Transcript Unusual Pituitary Tumors

Outlaws in the Saddle: What the
Sheriff Needs to Know
Tumors and Cancer Related Disease of the Pituitary
Komal B. Shah, T. Linda Chi, Charles Kim, Ian
McCutcheon, Steven Waguespack
Goals
• Recognize unusual presentations of pituitary adenoma.
– Similar histologic appearance of pituitary adenoma, neuroendocrine
carcinoma and olfactory neuroblastoma
– Ectopic location
– Multiple endocrine neoplasia type 1
– Skull base invasion
• Identify extreme post-treatment changes on imaging.
– Very slow response to radiation treatment
– Inferior chiasmal displacement or tethering after surgery
• Be alert to metastatic pituitary carcinoma.
• Review the pituitary effects of cancers at other sites.
– Metastasis to the pituitary
– Ipilimumab induced hypophysitis
UNUSUAL PITUITARY ADENOMAS
Pituitary Adenoma as a
Neuroendocrine Tumor
o
*
A
B
C
D
41 year old man with a history of inflammatory sinus disease and sinus surgery 3 years
prior was undergoing evaluation for possible 2nd sinus surgery. Noncontrast CT of the
sinuses (A-C) was interpreted as mucosal thickening, possible nasal polyps (*) and
opacification of the sphenoid sinuses (o). Erosion of the floor of the sella (black arrow)
was present, in retrospect.
Biopsy during endoscopic sinus surgery was interpreted as olfactory neuroblastoma at
outside facility. This was further evaluated with MRI (D, coronal T1+Gd), revealing a
sellar and suprasellar mass (white arrow). Further history and imaging follows on the
next slide.
Pituitary Adenoma as a
Neuroendocrine Tumor, continued
*
Review of the outside tissue at our
institution was interpreted as
sinonasal neuroendocrine tumor.
Staging PET/CT (A) demonstrated
the hypermetabolic sphenoid sinus
and sellar mass (*).
The PET/CT and MRI (B) were
interpreted as neuroendocrine
carcinoma invading the sella. The
patient was to receive induction
chemotherapy. Because of the
suprasellar extension on MRI
(arrow), a second opinion on the
histology was requested. The
diagnosis was changed to pituitary
adenoma, and was confirmed on
transsphenoidal resection.
Pituitary
adenoma
H&E stained sections of pituitary adenoma,
neuroendocrine carcinoma and olfactory
neuroblastoma share similar features:
uniform round cells with round to ovoid
nucleoli that have finely stippled chromatin.
Mitoses, atypia and necrosis are uncommon.
Neuroendocrine
carcinoma
Olfactory
neuroblastoma
Courtesy of Michele Williams MD
Sagittal T1+Gd fat saturated
MRI of proven olfactory
neuroblastoma demonstrates a
sinonasal mass (arrow) crossing
the cribriform plate.
What the Sherriff Needs to Know
• Pituitary adenoma, neuroendocrine carcinoma and olfactory
neuroblastoma (ONB) all have a similar microscopic appearance.
• Location is key to differentiation.
• Serum prolactin, adrenocorticotropic hormone (ACTH), insulin-like
growth factor-1 (IGF-1), growth hormone (GH), follicle stimulating
hormone FSH), and luteinizing hormone (LH) levels can indicate
pituitary adenoma if elevated.
• Immunohistochemical studies for pituitary hormones and
cytokeratin are helpful. ONB should not stain positively for
cytokeratin.
Ectopic Adenoma
m
A
B
C
A 63 year old man was hospitalized for schizophrenia. Imaging was obtained to evaluate for organic
cause. (A) Sagittal T1+Gd shows a heterogeneously enhancing sphenoid sinus mass (m). (B) Axial T2
post contrast 1.8mm image obtained for surgical navigation shows a plane between the pituitary gland
and the sphenoid sinus mass (arrow). Transsphenoidal resection of the sphenoid sinus mass was
undertaken. The surgeon did not enter the dura of the sella. Operative histology showed nests of
pituitary adenoma in bone, respiratory mucosa and nasopharyngeal mucosa. (C) sagittal T1 post
contrast obtained 6 weeks after surgery shows the intact appearance of the pituitary gland.
Ectopic Adenoma
• The ectopic pituitary adenoma by definition must
not be in continuity with the normal pituitary
gland. There should be no defect in the dura of
the sellar floor at operation.
• 40% of ectopic adenomas are located in the
sphenoid sinus.
• An association with empty sella has been
described but is rare.
