Tumors

Question 1

Incidence

Answer 1

• 10-17 per 100,000 people, more than double the number of cases of Hodgkin’s disease, and over
  half the number of cases of melanoma
• 50 - 75% – primary tumors
• 25 - 50% – metastastic tumors (stats vary depending upon source)
• Children:
• Cancer is #2 cause of death
• Of cancers, #1 Brain tumors (20%), #2 Leukemias
• 70% in posterior fossa
• Adults, 70% above tentorium

Question 2

Unique Characteristics of brain tumors

Answer 2

• more difficult to tell benign from malignant; some tumors that look
  benign act malignant
• difficult to completely resect glial tumors without serious neurological effects
• if brain tumors occur in a vital location, does not matter if it is benign
  or malignant
• rarely get mets outside the CNS, can seed along the spinal cord and
  lead to leptomeninigitis

Question 3

Primary Brain Tumors: Clinical presentation:

Answer 3

depends upon location and rate of growth, can be focal or generalized
Generalized: due to increased ICP, can present with headache, nausea and vomiting, sixth nerve palsy; on physical exam will see papilledema if have increased ICP

Focal: hemiparesis, aphasia, seizures
-tumors in the ventricles (especially posterior fossa ependymomas) present with hydrocephalus

Question 4

Primary Brain Tumors: Diagnosis and Risk Factors

Answer 4

only necessary test – MRI with contrast; CT can miss some lesions
Normally blood vessels in CNS (blood-brain barrier) will not accept contrast from peripheral circulation  so
no contrast would go through. With high grade tumor, new blood vessels form which are leaky and contrast can
pass through. These lesions called contrast enhancing.

Risk Factors: only unequivocal risk factor is ionizing radiation

Question 5

Gliomas

Answer 5

• Used to think these tumors were derived from their specific mature cell types in the CNS
  (astrocyte->astrocytoma, oligodenodrocytes ->oligodendroglioma, ependymal cells->ependymoma,
  etc)
• Now, the tumors are thought to originate from progenitor cells that preferentially
  differentiate down one of the cellular lineages

Question 6

Gliomas: Astrocytomas include variety of tumors

Answer 6

ytomas include variety of tumors. WHO histologic grading for astrocytomas, I-IV:

I: well-differentiated - pilocytic astrocytoma

II: diffuse growth of well-differentiated astrocytes - diffuse astrocytoma

III: Anaplastic features (pleomorphism, increased mitoses) - anaplastic astrocytoma

IV: undifferentiated with vascular proliferation and necrosis - glioblastoma (formerly
known as glioblastoma multiforme or GBM).

Question 7

Gliomas: Astrocytoma: Infiltrating astrocytomas

Answer 7

• Account for 80% of primary brain tumors
• spectrum of tumors from diffuse astrocytoma (grade II/IV) to anaplastic
  astrocytomas (grade III/IV) to glioblastoma (grade IV/IV)
• some tumors progress from low grade to glioblastoma
• occurs due to ordered accumulation of mutations
• see uniform sequence of tissue changes which meet the histologic criteria of malignancy
• most common mutations are affect p53 and overexpression of platelet derived growth factor

Question 8

Gliomas: Astrocytoma: Infiltrating astrocytomas: Diffuse astrocytoma (II/IV):

Answer 8

• Most initially occur as low-grade tumors in younger adults, may
  present with a seizure, HA, focal neurologic deficits.
• Histologically: increase in number of glial cells, variable nuclear
  pleomorphism, GFAP-positive astrocytic processes give a fibrillary background
• Transition between neoplastic and normal tissue is indistinct
• Median survival: 5 years
• May recur as high-grade tumor

Question 9

Gliomas: Astrocytoma: Infiltrating astrocytomas: Anaplastic astrocytoma (III/IV):

Answer 9

• Have regions that are more densely cellular with greater nuclear pleomorphism,
  mitotic figures
• MRI: non-enhancing lesion, may not be seen on CT
• Treatment: surgical resection but often cannot be resected due to size &
  location. Radiation is most effective nonsurgical treatment
• Median survival: ~ 2 years, most tumors progress to high-grade

Question 10

Gliomas: Astrocytoma: Infiltrating astrocytomas: Glioblastoma

Answer 10

• high grade end of spectrum of astrocytomas, most atypical & mitotically active
• Primary
  ▪ Most common type
  ▪ New onset disease in older people
• Secondary
  ▪ Younger patients
  4
  ▪ Due to progression of a lower grade astrocytoma
• Four molecular subtypes: (most affect two cancer hallmarks: sustained proliferative signaling and
  evasion of growth suppressors)
• Histology: characteristically have necrosis & vascular proliferation, get
  pseudopalisading
• MRI shows a contrast enhancing lesion (usually ring enhancing)
• treatment: surgery, radiation, chemotherapy
• uniformly fatal, survival ~15 mos, 25% alive at 2 years, shorter survival in older patients

Question 11

Gliomas: Astrocytoma: Non-infiltrating Astrocytomas: Pilocytic astrocytoma (I/IV)

