Sellar Region Tumors.pptx

SELLAR REGION TUMORS
[Chapter 12: WHO CNS 5th Ed]
DR. VASU NALLALUTHAN
M.S NEUROSURGERY
SUPERVISOR:
ASSOC PROF. AILA ANANI

OUTLINES
• ANATOMY
• PHYSIOLOGY
• Sellar Region Tumours WHO CNS 5th
ED Classification
• Adamantinomatous
Craniopharyngioma (ACP)
• Papillary Craniopharyngioma (PCP)
• Pituicytoma
• Granular cell tumor (GCT) of the sellar
region
• Spindle cell oncocytoma
• Pituitary adenoma/PitNET
• Pituitary blastoma

aNaToMiCa
• Sellar region and parasellar region
• tiny anatomic complex compartment
• area immediately around the pituitary
• Pituitary gland and sella  below the
center of the brain at the center of
the skull base.
• Above  optic nerves, chiasm and
the circle of Willis
• Lateral  cavernous sinuses and
both ICA
• Behind  Brainstem and basilar artery.

PHYSioLoGia
• The sellar region  sella turcica and the pituitary gland, with the ventral
adenohypophysis and dorsal neurohypophysis.
• The parasellar region  the cavernous sinuses, suprasellar cistern, hypothalamus,
and ventral inferior third ventricle.
• Anatomic localization is essential in the creation of a differential diagnosis
between sellar and parasellar lesions.
• The sellar and parasellar regions can be involved in neoplastic,
inflammatory/ granulomatous, infectious, and vascular diseases,
• arise from the pituitary gland, infundibular stalk, hypothalamus, cranial nerves,
vascular structures, leptomeninges, or skull base.

ADAMANTINOMATOUS
CRANIOPHARYNGIOMA

In GENERAL…
• Histologically benign
• Mixed solid and cystic squamous epithelial neoplasm of the suprasellar or
sellar region
• Resembling ameloblastoma or keratinizing and calcifying odontogenic cyst
• Always WHO grade I
• Tumor with palisading epithelium, wet keratin and stellate reticulum
associated with surrounding gliosis and Rosenthal fibers
• Shows CTNNB1 mutations and aberrant nuclear expression of β-catenin in
up to 95% of cases

LOCALIZATION
• Arise anywhere along the
craniopharyngeal canal
• Most occur in the sellar and
infundibulotuberal region.
• Suprasellar  The majority (~95%)
• Purely suprasellar, 20-41% of cases;
• Both suprasellar and intrasellar, 53-
75%)
• Purely Intrasellar craniopharyngiomas
 less common (~5%).
• Tumour extends 
• Anterior fossa (9%)
• Middle fossa (8%)
• Posterior fossa (12%)
• Very rare examples occur in the
cerebellopontine angle and other
ectopic sites

EPIDEMIOLOGY
• Incidence: low (1.2 – 4.6% of all intracranial tumors)
• Age: bimodal, with peaks at 5 - 15 years and 45 - 60 years
• Rare neonatal and fetal cases have been reported
• Most common non- neuroepithelial intracerebral neoplasm  children
• More common than papillary craniopharyngioma (even in adults)
• No sex predilection
• Etiology is unknown.
• Occasional familial adenomatous polyposis 1-associated cases of adamantinomatous
craniopharyngioma that lack CTNNB1 mutation and instead harbour germline APC
mutation with somatic loss of heterozygosity have been reported.

PATHOGENESIS
• Arise from cellular elements related to the Rathke pouch (craniopharyngeal duct),
which is integral to pituitary development.
• Expression of oncogenic β-catenin in early embryonic precursors and in stem cell of the
pituitary  formation of tumours resembling adamantinomatous craniopharyngioma.
• SOX2-positive progenitors  formation of papillary craniopharyngiomas and Rathke cleft
cysts.
• Contribute to the formation of epithelial whorls with nuclear localized ß-catenin.
• The whorls are quiescent and secrete numerous factors  sonic hedgehog,FGF, TGF-ß, BMPs, and
proinflammatory mediators.
• These signaling centres are analogous to the enamel knot that controls tooth morphogenesis
occasional presence of teeth in adamantinomatous craniopharyngioma
• Characterized by mutations in exon 3 of CTNNB1
• Gene that encodes the WNT signaling pathway regulator ß-catenin.
• These are activating mutations, as evidenced by overexpression of ß-catenin targets such as AXIN2 and
LEF1

PATHOGENESIS
Wnt signaling pathway.
• The pathway is maintained in
the off state by the β-catenin
degradation complex and the
proteasome.
• When a Wnt ligand is present,
the complex cannot assemble
and β-catenin translocates to
the nucleus and initiates
transcription of its target genes
Larkin SJ, Ansorge O. Pathology and pathogenesis of craniopharyngiomas. Pituitary.
2013 Mar;16(1):9-17.

CLINICAL FEATURES
• Rarely detected incidentally (in < 2% of
cases).
• Dx  1 -2 years after initial
manifestation of nonspecific
symptoms related to increased ICP 
headache.
• Primary manifestations
• Visual impairment (62-84%)  Children
• Endocrine deficits (52-87%)
• Growth hormone (75%)
• LH or FSH (40%)
• TSH (25%)
• ACTH (25%)
• ADH (17-27% of patients have central DI at
Dx).
• Reduced growth rates before diagnosis
may occur (even 12 months).
• Weight gain, predictive of
hypothalamic obesity later
manifestation
• Hypothalamic syndrome (50%) from
disease- or treatment-related
hypothalamic involvement or damage
• Morbid obesity
• Cognitive impairment
• Personality changes
• Psychiatric symptoms

DIAGNOSIS
• Best diagnostic clue is preoperative
imaging
• Usually extra-axial and suprasellar
• Multilobulated and multicystic lesions
• Variable in size, often > 5 cm
• Recurrences may be massive
• Imaging
• CT:
• Better than MRI  calcifications
• Solid regions and cyst wall enhancement
• Calcifications visible
• MRI:
• T1: solid regions are hypo- or isointense,
cystic regions are hyperintense
• Strong heterogeneous enhancement
• Hyperintense on T2
• Fluid levels consistent with cystic
components
• Spread
• Local invasion of hypothalamic, visual
tract, and vascular structures (including
encasement of the internal carotid
arteries) is common (occurring in ~25% of
cases).
• Subarachnoid dissemination or
implantation along the spinal cord, the
surgical track, or the path of needle
aspiration is rare

IMAGING
The lateral skull film shows marked expansion of the sella and a large faint rim-like area of calcification projecting over the
suprasellar region. Axial CT images show a large sellar region mass with internal low density and thick rim like calcification,
associated with hydrocephalus. No central enhancement is present.

IMAGING
Brain magnetic resonance imaging before the first surgery, showing a suprasellar mass lesion with enhanced solid and
multiseptated cystic components. A : Axial. B : Coronal. C : Sagittal
Jeong TS, Yee GT, Kim NR. Malignant Transformation of Craniopharyngioma without Radiation Therapy: Case
Report and Review of the Literature. J Korean Neurosurg Soc. 2017 Jan 1;60(1):108-113. doi:
10.3340/jkns.2015.0707.022.

