: less then 1 % of pituitary tumors

Pituitary macroadenoma

Microadenoma

Microadenoma- Relative circumscription and early compression of surrounding parenchyma are seen, acinar architecture is effaced

Pituitary adenoma-lack of reticulin content and the compression of surrounding parenchyma are demonstrated (reticulin stain).

Pituitary adenomas- H&E-staining shows -Diffuse (A), papillary (B), ribbon (C), and pleomorphic (D) patterns, illustrates their broad morphologic spectrum and highlights the diagnostic use of immunohistochemistry.

CLASSIFICATION OF PITUITARY ADENOMAS

FAMILIAL PITUITARY TUMOR SYNDROMES

PITUITARY TUMOR SYNDROME

NEUROLOGIC SYMPTOMS: Headache Nerves III, IV and VI which cross the cavernous sinus Temporal seizures Other seizures Meningeal signs

OPHTHALMOLOGIC SIGNS: Decreased visual acuity Reduction of visual field according to tumor extension Exophtalmos : rare

RADIOLOGICAL SIGNS: Enlarged surface of sella turcica Radiologic signs specific for some pituitary adenomas: acromegaly

APPROACH TO DIAGNOSIS

1.Clinical evaluation of pituitary adenoma

2.Radiological evaluation of suprasellar mass- MRI/CT

3.Ophthalmic evaluation

4.Laboratory investigations- -Initial hormonal evaluation- -Basal prolactin

-Insulin like growth factor

-24hr urinary free cortisol(UFC)/overnight oral dexamethasone(1mg) suppression test

-ᾳ subunit FSH&LH

-Thyroid function test

5.Histological evaluation-

Routine H&E Sections

Histochemical staining: -Periodic acid-Schiff (PAS), Reticulin stain

Immunohistochemistry:-PRL,ACTH,GH,TSH, LH, FSH, ± α-subunit, EMA,cytokeratin(ck),chromogranin

Electron microscopy(ultrastructural changes)

PROLACTIN CELL ADENOMA

Prolactinomas are the most frequently occurring adenoma in MEN1

Microadenomas generally occur in reproductive-age women

In men and postmenopausal women, often appear to be clinically nonfunctional, growing to macroadenoma dimensions and exhibiting invasion .

50% of prolactinomas are grossly or radiographically invasive at initial surgery

Frequency of invasion increases with tumor size

Serum PRL levels are uniformly elevated in patients with prolactinoma

LACTOTROPH ADENOMAS ARE OF TWO TYPES:

Sparsly Granulated-25%Densly Granulated-1%

C/F-Amennorhea -Galactorrhea -Impotence, loss of Libido

DIAGNOSIS:

BLOOD HORMONE LEVELS-↑↑↑ PROLACTIN LEVELS, little more than normal (approximately 20 ng/mL) to extremely high (≥2000 ng/mL)

HISTOPATHOLOGY-

Gross-1.Microadenomas-33% 2.macroadenomas-67%

Microscopy: –Sparsly granulated-chromophobic -Densly granulated-Mostly-Eosinophilic

10 to 20%-microcalcification.

-HISTOCHEMICAL STAINING :A-C (densely to sparsely granulated); eosin, phloxine; orange G

-IMMUNOREACTION:+ for PRL

(A)Prolactin cell adenomas are nearly all chromophobic, and they often contain spherical microcalcifications.

(B)IHC: Prolactin shows a characteristic globular reaction in the paranuclear Golgi zone.

DIAGNOSIS:

-EM : Abundant rich ER, misplaced exocytosis between neoplastic cells

-TREATMENT-Medical-Dopamin agonist. -Surgical-for macroadenomas.

-DIFFERENTIAL DIAGNOSIS-Acidophil stem cell adenoma.

(A)Prolactinoma with amyloid deposition. (B) polarization Such spherical bodies are virtually diagnostic of a prolactin cell adenoma

(A)Prolactin cell adenoma-sparsly granulated-Abundant RER and golgi apparatous and misplaced exocytosis(B)PRL Adenoma treated with bromocriptine,hyperchromatic nuclei,small cell,cytoplasm contains scanty organelles.

