Imaging of the Pediatric Hypothalamic-Pituitary Axis: How Embryology Sheds Light on Pathology ASNR 2015 Annual Meeting Jayant Boolchand, MD Bruno P Soares,

Imaging of the Pediatric Hypothalamic-Pituitary Axis: How Embryology Sheds Light on Pathology

ASNR 2015 Annual Meeting

Jayant Boolchand, MD

Bruno P Soares, MD

Abstract No: eEdE-171

Submission Number:275

Department of Radiology and Imaging Sciences

Division of Neuroradiology

Disclosures

The authors have no relevant disclosures.

Pituitary embryology

Schroeder JW, Vezina LG. Pediatric sellar and suprasellar lesions. Pediatr Radiol. 2011 Mar;41(3):287-98; quiz 404-5. doi: 10.1007/s00247-010-1968-0. Epub 2011 Jan 26. Review. PubMed PMID: 21267556.

Spampinato MV, Castillo M. Congenital pathology of the pituitary gland and parasellar region. Top Magn Reson Imaging. 2005 Jul;16(4):269-76. Review. PubMed PMID: 16785842.

Shields R, Mangla R, Almast J, Meyers S. Magnetic resonance imaging of sellar and juxtasellar abnormalities in the paediatric population: an imaging review. Insights Imaging. 2015 Apr;6(2):241-60. doi: 10.1007/s13244-015-0401-5. Epub 2015 Mar 21. PubMed PMID: 25794595.

Adenohypophysis

Derives from Rathke’s pouch, an ectodermal outpouching of stomodeum

and infundibulum, at approximately 24 days gestation

Rathke’s pouch consists of: anterior wall, a precursor of the anterior lobe and pars

tuberalis; posterior wall, which develops into the pars intermedia; and a central cleft

Course and development of Rathke’s pouch:

Originates rostral to the oropharyngeal membrane

Migrates dorsally via a canal in the body of the sphenoid bone

Separates from the oral cavity in the 7th week of life

Craniopharyngeal canal regresses and normally becomes obliterated by six months

Primitive pituitary cells undergo differentiation and produce hormones

(TSH, GH, prolactin, LH, FSH)



Castillo M. Pituitary gland: development, normal appearances, and magnetic resonance imaging protocols. Top Magn Reson Imaging. 2005 Jul;16(4):259-68. Review. PubMed PMID: 16785841

Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. AJR Am J Roentgenol. 2007 Mar;188(3):W223-32. PubMed PMID: 17312027.

Adenohypophysis

Consists of:

Pars tuberalis – surrounds the infundibulum

Pars intermedia – portion of midline cells in Rathke’s pouch; separates adenohypophysis from

neurohypophysis

Pars distalis – enlarges and becomes the anterior lobe; extends superiorly along the anterior aspect

of infundibulum

Neurohypophysis

As Rathke’s pouch is developing, the posterior lobe originates from neuroectodermal

evagination of tissue from the hypothalamus/floor of the third ventricle/diencephalon

Functionally composed of: posterior lobe, the infundibulum and the medial eminence

of the hypothalamus

Secretes oxytocin and vasopressin synthetized in the hypothalamus




Pituitary Stalk

Variably hollow tube that arises from the ventromedial

hypothalamus and is contiguous with the infundibular recess of

the third ventricle

Though the most distal aspect of the infundibulum differentiates

into the neurohypophysis, the pituitary stalk has components of

both the anterior and posterior lobes, which explains the

presence of adenomas arising in the stalk

Pars tuberalis encircles the infundibulum as it enters the

adenohypophysis

Normal development of the pituitary gland


Normal pituitary anatomy



Delman BN. Imaging of pediatric pituitary abnormalities. Endocrinol Metab Clin North Am. 2009 Dec;38(4):673-98. doi: 10.1016/j.ecl.2009.09.001. Review. PubMed PMID: 19944287.


Delman BN. Imaging of pediatric pituitary abnormalities. Endocrinol Metab Clin North Am. 2009 Dec;38(4):673-98. doi: 10.1016/j.ecl.2009.09.001. Review. PubMed PMID: 19944287.