LABORATORY
• Same for both types of craniopharyngiomas
• Full pituitary endocrine workup is usually mandatory
• Visual acuity and visual field assessment is also performed to show any
deficits and rule out papilledema

PROGNOSTIC FACTORS
• 5 year survival excellent
• Patients may be left with variable endocrinologic deficiencies
• Cystic recurrence common after incomplete excision
• Very rare malignant transformation

TREATMENT
• Gross total excision or subtotal resection
followed by radiation therapy
• Surgery
• Approach  Anatomic location, size, invasion
of the nearby structures and the nature of the
tumor
• Indication  neurologic compromise from
tumor mass effect
• In children  hypothalamic and endocrine
dysfunction may develop before visual defects
are noticed
• Radiotherapy is indicated for treatment of
residual tumor or recurrence

HISTO_PATHOLOGY
• Gross description
• Lobular and cystic tumor with
calcifications
• Cysts with dark "motor oil" fluid
composed of cholesterol and
hemorrhage
• Irregular tumor interface with adjacent
brain
• Can be densely adherent to brain

HISTO_PATHOLOGY
• Microscopic (histologic) description
• May appear well circumscribed
• Cords, lobules, nodular whorls and trabeculae of well differentiated squamous epithelium
bordered by palisading columnar epithelium
• Peripheral cells surround looser plumper cells called stellate reticulum
• Nodules of plump, anucleate squamous cells (ghost cells) and wet keratin
• Intralobular whorl-like formations
• May have degenerative changes with cystic degeneration, calcifications and
xanthogranulomatous reactions with giant cells
• Piloid gliosis and Rosenthal fibers in adjacent brain
• Rarely, melanin pigment
• Microscopic brain invasion common with tongues of tumor extending into hypothalamic
parenchyma

HISTO_PATHOLOGY
This H & E Stain image shows most of
the key diagnostic features :
a) sheets of squamous epithelial cells
with peripheral palisading (PP)
b) a loose meshwork of epithelial cells
called the stellate reticulum(SR)
c) nodules of anucleated squames
(ghost cells (GC) with brightly
eosinophilic cytoplasm termed wet
keratin.
• Wet keratin is considered diagnostic even
in the absence of viable epithelium.
SR
GC
PP

HISTO_PATHOLOGY
• The presence of nodules of
plump anucleated squames - the
so-called "wet keratin" is a
helpful diagnostic feature of
adamantinomatous
craniopharyngioma even in the
absence of viable epithelium.
• Keratin nodules may be
associated with
• Foreign body giant cell reaction
• Granulomatous inflammation
• Dystrophic calcification
• Ossification

Epithelial nodules (arrows) within the advancing front of the tumour commonly show nuclear β-catenin
expression.
Clusters and individual tumour cells show
nuclear β-catenin translocation. Note that in
most tumour cells β-catenin remains at the
cell membrane.
Larkin SJ, Ansorge O. Pathology and pathogenesis of craniopharyngiomas. Pituitary.
2013 Mar;16(1):9-17.

IMUNOHISTOCHEMISTRY
• Positive stains
• CK7, CK8, CK19, pancytokeratin, CK5/6, EMA, CK14
• Beta catenin: in whorls, both intranuclear (translocated) and cytoplasmic
• Ki67 (low, usually concentrated along the peripheral palisading cells)
• Negative stains
• Most cases are negative for mutant BRAF (V600E)
• Molecular / cytogenetics description
• Activating mutations of the WNT pathway gene CTNNB1 encoding beta catenin in
almost all cases

IMMUNOHISTOCHEMISTRY
10.3340/jkns.2015.0707.022.
Survivin protein expression levels in adamantinomatous craniopharyngioma tissues (magnification, x400).
The immunological tests showing overexpression of p53 (C).

10.3340/jkns.2015.0707.022.
The immunological tests showing overexpression of Ki67 (D), and positive results for pancytokeratin (E) and
vimentin (F).

DIFFERENTIAL DIAGNOSIS
• Epidermoid cyst:
• Uniloculate with thin layer of keratinizing squamous epithelium and keratohyalin granules
• Papillary craniopharyngioma:
• No palisading, no wet keratin, no calcifications, no "motor oil" cystic fluid, no xanthogranulomatous
reaction
• Harbors a BRAF V600E mutation and is negative for beta-catenin
• Pilocytic astrocytoma:
• Much greater cellularity than piloid gliosis, biphasic and may have eosinophilic granular bodies
• Rathke cleft cyst with squamous metaplasia:
• Intrasellar, squamous epithelium, as well as ciliated or mucus containing cells, no wet keratin, no
calcifications
• Beta catenin negative nuclei
• Xanthogranuloma of sellar region:
• Sellar region cholesterol clefts, lymphoplasmacytic infiltrates, marked hemosiderin deposits, fibrosis,
multinucleated giant cells around cholesterol clefts, eosinophilic granular necrotic debris and
accumulation of macrophages, no true epithelium and may be associated with Rathke cleft cyst
leakage / rupture / hemorrhage

In GENERAL…
• Suprasellar (usually) epithelial encapsulated neoplasm with well
differentiated nonkeratinizing squamous epithelium and papillary
fibrovascular stroma
• BRAFp.V600E mutation in almost all cases
• WHO grade 1
• Localization  suprasellar or intraventricular (3rd ventricle)
• Incidence: 10% of all craniopharyngiomas
• Age: almost always adults
• No sex predilection

Localization
• Arise anywhere along the hypo-thalamic-pituitary axis
• Intrinsic localization within the infundibulum and tuber cinereum of the 3rd ventricle
floor.
• They can expand into the third ventricle cavity, and they can be located
entirely within the ventricle above an intact ventricular floor.
• Intrasellar involvement is not common

CLINICAL FEATURES
• Headache (70% )
• Visual deficits (63%)  compression
of the optic chiasm
• Hypopituitarism (partial or
panhypopituitarism in a 70:30 ratio)
• Hypothyroidism (80%)
• Hypogonadotropic hypogonadism
(56%)
• Hypocortisolaemia (50%)
• Growth hormone deficiency (20%).
• Hyperprolactinemia (30%) due to
stalk effect
• Diabetes Insipidus (25% is a primary
manifestation)
• Hydrocephalus (30%).
• Preoperative hypothalamic
disturbances (63%)
• Weight gain
• Psychiatric and cognitive disturbances
• Alterations
• Core body temperature
• Sleep-wake cycles.

DIAGNOSIS
• More spherical in outline and usually
lacks the prominent cystic component
• Solid or contains a few smaller cysts
• May have cyst and mural nodule
configuration
• Tends to displace adjacent structures
• CT:
• Cysts small and insignificant
• Near cerebrospinal fluid (CSF) density
• Solid component near soft tissue density
• Vivid enhancement
• Calcifications very rare
• MRI:
• T1 weighted images: 85% of cysts are
hypointense
• T1 weighted images: solid component iso
to hypointense
• Vividly contrast enhancing
• Spread
• Occurs in about 25% of patients who have
involvement in the hypothalamus and
other vital neural and vascular structures.
• Ectopic recurrence is a rare complication
that occurs along the surgical track or at
other sites in the CNS via cerebrospinal
fluid spread in the subarachnoid space.