Invasive Adenoma: Use Fat Saturation
A
A
B
B
A 67 year old woman had a long history of pituitary adenoma
treated with transsphenoidal and transfacial resections, as well as
gamma knife and intensity modulated radiation treatment. She
had surveillance MRI. Noncontrast (A) and post contrast (B)
coronal T1 images of the sella showed residual adenoma in the
right cavernous sinus (black arrow). A subtle minimally enhancing
mass lesion in the right skull base (white arrows) was not
identified. It is best seen by comparison to normal fat signal in the
opposite skull base.
C
Images obtained 2 years later show growth
of the mass, outlined in blue on noncontrast T1 coronal (A) and seen also on
post contrast T1 coronal (B). Epidural mass
effect on the right temporal lobe is noted.
The axial T1 post-contrast image with fat
saturation (C) best demonstrates growth of
the right masticator space mass centered
on the pterygoid process.
Multiple Endocrine Neoplasia Type 1
*
*
A
B
C
41 year old man had a 10 year history of nephrolithiasis. A pancreatic mass was found on CT renal stone protocol.
Resection of the tail of pancreas mass revealed pancreatic neuroendocrine tumor. The patient’s wife learned of
the MEN-1 syndrome and requested brain MRI, showing a pituitary tumor. Further testing was positive for a
mutation in the MEN1 gene, as well as multifocal metastatic gastrinoma and duodenal neuroendocrine tumor.
A, nuclear medicine sestamibi scan shows a large sestamibi-avid nodule along the right tracheo-esophageal
groove (black arrow) consistent with parathyroid adenoma, likely cause of kidney stones. Smaller left sestamibiavid nodules (asterisks) were also suspected to be parathyroid adenoma. At operation, multi-glandular
hyperplasia was found. B, Abdominal axial CT with contrast shows the pancreatic tail neuroendocrine tumor
(white arrow). C, Sagittal T1+Gd fat saturated image shows the presumed pituitary adenoma (wide white arrow),
currently under surveillance.
Multiple Endocrine Neoplasia Type 1
•
Parathyroid: hyperparathyroidism in >=90%
•
Pancreas: pancreatic islet cell tumors in 60-70%
•
Pituitary: adenoma in 15-50%
•
Other associated tumors: gastrinoma, adrenal adenoma, carcinoid tumor, facial
angiofibromas
•
Over 1,000 mutations in the MEN1 gene, which codes for the menin protein, have
been identified.
•
Recommended screening for pituitary adenoma beginning at age 5 in case of
inherited MEN-1:
– Brain MRI every 3-5 years
– Serum levels of prolactin and/or IGF-1 every year
Slow Response of Pituitary Adenoma
to Radiation Treatment
3/2006
1/2007
9/2007
10/2008
• 49 year old woman had 2 prior resections of pituitary adenoma.
Stereotactic radiosurgery 15Gy was performed in 2/2006 for residual
adenoma in the left cavernous sinus (arrow). Response to SSRS evolved
over 2.5 years and then was stable.
• Slow response is expected as cell turnover is low (MIB-1 < 3%).
• Bromocriptine is a cytostatic agent and is discontinued prior to radiation
treatment, in order to encourage cells to respond.
Symptomatic Inferior Tethering of
Optic Chiasm as an Effect of Treatment
3/2007
7/2008
1/2009
37 year old man presented with headache, blurry vision and CSF rhinorrhea to outside facility. He had
transsphenoidal resection and craniotomy for resection of growth hormone positive pituitary adenoma.
He presented to our institution 3/2007 for treatment of residual adenoma and acromegaly 3/2007. In
7/2008, he had severe visual changes and CSF leak, treated surgically with untethering of the optic
chiasm. Surgery resulted in visual improvement which has been stable to the present.
Coronal MRI images of the sella. A, T1+Gd shows residual adenoma and inferior displacement of the
optic chiasm (arrow) and residual adenoma in the sella and skull base (blue line). B, T1+Gd at time of
severe visual changes shows further inferior tethering of the chiasm. C, Noncontrast T1 obtained 6
months after surgical untethering of the chiasm shows relief of the inferior traction on the chiasm.
PITUITARY CARCINOMA
Pituitary Carcinoma
• Carcinoma may occur in only 0.1-0.2% of all pituitary tumors (Pernicone
1997). Most are biochemically active.
• Histology of invasive adenoma and carcinoma is the same. Metastases
make the diagnosis of pituitary carcinoma.