Imaging appearance of neonatal gland




Adenohypophysis

In newborns T1 hyperintense, gradually becomes T1 isointense to the pons by 6-8 weeks

Signal intensity reflects the newborn’s postnatal age and not the gestational age at birth

At birth, the gland is physiologically enlarged with a concave superior margin; then flattens, and

takes a more globular shape

Height of gland decreases in the first 8 weeks

In preterm infants the gland is taller than in normal-term infants, thought to be due to reduced IGF-

1 and higher levels of growth hormone in premature infants

Neurohypophysis

T1 hyperintense

Infundibulum

Usually midline, but may insert off center in up to 46% of patients

Should be no larger than 2.6 mm

May be seen by MRI after fetus is 25 weeks

Normal T1 hyperintense appearance of the neonatal gland

Normal globular appearance of the neonatal gland

Imaging appearance of childhood and adolescent gland


Experiences linear and constant growth, reaching a height

of approximately 6 mm

At puberty, the gland enlarges, and tends to be slightly

larger in height in girls (10 mm) than in boys (8 mm)

In girls, it is not uncommon for the gland to convex

superiorly; the size of the gland may also vary with the

menses, becoming slightly larger just before menstruation;

generally does not measure more than 10 to 12 mm in

height

Normal physiologic prepubertal pituitary hyperplasia

Gland during pregnancy

Castillo M. Pituitary gland: development, normal appearances, and magnetic resonance imaging protocols. Top Magn Reson Imaging. 2005 Jul;16(4):259-68. Review. PubMed PMID: 16785841.

Increase in gland size from 30-100%, particularly in the third

trimester; upwardly convex border

Occasionally, the adenohypophysis becomes somewhat T1

bright

Reaches it maximum size a few days after birth and gradually

returns to normal (regardless of breast-feeding choices)

May cause bitemporal hemianopsia

Histologically, the number of lactotrophs increases until it

compromises nearly 60% of total cell population of the gland

Normal postpartum gland

Imaging appearance of pituitary infundibulum



Tapers from superior to inferior

3.45 +/- 0.56 mm at the level of the optic chiasm and narrows to 1.91 +/- 0.4 mm

at its insertion

Signal intensity on T1 usually less than optic chiasm

Lacks blood brain barrier and thus normally enhances

Deviation is common and does not necessarily imply underlying disease,

especially in cases where the floor of the sella may slope normally to one side

Insertion of intersphenoid septum at the floor of the sella may result in

artifacts that may be confusing. Magnetic susceptibility-induced signal loss in

the gland at the level of the septal insertion must not be confused with an

adenoma

Imaging appearance of the neurohypophysis


Etiology of increased T1 signal (“bright spot”) is controversial– believed

to be related to vasopressin neurosecretory granules (neurophysin);

lipoid bodies in pituicytes; presence of phospholipid vesicles

If the stalk is anatomically and functionally normal, an intrasellar bright

spot is present. Functional damage to the stalk results in absence of the

bright spot

Dehydration results in a smaller bright spot, due to active secretion of

ADH

Overhydration results in a larger bright spot, due to accumulation of the

hormone in the posterior lobe

Persistent craniopharyngeal canal



Skull base midline defect at the level of the sphenoid, connecting

the floor of the sella with the superior wall of the nasopharynx;

usually measures less than 1.5 cm

Lack of involution of the craniopharyngeal canal can contain

pituitary tissue

Pathway of Rathke’s pouch is the craniopharyngeal canal, which

progressively normally involutes by 6-7 weeks of gestation

In cases where the canal persists, can be associated trans-

sphenoidal meningoencephaloceles, ectopic pituitary tissue,

sphenoid teratoma and infrasellar craniopharyngiomas

Insult during 42-45 days of gestational life can lead to persistence of

canal

Ectopic pituitary tissue within a persistent craniopharyngeal canal

Ectopic pituitary tissue within a persistent craniopharyngeal canal

Transsphenoidal encephalocele



Wide spectrum of congenital abnormalities affects the skull base in the region of the sella

turcica, ranging from persistent craniopharyngeal canal to transsphenoidal and

sphenoethmoidal cephalocele

Congenital malformation involving the lack of separation of neuroectoderm from surface

ectoderm results in failure of localized bone formation or from failed fusion of ossification

centers

Herniation of CSF filled sac containing neural and vascular tissue

Content may include the hypothalamus, pituitary gland, third ventricle, anterior cerebral

arteries, optic nerves and chiasm

May present with feeding and nasal obstruction in the first year, and potential for CSF leaks

and meningitis

Associated with agenesis of the corpus callosum, hypertelorism, craniofacial midline

defects, dysfunction of the hypothalamopituitary axis, and optic pathway abnormalities