IMAGING
Multiple MR images demonstrate a
heterogeneously enhancing mostly solid
suprasellar mass which is inseparable
from the optic chiasm and is associated
with signal alterations within the bilateral
optic tracts. A punctate zone of
hypointensity on the GRE sequence may
reflect calcification. The mass is also
inseparable from the hypothalamus.

HISTO_PATHOLOGY
• MACROscopic
• Discrete, encapsulated mass
• Not densely adherent to adjacent brain
• No cholesterol rich, thick, oily cyst
contents
• If cystic, contains clear liquid
• MICROscopic
• Low power highlights papillary
configuration with cauliflower-like
morphology
• Solid sheets of well differentiated
nonkeratinizing squamous epithelium
• Crude papillae around fibrovascular
cores
• Small collagenous whorls

HISTO_PATHOLOGY
Higher magnification showing well-
differentiated non-keratinizing
squamous epithelium arranged around
a fibrotic stromal core. Note the
dehiscence of epithelium at the
peripheral portions which results in
pseudopapillae formation. The mature
squamous cells retain their nuclei
(unlike the anucleated squames of
adamantinomatous
craniopharyngioma). Wet keratin is not
seen. Peripheral palisading is not as
prominent as in adamantinomatous
subtype.

HISTO_PATHOLOGY
Squamous‐papillary craniopharyngioma section images
captured using light microscopy (stain, hematoxylin
and eosin; magnification, x400).
Sheets of well-differentiated non-keratinizing squamous
epithelium in a papillary craniopharyngioma. The epithelium
immediately surrounding the fibrovascular cores is tightly
adherent. Dehiscence of epithelium in between such areas
results in pseudopapillary appearance.

HISTO_PATHOLOGY
Transferase dUTP nick end labeling‐peroxidase staining of
craniopharyngioma sections demonstrating cell apoptosis in
squamous‐papillary craniopharyngioma tissue samples
(magnification, x400)
Survivin protein expression levels in squamous‐papillary
craniopharyngioma tissues (magnification, x400

• Positive stains
• CK7, EMA
• BRAF VE1 parallels presence
of BRAF V600E mutation in 95% of
cases
• Can have scant PAS positive goblet cells
• Only membranous beta catenin; nuclei
and cytoplasm negative
• Negative stains
• CK8, CK20
BRAF V600E immunostain

• Adamantinomatous Craniopharyngioma:
• Irregular, infiltrative borders
• Complex architecture
• Wet keratin
• Calcifications
• Peripheral palisading
• Loose stellate reticulum
• Positive nuclear β-catenin in keratin whorls (may be focal)
• Epidermoid cyst:
• Uniloculate with thin layer of keratinizing squamous epithelium and keratohyalin granules
• Rathke cleft cyst with squamous metaplasia:
• Cystic without solid component, squamous epithelium with ciliated or mucus containing cells

MANGEMENT
H&E stained sections of pre- and post-treatment papillary
craniopharyngioma.
• Top panel shows the recurrent tumor.
• The lower panel shows the tumor following treatment with
dabrafenib and trametinib.
• Side panels are sketch renditions of MRI images from our
exceptional responder patient
• The treatment of choice for papillary
craniopharyngioma is total resection.
• The prognosis is somewhat better than the
adamantinomatous subtype

In GENERAL…
• Tumor of the specialized modified glial cells of the posterior pituitary.
• These cells are known as “pituicytes”,  tumor has been recognized as “pituicytoma”
• Pituicytes, which are specialized gliocytes of the posterior pituitary, had 5 ultrastructural variants:
• Major cells
• Dark cells
• Granular cells
• Ependymal cells
• Oncocytic cells.
• It takes the classical form of a spindle cell tumor
• Similar to normal pituicytes that derive from the basal hypothalamus and express TTF1
(clone SPT24)
• Hallmark expression of the TTF1 transcription factor
• Hormonally inactive intrasellar or suprasellar mass

CLINICAL FEATURES
• Headache, visual disturbance, and hypopituitarism.
• The granular cells variant tends to be slower growing, and is often found as
a small, clinically asymptomatic incidental finding; many are seen only at
autopsy.
• Rarely associated with diabetes insipidus
• Location in the posterior lobe
• That the cell bodies of the vasopressin-secreting neurons remain intact in the
hypothalamus.

HISTO_PATHOLOGY
• Elongated eosinophilic spindle-shaped cells form interlacing fascicles known
as a “storiform pattern”.
• The tumor cells have distinct cell borders and minimal nuclear atypia.
• Oncocytic variant (spindle cell oncocytoma)  plump epithelioid cells with more
abundant eosinophilic granular cytoplasm.
• Granular cell variant  polygonal cells with conspicuous granular eosinophilic
cytoplasm, and
• Ependymal variant  ependymal-type rosettes.

HISTO_PATHOLOGY
• Electron microscopy
• The tumor cells are spindled or polygonal with well-formed desmosomes and
intercellular junctions
• No secretory granules;
• Oncocytic variants have abundant dilated mitochondria
• Granular cell variants have phagolysosomes with electron-dense membranous debris

• IHC localizes the S100 protein, vimentin, and GFAP that may be focal or weak;
epithelial membrane antigen (EMA) is usually positive, but may be negative.
• Pituicytomas are negative for synaptophysin, chromogranin, neurofilaments, and
keratins, as well as adenohypophysial transcription factors and hormones, CD34,
bcl-2, smooth muscle actin and desmin.
• They consistently stain for TTF1.
• They also express galectin-3, but this is not a distinguishing feature.
• The oncocytic variant stains avidly for mitochondrial antigens.
• Granular cell tumors show reactivity for biomarkers of lysozymes including CD68,
alpha-1-antitrypsin, alpha-1-antichymotrypsin, and cathepsin B, as well as strong
positivity with the periodic acid Schiff (PAS) stain.

HISTO_PATHOLOGY
Pituicytomas.
(a) H&E of a classical pituicytoma shows
spindle-shaped cells forming fascicles;
(b) An oncocytic variant that is composed of
round cells with granular eosinophilic
cytoplasm;
(c) TTF1 decorates the nuclei of the tumor cells;
(d) S100 is expressed by the tumor cells.
Asa SL and Mete O. Review Hypothalamic Endocrine
Tumors: An Update. J. Clin. Med. 2019, 8, 1741;
doi:10.3390/jcm8101741

HISTO_PATHOLOGY
Pituicytoma showing a
storiforme pattern of
growth (a)
composed of spindle
cells (b)
positive for TTF1 (c).
The Ki67-proliferative
index is very low (d)
Cossu G, Brouland JP, La Rosa S, Camponovo C, Viaroli E, Daniel RT, Messerer M. Comprehensive
Evaluation of Rare Pituitary Lesions: A Single Tertiary Care Pituitary Center Experience and Review
of the Literature. Endocr Pathol. 2019 Sep;30(3):219-236.

