ESSENTIAL NEUROSURGERY FOR MEDICAL STUDENTS
J. Bradley Elder, MD∗
Jonathan H. Sherman, MD‡
Daniel M. Prevedello, MD∗
Nicholas J. Szerlip, MD§
Daniel E. Spratt, MD¶
Ammar Shaikhouni, MD, PhD∗
Ahmed Mohyeldin, MD, PhD∗
Roberto J. Perez-Roman, MD||
Simon S. Buttrick, MD||
Sheikh C. Ali, BS#
Ricardo J. Komotar, MD||
Alexandre Todeschini, MD∗
Mostafa Shahein, MD∗
Juan Manuel Revuelta, MD∗
Douglas Hardesty, MD∗
Ricardo L. Carrau, MD∗∗
Gabriel Zada, MD‡‡
Steven Giannotta, MD‡‡
David Dornbos III, MD∗
Russell R. Lonser, MD∗
∗
Department of Neurological Surgery,
The Ohio State University, Wexner Medi-
cal Center, Columbus, Ohio; ‡ Department
of Neurosurgery, The George Washington
University, Washington, District of Colum-
bia; § Department of Neurosurgery, Uni-
versity of Michigan, Ann Arbor, Michigan;
¶
Department of Radiation Onco-
logy, University of Michigan, Ann Arbor;
||
Department of Neurological Surgery,
University of Miami Miller School
of Medicine, Miami, Florida; # Nova
Southeastern University College of Oste-
opathic Medicine, Fort Lauderdale,
Florida; ∗∗ Department of Otolaryn-
gology-Head and Neck Surgery, The
Ohio State University, Wexner Medical
Center, Columbus, Ohio; ‡‡ Department
of Neurological Surgery, Keck School
of Medicine, University of Southern
California, Los Angeles, California
Given constraints of this publication
modality (ie, a book rather than journal
articles), the citations and bibliography
are not to the level of detail of a journal
article. Readers are directed to the
suggested reading lists, which contain
references to subsequent references and
derivatives of the article content.
Correspondence:
J. Bradley Elder, MD,
410 W, 10th Ave,
Doan Hall, N1052,
Columbus, OH 43210
Email: Brad.elder@osumc.edu
Received, February 2, 2019.
Accepted, February 5, 2019.
Published Online, May 17, 2019.
Copyright 
C 2019 by the
Congress of Neurological Surgeons
Tumor
T
umors involving the central nervous
system (CNS) include a wide variety
of primary and metastatic entities. This
chapter provides a neurosurgical perspective
regarding some of the most common brain and
spine tumors. Each subsection presents a specific
tumor in the setting of a case presentation. The
goal for each subsection is to review diagnostic
and management pearls for the specific type of
tumor presented and provide the reader with a
starting point for more in depth reading.
The first chapter presents a patient with
a glioblastoma, which is the most common
primary malignant brain tumor. Glioblastoma
is the most malignant type of glioma, and
despite aggressive management including
surgery, radiation and chemotherapy have
a poor prognosis. Clinical trials are often
important components of treatment for patients
with gliomas in general, and glioblastoma in
particular.
Tumors involving the skull base occur outside
of the brain parenchyma and may involve
the leptomeninges or cranial nerves. Subsec-
tions devoted to skull base tumors include
those for meningioma, vestibular schwannoma,
pituitary adenoma, and Cushing’s disease. Of
ABBREVIATIONS: AED, anti-epileptic drug; ACTH,
adrenocorticotrophic hormone; CBTRUS, Cancer
Brain Tumor Registry of the United States; CNS,
central nervous system; CP, cerebellopontine;
CPA, cerebellopontine angle; CRH, corticotropin-
releasing hormone; CS, cavernous sinus; CSF,
cerebrospinal fluid; CT, computed tomography;
DWI, diffusion weighted imaging; EEA, endoscopic
endonasal approach; FSH, follicle-stimulating
hormone; GH, growth hormone; GBM, glioblastoma
multiforme; FLAIR, fluid-attenuated inversion
recovery; IDH, isocitrate dehydrogenase; IPSS,
inferior petrosal sinus sampling; KPS, Karnofsky
Performance Scale; LH, luteinizing hormone;
MGMT, O6-methylguanine DNA methyltransferase;
MRI, magnetic resonance imaging; NF, neurofibro-
matosis; OGTT, oral glucose tolerance testing; PET,
positron emission tomography; PRL, prolactin; RPA,
recursive partitioning analysis; SRS, stereotactic
radiosurgery; TSH, thyroid-stimulating hormone;
WBRT, whole brain radiation therapy; WHO, World
Health Organization
note, meningioma and schwannoma can occur
throughout the CNS including the spine.
Schwannomas can also occur in the peripheral
nerves. Essentially, any site with leptomeninges
can harbor a meningioma, and schwannomas can
arise in cranial nerves, spinal nerve roots, and
peripheral nerves.
Vestibular schwannoma, also sometimes called
acoustic neuroma, is the most common type of
intracranial schwannoma, and arises from the
vestibular portion of cranial nerve VIII. Cranial
nerves V and VII are less common nerves of
origin for schwannomas. Patients with neurofi-
bromatosis type 2 (NF-2) typically have bilateral
vestibular schwannomas, among other findings.
Surgical options require careful selection of the
approach based on the status of the patient’s
hearing and size of the tumor.
Meningiomas are among the most common
primary intracranial neoplasms. The vast
majority are benign (grade 1), although atypical
(15%) and malignant (1%) meningiomas do
occur. Benign tumors can grow very slowly and
reach a large size prior to patients developing
neurological symptoms. Management of these
tumors varies based on size, anatomic location,
and presenting symptoms. Tumors that are large
or causing neurological symptoms may require
surgical intervention. Because these tumors
can occur anywhere in the leptomeninges,
the complexity of surgical approach can vary
significantly. Radiation is an option for tumors
that cannot be completely removed. For smaller
or asymptomatic tumors, especially in older
patients, conservative management with serial
imaging is also an option.
Pituitary adenomas are benign tumors of
the pituitary gland with a unique management
algorithm due to their potential to secrete stimu-
lating hormones such as adrenocorticotrophic
hormone (ACTH), growth hormone (GH), and
prolactin (PRL). Classic presenting symptoms
may reflect this aberrant endocrine activity or
manifest as visual symptoms such as bitem-
poral hemianopsia due to direct compression
of the overlying optic chiasm. Endocrinologists
and ophthalmologists are involved in diagnosis
and management, which may include surgical
intervention for large, nonsecreting adenomas
ELDER ET AL
or medical management for prolactinomas. Some subtypes of
pituitary adenoma have high potential for long-term medical
morbidity due to their endocrine activity. One example is
Cushing’s disease, which is caused by an ACTH-releasing
pituitary adenoma. Aggressive surgical management, even for
tumors not visible on magnetic resonance imaging (MRI), is
important for preventing long-term endocrine morbidity in these
patients.
Metastatic tumors due to cancer such as melanoma, lung
cancer, and breast cancer can involve any part of the CNS.
As systemic treatments for cancer improve and patients live
longer, there may be an increase in the incidence of cancer
spreading to the brain and spine. Presenting symptoms are
typically reflective of the anatomic site of involvement. Sections
regarding brain metastasis and vertebral column metastasis discuss
the management of 2 of the most common CNS manifestations
of systemic cancer.
The 7 sections within the tumor section of this handbook
provide a primer for the diagnosis and management of some of the
most common neurosurgical oncology entities. However, there
are many other types of primary brain and spine tumors, each with
unique nuances in diagnostic workup and surgical management.
Careful attention to a patient’s history and neurological exami-
nation, as illustrated in the cases presented here, and an under-
standing of published evidence supporting various diagnostic and
management strategies are key first steps in providing optimal
treatment for these patients.
CHAPTER 1: GLIOBLASTOMA MULTIFORME
Case Presentation
A 58-yr-old male with past medical history that includes
type II diabetes mellitus and hyperlipidemia presents with
progressive headaches over the past few weeks. Symptoms started
with tussive headaches and progressed until he was having
frequent, daily global headaches. He also complains of disequi-
librium. He says when he reaches for things, especially with the
left hand, he will sometimes miss the target. He smokes about
a pack a day. He does not have a cancer history. He takes a
baby aspirin daily. He denies weakness, numbness, or tingling.
He denies blurry vision or visual issues. A brain MRI study with
and without contrast revealed a heterogeneously enhancing mass
in the right temporal lobe (Figure 1). Patient vitals: Temp-99.8 |
Pulse-88 | Resp Rate-18 | BP-142/68 | WBC-9.6 | HgB-15.4.
Questions
1. The presentation and MRI findings are most consistent with
which clinical presentation?
a. Brain abscess
b. Stroke
c. Low grade brain tumor
d. Parkinson’s disease
e. High-grade brain tumor
2. Which MRI sequence is most able to help distinguish between
a primary brain tumor from a cerebral abscess?
a. T1 with contrast
b. T1 without contrast
c. T2 sequence
d. Diffusion weighted imaging (DWI)
e. Fluid-attenuated inversion recovery (FLAIR)
3. Which craniotomy is most suitable for resection of the
following lesion?
a. Right pterional craniotomy
b. Right temporal craniotomy
c. Right frontal craniotomy
d. Interhemispheric craniotomy
4. The current first line treatment paradigm for glioblastoma
multiforme (GBM) is?
a. Radiation treatment only
b. Radiation treatment and gross total resection
c. Chemotherapy and gross total resection
d. Gross total resection only
e. Gross total resection, radiation, and chemotherapy
Epidemiology
Primary malignant brain tumors remain a daunting challenge
in medicine, with grade 4 astrocytoma (also known as grade 4
glioma or GBM) being the most common and aggressive of these
cancers. GBM epitomizes a class of brain tumors called gliomas
that represent a broad diagnostic category with diffuse malignant
cells known for their ability to infiltrate surrounding brain
parenchyma. Based on population-based incidence data from the
Cancer Brain Tumor Registry of the United States (CBTRUS),
gliomas account for 30% of all primary brain and CNS tumors
based on histology and 80% of all primary malignant tumors of
the CNS. Astrocytomas and glioblastomas account for 76% of all
gliomas. The incidence of GBM is ∼3/100 000 people per year
with a mean age of 64 yr and a peak incidence between the ages
of 65 and 74 yr with a male-to-female ratio of 1.5:1.
Imaging Characteristics
The appearance of GBM on MRI reflects major microen-
vironmental changes that characteristically develop in GBM
tumors. These include multiple areas of necrosis as well as tissue
edema and leaky tumor vessels, which result in strong peripheral
gadolinium contrast enhancement on MRI, often associated with
a nonenhancing central necrotic area. All of these factors combine
to create unique microenvironmental features in GBMs that
contrast sharply with normal brain tissue on histopathological
analysis. While head computed tomography (CT) may be an
initial screening study to identify brain masses, brain MRI with
and without gadolinium is the preferred study of choice for brain
tumors. GBMs and high-grade gliomas can readily be distin-
guished from low-grade gliomas because of their predilection
to have heterogeneous enhancement on MRI as well as signif-
icant surrounding edema. GBMs are rapidly growing tumors
 TUMOR

FIGURE 1. MRI of the brain showing different views of a right temporal glioblastoma. T1-weighted postcontrast coronal, axial, and sagittal images (left to
right) reveal a heterogeneously enhancing lesion with mass effect and edema consistent with glioblastoma. Far right is a diffusion-weighted MRI which shows
no significant restriction of diffusion, which helps to rule out abscess as the underlying lesion.