Ectopic neurohypophysis



When ectopic usually located along the ventral aspect of the hypothalamus

(median eminence)

Absent, truncated, or thread-like pituitary stalk; small adenohypophysis

Almost always accompanied by decreased hypothalamic – pituitary function

Most common imaging finding in children with growth retardation

Can be isolated finding or associated with other midline anomalies, such as

lobar holoprosencephaly, septic-optic dysplasia, pituitary dwarfism, delayed

skeletal maturation, Kallman syndrome, dysgenesis of the corpus callosum

May also develop following trauma

If stalk transected at the proximal aspect, axons from the hypothalamus may reorganize to store

and release vasopressin

Ectopic neurohypophysis

Rathke cleft cyst




Nonneoplastic cysts arising from failure of obliteration of the embryonic cleft of Rathke

pouch; arise from epithelial rests of the craniopharyngeal canal; usually between the

anterior and posterior lobes in the region of the pars intermedia

Walls of cyst lined with columnar or cuboidal epithelium; contains fluid and variable

amounts of protein, mucopolysaccharides and/or cholesterol

May be intrasellar only, but most are intra- and suprasellar (87%)

2-3 times more common in women

May be symptomatically related to compression of adjacent structures

Most are stable in size, some may disappear spontaneously; may slowly increase in size

because of imbalance between secretion and reabsorption of cyst contents

Cyst growth and/or intracystic hemorrhage or infection can occasionally cause visual

disturbances, headaches, diabetes inspidus, or pituitary dysfunction

Rathke cleft cyst


Intermediate or high signal intensity on T1 and T2; signal characteristics

vary based on protein content

Thin peripheral enhancement of the wall; no central or solid enhancement

Intracystic nodules – no enhancement; low signal intensity on T2

Mucinous mixed cholesterol and protein

ADC increased compared to cystic components of craniopharyngiomas and

hemorrhagic pituitary adenomas

May have mass effect on the infundibulum, pituitary gland or infundibulum

Pars intermedia cysts – less than 3 mm, asymptomatic, incidental and

difficult to distinguish from Rathke cleft cyst

Sellar/Suprasellar Rathke cleft cyst

Pars intermedia cyst

Craniopharyngioma


50% of pediatric suprasellar tumors; 3% of all intracranial

tumors

Histologically benign, locally aggressive; occur in bimodal

distribution in children (<10 years) and adults (>40 years)

Two types: adamantinomatous type (all age groups) and

papillary type (almost always adults)

Suprasellar component in 95% of cases

Extension in middle cranial fossae in up to 30% of cases

Frequently contain proteinaceous fluid (bright on T1), cysts,

lipid components and calcifications

Craniopharyngioma


Intermediate and/or high signal on T1 and T2 with or without

nodular or rim enhancement

Adamantinomatous (bimodal in children and adults)

Hyperintense cystic components (T1), lobulated shape and vascular

encasement

Squamous – papillary subtype (adults)

Hypointense cysts (T1), enhancing solid components- results in flip flop of

T1 signal between cystic and solid portions comparing pre and post imaging

Mets may occur via tumor transplantation during surgery or

CSF dissemination

Craniopharyngioma


Two hypotheses for development:

Embryogenetic theory: adamantinomatous subtype comes from remnants of Rathke

pouch or craniopharyngeal duct – the duct and pouch are derived from the

stomadeum, which form (among other things) teeth primordia

Metaplastic theory: squamous papillary subtype occurs from neoplasia of squamous

cell rests – remnants of the part of the stomadeum that contribute to the buccal

mucosa

Classified by size and relationship to the optic chiasm

Sellar CP

Prechiasmatic suprasellar CP

Retrochiasmatic CP

Giant CP (anterior, middle, or posterior cranial fossae)

Neurosurgeon needs to be aware of relationship to hypothalamus,

third ventricle and arteries of the Circle of Willis

Craniopharyngioma

50% suprasellar tumors

Adamantinous

90% have Ca++

90% cystic

90% enhance

May expand sella! (arises

along path of Rathke’s pouch)