GROWTH HORMONE-PRODUCING ADENOMAS

SOMMATOTROPHS:

25% of adenomas are associated with clinical or immunocytologic evidence of GH production,

only a minority makes GH alone,vast majority of adenomas produce both GH and PRL or are plurihormonal, also expressing TSH and/or α-subunit

Precursor lesions of GH cell adenomas include :

somatotroph hyperplasia caused by ectopic production of growth hormone-releasing hormone (GHRH) by :

Endocrine tumors in the McCune-Albright syndrome

GH adenomas in Carney complex

Sparsely granulated-5%Densely granulated-5%

C/F: Acromegaly or gigantism

DIAGNOSIS

-BLOOD HORMONES:↑↑GH

-SCREENING TESTS FOR FUNCT IONAL GH ADENOMAS

Acromegaly -Serum IGF-IOral glucose tolerance test with GH obtained at 0, 30, and 60 min

Interpret IGF-I relative to age and sex-matched controls

Normal subjects should suppress growth hormone to <1 g/L

Exclude medications,MRI of the sella should be ordered if PRL is also elevated.

-

The increased height and prognathism (A) and enlarged hand (B) and foot (C) of the affected twin are apparent. Their clinical features began to diverge at the age of approximately 13 years.

HISTOPATHOLOGY:

-GROSS:14% micro/86% macro-MICROSCOPY: C-A -IMMUNOREACTION: + FOR GH -INVASION:50% overall(chromophobic>eosinophillic tumors)

-TREATMENT:Long standing somatostatin analogs like octreotide

MICROSCOPY:

A) Growth hormone cell adenoma, sparsely granulated (chromophobic) type. Note the presence of paranuclear hyaline bodies. (B) Immunoreactivity for growth hormone may be weak and present in only a portion of cells

(A)Growth hormone (GH) cell adenoma, densely granulated (eosinophilic) type, prominent acidophilia &Lack of fibrous bodies.

(B) GH immunoreactivity is strong

Densly granulated GH adenoma with numerous large secretary granules 200 t0 600 nm diameter.

EM:

Sparsly granulated GH Adenoma with scant small granules (400-450 nm)and fibrous bodies trapping secretary granules ,mitochondria and few lysosomes.

ADENOMAS WITH COMBINED LACTOTROPIC AND SOMATOTROPIC FEATURES

1.Mixed GH cell/PRL cell(5%)- both A/C

2.Mammosomatotroph(3%)-A(GH/PRL/TSH)

3.Acidophil stem cell(1%)-C

C/F-Acromegaly or gigantism

± hyperprolactinemia(Amennorhea,Galactorrhea,Impotence, loss of Libido)

DIAGNOSIS:

BLOOD HORMONE LEVELS: ↑GH/PRL

HISTOPATHOLOGY: GROSS:

Mixed GH cell/PRL cell- 26% micro/74% macro ,Overall Invasion-31%

Mammosomatotroph- 50% micro/50% macro

Acidophil stem cell-Usually invasive macroadenomas

IMMUNOREACTION:+ FOR GH/PRL

ELECTRON MICRSCOPY:

Mixed growth hormone cell-prolactin cell adenoma

-Variable proportions of sparsely and densely granulated growth hormones and prolactin cells

Mammosomatotroph cell adenoma:cell-

Prominent, numerous immature secretory vesicles

Two populations of granules:

150-450 nm, electron dense, round to oval, apposed limiting membrane;

350-2000 nm, variably electron dense,elongated, loose limiting membrane (intracellular and extracellular); abundant

Mixed growth hormone (GH) cell-prolactin (PRL) cell adenomas

Such tumors consist of two distinct cell populations, one of which is reactive for GH (A) and one of which is reactive for PRL (B).