HISTO_PATHOLOGY
A, photomicrograph of section showing interlacing fascicles of spindle cells
with delicate vascular spaces (hematoxylin and eosin). B and C,
immunohistochemistry studies showing strong, diffuse immunoreactivity for S-
100 (B) and immunoreactivity of tumor cell processes for GFAP (C) (original
magnifications; x600).
Electron micrographs.
A, low-magnification view showing spindled
to slightly oval neoplastic cells with
elongated nuclei and non- granular
cytoplasm.
Area at lower right of A is magnified in B
(original magnification, x1050).
B, higher-magnification view showing
bundles of cytoplasmic intermediate
filaments and absence of mitochondria
(original magnification, x5800).

• Spindle cell oncocytoma
• Granular cell tumor
• Sellar ependymoma

GRANULAR CELL TUMOUR (GCT)
SELLAR REGION

IN GENERAL…
• First described by Boyce and Beadles in 1893.
• Sternberg classified this as a unique tumor entity in 1921.
• Uncommon
• Less than 0.5% of symptomatic lesions
• More commonly in women
• Sex incidence rate ratio of 1.4–3:1.
• In middle to advanced age  late 4th and early 5th decade of life
• WHO Grade 1
• Rarely reported progression and lack of invasive growth

PATHOGENESIS
• This tumor arises from the pituicytes, which are modified gliocytes of
ependymal cell lineage located in the neurohypophysis and pituitary stalk,
and the tumor exhibits a preference for the intrasellar and suprasellar
regions
• It is difficult to differentiate this tumor from other pituitary tumors
• due to the lack of specific radiological findings and its low incidence.
• The tumor infiltrate surrounding vital structures, such as the optic chiasm
and cavernous sinus, more than other suprasellar tumors.
• Make it difficult to safely achieve gross total surgical resection.

CLINICAL FEATURES
• May present with an array of symptoms secondary to its location and mass effect
• Visual field deficits  bitemporal hemianopia or diplopia
• An endocrine evaluation can reveal a variety of hormonal perturbations.
• Hyperprolactinemia (most common)  secondary to pituitary stalk compression and lack of dopamine
inhibition.
• Partial or panhypopituitarism
• Headache
• Decreased libido
• Cranial nerve palsies, particularly of the nerves traversing the cavernous sinus
• It can be difficult to diagnose radiographically, and is often misdiagnosed as a
pituitary adenoma or craniopharyngioma prior to surgical resection, the most
common form of treatment

IMAGING
• CT and MRI show well-circumscribed, globular masses located in the sellar
region.
• CT
• The solid tumors almost always appear relatively hyperattenuated on CT, and
calcification is extremely rare.
• MRI.
• The tumor tends to be suprasellar, with intimate association with the infundibulum
and separation from the pituitary gland.
• It is often isointense to gray matter on T1-weighted imaging, and hypo/isointense on
T2-weighted imaging.
• Contrast enhanced T1-weighted imaging demonstrate enhancement in most cases,
most commonly with heterogenous enhancement.

HISTO_PATHOLOGY
• Microscopically
• Mainly of densely packed polygonal cells with abundant granular eosinophilic
cytoplasm, which was confirmed as lysosomes on electron microscopy, apparently
different from neuroendocrine granules.
• The nuclei are a small round shape with little pleomorphism, and mitotic figures are
rare.

• Positive staining for S100, GFAP, and TTF-1
• Immunonegative for pituitary hormones or neuroendocrine markers.
• TTF-1 is an important molecule for exploring the origin of GCT of the sellar
region, but it seems less necessary in terms of performing accurate
pathological diagnosis of this tumor.

Histopathology of the resected tumor shows round or polygonal cells with abundant granular
eosinophilic cytoplasm and perivascular lymphocytic aggregates. Most nuclei are round to
oval in appearance without evidence of cellular atypia and mitotic figures ( hematoxylin and
eosin staining) ( a, b ).
Kusakawa A, Inoue A, Nakamura Y, Nishida N, Fukushima M, Senba H, Suehiro S, Matsumoto S, Nishikawa M, Ozaki S,
Shigekawa S, Watanabe H, Matsuura B, Kitazawa R, Kunieda T. Clinical features and endoscopic findings of granular cell
tumor of the sellar region: A case report and review of the literature. Surg Neurol Int. 2020 May 9;11:101.

Periodic acid S chiff (PAS) staining of cytoplasmic granules is resistant to diastase digestion (c:
PAS staining, d: diastase resistant-positive PAS reaction).
Kusakawa A, Inoue A, Nakamura Y, Nishida N, Fukushima M, Senba H, Suehiro S, Matsumoto S, Nishikawa M, Ozaki S,
Shigekawa S, Watanabe H, Matsuura B, Kitazawa R, Kunieda T. Clinical features and endoscopic findings of granular cell
tumor of the sellar region: A case report and review of the literature. Surg Neurol Int. 2020 May 9;11:101.

HISTO_PATHOLOGY
• It is comprised of densely packed sheets and spindles of polygonal granular
cells.
• Cytoplasmic granules stain positively with periodic-acid Schiff stain, which
tends to be diastase resistant.
• The cytoplasm is eosinophilic and granular.
• Perivascular lymphocytic infiltrates are commonly noted.
• Immunopositive for TTF-1and S-100 protein.
• Positive stain only occasionally for GFAP.
• MIB-1 (Ki-67) index of cellular proliferation is usually low (< 5%).

HISTO_PATHOLOGY
Histological features of the granular cell tumor were shown in a hematoxylin–eosin stain and revealed polygonal-shaped
cells with prominent eosinophilic granular cytoplasm, original magnification×100. The tumor cells were diffusely positive
for TTF-1 (immunohistochemistry – original magnification ×100) (d, e)
Rubino F, Martinez-Perez R, Vieira S, Voscoboinik DS, Mural M, Orr AJ, Hardesty DA, Carrau RL, Prevedello DM.
Granular cell tumors of the sellar region: what should be done after subtotal resection? A systematic review.
Pituitary. 2020 Dec;23(6):721-732.

Photomicrographs showing the histopathology of the tumor. Most tumor cells are immunoreactive
for S-100 protein (a), but immune-negative for glial fibrillary acidic protein (GFAP) (b). Magnification,
a, b ×400
Kusakawa A, Inoue A, Nakamura Y, Nishida N, Fukushima M, Senba H, Suehiro S, Matsumoto S,
Nishikawa M, Ozaki S, Shigekawa S, Watanabe H, Matsuura B, Kitazawa R, Kunieda T. Clinical
features and endoscopic findings of granular cell tumor of the sellar region: A case report and
review of the literature. Surg Neurol Int. 2020 May 9;11:101.

