Gen Pathology (Dr.

Yabut)

CNS PART 2: CNS TUMORS

16 February 2008

CNS TUMORS • variable nuclear pleomorphism

• GFAP (+) astrocytic cell processes
• intracranial 10-17 : 100,000 population
• Intraspinal 1-2: 100,000 population Anaplastic
• densely cellular
• Primary ½-¾ • Mitotically active
• Metastatic – remainder
• 20% of childhood tumors Gemistocytic
• Posterior fossa (70%) • Neoplastic astrocytes
• Adults – cerebral hemispheres • Brightly eosinophilic cell body, stout processes

• Distinction between benign and malignant less distinct ASTROCYTOMA

• Limited ability to resect without compromise of neuro
function
• Anatomic site can have lethal consequences
• Rarely metastasize outside CNS
• subarachnoid space – brain and spinal cord
seeding

4 MAJOR CLASSES
 Gliomas
 Neuronal tumors
 Poorly differentiated neoplasms
 Meningiomas

GLIOMAS

• Astrocytomas
• Oligodendrogliomas
• Ependymomas

A. ASTROCYTOMAS
Categories:
• Fibrillary
• Glioblastoma
• Pilocytic
• Pleomorphic Xanthoastrocytoma

1. Fibrillary (Diffuse) Astrocytoma

• 80% of adult primary brain tumors
• Cerebral hemisphere
• Cerebellum, brainstem, spinal cord
• Age: 40 – 60
• Symptoms: seizures, headaches, focal neuro deficits
Morphology:
• well differentiated GEMISTOCYTIC ASTROCYTOMA
• less differentiated
• poorly defined 2. Glioblastoma (Glioblastoma Multiforme)
• gray infiltrative tumor expand and distort the • variable gross appearance
brain • Firm white to soft and yellow
• few cm’s to displace entire hemispheres • Well demarcated with infiltration beyond outer margin
• firm or gelatinous Microscopic:
• cystic degeneration • Similar to Anaplastic
• Necrosis – “pseudopalisading”
Gliomatosis cerebri - multiple regions of the brain • Vascular or endothelial proliferation –
infiltrated by neoplastic astrocytes “glomeruloid body”

Microscopic:
• mild to mod inc in number of glial cell nuclei
brim, leu, virns 1 of 7
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 2 of 7

PILOCYTIC ASTROCYTOMA

Clinical
• Grow very slowly
• Cerebellar tumors treated with resection
GLIOBLASTOMA • Rarely have p53 mutations or other changes
found in diffuse fibrillary
WHO Grading
4. Pleomorphic Xanthoastrocytoma
Grade I/IV Pilocytic • Relatively superficial
Grade II/IV Well differentiated astrocytomas • Temporal lobe
Grade III/IV Anaplastic
• Children and young adults
Grade IV/IV Glioblastoma
• Long history of seizures
Molecular Genetics Microscopic:
• Inactivation of p53 • neoplastic occ bizarre astrocytes
• Overexpression of PDGF-A and its receptors • nuclear atypia can be extreme and may suggest
high grade astrocytoma
• Transition to higher grade associated with
• abundant reticulin deposits
additional disruption of tumor suppressor genes,
the RB genes, p16/CDKNZA gene, putative tumor • relative circumscription
suppressor on chromosome 19q • chronic inflammatory cell infiltrates
• absence of necrosis and mitotic activity
Clinical Features: • WHO grade II/IV
• Presenting symptoms depend in part on location • 80% survival rate at 5 years
of tumor and growth rate
• Well-differentiated remain static, progress slowly B. OLIGODENDROGLIOMAS
• Mean survival 5 years • 5 - 15%
• Anaplastic present with rapid deterioration, very • Age: 40 – 50
poor prognosis • Seizures for several years
• Current treatment (resection, radiotx, chemotx) • Predilection for white matter, cerebral hemispheres
• 8 – 10 mos surivival Morphology:
• < 10% alive after 2 yrs • well-circumscribed, gelatinous, gray masses
• often with cysts, focal hemorrhage and
3. Pilocytic calcification
• Children and young adults Microscopic:
• Cerebellum, floor and wall of 3rd ventricles, optic • Sheets of regular cells with spherical nuclei
nerves, cerebral hemispheres containing finely granular chromatin surrounded
Morphology by clear halo of cytoplasm
• often cystic, with mural nodule in the cyst wall • Delicate network of anastomosing capillaries
• If solid, well circumscribed, less frequently • Calcifications in 90%
infiltrative • Low mitotic activity
Microscopic: • WHO grade II/IV
• Bipolar cells with long thin “hairlike” processes • Anaplastic oligodendrogliomas – increased cell
that are GFAP (+) density, nuclear anaplasia, inc mitotic activity,
• Rosenthal fibers necrosis
• Eosinophilic granular bodies Molecular genetics:
• Microcysts • loss of heterozygosity for chromosomes 1p and
• Increase no. of blood vessels 19q
• Necrosis and mitosis uncommon • If without other alterations consistent and long
• Narrow infiltrative border lasting response to chemotherapy and radiation
Clinical Features:
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 3 of 7