Mixed adenoma showing sparsly granulated PRLcells and densly granulated GH Cell,Note RER& large golgi bodies.

ACIDOPHIL STEM CELL ADENOMA

Although definitive diagnosis of this uncommon lesion requires IHC and EM, H&E stains may show paranuclear vacuolization, a feature corresponding to giant mitochondria

Acidophil stem cell adenoma: EM:

Moderate; few associated secretory granules

granule morphology:50-300 nm, electron dense; sparse

Paranuclear fibrous bodies, SER, multiple centrioles, misplaced exocytosis, frequent abnormal or giant mitochondria, variable oncocytic transformation

Acidophilic stem cell adenoma:showing oncocytic change with giant mitochondria

CORTICOTROPH CELL ADENOMAS

Adenomas that produce ACTH fall into Four major groups: Endocrinologically active tumors associated with either

Cushing disease

Nelson syndrome

Clinically nonfunctioning or silent corticotropic adenomas.Crook cell adenoma

Hypothalamoadrenal axis(HPA)

CUSHING DISEASE

Although Cushing disease is rarely caused by corticotroph cell hyperplasia, the vast majority of cases are caused by an ACTH-producing adenoma.

Incidence of the disease is-1 to 10 cases per million per year.

3.5% of cases occur in the setting of MEN1

Isolated familial Cushing disease is very rare

ACTH-producing tumors represent nearly 15% of all adenomas.

peak incidence is 30 to 40 years

Female-to-male ratio is 8:1.

.

A low value, especially after corticotropin-releasing hormone (CRH) stimulation, indicates an extrapituitary source.

15% to 20% of all ACTH cell adenomas are found to be invasive

Postoperative remission is achieved in 90% of microadenomas but only 65% of macroadenomas

C/F- Hypercortisolism

DIAGNOSIS:

1.Clinical sign and symptoms

2.Radiological evidence of supra sellar mass-CT/MRI

3.Blood hormone levels-ACTH, Blood ACTH levels may be high but are generally less than 200 pg/mL(normal range4-22pg/l)

-Screening Tests for Cushing’s disease -24-h urinary free cortisol-(UFC)-is precise and cost effective,ensure urine collection is total and accurate.

-Dexamethasone suppression test-(1 mg),at 11 p.m. and fasting plasma cortisol measured at 8 a.m. -Normal subjects suppress to<5 g/dL

-Basal plasma-ACTH assay-Distinguishes adrenal adenoma (ACTH suppressed)from ectopic ACTH or(pituitary adenoma,Cushing’s disease (ACTH normal or elevate)

-Inferior petrosal sinus sampling(IPSS) –Sampling is performed at baseline and 2, 5, and 10 min after intravenous bovine CRH (1 μg/kg) injection

-Basal inferior petrosal:peripheral vein ACTH ratio (>2)-confirms pituitary Cushing’s syndrome.

-After CRH injection, peak petrosal:peripheral ACTH ratios ≥3 confirm the presence of a pituitary ACTH-secreting tumor.

4.LM: GROSS:ACTH adenomas are amphophilic or basophilic (87%) are

- Microadenomas 87%(mean size, 5 mm), -Invasion ,microadenomas (8%) than in macroadenomas (62%) - Extratumoral pituitary typically shows Crooke hyaline change, which is the result of massive perinuclear accumulation of cytokeratin filaments

5.HISTOCHEMICAL STAINING:PAS positive

(A) Amphophilic and granule rich (B) periodic acid-Schiff positive

ACTH ADENOMAS

Crooke hyaline change in the corticotropic cells is a regular accompaniment of ACTH-producing adenomas,peripherally situated hyaline band (left) is composed of cytokeratin, and thus, it is not ACTH immunoreactive (right).

Corticotroph Adenoma Showing Crook’s Hyalinization most of the cytoplasm replaced by thick rim of cytokeratin filaments displacing secretary granules to cell periphery.