Photomicrographs showing the histopathology of the tumor. This tumor shows slightly positive
staining for Ki-67 (MIB-1) (MIB-1 labeling index: 2.0%) (c). In addition, almost all tumor cells are
strongly positive for TTF-1 (d). Magnification d ×400; c) ×100.
Kusakawa A, Inoue A, Nakamura Y, Nishida N, Fukushima M, Senba H, Suehiro S, Matsumoto S,
Nishikawa M, Ozaki S, Shigekawa S, Watanabe H, Matsuura B, Kitazawa R, Kunieda T. Clinical
features and endoscopic findings of granular cell tumor of the sellar region: A case report and
review of the literature. Surg Neurol Int. 2020 May 9;11:101.

DIFFERENTIAL DIAGNOSES
• Pituitary adenoma
• Craniopharyngioma
• Rathke’s cleft cyst
• Meningioma
• Glioma
• Germinoma
• Hamartoma

MANAGEMENT
• Treated with surgical resection with post-operative radiation therapy.
• Surgical approaches include frontal craniotomy, frontotemporal craniotomy,
pterional craniotomy, and transsphenoidal resection.

IN GENERAL…
• First described in 2002
• Mean 62 years, range 53 - 71 years
• Associated with panhypopituitarism and variable visual field defect
• Benign; no recurrence if totally excised
• May derive from adenohypophyseal folliculostellate cells
• Radiology description
• Suprasellar extension
• Resembles pituitary adenoma
• No dural involvement

HISTO_PATHOLOGY
• Fascicles of spindle cells with granular
and eosinophilic cytoplasm
• No / rare mitotic figures
• No necrosis
• Electron microscopy description
• Mitochodria rich in lamellar cristae
• Intermediate junctions and
desmosomes, rough endoplasmic
reticulum
• No secretory granules
• Positive stains
• Vimentin, EMA, S100, galectin3
• Negative stains
• Pituitary hormones, synaptophysin,
chromogranin, GFAP, CAM 5.2
• Smooth muscle actin, CD34, CD68

HISTO_PATHOLOGY
Photomicrographs of the primary tumor.
(A) Tumor is composed of spindle cells
arranged in intersecting fascicular
architecture.
(B) Intervening blood vessels can be seen.
(C) Individual tumor cells are plump and
lack fibrillary matrix.
(D) Occasional scattered pleomorphic cells
are noted. Original magnification.
A Sali et al. Spindle cell oncocytoma of adenohypophysis: Review of literature and report of
another recurrent case. Neuropathology 2017. doi:10.1111/neup.12393

HISTO_PATHOLOGY
MRI and photomicrographs of the
recurrent tumor. (A) MRI showing sellar
and suprasellar space-occupying lesion. (B-
D) Show recurrent tumor with similar
histomorphological features. Spindle cell
tumor composed of plump cells showing
intersecting fascicular architecture and
intervening thin blood vessels. Original
magnification (B) ×100, (C) ×200, (D) ×400.

HISTO_PATHOLOGY
Immunohistochemistry of the tumor.
The tumor was strongly positive for
(A) Epithelial membrane antigen
(B) Thyroid Transcription Factor-1
(C) Synaptophysin showing focal weak
positivity.
(D) MIB-1 labelling index was
approximately 6–8%.
Original magnification (A-D) ×200.

• Ectopic salivary gland rests undergoing oncocytic transformation
• Meningioma with oncocytic change:
• EMA+ but intrasellar extension is rare; also whorls, interdigitation of cell membrane,
• S100- (except in fibrous meningioma)
• Metastatic extracranial oncocytic tumor
• Pituitary adenoma with oncocytic change:
• Immuno positive  keratin, synpatophysin, neurosecretory granules; chromogranin
• Immuno negative  S100, vimentin, EMA

In GENERAL
• Neuroendocrine tumor of the anterior pituitary gland composed of
secretory cells with pituitary hormone production
• Main tumor types classified (based on pituitary cell lineage)include
• Somatotroph
• Lactotroph
• Thyrotroph
• Corticotroph
• Gonadotroph
• Null cell and
• Plurihormonal

PITUITARY CELL LINEAGE
Pituitary neuroendocrine
cells and their tumors.
Adenohypophysial
hormone-secreting cells
differentiate along three
lineages to form multiple
mature cell types. Each
mature cell type is
associated with at least one
tumor type, but several cell
types give rise to multiple
tumor variants. In addition,
there are tumors composed
of cells that lack terminal
differentiation; some of
these show lineage
differentiation but others,
most commonly those
classified as null cell
tumors, lack evidence of
any lineage specificity

ESSENTIAL FEATURES
• Routine assessment of histology includes determination of mitoses,
pleomorphism, giant cells, inclusions, inflammatory changes, stroma,
hemorrhage and vascular features
• Evaluation of tumor proliferation potential by mitotic count and Ki67
labeling index
• Evaluation of tumor invasion to identify clinically aggressive adenoma
• Routine stains including ACTH, prolactin, growth hormone, TSH, LH, FSH,
chromogranin, p53 and in some cases hormone receptor stains and
transcription factors
• Classification is based on a combination of histopathologic features,
hormone content as assessed by immunohistochemistry and routine use of
transcription factors (SF1, T-PIT, PIT1) IHC to determine adenoma lineage

EPIDEMIOLOGY
• 10 - 15% of intracranial neoplasms
• Mainly fourth to seventh decade; women have slightly greater incidence
• Highest incidence is between ages 65 - 74;
• Lowest incidence 15 - 24 years or before fourth decade
• Incidental adenoma seen in ~25% of autopsies
• Prevalence of 0.2% for incidental pituitary macroadenoma (> 1 cm) in living
patients
• Location
• Majority occur in sella turcica within the adenohypophysis / anterior pituitary lobe
• Rare examples occur in extrasellar region on pituitary stalk
• Rare prolactinomas as part of ovarian teratoma

DIAGNOSIS
• Classification requires immunohistochemical staining for main pituitary
hormones (GH, PRL, ACTH, beta TSH, beta LH, beta FSH and alpha subunit of
glycoproteins) and when required, pituitary transcription factors (PIT1, SF1,
T-PIT)
• Diagnosis of pituitary carcinoma is based on presence of cerebrospinal fluid
or systemic metastases
• There is no histologic distinction between typical pituitary adenoma and
carcinoma

PATHOPHYSIOLOGY
• Cell differentiation driven by transcription factors lead to 3 main cell
lineages:
• Acidophilic
• Gonadotrophic
• Gorticotrophic
• Transcription factors:
• PIT1 (pituitary specific POU class homeodomain transcription factor): differentiation
of somatotrophs, lactotrophs and thyrotrophs
• SF1 (steroidogenic factor 1): Gonadotroph cell differentiation
• T-PIT (T-box family member TBX19): proopiomelanocortin (POMC) lineage with
differentiation of corticotrophs

ETIOLOGY
• Multistep, multicausal process including initiation and progression phases
• Endocrine factors may induce cell proliferation: excess production of
hormones (e.g. growth hormone, corticotropin or gonadotropin)
• Inherited syndromes:
• MEN1 with involvement of 11q13 (OMIM: Multiple Endocrine Neoplasia, Type I;
MEN1)
• Carney complex with involvement of 17q and 2p16 (OMIM: Carney Complex, Type 1;
CNC1)
• Familial acromegaly with involvement of 11q13 and their loci (OMIM: Pituitary
Adenoma 1, Multiple Types; PITA1)
• McCune-Albright syndrome with involvement of 20q13.2 (OMIM: McCune-Albright
Syndrome; MAS)