FIGURE 2. Axial MRI scans showing paired T1-weighted postcontrast and DWI sequences of 2 patients with deep brain lesions. Note the ring-enhancing
lesion seen in the patient with a GBM on the far left and the ring-enhancing lesion of the patient with the cerebral abscess on the middle right. DWI may
help distinguish GBM on the middle left from cerebral brain abscesses far right because the latter tends to strongly diffusion restrict on DWI as can be seen
in this case example. The purulent necrotic center of the abscess strongly diffusion restricts and a component of this purulence has already breached in the
ventricular system and is layered in the left occipital horn.

and usually exhibit mass effect, edema, hemorrhage, necrosis,
and secondary evidence of increased intracranial pressure. DWI
may help distinguish GBM from cerebral brain abscesses because
the latter tends to strongly restrict on DWI (Figure 2). FLAIR
sequences can determine the extent of edema surrounding a
tumor.
Functional MRI may play a critical role in the workup of
GBM patients because it can readily identify areas of eloquent or
functionally important cortex and their relationship to the tumor
(Figure 3). This can guide resection and is important for preop-
erative planning. In the case depicted in Figure 3, the patient
presented with a large left temporal lobe GBM. Functional MRI
ELDER ET AL
FIGURE 3. Functional MRI scans identifying white matter tract mapping (left panel), speech mapping (middle panel) and
bilateral hand grasp (right panel).
localized Wernicke’s area (receptive speech) immediately adjacent
to the tumor in the posterior banks of the left superior temporal
gyrus. This patient underwent an awake craniotomy with speech
mapping to help maximize tumor resection while minimizing
risks of permanent aphasia. During awake surgery, the patient is
asked to perform a variety of neurological tasks related to speech
while the surgeon stimulates the brain with an electrical probe.
Any critical speech areas identified are not removed, even if the
tumor infiltrates these areas.
Genetic Abnormalities and Natural History
Most GBMs appear to be sporadic in origin with no mecha-
nistic link to environmental or behavioral factors such as
smoking or electromagnetic fields. GBMs either arise de novo
(primary GBM) or progress from lower-grade astrocytomas
(secondary GBM) through multiple genetic alterations. Amplifi-
cations of epidermal- and platelet-derived growth factor signaling
pathways, p53 mutations, retinoblastoma pathway alterations,
and chromosome 10 alterations, including PTEN (phosphatidyli-
nositol 3-phosphatase) mutations, are among the most common
molecular alterations associated with progression of astrocytomas
to GBMs. Alterations in several intracellular signaling pathways
leading to the loss of senescence and cell cycle checkpoints
contribute to pleomorphism and karyotypic heterogeneity in
GBM cells.
O6 -methylguanine DNA methyltransferase (MGMT) gene
methylation status and isocitrate dehydrogenase (IDH) mutations
have been 2 recent genetic discoveries that have had prognostic
clinical implications in GBM patients. The MGMT gene codes
for a DNA repair enzyme that repairs damaged DNA. Patients
with hypermethylated MGMT status have reduced DNA repair
capacity and have improved survival responses to treatment
with alkylating chemotherapeutics such as temozolimide. Alter-
natively, IDH mutations have been found predominantly in
secondary GBM and in the vast majority of low-grade gliomas.
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IDH mutations are associated with improved survival in patients
with gliomas via a mechanism the remains largely unknown at
this time.
Clinical Presentation
GBMs either arise de novo or progress from lower grade astro-
cytomas through multiple genetic alterations as mentioned above.
Patients with secondary GBM will often have a clinical course
that starts in their 20 to 30 s, with an initial low-grade glioma
(grade 2) that progresses with time into a high-grade glioma
(grade 3 or 4). Primary GBM patients will usually present later in
life between the fifth and seventh decade and lack a history of a
previously identified lesion. Their symptoms usually develop over
a short period of time and they present with a sizeable enhancing
mass on MRI. Because of their rapid proliferative rate, GBMs
often outstrip their vascular supply and develop numerous foci
of necrosis and hypoxic gradients that stimulate angiogenesis.
Unfortunately, newly recruited blood vessels to the tumor are
often faulty, with multiple shunts and a leaky blood brain barrier
that often leads to focal edema and mass effect on surrounding
brain. Patients will commonly present with elevated intracranial
pressure, which manifests with global headaches that are exacer-
bated by coughing or lying down. Patients will often develop
other symptoms including nausea and emesis, blurred vision,
papilledema and possibly even cranial nerve palsies with motor
and sensory deficits. If the mass effect on the brain is large enough
and there is profound midline shift, mental status and arousal
can be compromised. Alternatively, as tumors infiltrate eloquent
structures in the brain, both vision and speech can be affected on
initial presentation.
Extent of Resection
The percentage of tumor that is removed surgically (extent
of resection) has been shown to impact overall survival in that
increasing the amount of tumor removed improves survival.

Gliomas are notoriously invasive and readily infiltrate normal
brain making complete surgical resection essentially impossible.
So devastating is the prognosis of this disease that despite
aggressive surgical resection followed with optimized radiation
and chemotherapy treatment, the median survival for a GBM
patient today remains at around 15 mo. To put the dismal
prognosis of this cancer more into perspective, a majority of
patients succumb to their disease within 2 yr and nearly all that
survive die by 5 yr, making GBM an inevitably fatal cancer. Extent
of resection for GBM appears to correlate with overall survival
and patient outcomes but is largely based on retrospective case
series with inherent study biases and confounders. Randomized
controlled trials directly testing this concept are lacking due to
lack of clinical equipoise to execute them. The aggressive biology
of this neoplasm, as evidenced by clinical survival metrics and
basic science data, has led some experts to insightfully point out
that “significant improvements in survival will not result from
more extensive surgery” (Stummer et al, Neurosurgery, 2008).
Although advances in imaging, surgical technique, drug delivery
and molecular stratification of these cancers have demonstrated
modest improvements in our management in the past 3 decades,
significant breakthroughs in treatment are still lacking and will
come from better insight into the disease process and more
rational molecular targeting.
Surgical and Medical Management
Patients who acutely present with large enhancing lesions,
surrounding brain edema and mass effect are often symptomatic
and will require hospitalization and palliation with steroids in
addition to an oncological work up to determine if the lesion is
a primary or metastatic brain tumor. Dexamethasone is typically
used to treat the edema initially and often leads to improvements
in the presenting neurological symptoms. If patients present with
seizures, antiepileptic drugs (AEDs) are administered. At this
point, surgical decisions are made. The goal of surgery is maximal
resection with minimal neurological morbidity. Patients with
deep-seated tumors or tumors involving eloquent structures may
not be candidates for aggressive surgery or instead undergo biopsy
to achieve diagnosis and provide tissue for molecular testing.
Patients with surgically accessible tumors undergo maximal
safe resection. Once surgical resection is complete, patients can be
weaned off their steroids or reduced to a basal rate based on the
extent of their residual disease, degree of edema and preference
of the neuro-oncologist and radiation oncologist. The mainstay
treatment protocol after surgery is based on a randomized control
trial that was shown to improve 2-yr survival rates and now has
conventionally been called the Stupp Protocol:
r Radiotherapy
- Total 60 Gy
- 2 Gy per daily fraction (Monday to Friday) over 6 wk
r Temozolomide
- During radiotherapy: 75 mg per square meter of body-
surface area per day, 7 d per week
TUMOR
VIDEO 1. Operative setup and surgery for resection of the right temporal
glioblastoma shown in Figure 1.
- Postradiotherapy (adjuvant): 6 cycles consisting of 150 to
200 mg per square meter for 5 d during each 28-d cycle
The goals of surgery for any GBM patient is (1) obtain
tissue for a histopathological diagnosis (2) decompress the brain
from the mass effect, and (3) cytoreduction of the tumor
burden. Gross total resection is often the goal with the intent
to minimize postoperative functional deficits. The use of preop-
erative navigation systems has helped guide surgical resection
and makes preoperative craniotomy planning more efficient
and safe by avoiding critical neural and vascular structures.
Video 1 demonstrates a typical operative room set up and patient
positioning for the case presented here. Patients are positioned to
optimize the approach to the tumor, and stereotactic navigation
systems are oriented to register patient’s facial landmarks preop-
eratively with anesthesia and surgical tables oriented for efficient
and functional workflow. Once the patient’s facial landmarks are
registered, the tumor can be topographically projected on the
surface of the scalp and an appropriate incision can be mapped
out.
Patient positioning and incision planning is critical and is often
the key to a good approach. Navigation systems that rely on
preoperative high resolution MRI allow for excellent incision and
craniotomy planning, however once resection of the tumor begins
and brain fluid shifts result from dissection, navigations systems
cannot be confidently relied on intraoperatively for accuracy.
Intraoperative MRI and intraoperative ultrasound are important
tools in the surgeon’s armamentarium that allow for live imaging
feedback of the brain as it responds to dynamics shifts. Both intra-
operative imaging modalities allow for immediate assessment of
residual tumor and can help maximize extent of resection. The use
of intraoperative microscopes can dramatically improve visual-
ization of tumor brain interfaces and allows for 2 surgeons to
visually see the field and participate in surgery (Figure 4).
ELDER ET AL

has helped surgeons define infiltrating margins of the tumor to

maximize extent of resection, although further clinical trials are
needed to validate these agents.

Pearls
√
GBM is the most common primary malignant primary brain
√ tumor and carries a poor prognosis.
The differential for peripherally enhancing lesions is broad and
√ MRI can help distinguish GBM from other pathologies
The current first line treatment paradigm for GBM is maximal
√ safe resection, followed by radiation and chemotherapy
The goals of surgery for any GBM patient is (1) obtain tissue
for a histopathological diagnosis and genetic/molecular studies
(2) decompress the brain from the mass effect, and (3) cytore-
duction of the tumor burden.

SUGGESTED READING
FIGURE 4. Intraoperative setup and patient positioning for a brain tumor
resection. The patient is in the supine position with his head turned to the left,
optimizing access to the right temporal region. The patient’s head is rigidly fixed to
the bed using pins. Navigation equipment and an intraoperative ultrasound are
ready for use. The incision is mapped and marked, and then the area is prepped
and draped. The final panel shows use of the operative microscope during tumor
resection. The preoperative MRI is displayed in the background. This is the same
case as shown in Figure 1 and the operative experience further described in the
accompanying video (Video1).
1. Stummer W, Reulen HJ, Meinel T, et al. Extent of resection and survival in
glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery.
2008;62(3):564-576; discussion 564-76.
2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and
adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
3. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ.
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant
glioma: a randomised controlled multicentre phase III trial. The Lancet Oncology.
2006;7(5):392-401.
4. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from
temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
5. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: primary brain
and central nervous system tumors diagnosed in the United States in 2007–2011.
Neuro Oncol. 2014;16(Suppl 4):iv1-63.

CHAPTER 2: MANAGEMENT OF BRAIN

Finally, the integration of neuromonitoring and the use of
awake craniotomies have been important advances that have
allowed surgeons to navigate around eloquent areas of the brain
while focusing their resection to areas of disease and avoiding
critical structures. More recently the introduction of dyes, like
5-aminolevulinic acid that is preferentially taken up the tumor
METASTASES
Case Presentation
A 59-yr-old male with a history of 30 pack-year of smoking
presents with 3 wk of progressive headaches and unsteady gait.
He denies history of seizures, weakness, or vision changes. His
 TUMOR

neurological exam is significant for right-sided dysmetria and gait b. SRS alone
ataxia. Brain MRI was obtained and is shown in Figure 5. CT of c. Chemotherapy
the chest shows a lung mass. d. Surgical resection followed by whole brain radiation
5. All the following tumors are considered ‘radiation sensitive’
except:
Questions
a. Lymphoma
1. The 5 most common sources of brain metastases are: b. Melanoma
a. Lung, breast, melanoma, colorectal, and renal c. Small cell lung cancer
b. Lung, breast, prostate, melanoma, and ovarian d. Germ cell tumors
c. Lung, breast, melanoma, prostate, and renal
d. Breast, prostate, thyroid, melanoma, renal
e. Breast, melanoma, GI tract, thyroid, renal Epidemiology
2. All the following are part of the treatment and workup for this Brain metastases are the most common type of malignant brain
patient except: tumors. They constitute over 50% of all malignant brain tumors
a. Steroids seen in the population. Almost all types of cancer can metastasize
b. Hyperosmolar therapy to the brain. However, lung and breast cancer account for the
c. Brain radiation majority of diagnosed metastases due to the higher incidence of
d. Craniotomy for resection of mass these tumors among the population. Other common sources of
e. Biopsy of chest mass brain metastases are listed in Table 1.
3. The most important factor that predicts the prognosis of Reported incidence of brain metastasis varies widely among
patients with brain metastases is: studies. In the USA, the incidence of newly diagnosed brain
a. Age metastasis is about 170 000 per year. In autopsy studies, more
b. Extent of extracranial disease patients are found to harbor brain metastases than reported in
c. Karnofsky Performance Scale (KPS) premortem studies. This is likely because patients die from their
d. Number of brain metastases primary tumor prior to developing symptoms from brain metas-
e. Specific tumor type tasis. On the other hand, studies also show that the number of
4. All the following are evidence supported treatment options for newly diagnosed brain metastases is increasing. There are various
a patient with solitary brain metastasis except: reasons for the observed increased incidence of brain metastasis.
a. Surgical resection followed by stereotactic radiosurgery The more frequent use of sensitive diagnostic studies (MRI and
(SRS) positron emission tomography [PET] scans) is 1 reason for the