• Adenoma must be invasive to become carcinoma but invasion on histology
is extremely nonspecific for carcinoma.
• Studies have been performed to find a distinguishing factor between
invasive adenoma and carcinoma in the sellar phase. (Hansen 2014)
–
–
–
–
Cytologic atypia and mitotic activity
MIB-1 and Ki-67, p27, galectin-3
P53 immunoreactivity
MGMT and MMP-9
Importance of MIB-1 and p53
• MIB-1 is a monoclonal antibody
of Ki-67, a cellular marker of
proliferation. The MIB-1
percentage is the percent of cells
that were undergoing active
phases of the cell cycle.
• P53 gene is a regulator of cell
cycle and a tumor suppressor
gene.
• WHO 2004 definition of atypical
pituitary adenoma
–
–
–
–
MIB-1 > 3%
Significant p53 immunoreactivity
Increased mitotic activity
Invasion not a criterion
•
Studies from Thapar in 1996 evaluated 37
noninvasive adenomas, 33 invasive
adenomas and 7 pituitary carcinomas .
– MIB-1 labeling
• Mean 12% in carcinomas
• Mean 4.5% invasive adenomas
• Mean 1% non-invasive adenomas
– Extensive p53 immunoreactivity
• 100% of carcinomas
• 15% of invasive adenomas
• 0% of non-invasive adenomas
Pituitary Carcinoma: Sites of
Metastasis
• Direct parenchymal spread
• CSF dissemination
– Brain
– Spinal cord
• Hematogenous spread (may be more common with ACTH
secretors)
– Liver
– Bone
– Lung
Pituitary Carcinoma Case 1
f
A
f
B
C
A 37 year old man presented with Cushing’s disease and had partial transsphenoidal
resection of a pituitary adenoma. Histology showed adrenocorticotrophic hormone
(ACTH) staining pituitary adenoma with rare MIB-1 labeling and no p53
immunoreactivity.
A, T1+Gd sagittal image demonstrates the residual suprasellar component of
pituitary adenoma, and fat packing (f) within the sphenoid sinus. B and C, coronal
T1+Gd fat saturated images show residual cavernous sinus (black arrow) and
suprasellar (white arrow) adenoma.
Pituitary Carcinoma Case 1 continued
Four years later, the patient developed abdominal pain.
T1+Gd fat saturated axial image in (A) showed a nonenhancing lesion in the right lobe of the liver (arrow)
that was biopsy proven metastasis. The pathology
report indicated metastatic neuroendocrine carcinoma
with MIB-1 10%.
A
m
*
B
C
Two years after the liver metastasis, axial
T1+gd fat saturated axial images in B and
C showed development of right orbital
metastasis (m) with superior orbital
fissure (*) and pterygopalatine fossa
(arrow) involvement. Orbital
exenteration was followed by radiation
treatment. Bilateral aderenalectomy
was performed subsequently, for
uncontrollable Cushing’s disease related
to metastatic tumor burden. He has
been treated with chemoablation of liver
metastases, as well as systemic
temozolomide and capecitabine.
Intradural Pituitary Carcinoma, Case 2
A 46 year old man with recurrent progressive
nonfunctional pituitary adenoma was treated
with multiple surgeries and radiation
treatments after which he developed difficulty
walking.
A
C
T1+Gd axial and sagittal images (A) and (B)
showed small dural based nodules along the
right tentorium and down the clivus. An
intradural extramedullary enhancing nodule at
C2 level was also noted. Biopsy of a dural
based nodule showed pituitary carcinoma.
Despite treatment with radiation and
temozolomide, MRI 14 months later (C and D)
showed progressive metastasis.
B
D
*
(C) Axial T1+Gd shows progression of dural
based nodules and new leptomeningeal
disease of the basal cisterns. (D) Sagittal fat
saturated T1+Gd shows progressive
leptomeningeal disease extending to thoracic
levels and below (*).
PITUITARY EFFECTS OF CANCER AT
OTHER SITES
Pituitary Mass as Presenting Sign of
Lung Cancer
A
B
35 year old man with headache, increased thirst and increased urination presented to
the EC. Noncontrast axial CT scan in (A) showed a suprasellar mass (arrow). Sagittal fat
saturated T1+Gd in (B) showed a sellar and suprasellar mass, presumed to represent
pituitary adenoma. Partial transsphenoidal resection revealed lung adenocarcinoma.
Diabetes insipidus (suggested by increased thirst and urination in this patient) is
not generally associated with pituitary adenoma.