CLINICAL FEATURES
• Most patients have clinical features of hormone excess (usually
microadenoma)
• Larger adenomas (macroadenoma defined > 1 cm) have mass effects, such
as headache and visual disturbance
• Hemorrhagic necrosis of large adenoma (pituitary apoplexy)  surgical
emergency

LABORATORY
• Serum prolactin level > 200 mcg/L  macroadenoma > 10 mm in size 
prolactinoma
• Oral glucose tolerance test is the definitive test for diagnosis of acromegaly
• Serum insulin-like growth factor 1 (IGF1) level is also a good test for acromegaly
• Serum levels of ACTH and high dose dexamethasone suppression testing are
useful
• Increased T3 and T4 levels, hyperthyroidism and goiter  TSH secreting adenoma
• Serum levels of FSH, LH and testosterone levels in men may indicate a pituitary /
hypothalamic disorder affecting the gonadotropin / testosterone axis
• CSF may be xanthochromic, with crenated RBCs and high protein levels in pituitary
apoplexy

IMAGING
• Method of classification based on tumor size and degree of invasion
• Important for planning of surgical resection
• Microadenomas  less than 1 cm in diameter
• Macroadenomas  larger than 1 cm
• Identification of tumor extension is important:
• Suprasellar
• Lateral (cavernous sinus)
• Inferior (sphenoid sinus)
• Posterior fossa

IMAGING (A) Contrast-enhanced coronal T-1
weighted MRI showed a sellar and
suprasellar tumor.
(B) Residual tumor 5 months after
gamma knife therapy.
(C) Sagittal image showed the apparent
shrinkage of tumor and the
decompressed of optic nerve 7
months after the initiation of
cabergoline.
(D) Regrowth of tumor mass 26 months
after cabergoline.
(E) Preoperative MRI demonstrated a
3.5cm×3.1cm×3.7cm tumor mass
compressing pituitary stalk and optic
chiasma.
(F) MRI indicated a residual tumor 5
months after operation.
(G) MRI indicated that the residual tumor
expanded again after second course
of gamma knife.
(H) Sellar tumor remarkable reduction
with cystic degeneration after 22
months of temozolomide treatment.
Chen C, Yin S, Zhang S, Wang M, Hu Y, Zhou P, Jiang S. Treatment of aggressive prolactinoma
with temozolomide: A case report and review of literature up to date. Medicine (Baltimore).
2017 Nov;96(47):e8733.

HISTO_PATHOLOGY
• Most adenomas show moderately abundant cytoplasm with a uniform nuclear morphology,
stippled chromatin and inconspicuous nucleoli
• Cells may be classified as acidophilic, basophilic or chromophobic based on tinctorial
differences
• Cytoplasmic appearance usually correlates with content of hormone containing secretory
cells (i.e. densely versus sparsely granulated)
• Crush artifact is common and is often present during intraoperative consultation
• Crooke hyaline change is characterized by large chromophobic or eosinophilic cells with a
glassy hyaline appearance (due to accumulation of keratin filaments)
• Seen in neoplastic and nonneoplastic corticotrophs
• If prominent, called Crooke hyaline adenoma; the WHO terminology is Crooke cell adenoma
• Null cell adenomas are composed of adenohypophysial cells that do not exhibit any cell type
specific differentiation, including pituitary transcription factors (Brain Pathol 2012;22:443)

HISTO_PATHOLOGY
Monomorphic cells in a sheet-like growth pattern without acinar architecture Prolactinoma with monomorphic cells

HISTO_PATHOLOGY
Densely granulated adenoma Growth hormone

HISTO_PATHOLOGY
Crooke cell adenoma Prolactin immunostain

HISTO_PATHOLOGY
• Positive stains
• All synaptophysin positive (less frequently
for chromogranin A)
• Routine hormone stains
• Prolactin
• ACTH
• GH
• TSH
• LH, FSH
• Alpha subunit
• Reticulin
• Identifying normal acinar architecture vs
distorted and fragmented staining pattern in
adenomas
• CAM5.2:
• Perinuclear pattern is a feature of densely
granulated somatotroph adenomas
• Paranuclear fibrous bodies are a
conspicuous feature of sparsely
granulated somatotroph adenomas
• Occasional fibrous bodies can be seen in
acidophil stem cell adenomas
• Diffuse and strong cytoplasmic staining
characteristic of corticotroph adenomas
• Ring-like positivity characteristic of Crooke
cell adenomas
• Ki67 often used proliferative indices
• Specific transcription factors:
SF1, PIT1 or T-PIT
Negative stains: GFAP; CK7; CK20 TTF1

Pituitary adenoma
• Cytology description
• Normal pituitary has mixed cell types on smear preparation; adenomas show
uniform morphology and cell type with uncommon cytologic atypia

Pituitary adenoma
• Molecular / cytogenetics description
• No specific molecular characteristics in
routine clinical diagnostic workup
• Most pituitary adenomas are sporadic
tumors; minority are part of hereditary
or familial syndromes
• Somatic mutations
in GNAS and USP8 genes have been
found in about 40% of sporadic
somatotroph adenomas and 30 - 60%
of sporadic corticotroph adenomas,
respectively
• Syndromes associated with pituitary
adenoma include:
• Multiple endocrine neoplasia (MEN)
syndromes MEN1 and MEN4,
• Carney complex,
• McCune-Albright syndrome,
• X linked acrogigantism (XLAG) associated
with GPR101 microduplication and
hereditary pheochromocytoma and
paraganglioma syndrome related to
succinate dehydrogenase (SDH) genes

• Ependymoma:
• Positive for GFAP, negative for synaptophysin
• Metastatic carcinoma:
• Greater degree of cytologic atypia, rarely produce hormones, clinical findings are essential,
usually either CK7 or CK20 will be positive
• Normal adenohypophysis:
• Normal acini by reticulin staining
• Pituitary blastoma:
• Early childhood tumor, small blastema-like cells, true rosettes, large glandular structures,
DICER1 mutation
• Pituitary nodular hyperplasia:
• Enlarged acini by reticulin staining

NEURO-ENDOCRINE TUMOR (NET)
A.K.A CARCINOMA
PITUITARY

In GENERAL…
• 0.2 to 0.5% of adenohypophyseal tumors
• Considered to derive from pituitary adenoma
• Defined as tumors that have metastasized, since cannot differentiate based
on histology (like other endocrine tumors)
• Usually secrete ACTH or prolactin
• "Silent" pituitary tumors rarely metastasize
• Highly aggressive, eventually causing death

IMAGING
• Magnetic resonance imaging of an aggressive
pituitary neuroendocrine tumor.
• Contrast enhanced T1-weighted MRI of sella of
a locally invasive macrotumor
• The tumor surrounds the pituitary gland,
which is seen as an ill-defined focus of
enhancement in the middle of the sella, and
fills both cavernous sinuses (both Knosp grade
4), with suprasellar extension through the
oculomotor triangle into the basal cistern just
above the right cavernous sinus, involvement
of the clivus, and invasion into the sphenoid
sinus.