A B

FIGURE 5. T1-weighted MRI sequences A, with and B, without contrast showing right cerebellar heterogeneously enhancing
lesion consistent with a brain metastasis.
ELDER ET AL
TABLE 1. Most Common Sources of Metastatic Brain Tumors Based
on Autopsy Data
Primary tumor Percentage (%)
Lung 40-50
Breast 10-20
Renal 5-10
Melanoma 5-10
Colorectal 1-5
increased rate of diagnosis. However, the most likely reason for
this observed increase is the development of more efficacious
systemic cancer treatments leading to longer patient survival. For
example, the development of HER2 targeted therapy for HER2
positive breast cancer has led to an increase in median patient
survival by many months. However, these therapeutic agents show
poor CNS penetration and therefore do not efficaciously treat
brain metastases. Patients surviving longer due to better treatment
of their systemic disease give an opportunity for existing brain
metastases to continue to grow and become symptomatic, and
also give more time for systemic disease to potentially spread to
the brain. Both scenarios effectively increase the incidence of brain
metastases. Similar observations have been made in many other
cancers.
Pathophysiology
Metastatic brain tumors are thought to mainly spread to the
brain via hematogenous routes. Tumor cells first accumulate
enough genetic transformation to grow in their primary location.
Further genetic transformation promotes angiogenesis and local
invasion. Eventually tumor cells are shed into the systemic circu-
lation and make their way into the pulmonary circulation. Here
some tumor cells get trapped in the pulmonary capillary beds
where they form metastatic deposits in the lungs. Eventually
tumor cells may escape the pulmonary capillary bed and reach
the brain where they enter the local capillary beds. Tumor cells
are able to penetrate the blood brain barrier and form metastatic
deposits. As such, brain metastasis tend appear at the junction of
the gray and white matter where the smaller arterial diameters act
as a trap for metastatic cells. In agreement with this mechanical
spread theory, the probability of finding a brain metastasis in any
area of the brain is proportional to the percentage of total brain
blood flow it receives. As such, 80% of metastases appear in the
cerebrum vs 20% in the posterior fossa. This theory also explains
why a majority of brain metastases are usually diagnosed either
concurrently or after the discovery of lung metastases. On the
other hand, this theory does not explain the predilection of certain
tumors to seed other areas of the brain preferentially (eg, pelvic
and GI tumor seem to favor the posterior fossa) or for certain
tumors to target the brain more preferentially than other organs
(eg, melanoma).
Once tumor cells reach the brain, they can remain dormant
or divide and grow. As they grow, brain metastases produce
TABLE 2. Common Symptoms on Presentation
General symptoms Focal symptoms
Headache Focal seizure
Nausea/emesis Face/arm/leg weakness
Generalized Seizure Aphasia
Confusion Visual field deficits
Lethargy Dysphagia
symptoms by local invasion of normal cortex. A second
mechanism through which tumors produce symptoms is due
to surrounding cerebral edema. The cerebral edema is a result
of disruption of the blood brain barrier. This disruption is
primary mediated by effect of growth factors, especially vascular
endothelial growth factor, on endothelial cells. As a result, fluids
start leaking into the brain extracellular space through the leaky
endothelium of blood vessels surrounding metastases.
Clinical Presentation
Patients with brain metastases can present with a variety of
symptoms (Table 2).
Headache
Headache is the most common presentation. The headache
may be related to increased intracranial pressure from tumor
size or tumor-related cerebral edema, obstruction of a ventricle
leading to hydrocephalus, or due to direct meningeal irritation
from dural-based metastatic deposits. Headaches that arise due
to increased intracranial pressure tend to be positional. The
headaches are worse at night during sleep. Most patients with high
intracranial pressure describe a history of progressively worsening
headache, eventually accompanied by other symptoms such as
nausea and altered mental status. The location of metastases rarely
coincides with the location of the headaches. In many patients,
metastases are found as incidental findings as part of the workup
of patients without headaches.
Nausea and Emesis
Nausea and emesis often accompany headache. In addition to
causes including high intracranial pressure, these symptoms can
also be due to direct invasion or mass effect on the medulla or area
postrema.
Neurological Deficits
Direct mass effect from the tumor and accompanying edema
on nearby normal brain can cause neurological symptoms. The
specific neurological symptom depends on the anatomic location
of the metastasis (Table 3). Patients with this presentation usually
relate a history of progressive symptoms rather than sudden
presentation.
Sudden onset of focal deficits in metastases is usually due
to hemorrhagic infarction of the tumor or as a sequelae of

TABLE 3. Location of Tumor and Focal Deficits
Location Symptoms
Prefrontal area Personality changes
Motor cortex Contralateral weakness
Parietal cortex Contralateral neglect
Occipital cortex Contralateral visual field deficits
Cerebellum Ipsilateral dysmetria, gait ataxia
Dominant inferior frontal gyrus Expressive aphasia
Dominant superior temporal gyrus Receptive aphasia
seizures. Approximately 10% of patient with metastases present
with hemorrhagic stroke, most commonly from metastases due
to melanoma, renal cell carcinoma, choriocarcinoma, and thyroid
cancers.
Seizures
Seizures are the presenting symptoms in approximately 15%
of patients. Patients can present with focal seizure due to cortical
irritation caused by local invasion or vasogenic edema due to
disruption of the extracellular space ionic and molecular compo-
sition. Less commonly, patients can present in status epilepticus.
Seizures are more frequently observed in metastases to frontal,
temporal, and limbic lobes. They are almost never seen with
metastases to the brainstem or cerebellum.
Evaluation
Patients with no known history of malignancy should undergo
further workup prior to planning treatment.
Imaging Studies
Head CT
Most metastases are first seen on noncontrasted head CT
findings obtained to work up presenting symptoms. However,
head CT has low sensitivity for brain metastases and many small
metastases are missed. In addition, noncontrasted CT has low
specificity as many other lesions may have similar appearance.
Therefore most patients will undergo brain MRI. However, in
some patients MRI may be contraindicated. In these patients a
head CT with and without contrast is usually obtained. Even with
this scan, smaller metastasis can be missed.
Brain MRI
This is the best test to obtain to evaluate radiographically for
brain metastases. Brain MRI are obtained for diagnostic purpose
as well as for treatment planning. High resolution MRI is used for
computer navigation during surgery and radiotherapy. Functional
MRI studies measure changes in regional blood flow related to
performance of motor and verbal task to delineate eloquent brain
tissue surrounding a tumor thought to be in or near functionally
important cortex such as the motor strip. This information is used
to help plan surgery.
TUMOR
Body CT and PET Scans
Patients who present with newly found brain tumors should
undergo a search for a primary malignancy. This workup usually
includes chest, abdomen, and pelvis CT scans. A negative
metastatic workup does not rule out the diagnosis of metastatic
disease. PET is another diagnostic tool that is more sensitive at
picking up occult disease (eg, enlarged lymph nodes). Despite an
extensive imaging workup, a primary cancer is not always found
in patients with biopsy-proven brain metastases.
Mammogram and Colonoscopies
Mammography and colonoscopies are rarely used during the
workup of newly found brain metastases as breast cancer and
gastrointestinal cancers usually have metastasized widely prior to
reaching the brain. However, they may reveal an accessible region
to biopsy in cases where above tests fail.
Biopsy
In patients with known cancer, presentation with multiple
enhancing brain lesions is safely presumed to be due to metastatic
disease and a biopsy is not necessary.
In patients with unknown diagnosis and either single or
multiple brain metastasis, a biopsy is needed to establish the
diagnosis and help formulate an overall treatment plan. A biopsy
can be obtained from any accessible mass that is revealed with
the above studies to determine the source and type of primary
malignancy. For example, if a patient presents with multiple brain
tumors consistent with metastatic disease and CT of the chest
reveals a tumor in the lung, the patient will often undergo a CT-
guided biopsy of the lung mass to establish their cancer diagnosis.
If no lesion is revealed with the above workup, the next step is to
biopsy the most accessible brain metastasis to establish diagnosis.
In many cases, the brain metastasis is completely excised rather
than biopsied, if possible. For large brain tumors, complete
resection not only achieves diagnosis but also aids in the overall
treatment of the patient.
In patients with known history of cancer and a single brain
lesion, the situation is more complicated. In about 10% of these
patients, the etiology of the brain lesion is found to be infectious,
immune mediated, or a primary brain neoplasm. Therefore, it is
prudent to consider biopsy of the brain lesion in such patients if
there are any doubts.
Prognosis
The management of brain metastases depends heavily on
overall prognosis. Some treatment modalities (especially surgery)
should not be offered to patients with overall poor prognosis, as
the risks of surgery and the time involved with recovery from
surgery likely outweigh benefits. Using recursive partitioning
analysis (RPA) based on radiation therapy outcomes, 3 factors
have been found to predict prognosis. For patients with brain
metastases who have KPS >70, age <65, and controlled systemic
disease, the median survival is 7 mo compared to 2 mo for patient
ELDER ET AL
TABLE 4. Karnofsky Performance Scale
Score Description
100 Normal; no complaints; no evidence of disease
90 Able to carry normal activity; minor signs or symptoms of disease
80 Normal activity with effort; some signs and symptoms of disease
70 Cares for self; unable to carry on normal activity or do active work
60 Requires occasional assistance but able to care for personal needs
50 Requires considerable assistance and frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled, hospital admission indicated although death is not
imminent
20 Very sick; hospital admission necessary; active supportive treatment
necessary
10 Moribund; fatal processes progressing rapidly
0 Dead
with KPS <70. RPA analysis taking into account the type of
primary cancer was later developed. While these later studies
showed that other factors can also influence the prognosis, the
KPS (Table 4) remains the most important prognostic predictor
for metastatic brain disease regardless of type of cancer. It should
be noted that newer studies do show longer survival of patients
with brain metastases than shown in the earlier radiation therapy
oncology group RPA study. This is mostly a result of newer treat-
ments for systemic disease as most patients expire as a result of
systemic disease progression rather than a result of progression of
their brain metastases.
Treatment
Symptom Management
Steroids. For patients with severe symptoms due to vasogenic
cerebral edema, steroids are used to palliate the symptoms.
Steroids stabilize leaky blood brain barriers. They typically show
an effect within 24 h of initiation. Steroids have significant side
effects. Mental status changes such as irritability, insomnia, and
confusion are common and can lead to significant challenges
for the care of cancer patients. Gastrointestinal irritability and
bleeding are potential side effects that can be mitigated with the
use of proton pump inhibitors or H2 blockers. Steroids can also
lead to significant hyperglycemia, especially in diabetic patients.
Finally, steroids inhibit the immune system response and can
increase the risk of infections, especially in patients who are
already immunosuppressed by chemotherapy. For all these reason,
steroids are usually used at the lowest effective dose and for the
shortest duration of time possible.
AED. Patients who present with seizures are started on AED.
Newer AEDs, such as leviteracitam are used more frequently
that dilantin. These drugs have a better side effect profile. They
have less drug interactions, making them preferable in patients
undergoing chemotherapy where careful dosing of medication is
needed to avoid the toxicity of chemotherapy. Use of prophylactic
AEDs in patients who present without seizure is not proven to be
Level Definition
80-100 Able to carry on normal activity and
to work; no special care needed
50-70 Unable to work; able to live at home and
care for most personal needs; varying
amount of assistance needed
<50 Unable to care for self; requires
equivalent of institutional or hospital
care; disease may be progressing rapidly
effective and is better avoided as most AEDs have significant side
effects.
Role of chemotherapy. Currently, there is minimal evidence
supporting a role for chemotherapy as treatment for brain metas-
tases. However, chemotherapy agents may help to prevent brain
metastases from occurring. On the other hand, as the effectiveness
of chemotherapy improves for systemic cancer and patients live
longer, brain metastases may be occurring in a higher percentage
of cancer patients. In the future, systemic therapy agents such as
chemotherapy, immune therapy, and molecular targeted agents
may be developed which can be used to treat brain metastases as
well as systemic disease.
Role of radiation. The role of radiation vs surgery in treatment
of brain metastases continues to be the subject of clinical studies.
The main treatment modalities currently include whole brain
radiation, stereotactic radiation, and surgery or combination of
these modalities. Treatment decisions are partially determined by
sensitivity of the tumor to radiation. Radiation resistant tumors
are typically approached with a combination of strategies. For
tumors sensitive to radiation (Table 5), the first step in treatment
of the brain metastases is typically radiosurgery or whole brain
radiation.
Whole brain radiation therapy (WBRT). In WBRT, patients
undergo treatment to the whole brain over multiple days. The
most common prescribed dose is 30 Gray divided over 10 d,
TABLE 5. Favorable Prognostic Factors
Karnofsky Performance Scale > 70a
Age < 65 yr
Controlled systemic disease
Specific tumor type
Number of brain metastases
a
Most important prognostic variable