6.IHC:+ ACTH, pro-opiomelanocortin (POMC), precursor molecule{ β-lipotropin, endorphin, enkephalins, and melanocyte-stimulating hormone (MSH)}

7.EM:

Abundance of secretory granules

perinuclear cytoplasmic intermediate filament bundles composed of keratin .

Their presence explains the variable cytokeratin immunoreactivity of corticotropic adenomas.

NELSON SYNDROME

Incidence-2%

Lesion underlying this disorder, undetectable by radiographic means and thus prompting an adrenalectomy. (To control hypercortisolism and cushings syndrome)

Continued tumor growth is then furthered by lack of inhibitory feedback effects of glucocorticoids.

Most are invasive macroadenomas

Unlike cushing adenoma,these are variably PAS positive,crook hyaline change is lacking.

BLOOD HORMONE LEVELS-↑ACTH, β-LPH, endorphins, and POMC

LM:, GROSS:100% macro, MICROSCOPY: B-C82% INVASION

HISTOCHEMICAL REACTION:variably PAS positive.

IHC:+ FOR ACTH , β-LPH, endorphins, and POMC

EM: perinuclear cytoplasmic microfilament bundles are sparse or absent. Crooke hyaline change is lacking in extratumoral ACTH cells.

Malignant transformation of Nelson adenomas accounts for a significant proportion of pituitary carcinomas

TREATMENT-SURGERY.

CROOKE CELL ADENOMA

INCIDENCE:<1%

C/F-Hypercortisolism

HISTOMORPHOLOGY: GROSS- 25% micro/75% macro MICROSCOPY:B -C, INVASION-85%

BLOOD HORMONES:-↑ACTH, β-LPH, endorphins, and POMC

IHC+ FOR ACTH, β-LPH, endorphins, and POMC

EM: Same as ACTH adenoma but with marked to massive accumulation of macrofilaments

SILENT CORTICOTROPIC-

INCIDENCE-3%

C/F-Mass symptoms; hypopituitarism

DIAGNOSIS:

BLOOD HORMONE LEVELS:↑ACTH, β-LPH, endorphins and POMC

HISTOPATHOLOGY: GROSS-100% macro adenomas MICROSCOPY-B-C

IHC:+ACTH, β-LPH, endorphins, and POMC

EM:

Silent subtype 1-Resembles densely or sparsely granulated Cushing adenoma

Silent subtype 2

Numerous RER, prominent Golgi bodies

150-300 nm, Irregular Drop-shaped; Sparsegranules:

Miscelleneous :No perinuclear and cytoplasmic microfilaments

Silent corticotroph adenoma type 2:small granules with no hyalinisation

GONADOTROPIC ADENOMAINCIDENCE-7%-15%

Tumors producing LH and FSH are relatively common and represent the majority of nonfunctioning adenomas

Few are associated with MEN1

Most occur in older adults, with men being preferentially affected.

Elevation of serum LH and FSH levels is best seen in males because physiologic elevation of gonadotropins is normal after menopause.

C/F:1.Hypogonadism; 2.Functionally silent3.Mass effects -neurologic and visual symptoms (72%), as well as hypopituitarism (67%)

Hypothalomogonadal axis

DIAGNOSIS:% Radiographic or gross apparent invasiveness is noted in only 20% to 30% of cases

BLOOD HORMONE LEVELS:↑↑ FSH and LH,(ONLY IN15%) rest are non functional

LH, FSH LH, FSH, testosterone, estrogen Basal measurements –

-Basal LH and FSH should be increased in postmenopausal women

-Low testosterone levels in the setting of low LH and FSH indicate pituitary insufficiency

-Free α subunit levels may be elevated in 10–15% of patients with Non functioning tumors.

-In female patients, peri- or postmenopausal basal FSH concentrations are difficult to distinguish from tumor derived FSH elevation..

Premenopausal women have cycling FSH levels, also preventing clear-cut diagnostic distinction from tumor derived FSH.

