CNS Tumors

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

CNS TUMORS

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intracranial Intraspinal

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

Anaplastic •

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

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densely cellular Mitotically active

Gemistocytic •

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variable nuclear pleomorphism GFAP (+) astrocytic cell processes

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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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subarachnoid space – brain and spinal cord

seeding 4 MAJOR CLASSES    

Gliomas Neuronal tumors Poorly differentiated neoplasms Meningiomas

GLIOMAS GLIOMAS • • •

A.

Astrocytomas Oligodendrogliomas Ependymomas

ASTR ASTROC OCYT YTOM OMAS AS Categories: Fibrillary Glioblastoma Pilocytic Pleomorphic Xanthoastrocytoma • • • •

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Fibril Fibrillar lary y (Diffu (Diffuse) se) Astr Astrocy ocytom toma a

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 • • • • •

GEMISTOCYTIC ASTROCYTOMA

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Gliobl Glioblast astoma oma (Gliob (Glioblas lastom toma a Multi Multifor forme me) )

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

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- mu multi ltipl ple e regio regions ns of the the brai brain n infiltrated by neoplastic astrocytes

Gliomatosis Gliomatosis

cerebri  cerebri 

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Microscopic: •

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

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PILOCYTIC ASTROCYTOMA Clinical • •

GLIOBLASTOMA

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WHO Grading

Grade I/ I/IV Grade rade II/I II/IV V Grade III/IV Grade IV/IV

Pilocytic Well ell dif differe ferent ntia iate ted d ast astro rocy cyto tom mas Anaplastic Glioblastoma

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Pleomo Pleomorph rphic ic Xanth Xanthoas oastro trocyt cytoma oma

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 • • • •

Molecular Genetics •

Grow very slowly Cerebellar tumors treated with resection Rarely Rarely have have p53 mutat mutation ions s or other other change changes s found in diffuse fibrillary

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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

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Clinical Features: •

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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 •

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B.

OLIG OLIGOD ODEN ENDR DROG OGLI LIOM OMAS AS

5 - 15% Age: 40 – 50 Seizures for several years Predilection for white matter, matter, cerebral hemispheres Morphology: well-circumscribed, gelatinous, gray masses ofte often n with ith cyst cysts, s, foc focal hem hemorrh orrha age and and calcification Microscopic: Shee Sheets ts of regu regula larr cells cells with with sphe spheric rical al nucl nuclei ei 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 Anaplasti Anaplastic c oligodendro oligodendrogliom gliomas as – increased increased cell density density,, nuclear nuclear anaplasia, anaplasia, inc mitotic mitotic activity 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: • • • •

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3.

Pilocytic

Children and young adults Cerebe Cerebellu llum, m, floor floor and wall wall of 3rd ven ventri tricles cles,, optic 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 • •

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Better prognosis than astrocytomas Ave 5 – 10 years survival

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Poste Posterior rior fossa fossa ependy ependymom momas as manife manifest st with with hydrocephalus sec to obstruction of 4th ventricle Prognosis is poor CSF dissemination is common

OTHER TUMORS OTHER TUMORS ASSOCIATE ASSOCIATED D WITH TYPE WITH OTHER OTHER OTH ER CELL TYPE THAT FORMS THE VENTICULAR SYSTEM: • • • • • •

Subependymomas Choroid plexus papillomas Colloid cyst of the third ventricle

NEURONAL TUMORS A.

GANG GANGLI LION ON CELL CELL TUM TUMOR ORS S • • •

Contain ganglion cells Gangliocytoma – entire population of lesion Ganglioglioma – admixture with glial neoplasm

OLIGODENDROGLIOMA •

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EPEND ENDYMOMAS

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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 Cells with with regula regularr, round round to oval oval nuclei nuclei with with abundant granular chromatin Dense fibrillary background Rosettes, canals Perivascular pseudorosettes GFAP (+) • • • •

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

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B.

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OTHER TUMO UMORS COMPONENTS

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WIT WITH

Dysembry Dysembryopla oplastic stic (DNT)

GLI GLIAL

AND AND

NEURO URONAL

Neuroep Neuroepithe ithelial lial

Tumor Tumor

Low grade tumor of childhood Seizure disorder Slow growth Good prognosis

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C.