Pituitary hyperplasia


May enlarge from stimulation by the hypothalamus

and mimic true mass

Homogeneous appearance on all pulse sequences

May be physiological – can reach 10 mm or even

higher, especially in females

Thyrotrophs will enlarge in the setting of chronic hypothyroidism

Somatotrophs will enlarge in the setting of pheochromocytomas

Lactotrophs will enlarge during pregnancy

Empty sella



Pituitary gland measuring 2 mm or less

Can result from weakened or fenestrated diaphragma sella allowing CSF

pulsations to flatten the pituitary gland

Associated with elevated intracranial pressure, a posteriorly placed optic chiasm, and

considered a normal variant or termed “primary empty sella turcica” in the absence of

surgery, radiation therapy or medically treated intrasellar tumor

CSF occupying more than half of the sella

Found in just over 1% of patients but in almost 11% of those with

possible hypothalamic – pituitary abnormalities

Possible etiologies: congenital abnormalities as well as adverse

perinatal events

Agenesis and hypoplasia of the pituitary gland


Rare

Newborn with jaundice, metabolic acidosis, liver

dysfunction, adrenal and thyroid insufficiency,

severe hypoglycemia

Associated with developmental disorders of the

midline forebrain and craniofacial structures

Can survive with hormone replacement therapy

Pituitary dwarfism


Heterogeneous group of diseases caused by isolated GH deficiency or

deficiency of multiple pituitary hormones

Imaging does not always correlate

Normal to hypoplastic to absent

Pathogenesis of MRI abnormalities is uncertain

Higher frequency in difficult deliveries (breech, perinatal asphyxia, low

Apgar)

Traumatic transection of the pituitary stalk, hypoxic injury of the hypothalamus could

result in hypoplasia of adenohypophysis, whereas regenerated hypothalamic axons

would reconstitute the neurohypophysis in a more proximal insult

Genetic causes of an abnormal interaction between the Rathke pouch and the

diencephalon have been postulated

Duplicated pituitary gland


Very rare

Frequently accompanied by duplication of stalk

Enlargement of the hypothalamus with fusion of the

mammillary bodies and tuber cinereum or hamartoma of the

tuber cinereum can be seen

May result from abnormal splitting of the anterior end of the

notochord and prechordal plate due to teratogenic factors

during early embryogenesis

May represent a variant of the median cleft face syndrome



Associated with:

Dysgenesis of the corpus callosum

Duplication of the anterior third ventricle

Absence of the olfactory bulbs and tracts

Duplication of the optic chiasm, hypothalamic hamartoma

Hypertelorism

Fenestration or complete duplication of the basilar artery

Dandy-Walker spectrum

Cleft of the basisphenoid

Craniofacial clefting, oral midline tumors (teratomas and dermoids)

Malformations of the spine (diplomyelia, Klippel-Feil anomaly, and clefting of

cervical posterior elements, and duplicated cervical or thoracic vertebral bodies


Duplicated pituitary

glands

Duplicated pituitary stalks

Hypothalamic hamartoma

Hypothalamic hamartoma


Li CD, Luo SQ, Tang J, Jia G, Ma ZY, Zhang YQ. Classification of hypothalamic hamartoma and prognostic factors for surgical outcome. Acta Neurol Scand. 2014 Jul;130(1):18-26. doi: 10.1111/ane.12209. Epub 2014 Jan 2. PubMed PMID: 24382157.


Congenital developmental non-neoplastic grey matter heterotopia

involving the tuber cinereum, inferior hypothalamus and/or mammillary

bodies which are composed of small neuronal cells within a neutrophil-

like stroma and scattered fibrillary astrocytes

Nonenhancing hypothalamic mass contiguous with the tuber cinerum

Sessile or pedunculated

Large sessile lesions seizures

Small pedunculated lesions central precocious puberty

Mass located between mammillary bodies and infindibulum

On MR spectroscopy, there may be an elevated myoinositol peak

Hypothalamic Hamartoma

Sessile or Pedunculated

More common in boys

Associated with:

Gelastic Seizures or Precocious Puberty

Hypothalamic Hamartoma

Septo-optic dysplasia


Pediatric Neuroimaging. A. James Barkovich, Charles Raybaud. Edition 5. Lippincott Williams & Wilkins, 2012