In men, GnRH tumors may be diagnosed because of slightly ↑gonadotropins (FSH > LH) in the setting of a pituitary mass.

In majority of pts with gonadotrope adenomas, TRH administration stimulates LH β subunit secretion; this response is not seen in normal individuals.

GnRH testing, however, is not helpful for making the diagnosis.

For nonfunctioning & GnRH secreting tumors, the diagnosis usually rests on immunohistochemical analyses of surgically resected tumor tissue,

GROSS: 5% micro/95% macro ( large macroadenomas with suprasellar extension)

LM: C-B

Adenoma cells are polygonal to elongated. Some are diffuse in pattern, but others show perivascular pseudorosettes or even papillae.

Chromophobic or oncocytic,

contain only scant, peripherally situated, PAS-positive granules.

LM:Adenoma cells are polygonal to elongated. Some are diffuse in pattern, but others show perivascular pseudorosettes or even papillae.

Treatment: Only approx.5% of gonadotropic adenomas require reoperation ..

Pituitary apoplexy is a recognized complication

.

IHC: Chromogranin staining is strong.

MIB-1 labeling is typically low (<3%).

Steroidogenic factor 1 (SF1), the transcription factor associated with gonadotrophs, is also demonstrable.

Immunostains :+ FSH and/or LH and often for the α-subunit as well.

EM: Polar cells with process formation and small numbers of minute secretory granules disposed beneath the plasmalemma.

Pituitary apoplexy-The sellar region in coronal sections shows a massive hemorrhage within a macroadenoma.

Gonadotropic Adenoma:Honey coombing and vacuolisation of golgi complex .

THYROTROPH CELL ADENOMA

Thyrotropic tumors - least common of the pituitary adenomas.( Incidence1%)

Majority occur in adults and affect females

TSH-producing adenomas are seen in the setting of MEN1 and Carney complex, some as plurihormonal lesions .

Most arise in the setting of hyper- or hypothyroidism

A significant number cause elevated serum TSH levels in association with normal T3&T4 levels, a condition termed “inappropriate TSH elevation”.

Administration of TRH does not further increase TSH levels, thus distinguishing TSH adenoma from pituitary resistance to thyroid hormone

In the setting of hypothyroidism, combined TSH and PRL cell hyperplasia causes pituitary enlargement that may mimic an adenoma

C/F:hypothyroidism or hyperthyroidism

DIAGNOSIS:

BLOOD HORMONE:↑↑ TSH

1.Basal thyroid function tests: T4, T3, TSH –

- Low free thyroid hormone levels in the setting of TSH levels that are not appropriately increased indicate pituitary insufficiency

2.TRH test: 200–500 μg IV 0, 20, 60 min for TSH and PRL - TSH should increase by >5 mU/L unless thyroid hormone levels are increased

HYPOTHALMO -THYROID AXIS

HPE: GROSS: Usually invasive macroadenomas (75%)

MICROSCOPIC:C-B ,majority of these adenomas are chromophobic tumors showing only mild PAS positivity.

HISTOCHEMICAL STAINING: PAS; aldehyde fuchsin; aldehyde thionin

(A)Glycoprotein adenomas often contain spindle-shaped cells and they show little or no PAS reactivity. (B) Immunoreaction for TSH varies in intensity

IHC :TSH , most are also immunoreactive for α-subunit.

EM:

Ultrastructurally, their cells resemble normal thyrotrophs, featuring processes containing microtubules,

prominence of lysosomes,

sparse, minute secretory granules

TREATMENT: medical therapy and/or radiotherapy are often required

Thyrotroph cell adenoma:angular shape cell accentuated by small secretary granules

PLURIHORMONAL ADENOMAS INCIDENCE-10%

C/F:Usually acromegaly ± hyperprolactinemia; glycoprotein hormone production rarely expressed

BLOOD HORMONES:

Usually GH, PRL, and TSH, α-subunit; includes other unusual combinations

-Combined anterior pituitary test: GHRH(1 g/kg), CRH (1 μg/kg), GnRH (100 g),TRH (200 μg) are given IV