but considerable variation exists. WBRT used to be the main
therapy for brain metastases. However, randomized controlled
trials showed longer survival with surgery followed by WBRT
in patients with single brain metastasis compared to biopsy and
WBRT only. Further studies have also shown that SRS combined
with WBRT is better than WBRT alone for patients with up to
4 metastatic deposits. Because of this, WBRT today is used either
in combination with other treatment modalities to help control
disease recurrence or in cases where more than 3 to 4 metastases
are seen.
WBRT has significant short- and long-term side effects. In
the short term, alopecia and fatigue as well as worsening of pre-
existing neurological symptoms are the main side effects. These
side effects improve with time. In the long term, many patients
develop neurocognitive decline and dementia. These symptoms
are usually irreversible. Because of this, the use of WBRT has been
declining in favor of more focused treatments such as SRS and
surgery. Based on the observation that increased radiation dose
to the hippocampus correlates with neurological decline, WBRT
with dosing that spares the hippocampi has been developed and
is showing promise in early trials in reducing the long-term side
effects of WBRT.
SRS. SRS involves 1 to 5 radiation “sessions” utilizing focused
high-dose radiation to the tumor. This technique helps minimize
radiation to the surrounding normal brain. Gamma knife radio-
surgery is one common type of SRS in which treatment is
completed in one session. SRS has shown to be superior to WBRT
alone for treatment of a solitary metastasis. SRS has been shown
to be effective for treatment of multiple metastases at the same
time. Today it is typically used to treat up to 4 metastases at the
same time. SRS is also used for small inaccessible metastases where
surgery is not feasible or contraindicated.
In SRS, only tumors noted on MRI or CT are treated using
SRS techniques, so microscopic disease not visible on imaging
may not be treated. For this reason, some centers treat radio-
graphically visible metastases with SRS, and then also use WBRT
to treat presumed microscopic disease. Other centers, because of
the side effect of WBRT, choose to use frequent MRI monitoring
after SRS rather than use SRS plus WBRT prophylactically. This
practice has been supported by studies that show that use of
WBRT in addition to SRS does not increase survival compared to
SRS alone, despite the better tumor control rate with the combi-
nation therapy.
Another use of SRS is for radiation resistant tumors. Some
tumors that are resistant to WBRT may respond to high dose
focused radiation delivered via SRS. Therefore SRS is widely used
either alone or in combination with surgery for treatment of
radiation resistant metastases such as renal cell carcinoma.
SRS is typically delivered using various dosages based on the
size of the tumor. Larger tumors receive smaller radiation doses
because of the difficulty in controlling the dose to the surrounding
normal brain as the size of the tumor increases. With tumors larger
than 3 cm, SRS is contraindicated as it is difficult to achieve an
TUMOR
adequate dose to the tumor without exposing the normal brain to
toxic levels of radiation.
Role of surgery. Based on results from randomized clinical trials,
patients with accessible solitary brain metastases and KPS >70
should undergo surgical resection if there are no contraindica-
tions such as medical comorbidities. Patients with poor prognosis,
poorly controlled systemic disease, or KPS <70 are usually
managed with radiation therapy alone.
For patients with multiple metastases, surgery is utilized for
large metastases, metastases causing neurological symptoms or
metastases that are life threatening due to obstructing ventricular
outflow thereby causing hydrocephalus or by producing large
amount of cerebral edema thereby threatening cerebral herni-
ation. For patients with a limited number of metastases that can be
removed in a single surgery, attempted removal may lead to better
prognosis, although this data is not as clear as that for patients
with solitary metastases.
Currently, surgery is usually followed by radiation to the
resection cavity. Surgery addresses the macroscopic disease, but
microscopic disease potentially remains. Some studies show that
“en-bloc” resection of the tumor, a technique in which the
tumor is resected as one mass without violation of its capsule,
is associated with better local recurrence rate than piecemeal
resection of the tumor. Nevertheless, not all tumors can be
approached this way, especially if large, and microscopic disease
may remain in the cavity regardless of the approach. Therefore
surgery is usually followed by radiation to the resection cavity or
whole brain radiation to minimize the chances of local recurrence
of disease.
Discussion of Case
The patient presentation is consistent with a right-sided
cerebellar lesion. This coincides with the location of the tumor
on the MRI. Since the chest CT showed a lung lesion, it is most
likely that the lesion in his brain is a metastatic deposit from
a primary lung cancer. The next step in management consists
of treating the patient’s presenting symptoms. Steroids will help
alleviate the cerebral edema surrounding the tumor. Because the
patient presented with no history of seizure and because of the
cerebellar location of the tumor, AEDs are not indicated. Because
the patient has no known history of malignancy, the lung mass is
biopsied and revealed lung adenocarcinoma, which is classified as
nonsmall cell lung cancer. Since the patient has a good prognosis
and a single brain metastasis, he was advised to undergo surgical
resection followed by SRS for his cerebellar tumor. This will give
him the fastest relief of his symptoms and decrease the duration
he will need to be on steroids for symptoms control. The patient
underwent surgery as shown in Video 2.
Pearls
√
Radiosensitive tumors (lymphoma, small cell lung cancer, and
germ-cell tumors) are treated with chemotherapy and radiation.
ELDER ET AL

TABLE 6. Radio-Sensitive vs Radio-Resistent Tumors

Highly
Radiosensitive resistant
tumors ———— ———— tumors

Small-cell lung Breast Colorectal Melanoma

Lymphoma Nonsmall Renal cell
cell lung
Leukemia Thyroid
Multiple myeloma
Germ-cell tumors

VIDEO 2. Posterior fossa craniotomy for resection of a cerebellar brain metas-

tasis.

√
Surgical resection should be considered in patients with
KPS > 70 and single accessible metastasis or with large or life-
√ threatening metastases.
Patients that have multiple metastasis that can be surgically
removed have similar prognosis to patients with surgically
removed single metastasis.
SUGGESTED READING
1. Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J
Neurooncol. 2005;75(1):5-14.
2. Kalkanis SN, Kondziolka D, Gaspar LE, et al. The role of surgical resection in the
management of newly diagnosed brain metastases: a systematic review and evidence-
based clinical practice guideline. J Neurooncol. 2010;96(1):33-43.
3. Linskey ME, Andrews DW, Asher AL, et al. The role of stereotactic radiosurgery
in the management of patients with newly diagnosed brain metastases: a systematic
review and evidence-based clinical practice guideline. J Neurooncol. 2010;96(1):45-
68.
4. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the
treatment of single metastases to the brain. JAMA. 1998;280(17):1485-1489.
5. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the
treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494-500.

CHAPTER 3: PITUITARY ADENOMAS

Case Presentation
A 52-yr-old woman presented with progressive vision loss
in both eyes and the sudden onset of severe headaches with
associated nausea. The patient complained that she kept bumping
into doorsills and could no longer see the lane to the left of her
car. Previous medical history was relevant for irregular menstrual
cycles that were considered to be due to the onset of menopause.
Examination showed a mild bitemporal hemianopsia with 20/80
vision. MRI revealed a sellar lesion with suprasellar extension
(Figure 6).

Questions
1. What is the most likely diagnosis?
a. Meningioma
b. Pituitary adenoma
c. Hypothalamic hamartoma
d. Optic glioma
2. What is the best management considering normal levels of
PRL?
a. Medical treatment (chemotherapy)
b. Surgical treatment (resection)