Answer 11

• occurs in kids & young adults
• relatively benign behavior
• occur in cerebellum, third ventricle
• often cystic, occurs as mural nodule
• Histology: cells with hair-like processes, eosinophilic fibers (Rosenthal
  fibers)
• Grow very slowly, recurrence often involves cyst enlargement rather than growth of solid component
• survival - patients have survived >40 years past incomplete excision

Question 12

Gliomas: Oligodendroglioma

Answer 12

• most occur in adults, 4th
  –5
  th decades
• relatively rare, slow growing
• occur mostly in cerebral hemispheres
• can result in bleeding
• Histology: sheets of regular cells with spherical nuclei, surrounded by clear
  halo of cytoplasm (poached egg appearance)
• calcifications - 90% of oligodendrogliomas
• Genetics:
  o Mutations in IDH1 and IDH2 (90% of tumors
  o Co-deletions in chromosome 1p and 19q (80% of tumors)
• median long-term survival-approx 5 - 10 years
• treatment: surgery, radiation & chemotherapy, depending upon presentation

Question 13

Gliomas: Ependymoma

Answer 13

• most often tumor of children & young adults
• Occur most often in ependymal-lined ventricular system
• Children and young adults: 4
  th ventricle
• Adults: spinal cord is most common location
• present with hydrocephalus, get CSF dissemination
• Histology: histologically are benign in appearance, occur as masses of small dark cells, variably
  dense fibrillary background between nuclei, form perivascular pseudorosettes
• Genetics: spinal cord ependymomas most commonly show a
  mutation in NF2 gene on chromosome 22, supratentorial ependymomas show
  alterations in chromosome 9
• prognosis: posterior fossa lesions ~ 5 years; resected supratentorial and spinal
  cord lesions have a better prognosis
• subtypes: myxopapillary ependymoma: occurs in fillum terminale of spinal
  cord, can be difficult to resect, due to location, so recurrence is likely

Question 14

Gliomas: Choroid plexus papillomas

Answer 14

• most common in children, in lateral ventricle
• in adults – fourth ventricle
• papillary growth with connective tissue stalk
• microscopically look just like normal choroid plexus
• present with hydrocephalus

Question 15

Gliomas: Colloid cyst of third ventricle

Answer 15

• Young adults
• Attached to roof of the ventricle
• Can obstruct the foramina of Monro
• Can cause hydrocephalus
• Can be rapidly fatal
• Clinical: may complain of positional headache

Question 16

Embryonal Tumors OR Primitive Neuroectodermal Tumors (PNET): Medulloblastoma

Answer 16

• WHO Grade IV/IV
• Highly malignant tumor of children
• Occurs in midline of the cerebellum – rapid growth may result in hydrocephalus
• Histology: Small round blue cell tumor, rosettes or perivascular pseudorosettes
• Molecular genetics: 4 groups
• Commonly get dissemination through the CSF – can spread down the spine even to the cauda
  equina called “drop” metastasis
• Very radiosensitive tumor
• 5-year survival with complete excision & radiation: 75%

Question 17

Embryonal Tumors OR Primitive Neuroectodermal Tumors (PNET): CNS supratentorial primitive neuroectodermal tumors (CNS PNET)

Answer 17

• Children
• Occur in cerebral hemispheres
• Resemble medulloblastoma in histology and poor degree
  of differentiation but differ in location
• Genetically distinct from medulloblastoma

Question 18

Other Lesions: Primary Brain Lymphoma

Answer 18

• Comprises 1% or less of all primary brain tumors
• Most common CNS neoplasm in immunosuppressed patients
• Patients get multiple tumor masses within the brain, rarely spreads to lymph nodes or outside
  the brain
• If patient has non-CNS lymphoma rarely involves brain parenchyma – although can spread to
  CSF
• Majority are B cell lymphomas,
  a. In immunosuppressed, contain EBV genes (think AIDS, transplantation)
  b. If not associated with immunosuppression, then phenotype is typical of postgerminal
  center B cell differentiation
• Aggressive disease, no role for resection, do not respond as well to chemotherapy
• Median survival- 4-5 years

Question 19

Other Lesions: Metastatic Tumors

Answer 19

• Most common sites: lung, breast, skin (melanoma), kidney, & GI tract
  (Lots of bad stuff kills glia)
• Usually occur as multiples masses
• Treatment may improve quality of remaining life

Question 20

Other Lesions: Meningiomas

Answer 20

• Most are WHO Grade I/IV, overwhelming majority of meningiomas are
  benign, few are III or IV/IV
  7
• Actually, not true brain tumors, arise from meningothelial cells of the
  arachnoid
• Constitute 20% of “brain tumors”
• Majority are found in adults as asymptomatic tumors discovered incidentally at autopsy
• Can present as headache or with neurologic sx
• Multiple meningiomas are found in patients with neurofibromatosis type 2 (NF2)
• Dural-based tumor
• Common sites
  a. Parasagittal aspect of the brain convexity
  b. Dura over the lateral convexity
  c. Wing of the sphenoid
  d. Olfactory groove
  e. Sella turcica
  f. Foramen magnum
• MRI –
  a. See adjacent to bone & have “dural tail” which indicates tumor is anchored to the
  dura
  b. Contrast-enhancing lesion
• Histology – have many patterns of growth
  a. Syncytial – Whorls of bland cells
  b. Psammomatous – Psammoma bodies
• Genetics: most common is loss of chromosome 22, deletions include NF2 gene (codes for
  merlin [restricts cell-surface expression of growth factor receptors])
• If occur as small lesion, can just be followed
• Surgery is “definitive therapy,” although even with complete resection,
  20% recur
• Prior RT is a risk factor