• Better prognosis than astrocytomas • Posterior fossa ependymomas manifest with

• Ave 5 – 10 years survival hydrocephalus sec to obstruction of 4th ventricle
• Prognosis is poor
• CSF dissemination is common

OTHER TUMORS ASSOCIATED WITH OTHER CELL TYPE

THAT FORMS THE VENTICULAR SYSTEM:
• Subependymomas
• Choroid plexus papillomas
• Colloid cyst of the third ventricle

NEURONAL TUMORS

A. GANGLION CELL TUMORS

• Contain ganglion cells
• Gangliocytoma – entire population of lesion
• Ganglioglioma – admixture with glial neoplasm
OLIGODENDROGLIOMA
• Slow growing
C. EPENDYMOMAS • Glial components occ become anaplastic and
• Arise next to ependyma-lined ventricular system progress rapidly
• First 2 decades – 4th ventricle • Present with seizure disorder
• 5 – 10% of primary brain tumors • WHO grade I-II/IV
• Adults – most common in spinal cord
Morphology: B. OTHER TUMORS WITH GLIAL AND NEURONAL
• In 4th ventricle, solid or papillary masses COMPONENTS
• Intraspinal, sharply demarcated i. Dysembryoplastic Neuroepithelial Tumor
Microscopic: (DNT)
• Cells with regular, round to oval nuclei with • Low grade tumor of childhood
abundant granular chromatin • Seizure disorder
• Dense fibrillary background • Slow growth
• Rosettes, canals • Good prognosis
• Perivascular pseudorosettes
• GFAP (+) C. TUMORS WITH ONLY NEURONAL ELEMENTS
i. Cerebral Neuroblastoma
• Rare, occur in children, highly aggressive
• Resemble peripheral neuroblastomas
• Homer Wright rosettes
ii. Central Neurocytoma
• Low grade neuronal tumors
• Lateral and third ventricles
• Resemble oligodendroglioma

POORLY DIFFERENTIATED NEOPLASMS

• Medulloblastoma
• Atypical Teratoid/Rhabdoid Tumor (AT/RT)

A. MEDULLOBLASTOMA
EPENDYMOMA • Predominantly in children
• Exclusively in the cerebellum
Morphology: • Largely undifferentiated
• Well-differentiated – WHO Grade II/IV Morphology
• Anaplastic ependymomas – WHO Grade III/IV • Midline of cerebellum
• Myxopapillary ependymomas – occur in filum • Lateral in adults
terminale of spinal cord • Well circumscribed, gray and friable
• Papillary elements in myxoid background Microscopic:
Molecular genetics: • Extremely cellular, sheets of anaplastic cells
• Spinal ependymomas associated with • Little cytoplasm
Neurofibromatosis 2 and NF2 gene on • Hyperchromatic nuclei, elongated or crescent
chromosome 22 shaped
Clinical features: • Mitosis abundant
• (+) Ki-67 markers
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 4 of 7