FIGURE 6. Preoperative coronal postgadolinium, T1-weighted MRI of a
patient with a large pituitary macroadenoma. The patient presented with
sudden headache and vision loss. There is significant, chronic superior
displacement of the optic apparatus. There are signs within the tumor
of previous apoplexy (note the heterogenous contrast enhancement of the
mass). There also appears to be erosion into the sphenoid sinus anteriorly.
c. No intervention, follow-up with serial MRIs
d. Radiation therapy (fractionated)
3. The most common type of secreting or functional pituitary
tumor is:
a. Somatotrophic
b. Corticotrophic
c. Lactotrophic
d. Gonadotrophic
4. Which surgical approach would be ideal for a mass confined to
the sellar region with small suprasellar extension?
a. Suboccipital approach
b. Transsphenoidal approach
c. Subfrontal approach
d. Pterional approach
General Information
Pituitary tumors (adenomas) represent approximately 10% to
15% of all intracranial tumors and are usually sporadic in nature.
Few risk factors have been identified for the development of a
pituitary adenoma, although they are associated with some rare
genetic syndromes, such as multiple endocrine neoplasia type 1.
These tumors affect both sexes equally, most commonly between
the third and sixth decades of life. Most pituitary adenomas are
benign, World Health Organization (WHO) grade I lesions and
arise from the adenohypophysis (anterior gland). Tumors arising
from the posterior gland or neurohypophysis are rare.
Pituitary tumors can be classified by different criteria.
According to size, they are divided into 2 categories:
TUMOR
FIGURE 7. Percentage of various types of pituitary adenomas based on hormonal
secretion. Adapted from multiple sources, numbers are approximate based on large
clinical and epidemiological series.
 Microadenomas: smaller than 10 mm in diameter
 Macroadenomas: greater than 10 mm in diameter
According to their hormonal activity and secretion, pituitary
adenomas are divided into functional (or hormone secreting), and
nonfunctional (or nonsecretory) tumors. Younger adults tend to
present with functional tumors while the incidence of nonfunc-
tional tumors increases with age.
Clinical Presentation of Pituitary Adenomas
Patients typically present due to endocrine syndromes from
hyper-secretion of hormone, mass effect (mainly nonfunctional
tumors) upon the optic nerves or other adjacent structures,
pituitary apoplexy, or as a silent lesion identified as an incidental
finding in neuroimaging exams done for unrelated reasons.
Endocrine Syndromes
Almost 70% of pituitary tumors are functional, ie, they secrete
an active hormone (Figure 7). The most frequently secreted
hormone is PRL, causing amenorrhea-galactorrhea in women and
impotence and gynecomastia in men. The second most frequent
secreting tumor produces GH, leading to acromegaly in adults
and gigantism in prepuberal children. Third most commonly
are the tumors that secrete ACTH, leading to central hypercor-
tisolemia or Cushing’s disease. Tumors that produce excessive
thyroid-stimulating hormone (TSH) leading to hyperthyroidism
are extremely rare.
ELDER ET AL
Another manifestation of a pituitary adenoma is hypopitu-
itarism of one or more axis of the gland that may be caused by
compression of the normal pituitary gland or the pituitary stalk,
seen with larger nonfunctional tumors. The gonadotrophins are
usually the first to be compromised by compression, followed
by the thyrotrophs, somatotrophs, and finally corticotrophs
are occasionally affected. Complete panhypopituitarism as the
presenting sign of a pituitary adenoma is usually only associated
with a large apoplexy event; most patients with even very
large nonfunctional adenomas with no obvious gland identified
on MRI have relatively intact pituitary function. Patients who
present with hypofunction will not always regain function after
surgical intervention, and hormonal hypofunction itself is not
considered a classic indication for surgery.
Many patients with a nonfunctional adenoma will have a mild
elevation in PRL levels upon laboratory examination. However,
the tumor fails to stain for PRL upon surgical resection. This
phenomenon has been classically attributed to a loss of the
normal negative feedback loop mediated by dopamine upon
the lactotrophs of the anterior gland due to compression of the
pituitary infundibulum. This “stalk effect” may result in clinical
symptoms of hyperprolactinemia, but levels are usually only
mildly elevated (less than twice the upper limit of normal in most
clinical labs) compared to prolactinomas, which are associated
with much higher levels of serum PRL.
Mass Effect
Mass effect is the clinical syndrome caused by the compression
of a nervous structure by any abnormal lesion occupying space in
the cranial vault such as neoplasms, hemorrhage, or infection. In
pituitary adenomas, mass effect is found in macroadenomas that
tend to be nonfunctional tumors. The functional tumors tend to
cause endocrine syndromes before causing mass effect, leading
to diagnosis while still in the size range of microadenomas. Due to
relatively indolent endocrine symptoms, prolactinomas are most
likely among the functional adenomas to become large enough to
cause mass effect. Mass effect can lead to nonspecific symptoms
(such as headaches and, rarely, seizures), but the clinical manifes-
tations depend mostly on the structures compressed.
1. Optic chiasm: Bitemporal hemianopsia due to compression of
the central portion of the optic chiasm. If a lesion is quite
eccentric to one side, a monocular acuity loss can be seen, but
this is less common.
2. Hypothalamus: A variety of vegetative disturbances (sleep,
appetite).
3. Third ventricle: Obstructive hydrocephalus and associated
symptoms (headache, lethargy, nausea/vomiting).
4. Cavernous Sinus (CS): Proptosis or cranial nerves palsies of the
nerves within the CS (III, IV, V, V1).
Pituitary Apoplexy
A pituitary tumor may expand suddenly from hemorrhage,
causing neurological and/or endocrinological deterioration. This
apoplexy is thought to occur due to venous infarction of the
tumor as it grows. Apoplexy typically presents with abrupt
onset of headache, nausea/vomiting, visual disturbances, alter-
ation of level of consciousness, hypopituitarism, and neuro-
logical deficits like cranial neuropathy up to ophthalmoplegia.
Usually, apoplexy is considered an indication for urgent surgical
resection aiming at reducing mass effect by evacuating blood
products and tumor. However, for symptoms that are not severe,
or patients with significant medical co-morbidities precluding safe
surgical resection, conservative management of apoplexy often
leads to tumor regression and symptom improvement without
surgery.
Incidental Finding
An increasing number of pituitary tumors, especially nonfunc-
tional tumors, are discovered incidentally due to the now-
common use of imaging exams (CT and MRI) as part of a workup
for migraine headaches, trauma, or sinusitis. The management
of these incidental findings is often conservative with surveil-
lance imaging if there is no impending mass effect upon the optic
nerves. Resection is then considered if the lesion grows over time
or workup indicates a functional tumor.
Evaluation
The pituitary gland represents less than one gram of the human
body but influences some degree of control, directly or indirectly,
over practically every physiologic system. The gland resides in
the sella, around which course numerous critical cranial nerves
and vascular structures. Therefore, the clinical evaluation of a
lesion arising from the pituitary gland is quite extensive and far-
reaching. Usually the first steps of an evaluation will be guided
by the clinical presentation, that is, if the lesion presents due
to symptoms from mass effect on surrounding structures, or
endocrinological disturbances, or as an incidental finding during
an unrelated imaging study.
As usual, the clinical evaluation should start with a careful
medical history and examination, with special attention to
endocrinological signs and symptoms of hyper- or hypofunction,
visual changes and cranial nerve deficits. After this, the inves-
tigation can be divided in a coordinated, 2-pronged diagnostic
approach (Table 7). One step is the anatomic diagnosis, seeking
to establish the lesion’s relation to the surrounding structures
such as the cavernous sinus, internal carotid artery and the optic
apparatus, relying mainly on noninvasive imaging exams. The
other step is an endocrine diagnosis to assess the gland function
via blood serum levels of various hormones. All patients should
undergo both steps, whether simultaneously or sequentially with
their order usually determined by the clinical presentation. For
example, a patient presenting with headaches and/or visual field
deficits will usually first undergo imaging examination, whereas
patients with endocrinological symptoms will undergo hormone
evaluation first.
 TUMOR

TABLE 7. General Diagnostic Workup for a Patient with Suspected Pituitary Lesion, Based on the Symptoms Related to Mass Effect and Hormonal
Dysfunction

Evaluation Rationale
Visual field testing Compression of optic chiasm (bitemporal hemianopsia)
Mass effect CT scan Evaluate sinonasal surgical corridor, bone anatomy of sella, and signs of hemorrhage
MRI Test of choice, with gadolinium contrast and thin-cut sub-1 mm image.
Prolactin Prolactinoma or stalk effect.
ACTH Central source of hypercortisolemia (Cushing’s disease)
Cortisol (serum and urine) Low in hypoadrenalism and elevated in Cushing’s syndrome and Cushing’s disease
Endocrine screening TSH and free T4 If both elevated, suspect TSH-producing adenoma (very rare).
FSH, LH, and sex steroids Low: mass effect of the tumor on the gland Elevated: tumor secretion (usually clinically silent)
GH and IGF-1 Elevated: acromegaly/gigantismLow: mass effect of the tumor on the gland

ACTH, adrenocorticotrophic hormone; CT, computed tomography; FSH, follicle-stimulating hormone; GH, growth hormone; IGF-1, insulin-like growth factor-1; LH, luteinizing
hormone; MRI, magnetic resonance imaging

Anatomic Diagnosis bitemporal hemianopsia, sometimes referred to as “tunnel vision,”

Historically, the first imaging studies used for evaluation of the
sella were skull radiographs looking for distortions of the usual
anatomy of the sella. As imaging techniques advanced, so did
the evaluation of the sella and pituitary gland. Currently, high-
resolution (sub-1 mm slice thickness), gadolinium-enhanced
MRI is used for precise anatomic diagnosis and is able to detect
most microadenomas. CT scans are useful for studying the
bony anatomy of the sella and paranasal sinuses for preoperative
planning. MRI and CT are complementary studies and infor-
mation from both is often used in surgery.
Microadenomas (lesions under 10 mm) are best seen in
coronal images and tend to appear hypo or isointense to the
normal pituitary gland on unenhanced T1-weighted images.
After contrast injection, the normal pituitary tissue displays an
earlier and more intense enhancement, making the adenoma
markedly hypointense. Dynamic sequences after rapid injection
of the contrast medium can help detect small lesions that usually
present with diminished and delayed enhancement.
With macroadenomas (lesions over 10 mm) the sensitivity of
the study is not an issue as the lesion will be quite apparent.
Rather, the relationships of the tumor to the surrounding struc-
tures such as encasement of the internal carotid arteries, invasion
of the cavernous sinus, and compression of optic apparatus must
be delineated. This information impacts surgical decisions such
as the surgical approach.
For patients with pituitary apoplexy, MRI and CT images will
show an expanded hemorrhagic or infarcted mass in the sella
and suprasellar region with compression and distortion of the
surrounding structures. Occasionally, subarachnoid hemorrhage
may be present, when blood products are not contained by the
diaphragm sellae, and this may lead to meningismus, seizures and
depression of consciousness. Interestingly, patients with a history
of apoplexy may still have blood products within the sella even
months after an apoplectic event, as blood within an adenoma is
not quickly absorbed.
Another useful test to determine local mass effect is the
formal visual field testing. The classic finding in sellar lesions is
in which both peripheral (temporal) visual fields are affected due
to central compression of the chiasm.
Endocrine Diagnosis
The history and physical examination provide the first clues to
the gland function and must be carefully validated by endocrine
testing, with measurements of the pituitary and target tissue
hormones in basal and dynamic states. The initial screen for every
patient should include PRL; ACTH and early morning (8 am)
serum cortisol; TSH and free T4; follicle-stimulating hormone
(FSH), luteinizing hormone (LH), and sex steroids (estradiol in
women and testosterone in men); GH and IGF-1 (insulin-like
growth factor-1). By identifying states of excess or deficiency, this
initial screening can provide an estimate of the various pituitary
axes. If all hormones are within normal limits, or if PRL is only
very mildly elevated (stalk effect), the tumor is most likely a
nonfunctional adenoma. With these results, a specific or global
(panhypopituitarism) hypofunction also can be identified and
hormone replacement therapy should be initiated and monitored.
Additional tests are performed to precisely define hypersecre-
tions syndromes if abnormalities are noted on this initial
screen.
PRL: PRL secreting adenomas are the most common secreting
tumors and account for about 45% to 50% of all pituitary
adenomas. However, the finding of moderately elevated serum
PRL (<200 ng/dL) should be interpreted carefully. Medications
(eg, tricyclic antidepressants, oral contraceptives), pregnancy,
mammary stimulation, breast feeding, excessive exercise, stress,
stalk effect and some prolactinomas may be the cause of such
elevations. A significant elevation in PRL levels (>200 ng/ml) is
highly indicative of a prolactinoma.
ACTH and cortisol: Around 6% of pituitary adenomas
are ACTH producing tumors, leading to Cushing’s disease
(central origin hypercortisolemia) that may cause diabetes, hyper-
tension, osteoporosis, purple striae, truncal obesity, moon facies,
amenorrhea, impotence and generalized weakness. Cushing’s
disease is reviewed in a separate chapter in this handbook.
ELDER ET AL
TSH and free T4: TSH producing adenomas occur in <1%
of adenomas, leading to hyperthyroidism, with both TSH and
free T4 elevations, in contrast with primary hyperthyroidism that
presents with a low TSH. These lesions are very rare.
FSH, LH, and sex steroids: Exclusive aberrant secretion of FSH
and LH is rare and usually clinically silent. FSH and LH secretion
are usually found in mixed tumors (ie, secrete more than one
hormone and occur in approximately 10% of cases).
GH and IGF-1: GH-producing adenomas leads to acromegaly
with its hallmarks of coarsening of facial features, growth of hands
and feet, carpal tunnel syndrome, frontal bossing, pragmatism,
macroglossia, joint pain, fatigue, and obstructive sleep apnea. The
GH serum values are not a reliable tool of diagnosis due to its
variable levels throughout the day. Therefore, the most useful test
is the IGF-1 level, an excellent marker of average GH secretion
that is produced in the liver after GH stimulation. IGF-1 levels
are variable throughout life and so normal values are standardized
by patient sex and age. In the setting of a high IGF-1 and clinical
acromegaly, with a pituitary tumor found on MRI, confirmatory
testing is usually not required. The gold standard for the diagnosis
of acromegaly is an oral glucose tolerance testing (OGTT), where
oral glucose is given to the patient and serum GH levels are serially
monitored over several hours. Normally, a high load of enteral
glucose will suppress serum GH levels to below 1 ng/mL. Failure
to suppress the GH level (a “positive” OGTT) is the gold standard
diagnostic test of acromegaly, and can be helpful when the IGF-1
level is borderline.
Decision-Making
After the diagnosis of a symptomatic pituitary adenoma has
been established, the treatment objectives are (1) eliminating mass
effect and restoring neurological function, (2) preserve normal
gland function, (3) normalize hypersecretion of hormones, (4)
obtain a definitive histologic diagnosis, and (5) prevent recur-
rences.
The therapeutic options available include surgical resection,
pharmacotherapy (receptor-mediated), and radiation (both tradi-
tional fractionated radiotherapy and SRS). For incidental lesions,
observation is also very reasonable in asymptomatic patients. Each
option has different risks and benefits depending on the case.
The most urgent indication for surgery is pituitary apoplexy
with vision loss or other cranial nerve deficits to quickly decom-
press the optic apparatus and cranial nerves, restoring vision and
neurological function. Apoplexy presenting without cranial nerve
deficits, or in patients who could not safely undergo surgery
due to medical comorbidities, may be managed with analgesics,
hormone replacement and serial imaging.
Patients presenting with progressive mass effect (macroade-
nomas), usually manifested as vision loss, should be strongly
considered for surgical decompression to restore neurological
function. Serum PRL should be measured for all patients before
surgery, because large prolactinomas may shrink dramatically with
medical therapy, even in the setting of significant mass effect and
therefore may not require surgery. An uncommon presentation
that should also be strongly considered for early surgery regardless
of tumor hormonal secretion is spontaneous cerebrospinal fluid
(CSF) leak due to tumor erosion of the sellar bone, with the focus
of the surgery being the repair of the leak and removal of the
tumor.
When no mass effect is present and the objective is endocrino-
logical treatment of a hypersecretory tumor, surgery is the
preferred treatment for ACTH-, GH- and TSH-producing
adenomas. The currently available pharmacological therapies for
these conditions are suboptimal in comparison to surgery which
gives the best chance for immediate and lasting remission. The
advances in somatostatin analogues for GH-producing tumors
show promising results but are still considered inferior to surgery.
For prolactinomas, medical therapy is the preferred option,
unless the tumor is unresponsive or the patient is intolerant to
the medication side effects. Patients started on cabergoline or
bromocriptine treatment should be closely monitored for signs of
apoplexy because initiation of medical therapy is a typical predis-
posing factor associated with apoplexy. Rarely, these tumors can
shrink rapidly on medical therapy and lead to a CSF leak from
the nose due to “unplugging” of a dural and bone defect due to
tumor regression.
Radiation therapy can take up to 2 yr to have an effect
in hormone secretions and usually do not cause a significant
reduction in tumor size. Radiation should be reserved for patients
that have failed surgical and pharmacological management or
small recurrent tumors to halt the tumor growth. Depending on
dose, most patients who undergo radiotherapy to the pituitary
gland suffer some degree of hypopituitarism and should be
monitored closely for signs of hypo-secretion.
Surgical Treatment of Pituitary Macroadenoma
Many approaches have been described to access the sella for
pituitary tumor resection since the origins of neurosurgery in the
early 20th century. Choosing the appropriate approach depends
on many variables such as the size of the tumor, extent of
suprasellar extension, and vital structures encased.
The transsphenoidal approach is the ideal approach to the
sella because it uses a natural corridor (sinonasal) to reach
the tumor without any need of brain manipulation, using
either the microscope or endoscope assisted technique, and
is considered the gold standard for the surgical treatment of
pituitary adenomas. The classic transsphenoidal approach used
for most of the latter 20th century utilized a nasal speculum
through either a nasal corridor or a sublabial incision, with the
aid of a surgical microscope. During the last 20 yr, the endoscopic
endonasal approach (EEA) described by Carrau and Jho has
grown in popularity. The attached video (Video 3) demonstrates
surgical resection of a macroadenoma via EEA.
The basic transsphenoidal surgical approach (microscopic
or EEA) involves first outfracturing or removing the middle
turbinate. The natural os of the sphenoid sinus is identified and