Pituitary Mass as Presenting Sign of
Lung Cancer, continued
A
B
C
Axial CT chest in (A) showed a spiculated, cavitary mass in the peripheral left lower
lobe. Two months later, progressive visual changes lead to repeat MRI showing rapid
growth of the sellar and suprasellar metastasis.
Suprasellar Germinoma
e
A
B
C
A 21 year old man presented to the ophthalmologist with recent vision loss,
headaches, nausea and vomiting. Coronal T2 (A), coronal T1 + contrast with
fat saturation (B) and sagittal T1 + contrast with fat saturation (C) showed an
enhancing and cystic sellar and suprasellar mass adherent to the
hypothalamus with hypothalamic edema (e). Subarachnoid or subependymal
nodularity was seen in the lateral, 3rd and 4th ventricles (arrows). Suprasellar
biopsy revealed a germinoma.
Differential Diagnosis: Sellar Mass with
Subarachnoid Lesions
• Lymphoma
• Leptomeningeal carcinomatosis
• Suprasellar Germinoma
• Langerhans cell histiocytosis
• Erdheim Chester disease
• Sarcoidosis
Ipilimumab Induced Hypophysitis
A
B
C
D
A 60 year old woman had melanoma metastatic to liver, lung and brain. Sagittal (A)
and coronal (B) T1+Gd images showed normal pituitary gland at the start of
ipilimumab treatment. (C) and (D) showed diffuse enlargement of the gland 3
months after initiation of ipilimumab. Clinically, the patient had developed
hypopituitarism in keeping with ipilimumab induced hypophysitis.
Ipilimumab-Induced Hypophysitis
• Ipilimumab is an antibody to CTLA-4, a protein receptor on
the surface of T-cells that down-regulates the immune
system.
• It is one agent within the class of immune checkpoint
blockade inhibitors.
• Anti CTLA-4 cross reacts with pituitary tissue, causing
hypophysitis, which manifests clinically as hypopituitarism.
• If ipilimumab is effective against the disease, typically
melanoma or prostate carcinoma, hypophysitis is treated
with steroids rather than withdrawal of the drug.
Take-Home Points
•
Use fat saturation for invasive adenomas.
•
Pituitary adenoma, sinonasal neuroendocrine carcinoma and olfactory
neuroblastoma have similar histologic appearance and share neighboring real
estate. Radiologists can help to avoid mistaken identity.
•
Pituitary adenoma responds very slowly to radiation.
•
Pituitary carcinoma is diagnosed by metastasis. In the sellar phase, MIB-1% and
p53 immunoreactivity may be obtained to identify adenomas that require
heightened surveillance.
•
Diabetes insipidus is not usually associated with pituitary adenoma; consider an
alternate diagnosis.
•
Ipilimumab treatment can cause hypophysitis; hypophysitis can be treated with
steroids rather than withdrawing a cancer-fighting agent.
Selected References
•
•
•
•
•
•
Ajler, P., Bendersky, D., Hem, S., & Campero, A. (2012). Ectopic prolactinoma within the sphenoidal
sinus associated with empty sella. Surg Neurol Int, 3, 47. doi: 10.4103/2152-7806.96066
Hansen, T. M., Batra, S., Lim, M., Gallia, G. L., Burger, P. C., Salvatori, R., … Redmond, K. J. (2014).
Invasive adenoma and pituitary carcinoma: a SEER database analysis. Neurosurg Rev, 37(2), 279285; discussion 285-276. doi: 10.1007/s10143-014-0525-y
Pernicone, P. J., Scheithauer, B. W., Sebo, T. J., Kovacs, K. T., Horvath, E., Young, W. F., Jr., . . .
Schoene, W. C. (1997). Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer, 79(4),
804-812.
Thapar, K., Kovacs, K., Scheithauer, B. W., Stefaneanu, L., Horvath, E., Pernicone, P. J., . . . Laws, E. R.,
Jr. (1996). Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an
analysis using the MIB-1 antibody. Neurosurgery, 38(1), 99-106; discussion 106-107.
Thapar, K., Scheithauer, B. W., Kovacs, K., Pernicone, P. J., & Laws, E. R., Jr. (1996). p53 expression in
pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions.
Neurosurgery, 38(4), 765-770; discussion 770-761.
Trouillas, J., Roy, P., Sturm, N., Dantony, E., Cortet-Rudelli, C., Viennet, G., . . . Tabarin, A. (2013). A
new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control
study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol, 126(1), 123-135.
doi: 10.1007/s00401-013-1084-y