• Express neuronal (neurosecretory granules, • Pineocytomas – well-differentiated

Homer Wright rosettes) and glial (GFAP) • Pineoblastomas – high grade tumors
phenotypes
Molecular Genetics: MENINGIOMAS
• Loss of short arm of chromosome 17
• Benign tumors of adults
• Attached to dura
• Arise from meningothelial cell of arachnoid
• External surface of brain as within the ventricular
system
Morphology:
• Rounded, bosselated, polypoid masses
• Well-defined dural base that compress underlying
brain but easily separated from it
• May extend to overlying bone
• Encapsulated with thin fibrous tissue
• “en plaque” variant – spreads in sheetlike fashion
along the surface of dura
• Most are WHO grade I/IV
TYPES
• Syncytial
• Fibroblastic
MEDULLOBLASTOMA • Transitional
• Psammomatous
Clinical features: • Secretory
• Highly malignant • Microcystic
• Prognosis dismal in untreated patients • Atypical meningiomas – mitotic index of 4 or
• radiosensitive more mitosis/10 hpf, 3 or more atypical features
• Better survival following complete resection (inc cellularity, small cells with high N:C ratio,
• 75% 5-year survival rate for total excision and prominent nucleoli, patternless growth, necrosis)
radiation • Anaplastic (malignant)Meningioma
• WHO grade III/IV
B. ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) • Mitosis >20/10 hpf
• Highly malignant tumor of young children
• Posterior fossa and supratentorial compartments
• “rhabdoid cells” resembling those of a
rhabdomyosarcoma
• 90% - Loss of genetic material from chromosome 22
• Very young patients – before age 5
• Live less than a year after diagnosis

OTHER PARENCHYMAL TUMORS

• Primary CNS Lymphoma

• Germ cell tumors
• Pineal Parenchymal Tumors

A. PRIMARY CNS LYMPHOMA

• 2% of extranodal lymphomas
• 1% of intracranial tumors
• Most common CNS neoplasm in immunosuppressed
(AIDS)
• Occur in multiple sites WITHIN the brain parenchyma
• Majority B-cell origin
• Poor response to chemotherapy

B. GERM CELL TUMORS MENINGIOMA

• Midline
• Most common in pineal and suprasellar regions Clinical Features:
• 0.2% to 1% of brain tumors among Europeans • Slow growing
• 10% of brain tumors in Japanese • Vague nonlocalizing symptoms or focal findings
• 90% occur during first two decades referable to compression of underlying brain
• More common are teratomas • Common sites: parasagittal aspect of brain
convexity, dura over latera convexity, wing of
C. PINEAL PARENCHYMAL TUMORS sphenoid, olfactory groove, sella turcica, foramen
• Arise from pineocytes magnum
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 5 of 7

• Usually solitary of moderate to high cellularity with little

• Multiple tumors assoc with acoustic neuroma or
glial tumors suggest neurofibromatosis type 2
METASTATIC TUMORS
• Mostly carcinomas
• Common primary sites (80%): lung, breast, skin
(melanoma), kidney, GIT
• Meninges are frequently involved
• Present clinically as mass lesions, may occasionally be
the first manifestation of cancer
• Grossly form sharply demarcated masses, at gray
matter-white matter junction, surrounded by zone of
edema
stromal matrix
• Antoni B – pattern of growth,less
densely cellular with loose meshwork of
cells along with microcysts and myxoid
changes
Clinical Features:
• Most common in cerebellopontine angle, attached
to vestibular branch of 8th cranial nerve
• Tinnitus and hearing loss
• “Acoustic neuroma” (vestibular schwannoma)

