Cns Tumors

Gen Pathology (Dr. Yabut) CNS PART 2: CNS TUMORS 16 February 2008 • •

CNS TUMORS • •

intracranial Intraspinal

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Primary ½-¾ Metastatic – remainder 20% of childhood tumors • Posterior fossa (70%) Adults – cerebral hemispheres

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10-17 : 100,000 population 1-2: 100,000 population

Anaplastic • densely cellular • Mitotically active Gemistocytic • Neoplastic astrocytes • Brightly eosinophilic cell body, stout processes ASTROCYTOMA

Distinction between benign and malignant less distinct • Limited ability to resect without compromise of neuro function • Anatomic site can have lethal consequences • Rarely metastasize outside CNS

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variable nuclear pleomorphism GFAP (+) astrocytic cell processes

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 • less differentiated • poorly defined • gray infiltrative tumor expand and distort the brain • few cm’s to displace entire hemispheres • firm or gelatinous • cystic degeneration Gliomatosis cerebri - multiple regions of the brain infiltrated by neoplastic astrocytes

GEMISTOCYTIC ASTROCYTOMA 2.

Glioblastoma (Glioblastoma Multiforme) • variable gross appearance • Firm white to soft and yellow • Well demarcated with infiltration beyond outer margin Microscopic: • Similar to Anaplastic • Necrosis – “pseudopalisading” • Vascular or endothelial proliferation – “glomeruloid body”

Microscopic: • mild to mod inc in number of glial cell nuclei brim, leu, virns

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Gen Pathology – CNS2: CNS Tumors by Dr. Yabut

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PILOCYTIC ASTROCYTOMA Clinical • Grow very slowly • Cerebellar tumors treated with resection • Rarely have p53 mutations or other changes found in diffuse fibrillary

GLIOBLASTOMA WHO Grading Grade Grade Grade Grade

I/IV II/IV III/IV IV/IV

Pilocytic Well differentiated astrocytomas Anaplastic Glioblastoma

4.

Pleomorphic Xanthoastrocytoma • Relatively superficial • Temporal lobe • Children and young adults • Long history of seizures Microscopic: • neoplastic occ bizarre astrocytes • nuclear atypia can be extreme and may suggest high grade astrocytoma • abundant reticulin deposits • relative circumscription • chronic inflammatory cell infiltrates • absence of necrosis and mitotic activity • WHO grade II/IV • 80% survival rate at 5 years

B.

OLIGODENDROGLIOMAS • 5 - 15% • Age: 40 – 50 • Seizures for several years • Predilection for white matter, cerebral hemispheres Morphology: • well-circumscribed, gelatinous, gray masses • often with cysts, focal hemorrhage and calcification Microscopic: • Sheets of regular cells with spherical nuclei containing finely granular chromatin surrounded by clear halo of cytoplasm • Delicate network of anastomosing capillaries • Calcifications in 90% • Low mitotic activity • WHO grade II/IV • Anaplastic oligodendrogliomas – increased cell density, nuclear anaplasia, inc mitotic activity, necrosis Molecular genetics: • loss of heterozygosity for chromosomes 1p and 19q • If without other alterations consistent and long lasting response to chemotherapy and radiation Clinical Features:

Molecular Genetics • Inactivation of p53 • Overexpression of PDGF-A and its receptors • Transition to higher grade associated with additional disruption of tumor suppressor genes, the RB genes, p16/CDKNZA gene, putative tumor suppressor on chromosome 19q Clinical Features: • Presenting symptoms depend in part on location of tumor and growth rate • Well-differentiated remain static, progress slowly • Mean survival 5 years • Anaplastic present with rapid deterioration, very poor prognosis • Current treatment (resection, radiotx, chemotx) • 8 – 10 mos surivival • < 10% alive after 2 yrs 3.

Pilocytic • Children and young adults • Cerebellum, floor and wall of 3rd ventricles, optic nerves, cerebral hemispheres Morphology • often cystic, with mural nodule in the cyst wall • If solid, well circumscribed, less frequently infiltrative Microscopic: • Bipolar cells with long thin “hairlike” processes that are GFAP (+) • Rosenthal fibers • Eosinophilic granular bodies • Microcysts • Increase no. of blood vessels • Necrosis and mitosis uncommon • Narrow infiltrative border

Gen Pathology – CNS2: CNS Tumors by Dr. Yabut • •

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Better prognosis than astrocytomas Ave 5 – 10 years survival

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Posterior fossa ependymomas manifest with 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.