VIDEO 3. EEA for resection of a pituitary adenoma.
widened, performing a large sphenoidotomy and removal of the
rostrum, exposing the sella, clivus, and opticocarotid recess. The
floor of the sella is drilled to expose the dura and the medial
edges of both cavernous and intercavernous sinuses. The dura
is opened (attached video starts here) and the tumor is resected
with identification and preservation of the normal pituitary gland.
Large tumors are usually entered and debulked internally, while
microadenomas can at times be dissected free of the normal gland
via a pseudocapsule, with en bloc resection. Careful hemostasis
followed by a multilayered closure is performed to prevent postop-
erative CSF leaks and promote mucosal healing. At times, an
abdominal fat graft is utilized to obliterate dead space and further
prevent CSF leak.
The main limitations to either a microscopic or endoscopic
transsphenoidal approach are the surrounding lateral neurovas-
cular structures. Tumors extending lateral to the optic nerve and
carotid artery should be considered for a craniotomy approach,
as these areas cannot be reached even with angled instru-
mentation through a nasal corridor. The pterional approach
(lateral frontotemporal craniotomy including the greater wing
of the sphenoid) with or without orbital zygomatic extension
is the classic anterolateral access to the pituitary. A subtemporal
approach, lifting the temporal lobe instead of splitting the Sylvian
fissure can also be used for lateral access.
In conclusion, there are many different surgical approaches that
should be carefully analyzed and chosen by an experienced neuro-
surgeon familiar with all the surgical options and tailored to each
individual case to achieve the greatest neurological and endocrino-
logical success for every patient.
Discussion of the Case
This 52-yr-old female patient presented with vision loss
and sudden onset headache with a visual field defect affecting
both temporal fields raising the suspicion of a growing lesion
affecting the visual pathway (chiasm). Investigation should
TUMOR
FIGURE 8. Follow-up coronal postgadolinium, T1-weighted MRI
approximately 4 mo after surgery for the case presented. There is excellent
resolution of the mass effect upon the optic apparatus and no signs of
residual tumor. The patient is asymptomatic and has returned to neuro-
logical baseline.
proceed with a contrast enhanced MRI of the pituitary region,
which revealed a sellar mass with suprasellar extension, causing
superior displacement and compression of the chiasm. The lesion
is heterogenous and demonstrates evidence of partial apoplexy.
A pituitary adenoma is the most likely diagnosis. Compromise of
the optic pathway with signs of apoplexy makes surgical treatment
the appropriate intervention for this patient to decompress the
optic nerve and chiasm. Before surgery, endocrinological evalu-
ation must be performed. If high serum levels of PRL were to
be found, suggesting a prolactinoma, a brief attempt with urgent
medical treatment might be chosen if there were not significant
signs of apoplexy on imaging. The EEA transsphenoidal approach
is an excellent choice for this lesion. A complete resection was
performed and no residual tumor was apparent on postoper-
ative imaging (Figure 8). The patient’s vision normalized and her
headaches resolved. No postoperative complications were noted.
Her pituitary gland function was otherwise preserved.
ELDER ET AL
SUGGESTED READING
1. Winn HR, ed. Pituitary tumors: functioning and nonfunctioning. In: Youmans
Neurological Surgery. 6th ed. 2011.
2. Greenberg MS, Arredondo N. Handbook of Neurosurgery. 8th edn. New York:
Thieme; 2016.
3. Micko AS, Wöhrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus
space in pituitary adenomas: endoscopic verification and its correlation with an
MRI-based classification. J Neurosurg. 2015;122(4):803-811.
4. Rennert J, Doerfler A. Imaging of sellar and parasellar lesions. Clin Neurol
Neurosurg. 2007;109(2):111-124.
5. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis,
and management. J Neurosurg. 2017;126(2):404-417.
6. Jho HD, Carrau RL. Endoscopy assisted transsphenoidal surgery for pituitary
adenoma. Acta neurochir. 1996;138(12):1416-1425.
CHAPTER 4: CUSHING’S DISEASE
Case Presentation
A 32-yr-old female with a history of hypertension, diabetes
mellitus and obesity present to clinic with amenorrhea for the
past 9 mo. On clinical examination, she is neurologically intact
but has abdominal striae, red cheeks, and extremity ecchymoses.
She has central obesity, a moon facies and large dorsocervical fat
pad. Endocrine evaluation is consistent with Cushing’s disease
and MRI reveals a small pituitary adenoma.
Questions
1. Cushing’s disease is associated with all of the following, except:
a. Obesity
b. Skeletal overgrowth
c. Hypertension
d. Hyperpigmentation
2. Which of the following lab results is most consistent
with a diagnosis of Cushing’s disease, and not an ectopic
ACTH/cortisol-secreting tumor?
a. Elevated ACTH, elevated cortisol level following dexam-
ethasone suppression test, positive corticotropin-releasing
hormone (CRH) stimulation test
b. Low ACTH, normal cortisol level following dexamethasone
suppression test, negative CRH stimulation test
c. Elevated ACTH, low cortisol level following dexamethasone
suppression test, positive CRH stimulation test
d. Low ACTH, elevated cortisol level following dexam-
ethasone suppression test, negative CRH stimulation test
3. If endocrinology evaluation indicates Cushing’s disease, but
MRI is negative, which of the following is the most appropriate
next step?
a. Medical management
b. Inferior petrosal sinus sampling (IPSS)
c. Repeat MRI in 6 mo
d. Surgical exploration and possible resection
4. The most appropriate initial treatment for this patient with a
pituitary microadenoma with a diagnosis of Cushing’s disease
is which of the following?
a. Medical management
b. Transsphenoidal surgical resection
c. SRS
d. Adrenalectomy
Cushing’s Disease
Cushing’s disease occurs secondary to overproduction of
ACTH from a benign pituitary adenoma, resulting in excess
cortisol production by the adrenal glands. These supraphys-
iological levels of cortisol cause a myriad of co-morbidities,
including hypertension, diabetes, obesity, and early mortality.
While ectopic ACTH-secreting tumors and adrenal tumors can
also lead to Cushing’s syndrome, an ACTH-secreting pituitary
adenoma is most frequently the underlying cause (approximately
80% of endogenous Cushing syndrome cases). Early identifi-
cation, endocrinology evaluation, diagnosis, and treatment are
critical for effective management and avoidance of adverse
sequelae.
Epidemiology
Cushing’s disease carries an incidence of up to 2.4 new cases
per million persons per year with a prevalence of 0.004%.
Adult patients are typically diagnosed in the fourth to fifth
decades of life, whereas pediatric patients tend to be diagnosed
at approximately 13 yr. There is no sex preponderance in
prepubertal patients. However, adult females are more likely to
be affected (3:1 to 6:1) than adult males. Given the initially
ubiquitous symptomatology, an average of 2 to 4 yr typically is
observed between symptom onset and diagnosis. Hypertension
and diabetes mellitus are major predictors of morbidity, and
vascular disease is the most common cause of mortality in
untreated patients.
Clinical Presentation
Due to persistent supraphysiologic circulating cortisol levels,
Cushing’s disease affects multiple organ systems (Table 8).
Most commonly, Cushing’s patients present with hypertension,
diabetes mellitus and a characteristic body habitus (accen-
tuated by moon facies, central obesity, and a dorsoscapular
fat pad). Patients will also frequently have facial plethora,
abdominal striae, and purpura. A common presenting symptom
 TUMOR

stress, systemic inflammation and normal physiologic circadian

TABLE 8. Systemic Effects of Hypercortisolism rhythm. CRH drives the release of ACTH from the anterior
pituitary gland, which enters the systemic circulation and triggers
System Signs/symptoms
the adrenal cortex to stimulate and produce glucocorticoids,
General Fatigue, immune suppression, poor wound including cortisol.
healing, glucose intolerance
Habitus Obesity, moon face, buffalo hump Cushing’s Disease
Neuropsychologic Headache, depression, anxiety, irritability,
emotional lability, cognitive decline
Cushing’s disease is caused by a benign monoclonal pituitary
Vascular Hypertension corticotrophic adenoma that secretes excess ACTH into the
Cutaneous Hirsutism, abdominal striae, acne, thinning of skin systemic circulation. These adenoma-related elevated levels of
Musculoskeletal Muscle wasting, osteoporosis ACTH result in supraphysiologic levels of cortisol production
Reproductive Decreased libido; females—amenorrhea; from the adrenal cortex (Figure 9). While elevated levels of cortisol
males—erectile dysfunction suppress CRH release from the hypothalamus via normal negative
Signs and symptoms are secondary to persistent elevations in systemic cortisol levels. feedback inhibition, the adenoma is relatively resistant to negative
feedback by circulating cortisol, allowing it to constitutively
in postpubertal women is amenorrhea. Pediatric patients may produce ACTH. Constant adenoma-related ACTH production
also present with slowed or arrested linear growth. Cushing’s in Cushing’s disease disrupts the normal circadian release of
disease can also lead to a myriad of psychiatric and neurocog- ACTH and cortisol.
nitive deficits, including depression, anxiety, psychosis, suicidal
ideation, paranoia, learning impairment, and memory deficits. Diagnosis
Endocrinologic Evaluation
Pathophysiology The most common cause of Cushing’s syndrome is exogenous
Normal Physiology or iatrogenic steroid administration. Once exogeneous sources
An understanding of the normal physiologic production of have been excluded, screening tests (Figure 10), including late
cortisol is critical to diagnosis, localization and treatment of night salivary cortisol, 24-h urine free cortisol and/or a low-
the underlying pathophysiology in Cushing’s syndrome patients. dose dexamethasone testing are used to establish the etiology
CRH is released from the paraventricular nucleus of the hypotha- of Cushing’s syndrome (Table 9). Once an endogenous source
lamus into the hypophyseal portal venous system in response to has been established, localizing the principle source of increased