- 0, 15, 30, 60, 90, 120 min for GH,ACTH, cortisol, LH, FSH, and TSH

-Combined or individual releasing hormone responses must be elevated in the context of basal target gland hormone values and may not be uniformly diagnostic

GROSS:25% micro/75% macro , MICROSCOPY:C-A

INVASION:52%

IHC:Usually +/+/+ GH, PRL, and TSH, α-subunit

SILENT SUBTYPE 3INCIDENCE-3%

C/F Mass effects; hyperprolactinemia or GH effects

BLOOD -No specific hormone

GROSS:Usually macro

MICROSCOPY: C to mild A and show some degree of nuclear pleomorphism and nucleolar prominence.

INVASION-Frequent

IHC:Scant to variable GH (10%), PRL (10%), or TSH; rare ACTH

EM: shows polar cells, Pleomorphic nuclei containing multiple spheridia.

Both RER & SER are abundant, whereas secretory granules are sparse and small.

Silent corticotroph adenoma type 3:large cells with nuclear pleomorphism,cytoplasm is packed with SER,RER & prominent golgi bodies.

NULL CELL ADENOMASIncidence-20%

Two types-Non oncocytic & oncocytic

These tumors are relatively devoid of organelles and lack specific differentiation —hence the term null cell adenoma.

Age- > 40 and come to clinical attention as a result of mass effects.

Majority of patients show laboratory evidence of hypopituitarism.

Prognosis is favorable, with a recurrence rate of approximately 10%

C/F: both present with Visual symptoms; hypopituitarism; headaches

BLOOD HORMONES-None ± mild hyperprolactinemia as a result of pituitary stalk compression

GROSS:5% micro/95% macro

NononcocyticIncidence-14%LM-Chromophobic

OncocyticIncidence-6%LM: Acidophilic

Null cell adenoma. (A) nononcocytic-chromophobic, (B) oncocytic as a result of mitochondrial accumulation.

Null cell adenoma with poorly developed ER & golgi complex with scant secretary granules

IHC-No reaction for hormones,but + for synaptophysin and chromogranin

HISTOCHEMICAL STAIN: PAS-VE

EM: contain only sparse, small, sub plasmalemmal secretory granules in association with poorly developed organelles

INVASION-42%

Pituitary oncocytoma with abundance of mitochondria

PITUITARY CARCINOMA

Pituitary carcinomas are rare; only approximately 100 cases have been reported

Most occur in gradual transition from typical or atypical, often invasive macroadenomas.

Latency period is generally 5 to 10 years,few arise de novo.

Only adults have been affected.

Cytologic atypia and a brisk mitotic index are predictive of aggressive behavior, some show neither.

Ultrastructural studies of pituitary carcinomas often show some loss of differentiation

pituitary carcinoma” is predicated on the finding of one or more of the following:

(a) Discontinuous spread within the cerebrospinal space

(b) Extracranial metastases, typically to liver, bone, lymph node, or lung, by way of the bloodstream or lymphatics

(c) Gross brain invasion ,LM or cytologic features alone are of little use in establishing the diagnosis of carcinoma

PITUITARY ADENOMA WITH NEURONAL METAPLASIA (GANGLIOCYTOMA)

Neurons are occasionally found within the substance of pituitary adenomas

Most are sparsely granulated GH-producing adenomas associated with acromegaly.

The neurons in such tumors often produce GHRH ,Similarly, CRH-producing neurons have been observed with Cushing disease.

The light microscopic, ultrastructural, and immunocytologic features of the neurons vary in terms of cell size, nuclear number, and content of Nissl substance

Occasional keratin staining of the neurons also supports the metaplasia concept.

Gangliocytoma of the pituitary-composed of hypothalamic-type neurons situated within the substance of a GH cell adenoma. Immunostains show that the neurons contain growth hormone-releasing hormone.