OLIGODENDROGLIOMA C.

EPENDYMOMAS • Arise next to ependyma-lined ventricular system • First 2 decades – 4th ventricle • 5 – 10% of primary brain tumors • Adults – most common in spinal cord Morphology: • In 4th ventricle, solid or papillary masses • Intraspinal, sharply demarcated Microscopic: • Cells with regular, round to oval nuclei with abundant granular chromatin • Dense fibrillary background • Rosettes, canals • Perivascular pseudorosettes • GFAP (+)

GANGLION CELL TUMORS • Contain ganglion cells • Gangliocytoma – entire population of lesion • Ganglioglioma – admixture with glial neoplasm • • • •

Slow growing Glial components occ become anaplastic and progress rapidly Present with seizure disorder WHO grade I-II/IV

B.

OTHER TUMORS WITH GLIAL AND NEURONAL COMPONENTS i. Dysembryoplastic Neuroepithelial Tumor (DNT) • Low grade tumor of childhood • Seizure disorder • Slow growth • Good prognosis

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 • • EPENDYMOMA Morphology: • Well-differentiated – WHO Grade II/IV • Anaplastic ependymomas – WHO Grade III/IV

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Myxopapillary ependymomas – occur in filum terminale of spinal cord • Papillary elements in myxoid background Molecular genetics: • Spinal ependymomas associated with Neurofibromatosis 2 and NF2 gene on chromosome 22 Clinical features:

A.

Medulloblastoma Atypical Teratoid/Rhabdoid Tumor (AT/RT)

MEDULLOBLASTOMA • Predominantly in children • Exclusively in the cerebellum • Largely undifferentiated Morphology • Midline of cerebellum • Lateral in adults • Well circumscribed, gray and friable Microscopic: • Extremely cellular, sheets of anaplastic cells • Little cytoplasm • Hyperchromatic nuclei, elongated or crescent shaped • Mitosis abundant • (+) Ki-67 markers

Gen Pathology – CNS2: CNS Tumors by Dr. Yabut •

Express neuronal (neurosecretory granules, Homer Wright rosettes) and glial (GFAP) phenotypes Molecular Genetics: • Loss of short arm of chromosome 17

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Pineocytomas – well-differentiated Pineoblastomas – high grade tumors

MENINGIOMAS • • • •

MEDULLOBLASTOMA Clinical • • • • • B.

features: Highly malignant Prognosis dismal in untreated patients radiosensitive Better survival following complete resection 75% 5-year survival rate for total excision and radiation

ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) • 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

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 • Transitional • Psammomatous • Secretory • Microcystic • Atypical meningiomas – mitotic index of 4 or more mitosis/10 hpf, 3 or more atypical features (inc cellularity, small cells with high N:C ratio, prominent nucleoli, patternless growth, necrosis) • Anaplastic (malignant)Meningioma • WHO grade III/IV • Mitosis >20/10 hpf

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 • Midline • Most common in pineal and suprasellar regions • 0.2% to 1% of brain tumors among Europeans • 10% of brain tumors in Japanese • 90% occur during first two decades • More common are teratomas

C.

PINEAL PARENCHYMAL TUMORS • Arise from pineocytes

MENINGIOMA Clinical Features: • Slow growing • Vague nonlocalizing symptoms or focal findings referable to compression of underlying brain • Common sites: parasagittal aspect of brain convexity, dura over latera convexity, wing of sphenoid, olfactory groove, sella turcica, foramen magnum

Gen Pathology – CNS2: CNS Tumors by Dr. Yabut • •

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Usually solitary Multiple tumors assoc with acoustic neuroma or glial tumors suggest neurofibromatosis type 2

of moderate to high cellularity with little stromal matrix

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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)

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

BRAIN METASTASES PARANEOPLASTIC SYNDROMES • • •

SCHWANNOMA B.

NEUROFIBROMA Two types:

Involve the peripheral and central nervous systems Most common in small cell carcinoma of the lung Examples • Paraneoplastic cerebellar degeneration • Limbic encephalitis • Subacute sensory neuropathy • Eye movement disorders, opsoclonus • Retinal degeneration • Stiff-man syndrome • Lambert-Eaton myasthenic syndrome

PERIPHERAL NERVE SHEATH TUMORS

A.