FIGURE 9. Hypothalamic–pituitary–adrenal axis in healthy patients, Cushing’s disease and in response to diagnostic testing. In normal physiology (far left), hypothalamic
secretion of CRH stimulates ACTH release from the anterior pituitary gland, prompting release of cortisol from the adrenal gland, which provides negative feedback
inhibition to the hypothalamus and pituitary gland. In Cushing’s disease (left), ACTH is constitutively produced by the pituitary adenoma, generating increased cortisol
production. While this provides negative feedback to the hypothalamus and decreased release of CRH, it is not enough to overcome the continual ACTH release from the
adenoma. CRH stimulation testing (right) produces a significant increase in ACTH from the adenoma, resulting in a profound increase in systemic cortisol levels. On the
other hand, high-dose dexamethasone testing (far right) is able to provide enough negative feedback to the pituitary adenoma, prompting a temporary decrease in systemic
cortisol.
ELDER ET AL

FIGURE 10. Diagnostic work-up of Cushing’s syndrome. Following initial clinical presentation, screening tests are used to
demonstrate the presence of elevated cortisol and Cushing’s syndrome. Next, ACTH dependency is established, after which the
primary source of ACTH is localized. If noninvasive diagnostic work-up is not definitive, IPSS can be undertaken to delineate
the primary source of elevated ACTH.

cortisol production is determined. Plasma ACTH levels are
obtained to evaluate ACTH dependency. Pathophysiologically
elevated ACTH-levels in Cushing’s syndrome patients indicates
an ACTH-secreting source, either due to Cushing’s disease or an
ectopic source, as opposed to primary cortisol production as seen
in adrenal tumors in which ACTH levels are suppressed.
While ACTH-dependent sources of elevated cortisol typically
are secondary to Cushing’s disease (ie, pituitary adenoma as the
source), ectopic sources must be ruled out. Although functional
corticotrophic pituitary adenomas produce ACTH in a consti-
tutive manner, they do contain CRH receptors and will respond
positively to CRH stimulation testing. Generally, a 50% increase

in ACTH or 20% increase in cortisol following CRH stimulation
indicates a pituitary adenoma, whereas no response following
CRH stimulation indicates an ectopic source. Similarly, high-dose
dexamethasone suppression testing (unlike low-dose suppression
testing) suppresses adenoma-associated ACTH production via
native receptors expressed by adenoma corticotroph cells via
negative feedback. Eighty percent of Cushing’s disease patients
will have a 50% or greater decrease in serum cortisol levels
after high-dose dexamethasone suppression testing, while ectopic
ACTH-secreting tumors will typically not suppress.
MRI: The majority (90%) of pituitary adenomas in Cushing’s
disease are microadenomas with an average diameter of 6 mm
at the time of diagnosis. Largely due to small size and imaging
constraints, only half of these adenomas are visible on MRI,
despite a positive clinical and biochemical diagnosis. To enhance
resolution of potential sellar adenomas, MRI with a specific
pituitary protocol are typically utilized. High-resolution spoiled
gradient recalled acquisition sequences can increase diagnostic
accuracy by up to 30% compared to other standard MR
sequences.
IPSS: When a Cushing’s syndrome patient is found to be
ACTH-dependent, but high-dose dexamethasone testing, CRH
stimulation testing and MRI fail to establish an ectopic or
pituitary source, IPSS can help delineate between a central or
peripheral source. Venous drainage from the pituitary gland
empties directly into the ipsilateral cavernous sinus and then
the inferior petrosal sinus. Comparing ACTH levels in blood
obtained directly from bilateral IPSS compared to simultane-
ously obtained systemic blood can differentiate between Cushing’s
disease and an ectopic ACTH source. Combining IPSS with
CRH stimulation testing can decrease false negatives and increase
diagnostic accuracy. While diagnostic accuracy approaches 100%,
IPSS carries a risk of venous infarction of the brainstem, resulting
in severe neurological deficits. While rare, the severity of this
potential complication limits the use of IPSS to cases with
conflicting biochemical analysis and radiologic studies or with
negative MRI.
Treatment
Surgical Resection
Given the significant morbidity and mortality associated with
Cushing’s disease and the immediate elimination of excess cortisol
production following selective adenomectomy, surgical resection
is the initial treatment of choice. Furthermore, surgical resection
of a pituitary adenoma allows for normal pituitary function
following surgery. Transsphenoidal surgery, either through an
endonasal or sublabial approach, is typically employed. As an
adenoma grows, it compresses the surrounding pituitary tissue
and forms a pseudocapsule that can be used to facilitate complete
resection while preserving the surrounding normal pituitary
gland. Partial or complete hypophysectomy can be used in cases
where an adenoma cannot be identified. Reports of the recent
TUMOR
surgical remission rates after surgery are between 65% and 85%
with recurrence rates between 10% and 35%.
Successful surgical treatment is associated with MR-visible
adenomas that do not invade the cavernous sinus. To determine
surgical success and biochemical remission, numerous criteria
have been proposed, including low morning serum cortisol, low
24-h urine free cortisol, low serum ACTH levels and low salivary
cortisol within the first week. One of the best positive predictors
of successful biochemical remission is a morning cortisol level of
less than 1 μg/dL on postoperative days 3 to 5 (96% positive
predictive value of remission). Importantly, as cortisol levels drop
precipitously following surgical cure, patients are at risk for devel-
opment of glucocorticoid withdrawal syndrome, which is treated
with exogenous steroid administration.
The presence of hypercortisolism (and some cases of
eucortisolism) following surgery indicates incomplete adenoma
resection. Absence of complete adenoma removal can be
secondary to several factors, including removal of abnormal
appearing tissue that is histologically normal pituitary, incomplete
removal of an adenoma within the pituitary and/or incomplete
removal of an adenoma that is locally invading dura of the
sella and/or the cavernous sinus. Early repeat surgery for incom-
plete adenoma removal offers an excellent chance biochemical
remission (especially in the first 2 described scenarios). Delayed
recurrence of Cushing’s disease can occur months to years
following initial remission. In these cases, recurrence typically
occurs secondary to regrowth of microscopic adenoma remnants
at the initial site of adenoma removal, for which surgical re-
exploration and resection is also recommended.
Adjuvant Therapy
Medical
While surgical resection is the initial treatment of choice,
medical therapy may be used as second-line treatment when
surgery fails to provide a biochemical cure or for unresectable
lesions. The following medications are typically utilized in the
interim period following radiation, before radiotherapy becomes
fully effective. Steroidogenesis inhibitors, such as ketoconazole
or metyrapone, which block adrenal cortisol production, may
be used. While ketoconazole was found to normalize urine free
cortisol in 49% of patients, it is associated with gastrointestinal
side effects, hepatic dysfunction and inhibition of testosterone
production (often used in females). Metyrapone has significant
gastrointestinal side effects and may exacerbate hypertension or
hirsuitism (often used in males). Inhibition of ACTH production
may also be achieved with the use of pasireotide or cabergoline,
which directly inhibit adenoma corticotrophic cells. Pasireotide
can achieve an average 50% reduction in urine free cortisol, but
is limited by gastrointestinal symptoms and significant hyper-
glycemia. Cabergoline is similarly effective. However, its effec-
tiveness is lost over time in 33% of patients. Mifepristone can
be used to block glucocorticoid receptors directly, although its
efficacy is limited. Side effects are limiting as well, and use in
ELDER ET AL

TABLE 9. Screening and Diagnostic Tests for Cushing’s Disease

Ectopic Ectopic
ACTH-secreting cortisol-secreting
Diagnostic test(s) Cushing’s disease tumor tumor

Cortisol
Late night salivatory cortisol Elevated Elevated Elevated
24-h urine free cortisol Elevated Elevated Elevated
Low-dose dexamethasone test Elevated Elevated Elevated
ACTH Dependency
Serum ACTH level Elevated Elevated Low
Pituitary source
CRH stimulation 50/20% ACTH/cortisol increase No change No change
High-dose dexamethasone test 50% cortisol decrease No change No change
MRI pituitary Visible tumor in 50% Normal Normal
IPSS IPS:peripheral ACTH > 1.4:1 1 : 1 ratio 1 : 1 ratio

ACTH, adrenocorticotrophic hormone; CRH, corticotropin-releasing hormone; IPS, inferior petrosal sinus; IPSS, inferior petrosal sinus sampling; MRI, magnetic resonance imaging
Diagnosis of Cushing’s disease begins by establishing hypercortisolism, followed by ACTH dependency, and ultimately establishing the pituitary as the primary source of endocrino-
logic dysfunction.

women of childbearing age is not advised given its abortifacient
properties.
Radiation
Whether administered in fractionated form or as SRS,
radiation therapy can be effective (40%-80% biochemical
remission) in Cushing’s disease patients. A disadvantage of
radiation therapy for Cushing’s disease is loss of pituitary function
over time, which has been seen in up to 40% of patients after
10 yr of follow-up. Use of this treatment modality is largely
limited to surgically unresectable adenomas invading the
cavernous sinus or other surrounding structures.
Adrenalectomy
Bilateral adrenalectomy may also be used in refractory cases,
achieving remission in 95% of cases. However, morbidity and
mortality rates are high at 18% and 9%, largely due to
stroke or myocardial infarction. Nelson’s syndrome is also of
significant concern after bilateral adrenalectomy (occurring in
21% of patients). Nelson’s syndrome, in which loss of cortisol
inhibition on corticotroph cells leads to progressive adenoma
growth and elevated ACTH levels, may require further pituitary
treatment, either through radiation therapy, surgical resection
and/or pharmacotherapy.
Discussion of Case Presentation
Given the patient’s presenting signs and symptoms, including
hypertension, diabetes, and obesity, Cushing’s syndrome was
suspected. She was not taking medication that could have exoge-
nously led to these cushingoid features. 24-h urine free cortisol
and a low-dose dexamethasone test confirmed the presence hyper-
cortisolism and her serum ACTH level was elevated. With a
visible pituitary microadenoma on MRI, no further testing was
required. Surgical resection was recommended and the patient
underwent successful microsurgical sublabial transsphenoidal
surgery. Forty-eight hours after surgery her morning cortisol level
was less than 1 μg/dL, consistent with biochemical remission.
Pearls
√
While Cushing’s syndrome may have numerous etiologies,
Cushing’s disease occurs secondary to a pituitary
√ microadenoma of corticotrophic cells.
Establishing the primary source of hypercortisolim can be
performed with a combination of biochemical, radiographic,
√ and invasive testing as needed to confirm a diagnosis.
Transsphenoidal surgical resection is the treatment of choice,
although other treatment modalities are available if this fails to
produce a biochemical cure.
SUGGESTED READING
1. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis,
and management. J Neurosurg. 2017;126(2):404-417.
2. Mehta G, Lonser RR, Oldfield EH. The history of pituitary surgery for Cushing
disease. J Neurosurg. 2012;116(2):261-268.
3. Esposito F, Dusick JR, Cohan P, et al. Clinical review: early morning cortisol levels
as a predictor of remission after transsphenoidal surgery for Cushing’s disease. J Clin
Endocrinol Metab. 2006;91(1):7-13.
4. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. The
Lancet. 2015;29(9996):913-927.
5. Molitch ME. Diagnosis and treatment of pituitary adenomas: A review. 2017;
317(5):516-524.
 TUMOR

d. Parasagittal
2. Which of the following exposures is most clearly associated
with meningioma?
a. Exogenous hormones
b. Low fiber diet
c. Cell phone use
d. Ionizing radiation
e. Premature birth
3. Which of the following would most likely prompt surgical
resection?
a. 80 yr of age or older
b. Homogenously enhancing lesion on MRI
c. Developing symptoms refractory to medical treatment
d. Multiple small meningiomas
e. Migraine-like headaches
4. Besides atypical histology, which of the following is the most
important risk factor for recurrence?
a. Location
b. Age at diagnosis
c. Preoperative embolization
d. Presenting symptom
e. Extent of resection