HISTO_PATHOLOGY
Neuroendocrine features of pituitary neuroendocrine tumors. A The ultrastructure of this PitNET from a patient with acromegaly
illustrates the neuroendocrine features of adenohypophysial cells. The tumor cell cytoplasm contains rough endoplasmic reticulum (*)
for hormone synthesis, a prominent Golgi complex (G) where hormone is packaged into forming secretory granules, and numerous
membrane-bound secretory granules that store hormone for release into the extracellular space. B The tumor cells show cytoplasmic
chromogranin reactivity. C Nuclear INSM1 positivity is a feature of pituitary neuroendocrine tumors.

Pituitary carcinoma shows
hypercellularity and is
composed of atypical cells.
Mitotic activity (Ki67) is
present (a).
Tumor cells are positive for
prolactin (b).
Nuclear p53 immunoreactivity
is observed in some cells (c)
and the Ki67 proliferative
index is 5% (d)
Cossu G, Brouland JP, La Rosa S, Camponovo C, Viaroli E, Daniel RT, Messerer M. Comprehensive Evaluation of
Rare Pituitary Lesions: A Single Tertiary Care Pituitary Center Experience and Review of the Literature. Endocr
Pathol. 2019 Sep;30(3):219-236.

HISTO_PATHOLOGY
• May have nuclear pleomorphism with prominent nucleoli, mitotic activity
• Positive stains
• May have high Ki67 labeling index
• p53
• Differential diagnosis
• Pituitary adenoma

IN GENERAL…
• Non-neoplastic absolute increase in the number of 1 or more
adenohypophyseal cell subtypes seen radiologically as enlargement of the
pituitary gland
• Relatively common due to physiological and pathological conditions
• Remains unrecognized and occurs in heterogenous setting
• Essential features
• Nodular or diffuse hyperplasia of polymorphic acini with intact reticulin, without
effacement of gland architecture
• MRI essentially shows symmetrical and diffuse enlargement, similar intensity to gray
matter

EPIDEMIOLOGY
• Very rare, accounting for < 1% of sellar surgical specimens
• Autopsy prevalence 26%
• Higher incidence in primary hypothyroidism
• Prolactin (PRL) cell hyperplasia in pregnancy
• Age: youth and menopause
• Sites: Adenohypophysis

ETIOLOGY
• Physiologic response
• Most common: prolactin cell hyperplasia in pregnancy and lactation, peaks immediately postpartum
• Puberty: pituitary height peaks in the 20 - 29 year age group (F > M)
• Elderly: nonfunctional hyperplasia due to basophil cells
• Pars intermedia derived proopiomelanocortin (POMC) cells invasion into the neurohypophysis, women in the 50 -
59 year age group
• Iatrogenic:
• treatment with antipsychotics and excess estrogen in transgender women are associated with
increased secretion of prolactin
• Syndromic:
• Mammosomatotroph hyperplasia in McCune-Albright syndrome, Carney complex, MEN1 related
GHRH associated, X linked acrogigantism syndrome (XLAG)
• Idiopathic
• Hereditary

ETIOLOGY
• Pathologic hyperplasia
• End organ insufficiency
• Longstanding primary hypothyroidism causes TSH cell hyperplasia, young females
• Gonadotroph hyperplasia and sellar expansion in primary hypogonadism due
to Klinefelter or Turner syndrome
• Polycystic ovary syndrome: hyperprolactinemia and lactotroph hyperplasia
• ACTH cell hyperplasia due to hypocortisolism in Addison disease
• Rare: pituitary transcription factor gene, PROP1 mutations
• Ectopic excess of releasing hormones
• GH releasing hormone (GHRH) or corticotropin releasing hormone (CRH) ectopic release causing
somatotroph or corticotroph hyperplasia secreted by pancreatic islet cell tumor,
pheochromocytoma, bronchial and thymic carcinoid tumors
• ACTH cell hyperplasia due to corticotropin releasing hormone secretion from hypothalamic
hamartoma or neuroendocrine tumors

CLINICAL FEATURES
• Mass effect
• Visual disturbance, bitemporal hemianopia, diplopia
• Headaches
• Hormone related hyperplasia
• GH cell: gigantism or acromegaly
• Prolactin cell: hyperprolactinemia
• ACTH cell: Cushing disease
• TSH cell:
• Longstanding primary hypothyroidism results in TSH hyperplasia
• Hyperprolactinemia
• Elevated levels of TRH that stimulates both pituitary TSH and PRL cells due to lack of negative
feedback of thyroxin (T4) on the hypothalamus
• LH / FSH: result of early onset hypogonadism

DIAGNOSIS
• History and physical
• Increase or decrease corresponding serum hormone levels
• Imaging
• Biopsy / excision
• Rarely removed surgically
• Most likely identified at autopsy
• Laboratory  Hormonal levels as indicated

IMAGING
• Symmetric 2 - 3x enlargement of
pituitary gland on CT / MRI
• Homogeneously enhancing gland
with convex superior margin
• No sellar destruction
• Intensity similar to gray matter
• Homogenous gadolinium uptake
Sagittal (A and B) and coronal (C and D) magnetic resonance
images showing an enlarged pituitary gland with suprasellar
extension.
Moumen A et al. An unusual pituitary mass revealing a primary hypothyroidism! Clinics and Practice 2015;
volume 5:733

TREATMENT & PROGNOSTIC FACTORS
• Usually correct underlying endocrinologic disturbance
• Surgery rarely indicated
• Visual field defects
• Progression in size to establish diagnosis by pathology
• GH and ACTH hyperplasia
• Excellent with medical treatment
• Rarely associated with adenoma

HISTO_PATHOLOGY
• Gross description
• At autopsy or in the rare event the entire gland is removed, it is diffusely enlarged
and tan-white with no discernible nodules
• Lack of well defined lesion
• Specimen may be fragmented
• Cytology description
• Hypercellular smear with heterogeneous cell populations

HISTO_PATHOLOGY
• Diffuse or Nodular hyperplasia
• Unevenly enlarged acini
• Usually single cell type
• Relative cellular monomorphism
within affected acinus
• Noncompressive; indistinct
demarcation
• Difficult to diagnose in fragmented
specimen
• Numerical increase in pituitary
cells without alteration in
architecture
• Rare mitotic activity

HISTO_PATHOLOGY
• GH cell hyperplasia: chromophobe to pale eosinophilic polygonal cells
• PRL cell hyperplasia: chromophobe with rare microcalcifications
• ACTH cell hyperplasia: amphophilic with large vacuoles (lysosomes) and
Crooke cell change
• TSH cell hyperplasia: chromophobe, occasional spindle cells and multiple
large PAS+ lysosomes
• LH / FSH hyperplasia: hypervacuolization (castration cells)