BRAIN METASTASES
SCHWANNOMA

PARANEOPLASTIC SYNDROMES B. NEUROFIBROMA

Two types:
• Involve the peripheral and central nervous systems • Cutaneous Neurofibroma (skin) or Solitary
• Most common in small cell carcinoma of the lung Neurofibroma (peripheral nerve)
• Examples • Dermis and subcutaneous fat
• Paraneoplastic cerebellar degeneration • Well-delineated, unencapsulated
• Limbic encephalitis • Spindle cells
• Subacute sensory neuropathy • Stroma highly collagenized
• Eye movement disorders, opsoclonus • Plexiform Neurofibroma – occur only in NF1
• Retinal degeneration • Involve major nerve trunks, potential for
• Stiff-man syndrome malignant transformation
• Lambert-Eaton myasthenic syndrome • Frequently multiple
• Loose myxoid background, low cellularity
PERIPHERAL NERVE SHEATH TUMORS • Schwann cells, multipolar fibroblastic
cells, inflammatory cells
 Arise from Schwann cells, perineurial cells, fibroblasts
 Express S-100 antigen, melanocytic differentiation C. MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
(MPNST, MALIGNANT SCHWANNOMA)
• Schwannoma • Highly malignant sarcoma
• Neurofibroma • Locally invasive, frequently leading to multiple
• Malignant Peripheral Nerve Sheath Tumor (MPNST, recurrences and metastasis
Malignant Schwannoma) • Arise de novo or from transformation of plexiform
neurofibroma
A. SCHWANNOMA • Assoc with NF type 1
• Neural crest-derived Schwann cell • “Triton tumor” – with rhabdomyoblastic differentiation
• Assoc with Neurofibromatosis type 2
• Well circumscribed, encapsulated masses attached to
nerve but can be separated from it FAMILIAL TUMOR SYNDROMES
• Firm, gray masses
• Cystic and xanthomatous change • Neurofibromatosis Type 1 (NF1)
Microscopic: • Neurofibromatosis Type 2 (NF2)
• Mixture of two growth patterns • Tuberous sclerosis
• Antoni A – pattern of growth of • Von Hippel Lindau Disease
elongated cells with cytoplasmic
processes arranged in fascicles in areas A. NEUROFIBROMATOSIS TYPE 1 (NF1)
• Autosomal-dominant disorder
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 6 of 7

• Neurofibromas (plexiform and solitary) Soaking wet, she decided to flag down the next car. A young white man
• Gliomas of optic nerve stopped to help her, generally unheard of in the conflict-filled 1960s. The
• Lisch nodules man took her to safety, helped her get assistance and put her into a
taxicab.
• Café au lait spots
• Propensity to undergo malignant degeneration She seemed to be in a big hurry, but wrote down his address and
thanked him.
B. NEUROFIBROMATOSIS TYPE 2 (NF2)
• Autosomal-dominant disorder Seven days went by and a knock came on the man's door. To his
• Bilateral VIII nerve schwannomas surprise, a
• Multiple meningiomas giant console color TV was delivered to his home. A special note was
• Ependymomas of spinal cord attached.
• Schwannosis It read: "Thank you so much for assisting me on the highway the other
• Meningioangiomatosis night. The rain drenched not only my clothes, but also my spirits. Then
• Glial hamartia you came along. Because of you, I was able to make it to my dying
husband's bedside just before he passed away... God bless you for
helping me and unselfishly serving others."
C. TUBEROUS SCLEROSIS
• Autosomal-dominant Sincerely, Mrs. Nat King Cole.
• Hamartomas
• Cortical tubers
• Subependymal hamartomas 3 - Third Important Lesson - Always remember those who
• Benign neoplasms involving the brain and other serve.
tissues
In the days when an ice cream sundae cost much less, a 10-year-old boy
• Renal angiomyolipomas entered a hotel coffee shop and sat at a table. A waitress put a glass of
• Retinal glial hamartomas water in front of him.
• Pulmonary lesions
• Cardiac rhabdomyomas "How much is an ice cream sundae?" he asked.
• Cysts in liver, kidneys, pancreas
• Cutaneous lesions e.g. "Fifty cents," replied the waitress.
Angiofibromas,Shagreen patches, ash-leaf
The little boy pulled is hand out of his pocket and studied the coins in it.
patches, subungal fibromas
"Well, how much is a plain dish of ice cream?" he inquired.
D. VON HIPPEL LINDAU DISEASE
• Autosomal-dominant By now more people were waiting for a table and the waitress was
• Capillary hemangioblastomas within the cerebellar growing impatient.
hemispheres, retina, less commonly in brain stem and
spinal cord "Thirty-five cents," she brusquely replied
• Cysts in pancreas, liver, kidneys
• Renal cell carcinoma The little boy again counted his coins.
• Associated with polycythemia in 10% of
"I'll have the plain ice cream," he said.
hemangioblastomas
The waitress brought the ice cream, put the bill on the table and walked
FIVE (5) lessons to make you think about the way we treat people. away. The boy finished the ice cream, paid the cashier and left. When the
waitress came back, she began to cry as she wiped down the table. There,
1 - First Important Lesson - Cleaning Lady. placed neatly beside the empty dish, were two nickels and five pennies.