Hypoplasia of the optic nerves, hypoplasia or

absence of the septum pellucidum, and in two thirds

of cases hypothalamic-pituitary dysfunction

Squared appearance of the frontal horns of the

lateral ventricles and low position of the fornices on

sagittal images

Ectopia of the posterior pituitary lobe and thin

infundibulum

Septo-optic dysplasia

Hypoplasic anterior pituitary, pituitary stalk, optic chiasm, hypothalamus Ectopic neurohypophysis Absent septum pellucidum

Germ cell tumors


Divided into germinomas and nongerminomatous germ cell tumors

(70%)

Pineal region most common in males

Suprasellar region most common females

In the suprasellar cistern, most commonly centered in the stalk, with or without

involvement of the hypothalamus

Presence of basal ganglia infiltration in the setting of abnormal thickening of the

infundibulum and hypothalamus is characteristic

Variable signal characteristics; solid components enhance

T2 signal of solid components is usually iso- to hypointense compared

to gray matter

Germ cell tumor Suprasellar and Pineal

5-10% Synchronous suprasellar and pineal involvement

Germ cell tumor

High risk of CSF spread: MRI of entire neuroaxis

Isolated Diabetes Insipidus: Suspect stalk involvement

Infundibular Lesions

Pediatric Neuroimaging. A. James Barkovich, Charles Raybaud. Edition 5. Lippincott Williams & Wilkins, 2012


Classically present with diabetes inspidus

Diabetes insipidus occurs due to dysfunction of supraoptic or paraventricular nuclei of the

hypothalamus. Infiltration of these nuclei can occur at a time when the infundibulum is still

normal in size.

At the time a child presents with diabetes insipidus, a pituitary stalk lesion such as a germ cell

tumor, granuloma or lymphocytic infiltration may not be visible yet by imaging, and in such

patients repeat imaging should be obtained in 3 to 6 months and, if still negative, a second

repeat examination should be obtained.

Three most common etiologies:

Langerhans histiocytosis (LCH)

Germ cell tumor (GCT)

Lymphocytic hypophysitis

Isolated thickening:

Sarcoidosis

Granulomatous infections, such as TB

Infundibular mass differential Germinoma


Langerhans cell histiocytosis

Adenoma or nonadenomatous pituitary tumors

Granulomatous disease (sarcoid, wegner granulomatosis,

tuberculosis)

Lymphoma

Metastatic disease

Other infiltration disease: Erdheim-Chester, Rosai Dorfman

Langerhans cell histiocytosis


LCH involves CNS in 4% of cases

In nearly all cases of LCH, the normal T1 hyperintensity of the neurohypophysis is absent

Hypothalamus and infundibulum are infiltrated in up to 20% (most common location in CNS)

When only neurohypophysis and infundibulum involved there is classically thickening of the

pituitary stalk greater than 3.5 mm with loss of the pituitary bright spot

When entire gland is involved, diffuse inflammatory changes may be present which may

involve optic chiasm or cavernous sinuses

Multiple CNS findings have been described:

White and gray matter lesions

Demyelination

Calvarial lesions

Partially empty sella

Extraparenchymal masses

Cerebellar degeneration

Thickening of the pituitary stalk in LCH



Classified by anatomical location

Adenophyophysis

Infundibulum

Neurohypophysis

When infundibulum and neurohypophysis are involved

diabetes insipidus is the most common symptom

In children – 50% of cases involve anterior and

posterior pituitary lobes

Sarcoidosis


Prevalence in children is unknown

Prepubertal children with neurosarcoid may

demonstrate seizure and hypothalamic

dysfunction

Thickening of the pituitary stalk in sarcoidosis

Conclusions The normal neonatal, pubertal and young adult pituitary gland have their own

distinct appearances that should not be confused with congenital pathology

Knowledge of normal embryology of the pituitary gland, particularly the

development of adenohypophysis from the Rathke pouch and of the

neurohypophysis from the diencephalon, is central to the understanding of

congenital pathology

When a child presents with diabetes insipidus, a pituitary stalk lesion may not be

visible yet by imaging, and in such patients repeat imaging should be obtained in

3 to 6 months and, if still negative, a second repeat examination should be

obtained

Interpretation of imaging features of acquired disorders also is enhanced by

grasping basic concepts of hypothalamic-pituitary axis embryology and function

Documents

Imaging of the Pediatric Hypothalamic-Pituitary Axis: How Embryology Sheds Light on Pathology ASNR 2015 Annual Meeting Jayant Boolchand, MD Bruno P Soares,