TUMORS TUMORS WITH WITH ONLY ONLY NEURONAL NEURONAL ELEMENT ELEMENTS S i. Cerebral Neuroblastoma

Rare, occur in children, highly aggressive Resemble peripheral neuroblastomas Homer Wright rosettes

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Central Neurocytoma

Low grade neuronal tumors Lateral and third ventricles Resemble oligodendroglioma

POORLY DIFFERENTIATED NEOPLASMS • •

A. EPENDYMOMA

Medulloblastoma Atypical Teratoid/Rhabdoid Tumor (AT/RT)

MEDU MEDULL LLOB OBLA LAST STOM OMA A

Predominantly in children Exclusively in the cerebellum Largely undifferentiated Morphology Midline of cerebellum Lateral in adults Well circumscribed, gray and friable Microscopic: Extremely cellular, cellular, sheets of anaplastic cells Little cytoplasm Hyperc Hyperchro hroma matic tic nucle nuclei, i, elonga elongated ted or cresce crescent nt shaped Mitosis abundant (+) Ki-67 markers • •

Morphology: • •

Well-differentiated – WHO Grade II/IV Anaplastic ependymomas – WHO Grade III/IV

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Myxopapillary ependymomas ependymomas – occur in filum

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terminale of spinal cord Papillary elements in myxoid background Molecular genetics: genetics: Spina inal ependymomas associa ciated wiit th ith Neu Neurofib fibromatosis sis 2 and NF2 gene on chromosome 22 Clinical features: • •

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Expres Express s neuron neuronal al (neuro (neurosec secreto retory ry granul granules, es, Home Homerr Wrigh rightt rose rosett ttes es)) and and glia gliall (GF (GFAP) AP) phenotypes Molecular Genetics: Loss of short arm of chromosome 17 •

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Pineocytomas – well-differentiated Pineoblastomas – high grade tumors

MENINGIOMAS

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Benign tumors of adults Attached to dura Arise from meningothelial cell of arachnoid Extern External al surfac surface e of brain brain as within within the ven ventric tricula ularr 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 Atypica Atypicall mening meningiom iomas as – mitotic mitotic index of 4 or more mitosis/10 hpf, 3 or more atypical features (inc cellularity cellularity,, small cells with high N:C ratio, prominent nucleoli, patternless growth, necrosis) Anaplastic (malignant)Meningioma (malignant)Meningioma WHO grade III/IV Mitosis >20/10 hpf  • • • •

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MEDULLOBLASTOMA

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Clinical features: • • • • •

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

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ATYPICAL ATYPICAL TERATOI TERATOID/RH D/RHABDO ABDOID ID TUMOR TUMOR (AT/RT) (AT/RT) • • •

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Highly malignant tumor of young children Posterior fossa and supratentorial compartments “rhabdoid cells” resembling those of rhabdomyosarcoma 90% - Loss of genetic material from chromosome 22 Very young patients – before age 5 Live less than a year after diagnosis

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OTHER PARENCHYMAL TUMORS • • •

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PRIM PRIMAR ARY Y CNS CNS LYMP LYMPHO HOMA MA • • •

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

GERM GERM CELL CELL TUMO TUMORS RS • • • • • •

C.

Primary CNS Lymphoma Germ cell tumors Pineal Parenchymal 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

PINE PINEAL AL PAREN PARENCHY CHYMA MAL L TUMO TUMORS RS •

Arise from pineocytes

MENINGIOMA Clinical Features: • •

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Slow growing Vague Vague nonlocaliz nonlocalizing ing symptoms symptoms or focal findings referable to compression of underlying brain Comm Common on site sites: s: para parasa sagi gitta ttall aspe aspect ct of brai brain n convexity convexity,, dura over latera latera convexity convexity,, wing of  sphenoid, olfactory groove, sella turcica, foramen magnum

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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 patter ern n of grow growth th,l ,les ess s B – patt 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) schwannoma) •