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Arise from Schwann cells, perineurial cells, fibroblasts Express S-100 antigen, melanocytic differentiation

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Schwannoma Neurofibroma Malignant Peripheral Nerve Sheath Tumor (MPNST, Malignant Schwannoma)

SCHWANNOMA • Neural crest-derived Schwann cell • Assoc with Neurofibromatosis type 2 • Well circumscribed, encapsulated masses attached to nerve but can be separated from it • Firm, gray masses • Cystic and xanthomatous change Microscopic: • Mixture of two growth patterns

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Antoni A – pattern of growth of elongated cells with cytoplasmic processes arranged in fascicles in areas

C.

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Cutaneous Neurofibroma (skin) or Solitary Neurofibroma (peripheral nerve) • Dermis and subcutaneous fat • Well-delineated, unencapsulated • Spindle cells • Stroma highly collagenized

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Plexiform Neurofibroma – occur only in NF1 • Involve major nerve trunks, potential for malignant transformation • Frequently multiple • Loose myxoid background, low cellularity • Schwann cells, multipolar fibroblastic cells, inflammatory cells

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST, MALIGNANT SCHWANNOMA) • Highly malignant sarcoma • Locally invasive, frequently leading to multiple recurrences and metastasis • Arise de novo or from transformation of plexiform neurofibroma • Assoc with NF type 1 • “Triton tumor” – with rhabdomyoblastic differentiation

FAMILIAL TUMOR SYNDROMES • • • • A.

Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 2 (NF2) Tuberous sclerosis Von Hippel Lindau Disease

NEUROFIBROMATOSIS TYPE 1 (NF1) • Autosomal-dominant disorder

Gen Pathology – CNS2: CNS Tumors by Dr. Yabut • • • • • B.

C.

D.

Neurofibromas (plexiform and solitary) Gliomas of optic nerve Lisch nodules Café au lait spots Propensity to undergo malignant degeneration

NEUROFIBROMATOSIS TYPE 2 (NF2) • Autosomal-dominant disorder • Bilateral VIII nerve schwannomas • Multiple meningiomas • Ependymomas of spinal cord • Schwannosis • Meningioangiomatosis • Glial hamartia TUBEROUS SCLEROSIS • Autosomal-dominant • Hamartomas • Cortical tubers • Subependymal hamartomas • Benign neoplasms involving the brain and other tissues • Renal angiomyolipomas • Retinal glial hamartomas • Pulmonary lesions • Cardiac rhabdomyomas • Cysts in liver, kidneys, pancreas • Cutaneous lesions e.g. Angiofibromas,Shagreen patches, ash-leaf patches, subungal fibromas VON HIPPEL LINDAU DISEASE • Autosomal-dominant • Capillary hemangioblastomas within the cerebellar hemispheres, retina, less commonly in brain stem and spinal cord • Cysts in pancreas, liver, kidneys • Renal cell carcinoma • Associated with polycythemia in 10% of hemangioblastomas

FIVE (5) lessons to make you think about the way we treat people. 1 - First Important Lesson - Cleaning Lady. 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.

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Soaking wet, she decided to flag down the next car. A young white man stopped to help her, generally unheard of in the conflict-filled 1960s. The man took her to safety, helped her get assistance and put her into a taxicab. She seemed to be in a big hurry, but wrote down his address and thanked him. Seven days went by and a knock came on the man's door. To his surprise, a giant console color TV was delivered to his home. A special note was attached. It read: "Thank you so much for assisting me on the highway the other night. The rain drenched not only my clothes, but also my spirits. Then 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." Sincerely, Mrs. Nat King Cole.

3 - Third Important Lesson - Always remember those who serve. In the days when an ice cream sundae cost much less, a 10-year-old boy entered a hotel coffee shop and sat at a table. A waitress put a glass of water in front of him. "How much is an ice cream sundae?" he asked. "Fifty cents," replied the waitress. The little boy pulled is hand out of his pocket and studied the coins in it. "Well, how much is a plain dish of ice cream?" he inquired. By now more people were waiting for a table and the waitress was growing impatient. "Thirty-five cents," she brusquely replied The little boy again counted his coins. "I'll have the plain ice cream," he said. The waitress brought the ice cream, put the bill on the table and walked 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, placed neatly beside the empty dish, were two nickels and five pennies. 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 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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