Epidemiology
Meningiomas are the most common benign intracranial
neoplasms, accounting for 33.8% of all primary brain and CNS
tumors. Prevalence of pathologically confirmed meningioma is
estimated to be approximately 97.5/100 000 in the United States.
The strongest risk factor for incidence is older age, with peak
at 45 yr of age. There is a 2:1 female to male predominance in
incidence. Because most meningiomas are benign in nature, the
overall 5-yr survival is above 90%. Atypical and malignant menin-
giomas comprise about 20% and 1%, respectively, of all menin-
giomas and have a slight male predominance. Ionizing radiation
is the most clearly associated environmental exposure factor with
meningioma, demonstrating a 6- to 10-fold increase in incidence.
There is an overall 2-fold increased risk noted among first-degree
relatives of affected individuals, and specific association with NF-
CHAPTER 5: SUPRATENTORIAL MENINGIOMAS 2 syndrome, chromosome 22 abnormalities, usually in the form
of loss of heterozygosity or partial deletion of 22q, BRCA1-
Case Presentation interacting protein 1, ATM, and others. An association between
A 57-yr-old female with an 8-mo history of progressive hormones and meningioma risk has been suggested by increased
headaches was sent for MRI with and without gadolinium by incidence of postpubertal disease in women vs men (2:1). These
her neurologist. The study revealed a 1.5 cm extra-axial homoge- factors include presence of estrogen, progesterone, and androgen
nously enhancing lesion along the right parietal convexity. She receptors on some meningiomas, an association between breast
was referred to clinic for evaluation. At examination, the patient cancer and meningiomas (see above), indications that menin-
has a normal neurological exam. giomas change in size during the luteal phase of the menstrual
cycle and pregnancy, and the regression of multiple meningiomas
Questions in a patient following cessation of estrogen agonist therapy.
1. Meningiomas are most commonly located in which of the
following locations? Pathology
a. Lateral ventricle Meningiomas are thought to arise from the meningothelial cells
b. Olfactory groove found in arachnoid granulations rather than the dura itself. In
c. Sphenoidal ridge 2000, the WHO released their fourth edition of the classification
ELDER ET AL
FIGURE 11. Meningiomas are commonly described based on their anatomic location as depicted in these illustrations. Printed with permission from
Health System.
of meningiomas. There are 3 grades based on degree of malig-
nancy, and 13 subgrades based on histopathology. Grade I
meningiomas comprise the most common of all meningiomas,
(70%-80%) with 9 subgrades. They contain no histopathological
characteristics of invasion (and are thus benign). The 3 most
common histopathological subgrades for grade I meningiomas
are meningothelial, fibrous, and transitional. Grade II menin-
giomas (∼20%) show more aggressive characteristics including
atypia and brain invasion. This last criterion was only included
in the last edition of the WHO guidelines, but appears to be
the strongest prognostic indicator. There are only 3 subgrades of
grade II meningiomas: chordoid, clear-cell, and atypical. Finally,
approximately 1% to 2.8% of meningiomas are grade III. They
are the most aggressive and have 3 subgrades: anaplastic, papillary,
and rhabdoid. WHO grade III meningiomas are characterized by
the presence of more than 20 mitoses per 10 hpf and evidence of
necrosis. On immunohistochemistry, these tumors show positive
staining for epithelial membrane antigen and vimentin, weak or
negative staining for S-100, and negative cytokeratin staining.
Proliferation indices, Ki-67 or MIB-1, are frequently used and
correlate with prognosis. The grade of the meningioma is an
important marker in determining progression free and overall
survival, with higher grade meningiomas, especially grade III,
faring far worse than their benign counterparts. While the WHO
classification is satisfactory in determining the treatment plan
for physicians and the health care team, it has some limita-
tions. Since 2000, there has been an effort to determine certain

C Mount Sinai
molecular markers within each grade with the aim of creating a
more accurate classification system in the future.
Location
Meningiomas arise from arachnoid cap cells and can thus be
present in any location where these cells are found (Figure 11).
Most commonly, they arise from the dura of the superior sagittal
sinus (parasagittal), convexity, anterior skull base, and sphenoid
wing (Table 10).
Clinical Presentation
Meningiomas are discovered incidentally in up to 50% of cases.
With the recent surge in cranial imaging, this percentage seems to
be increasing. Initial symptoms at presentation are mostly related
to mass effect/edema, tumor location and increased intracranial
pressure. In up to 48% of meningiomas the presenting symptom
is headache, but focal seizures, weakness, sensory changes, altered
mental status, or cranial nerve palsies can also be seen. There
are a number of classic syndromes which have been identified
for meningiomas arising from specific locations, such as person-
ality change, anosmia, ipsilateral optic atrophy, and contralateral
papilledema from large olfactory groove meningiomas (Foster
Kennedy Syndrome), or ipsilateral hearing loss, facial numbness,
and balance problems from meningiomas that arise in the internal
auditory canal.

TABLE 10. Locations of Meningiomas
Location
Parasagittal
Convexity
Tuberculum sellae
Sphenoidal ridge
Olfactory grove
Falx
Lateral ventricle
Tentorial
Middle fossa
Orbital
Yamshita J, Handa H, Iwaki K, et al. Recurrence of intracranial meningiomas, with special
reference to radiotherapy. Surg Neurol. 1908;14;33-40.
Radiologic Characteristics
Magnetic Resonance Imaging
MRI is currently the principal imaging modality in the
diagnosis, classification, and treatment planning of meningiomas.
Meningiomas are extra-axial lesions and demonstrate avid, usually
homogeneous contrast enhancement. In many cases, a dural tail
can be seen, and hyperostosis of the overlying bone is often
noted. On T2 sequences, flow voids can suggest increased vascu-
larity. Often a generous cleft of CSF can be seen separating the
tumor from the underlying brain and implies a good surgical
plane. Lack of a CSF cleft and presence of peritumoral edema
suggest a poor surgical plane and make complete resection more
challenging. Increased T2 signal in the tumor itself correlates with
water content and generally implies a more suckable tumor.
Computed Tomography
CT can serve as an adjunct to MRI as it more clearly delin-
eates bony anatomy. This can show hyperostosis and indicate the
origin of the tumor in more detail. In addition, it may show calci-
fications which are often seen with meningiomas and are thought
to correlate with more indolent behavior.
Treatment
The 3 main management strategies for intracranial menin-
giomas are observation, surgery, and radiation therapy. There
is very limited data to support the role of chemotherapy in
TABLE 11. Simpson Grade
Grade
I Gross total resection of tumor, dural attachment, and involved bone
II Gross total resection of tumor and coagulation of dural attachment
III Gross total resection of tumor without resection or coagulation of dural attachment
IV Subtotal resection of tumor
V Decompression of tumor or biopsy
TUMOR
meningiomas, although future treatments will be based upon an
improved understanding of their molecular biology.
%
Observation
20.8 The literature indicates that a large number (32% up to
15.2
78%) of meningiomas do not exhibit any evidence of growth
12.8
11.9
in a certain time frame. However, about 10% of patients who
9.8 are initially asymptomatic can become symptomatic over time.
8 Several studies have concluded that up to 40% of asymptomatic
4.2 meningiomas grow at a linear rate of ∼2 to 3 mm per year.
3.6 Although benign meningiomas follow a linear growth rate, higher
3 grade meningiomas may demonstrate exponential growth. Some
1.2
of the imaging characteristics that may suggest potential for
growth include T2 hyperintensity, peritumoral edema, irregular
tumor borders or lack of calcification.
Because most incidental meningiomas tend to show minimal
growth, they can be elected for observation with serial imaging
(every 6 mo). It is important to mention that some authors argue
that the threshold for treatment in younger patients is usually
lower because of the presumption that the tumor will eventually
grow and cause symptoms prompting surgical intervention. Some
studies recommend that surgery should be considered for patients
whose tumor growth rate is more than 1 cm3 /yr on repeated
examinations or who develop symptoms refractory to medical
treatment, but the patient’s age and medical condition should be
considered.
Surgery
In tumors that are symptomatic or growing and surgi-
cally accessible, surgery remains the mainstay of therapy. The
general goal is to achieve complete resection of the tumor and
surrounding dural margin, as well as removal of hyperostotic
bone. Donald Simpson, in 1957, documented the relationship
between extent of resection and recurrence rate of meningiomas,
and the commonly used Simpson grading system is based on these
observations (Table 11). Meningiomas are approached through
a generous craniotomy to allow for resection of a dural margin
(when feasible) along with the tumor. Resection proceeds by a
combination of internal debulking and detachment of the tumor
from underlying brain (Video 4). If the tumor overlies eloquent
cortex and does not have a good plane, a carpet of tumor can
be left behind. Early coagulation of feeding vessels assists in
decreasing blood loss. If high vascularity is suspected and the
Extent of resection Recurrence over 10 yr (%)
9
19
29
40
89
ELDER ET AL

√
Depending on symptomatology, presumed surgical risk, and
patient factors, management strategies can include surveillance,
√ surgery, and radiotherapy.
Most important risk factors for recurrence are atypical histology
and extent of resection.

VIDEO 4. Surgery for resection of a parafalcine meningioma.
SUGGESTED READING
1. Wiemels J, Wrensch M, Claus EB. Epidemiology and etiology of meningioma. J
Neurooncol. 2010;99(3):307-314.
2. Olivero WC, Lister JR, Elwood PW. The natural history and growth rate of asymp-
tomatic meningiomas: a review of 60 patients. J Neurosurg. 1995;83(2):222-224.
3. Perry A, Louis DN, Scheithauer BW, Budka H, von Deimling . Meningiomas.
In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification
of Tumours of the Central Nervous System. Lyon: IARC Press; 2007.
4. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J
Neurol Neurosurg Psychiatry. 1957;20(1):22-39.

anatomy of the tumor does not allow early devascularization,

preoperative embolization can be considered in some cases.

Radiation Therapy
Radiation is an excellent alternative treatment option for
meningiomas not amenable to surgical resection due to high
risk of neurological morbidity from surgery itself or medical
comorbidities increasing the risk of anesthesia. Several modalities
of radiotherapy have been studied. SRS such as Gamma Knife
(Elekta AB) or Cyberknife (Accuray) have been used with great
success for small, surgically inaccessible tumors. For example,
large series of cavernous sinus meningiomas have shown over
90% control rate at 5 yr. For larger tumors or those adjacent
to radiosensitive structures, fractionated radiotherapy can be
considered instead. In addition, radiotherapy is frequently used
for higher grade meningiomas after resection, and for benign
meningiomas with growing residual tumor after initial resection.

Outcomes
The most important risk factors for recurrence are extent of
resection and pathological grades, with 12%, 41%, and 56%
5-yr recurrence rates for grades I, II, and III, respectively. Thus,
even after complete resection of a grade I meningioma, continued
follow-up with surveillance imaging is indicated. Various studies
conclude that outcomes are superior at centers that perform a
higher number of meningioma resections.

Pearls
√
Meningiomas are the most common extra-axial brain tumors
√ and arise from arachnoid cells.
√ The majority are benign, though high-grade variants do exist.
Most common locations: parasagittal, convexity, and sphenoid
√ bone.
On imaging (MRI): Homogenously enhancing on gadolinium
sequences with dural tail.