HISTO_PATHOLOGY
• Positive stains
• Reticulin is essential for the diagnosis, highlights retention of acinar architecture and
may show some expanded acini
• Synaptophysin
• Cell type routine cytoplasmic stains prolactin, GH, TSH, LH, FSH, ACTH
• PAS highlights lysosomes in TSH hyperplasia
• Ki67 labeling may be mildly increased (normal gland is completely negative)
• Negative stains
• GFAP
• Neurofilament (2F11)

• Normal adenohypophysis:
• Normal size pituitary gland with heterogeneous cell populations within normal acini
• ACTH cells normally aggregate at the lateral wings of anterior pituitary
• Pituitary adenoma:
• Enlarged mass, well defined from normal pituitary gland
• Homogeneous cell populations with splayed and disrupted reticulin network
• Compresses adjacent normal acini
• Hyperplasia more likely to show strong cytoplasmic immunoreactivity to respective
hormones throughout the fragments when compared with adenoma

HISTO_PATHOLOGY
• Electron microscopy description 
Same as normal pituitary:
• GH producing somatotrophs:
• Rough endoplasmic reticulum
• Well formed Golgi complexes
• Numerous large, dense secretory
granules 100 - 250 nm
• GH & PRL producing
mammosomatotroph:
• Pleomorphic heterogenous granules
150 - 1,000 nm
• Misplaced exocytosis
• PRL producing lactotrophs:
• Elaborate rough endoplasmic reticulum
arranged in parallel arrays
• Concentric structures (occasional)
known as nebenkern formations.
• Prominent Golgi complexes
• Extrusion of secretory granules at the
lateral cell borders known as misplaced
exocytosis up to 700 nm

HISTO_PATHOLOGY
• TSH producing thyrotrophs:
• Short dilated rough endoplasmic
reticulum
• Small secretory granules that align
along the plasma membrane
• ACTH producing corticotrophs:
• Secretory granules
• are pleomorphic in shape
• electron density with indentations and
• evaginations of granule membranes,
resulting in heart and teardrop shapes.
• Small bundles of intermediate (keratin)
filaments throughout the cytoplasm

MOLECULAR / CYTOGENETICS DESCRIPTION
• No specific molecular / cytogenetics available
• Reported germline mutations in the aryl hydrocarbon receptor interacting
protein (AIP) gene in familiar cases
• Some syndromic association:
• Carney complex
• McCune-Albright syndrome
• X linked acrogigantism (XLAG)
• MEN1 related GHRH associated (Less likely)

IN GENERAL…
• Originally defined as a unique embryonal tumor of the pituitary gland by
Scheithauer et al.
• Rare triphasic pituitary tumor composed of a combination of 3 cell types
including
• Large secretory neuroendocrine cells of adenohypophysis
• Small immature folliculostellate cells, and
• Gland- or rosette-forming primitive Rathke’s cleft epithelial cells.
• The hallmark of DICER1 syndrome.

DICER1 SYNDROME
• An autosomal dominant condition arising from pathogenic variants in
DICER1 (14q32.13), which encodes the DICER1 protein, a ribonuclease
(RNase) III family of proteins.
• Endocrine disorders
• Features of nodular thyroid disease
• Predisposes to well-differentiated thyroid cancers
• Reaching 23% at 20 years
• 50–75% by 40 years
• Mainly in females.

HISTO_PATHOLOGY
S. L. Asa et al. (eds.), The Spectrum of Neuroendocrine Neoplasia, Springer Nature Switzerland
AG 2021. https://doi.org/10.1007/978-3-030-54391-4_18
On H&E stain (left), the lesion consists of small cells, and glandular structures surrounding aggregates of larger cells
with more abundant cytoplasm. The former resemble Rathke epithelium(right).

HISTO_PATHOLOGY
S. L. Asa et al. (eds.), The Spectrum of Neuroendocrine Neoplasia, Springer Nature Switzerland
AG 2021. https://doi.org/10.1007/978-3-030-54391-4_18
This unique tumor showed not only the architectural features of
blastoma but scant multifocal goblet cell transformation in
larger glands

REFERENCES
• Pathology Online
• Webpathology
• Brad DJ et al. Chapter 12: Tumors of the sellar region. In: WHO Classification 5Th Ed. CNS Tumor 2021.
• Larkin SJ, Ansorge O. Pathology and pathogenesis of craniopharyngiomas. Pituitary. 2013 Mar;16(1):9-17.
• Jeong TS, Yee GT, Kim NR. Malignant Transformation of Craniopharyngioma without Radiation Therapy: Case Report and Review of the Literature. J Korean
Neurosurg Soc. 2017 Jan 1;60(1):108-113. doi: 10.3340/jkns.2015.0707.022.
• Moumen A et al. An unusual pituitary mass revealing a primary hypothyroidism! Clinics and Practice 2015; volume 5:733
• Cossu G, Brouland JP, La Rosa S, Camponovo C, Viaroli E, Daniel RT, Messerer M. Comprehensive Evaluation of Rare Pituitary Lesions: A Single Tertiary Care Pituitary
Center Experience and Review of the Literature. Endocr Pathol. 2019 Sep;30(3):219-236.
• Asa SL and Mete O. Review Hypothalamic Endocrine Tumors: An Update. J. Clin. Med. 2019, 8, 1741; doi:10.3390/jcm8101741
• Pirayesh Islamian, A., Buslei, R., Saeger, W. et al. Pituicytoma: overview of treatment strategies and outcome. Pituitary 15, 227–236 (2012)
• Chen C, Yin S, Zhang S, Wang M, Hu Y, Zhou P, Jiang S. Treatment of aggressive prolactinoma with temozolomide: A case report and review of literature up to date.
Medicine (Baltimore). 2017 Nov;96(47):e8733.
• Ahmed AK, Dawood HY, Cote DJ, Bale TA, De Girolami U, Laws ER Jr, Smith TR. Surgical resection of granular cell tumor of the sellar region: three indications.
Pituitary. 2019 Dec;22(6):633-639.
• Rubino F, Martinez-Perez R, Vieira S, Voscoboinik DS, Mural M, Orr AJ, Hardesty DA, Carrau RL, Prevedello DM. Granular cell tumors of the sellar region: what should
be done after subtotal resection? A systematic review. Pituitary. 2020 Dec;23(6):721-732.
• Kusakawa A, Inoue A, Nakamura Y, Nishida N, Fukushima M, Senba H, Suehiro S, Matsumoto S, Nishikawa M, Ozaki S, Shigekawa S, Watanabe H, Matsuura B,
Kitazawa R, Kunieda T. Clinical features and endoscopic findings of granular cell tumor of the sellar region: A case report and review of the literature. Surg Neurol Int.
2020 May 9;11:101.
• A Sali et al. Spindle cell oncocytoma of adenohypophysis: Review of literature and report of another recurrent case. Neuropathology 2017. doi:10.1111/neup.12393
• S. L. Asa et al. (eds.), The Spectrum of Neuroendocrine Neoplasia, Springer Nature Switzerland AG 2021. https://doi.org/10.1007/978-3-030-54391-4_18

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