During my second month of college, our professor gave us a pop quiz. I
was a conscientious student and had breezed through the questions until
I read the last one:
"What is the first name of the woman who cleans the school? " Surely
this was some kind of joke. I had seen the cleaning woman several times.
She was tall, dark-haired and in her 50s, but how would I know her
name?
I handed in my paper, leaving the last question blank. Just before class
ended, one student asked if the last question would count toward our
quiz grade.
"Absolutely," said the professor. " In your careers, you will meet many
people. All are significant. They deserve your attention and care, even if
all you do is smile and say " hello".
I've never forgotten that lesson. I also learned her name was Dorothy.
2. - Second Important Lesson - Pickup in the Rain
One night, at 11:30 p.m., an older African American woman was
standing on the side of an Alabama highway trying to endure a lashing
rainstorm. Her car had broken down and she desperately needed a ride.
You see, he couldn't have the sundae, because he had to have enough left
to leave her a tip.
4 - Fourth Important Lesson - The obstacle in Our Path.
In ancient times, a King had a boulder placed on a roadway. Then he hid
himself and watched to see if anyone would remove the huge rock. Some
of the king's wealthiest merchants and courtiers came by and simply
walked around it. Many loudly blamed the King for not keeping the
roads clear, but none did anything about getting the stone out of the
way.
Then a peasant came along carrying a load of vegetables. Upon
approaching the boulder, the peasant laid down his burden and tried to
move the stone to the side of the road. After much pushing and
straining, he finally succeeded. After the peasant picked up his load of
vegetables, he noticed a purse lying in the road where the boulder had
been. The purse contained many gold coins and a note from the King
indicating that the gold was for the person who removed the boulder
from the roadway. The peasant learned what many of us never
understand!
Every obstacle presents an opportunity to improve our condition.
 Gen Pathology – CNS2: CNS Tumors by Dr. Yabut Page 7 of 7

5 - Fifth Important Lesson - Giving When it Counts...

Many years ago, when I worked as a volunteer at a hospital, I got to

know a little girl named Liz who was suffering from a rare & serious
disease. Her only chance of recovery appeared to be a blood transfusion
from her 5-year old brother, who had miraculously survived the same
disease and had developed the antibodies needed to combat the illness.
The doctor explained the situation to her little brother, and asked the
little boy if he would be willing to give his blood to his sister.

I saw him hesitate for only a moment before taking a deep breath and
saying, "Yes I'll do it if it will save her." As the transfusion progressed, he
lay in bed next to his sister and smiled, as we all did, seeing the color
returning to her cheek. Then his face grew pale and his smile faded.

He looked up at the doctor and asked with a trembling voice, "Will I

start to die right away."

Being young, the little boy had misunderstood the doctor; he thought he
was going to have to give his sister all of his blood in order to save her.
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