METASTATIC TUMORS • •

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Mostly carcinomas Common Common primar primary y sites sites (80%): (80%): lung, lung, breast breast,, skin skin (melanoma), kidney, GIT Meninges are frequently involved Present clinically as mass l esions, may occasionally be the first manifestation of cancer Grossly Grossly form form sharply sharply demarc demarcate ated d masses masses,, at gray gray matter-white matter junction, surrounded by zone of  edema

Anto Antoni ni

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BRAIN METASTASES SCHWANNOMA PARANEOPLASTIC SYNDROMES • • •

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NEUR NEUROF OFIB IBRO ROMA MA Two types:

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

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(skin) or Solitary Cutaneous Neurofibroma Neurofibroma (skin) Neurofibroma (peripheral nerve) •

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Plexiform Neurofibroma – occur only in NF1 •

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PERIPHERAL NERVE SHEATH TUMORS   • • •

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

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Schwannoma Neurofibroma Malignant Malignant Periphera Peripherall Nerve Sheath Sheath Tumor (MPNST (MPNST, Malignant Schwannoma)

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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 xanthomatous change Microscopic: Mixture of two growth patterns

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Involve major nerve trunks, potential for malignant transformation Frequently multiple Loose myxoid background, low cellularity Schwa Schwann nn cells, cells, multip multipola olarr fibrob fibroblas lastic tic cells, inflammatory cells

MALI MALIGN GNAN ANT T PERI PERIPH PHER ERAL AL NERV NERVE E SHEA SHEATH TH TUMO TUMOR  R  (MPNST, MALIGNANT SCHWANNOMA) •

SCH SCHWAN WANNOMA

Dermis and subcutaneous fat Well-delineated, unencapsulated Spindle cells Stroma highly collagenized

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Highly malignant sarcoma Loca Locally lly inva invasi sive ve,, freq freque uentl ntly y lead leadin ing g to mu mult ltip iple le recurrences and metastasis Arise Arise de novo novo or from from transf transform ormati ation on of plexif plexiform orm neurofibroma Assoc with NF type 1  “Triton  “Triton tumor” – with rhabdomyoblastic differentiation

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FAMILIAL TUMOR SYNDROMES

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– patt patter ern n of grow growth th of  elon elonga gate ted d cell cells s with with cytop ytopla lasm smic ic processes arranged in fascicles in areas

Anto Antoni ni

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

NEURO NEUROFI FIBRO BROMAT MATOSI OSIS S TYPE TYPE 1 (NF1) (NF1) •

Autosomal-dominant Autosomal-dominant disorder

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

B.

NEURO NEUROFIB FIBROM ROMAT ATOSI OSIS S TYPE TYPE 2 (NF2) (NF2) • • • • • • •

C.

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

Autosomal-dominant Autosomal-dominant disorder Bilateral VIII nerve schwannomas schwannomas Multiple meningiomas Ependymomas of spinal cord Schwannosis Meningioangiomatosis Glial hamartia

TUBE TUBERO ROUS US SCLE SCLERO ROSI SIS S • •

Autosomal-dominant Hamartomas Cortical tubers Subependymal hamartomas Benign Benign neoplas neoplasms ms involv involving ing the brain brain and other other tissues Renal angiomyolipomas angiomyolipomas Retinal glial hamartomas Pulmonary lesions Cardiac rhabdomyomas rhabdomyomas Cysts in liver, kidneys, pancreas Cutaneous lesions e.g. Angiofibromas,Shagreen Angiofibromas,Shagreen patches, ash-leaf  patches, subungal fibromas

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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 my clothes, but also my spirits. 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.

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3 - Third Important Lesson - Always remember those 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.

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D. VO VON N HIPP HIPPEL EL LIN LINDAU DAU DISEA DISEASE SE • •

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Autosomal-dominant Capillary Capillary hemangiob hemangioblasto lastomas mas within the cerebellar 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:

"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," 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 i ce 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.

"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.

In ancient times, a King had a boulder 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: CNS2: CNS Tumors by  Tumors by  Dr.   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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