Question 21

Other Lesions: Craniopharyngioma

Answer 21

– Usually suprasellar arising in pituitary stalk
– Arise from remnants of Rathke’s pouch
– Bimodal age distribution: 5 – 15 yrs and > 65 yrs
– 5 – 10% of brain tumors in children
– Slow growing, benign, malignant transformation to squamous cell cancer is very rare
– Solid or mixed solid and cystic
– Two histologic types:
a. Adamantinomatous
– Children
– Stratified squamous epithelium in nests or chords
– Spongy reticulum
– Calcifications
– Lamellar keratin formation
– Cysts with thick brownish-yellow fluid contents
b. Papillary
– Adults
– Solid sheets and papillae lined by squamous epithelium
– No keratin, calcifications or cysts
– Clinical
a. Visual symptoms from pressure on optic chiasm
b. Children: growth retardation 2° pituitary hypofunction and GH def’cy
c. Headache
– Treatment – surgery and / or radiation therapy

Question 22

Peripheral Nerve Sheath Tumors: Schwannoma

Answer 22

• Often arise directly from peripheral nerves, attached to but do not invade the nerve
• Commonly seen at cerebellopontine angle where attached to vestibular
  branch of 8th nerve - called acoustic neuroma
• Patients present with tinnitus and hearing loss
• Outside the dura they are commonly found associated with large nerves
• Associated with neurofibromatosis type 2 (NF2)
• See as well-circumscribed, encapsulated mass attached to nerve, but can be separated from
  the nerve
• Shows mixture of 2 growth patterns
• Antoni A: more cellular area with dense masses of nuclear
  palisading called Verocay bodies
• Antoni B: less cellular area, more myxoid
• Completely benign lesions – surgical removal is curative
• Genetics – inactivating mutations in NF2 gene on chromosome 22

Question 23

Peripheral Nerve Sheath Tumors: Neurofibroma

Answer 23

• Benign spindle cell lesions which occur in three forms:
  1. Superficial cutaneous: skin or peripheral nerve
• sporadic or associated with NFI
• never turn malignant
  2. Diffuse: large plaque-like elevation of skin, NF1-associated
  3. Plexiform:
• only in patients with NF1
• significant potential for malignant transformation to Malignant
  Peripheral Nerve Sheath Tumor (MPNST)
• occurs associated with large nerves, cannot be
  separated from the nerve
• Histology: Admixed
  1. Neoplastic Schwann cells
  2. Perineurial-like cells
  3. Mast cells
  4. CD34+ spindle cells
  5. Fibroblasts

Question 24

Familial Tumor Syndromes: Neurofibromatosis: NF Type 1

Answer 24

• AD
• Get multiple neurofibromas: superficial cutaneous, diffuse & plexiform
• Get gliomas of optic nerve
• Pigmented nodules of iris (Lisch nodules)
• Café au lait spots – brown spots on skin
• Genetics: NF1 gene neurofibromin, tumor suppressor,
  chromosome 17
• One of the more common genetic disorders
• Increased propensity for neurofibromas to undergo malignant
  transformation

Question 25

Familial Tumor Syndromes: Neurofibromatosis: NF Type 2

Answer 25

- AD - Develop range of tumors; bilateral acoustic neuromas, multiple meningiomas, ependymomas of spinal cord - Much less common than NF1 - Genetics: different gene involved, NF2 gene merlin, chromosome 22

Question 26

Familial Tumor Syndromes: Tuberous Sclerosis Complex

Answer 26

- AD, 70% occur as spontaneous mutation - Develop hamartomas & benign neoplasms involving brain & other tissues - Within CNS, hamartomas occur as cortical tubers – abnormal, broad, firm gyri (potato-like) - CNS hamartomas - occur as haphazardly arranged neurons which lack normal neural organization - Other lesions: renal angiomyolipomas, pulmonary lymphangiomyomatosis & cardiac rhabdomyomas, skin rash - Can have seizures, mental retardation – tumors are epileptogenic - neutral organization - Molecular genetics – 2 genes a. Hamartin, chromosome 9q b. Tuberin, chromosome 16p c. As a complex, the normal proteins suppress mammalian Target of Rapamycin (mTOR), a CNS growth promotor

Question 27

Familial Tumor Syndromes: Von-Hippel-Lindau Disease

Answer 27

- AD - Develop capillary hemangioblastoma in cerebellum, retina & spinal cord a. Highly vascular tumor which can occur as mural nodule associated with fluid-filled cyst b. Patients can have associated polycythemias in 10% cases (tumor produces erythropoietin) - Also, can have cysts in pancreas, liver & kidney - Increased risk of renal cell carcinoma and pheochromocytoma - Gene is tumor suppressor