patoloji-ders-notlari

Title

Serdar Balcı

Central Nervous System Tumors

Serdar BALCI, MD

CNS Tumors

• Annual incidence of CNS tumors
  • 10-17/100,000 persons intracranial tumors
  • 1-2/100,000 persons for intraspinal tumors
• 1/2-2/3 primary tumors
• Rest are metastatic
• 20% of all pediatric tumors
  • likely to arise in the posterior fossa
  • in adults, mostly supratentorial

Characteristics of CNS tumors

• Do not have detectable premalignant or in situ stages like carcinomas
• Low-grade lesions may infiltrate large regions of the brain
  • serious clinical deficits, nonresectability, and poor prognosis
• Anatomic site of the neoplasm influence outcome independent of histologic classification
  • local mass effects
    • benign meningioma may cause cardiorespiratory arrest from compression of the medulla
  • Nonresectability
    • brain stem gliomas
• Even the most highly malignant gliomas rarely spread outside of the CNS
  • Local infiltration
  • Spread in subarachnoid space

CNS Tumors

• Tumors of the CNS may arise from
• Cells of the coverings
  • meningiomas
• The brain
  • gliomas, neuronal tumors, choroid plexus tumors
• Other CNS cell populations
  • primary CNS lymphoma, germ cell tumors
• Elsewhere in the body
  • metastases

Classification of CNS Tumors

Cell of Origin based classification

The most important feature for differential diagnosis

Localization, localization, localization …

Age

Radiologic features

Histomorphologic features

Genetic features

Localisation of CNS tumors

• Distinct types of tumors affect specific brain regions
  • Cerebellum → medulloblastoma
  • Intraventricular location → Central neurocytoma
• Specific age populations
  • Pediatric age → medulloblastoma, pilocytic astrocytomas
  • Older patients → glioblastoma, lymphoma

Spread of CNS tumors

Metastatic spread of brain tumors to other regions of the body is rare

Spinal subarachnoid tumor seeding

Autopsy Pathology: A Manual and Atlas

Grading of CNS tumors

Grading is based on histological subtype

Grade I tumors

Grade II tumors

Grade III tumors

Grade IV tumors

Benign, Resection is cure

Progression can be seen

GLIOMAS

Gliomas

• Tumors of the brain parenchyma
• Resemblance to different types of glial cells
• Types of glial tumors
  • Astrocytomas
  • Oligodendrogliomas
  • Ependymomas
• Most common types are highly infiltrative or “diffuse gliomas”
  • astrocytic, oligodendroglial, and mixed forms
• Ependymomas form solid masses

Grading of CNS gliomas

Increasing tumor malignancy is associated with more cytologic anaplasia, increased cell density, necrosis, and mitotic activity

Grade I tumors

Grade II tumors

Grade III tumors

Grade IV tumors

Astrocytoma

• Pilocytic astrocytomas
  • Grade I
• İnfiltrating gliomas
  • Diffuse Astrocytoma, Grade II
    • Atypical nuclear features
    • İnfiltration
  • Anaplastic Astrocytoma, Grade III
    • Increased mitosis
  • Glioblastoma, Grade IV
    • Necrosis
    • Microvascular (endothelial) proliferation

Pilocytic Astrocytoma, Grade I

• Benign tumor
• Affecting children and young adults
• Location
  • Most commonly cerebellum
  • Third ventricle
  • Optic pathways
  • Spinal cord
  • Cerebral hemispheres
• Cyst associated with the tumor
  • Symptomatic recurrence from incompletely resected lesions is often associated with cyst enlargement, rather than growth of the solid component
• Tumors of hypothalamus are especially problematic because they cannot be resected completely

pilocytic astrocytoma

Autopsy Pathology: A Manual and Atlas

Pilocytic Astrocytoma

• Activating mutations in the serine-threonine kinase BRAF
  • a partial tandem duplication event
  • point mutation (V600E)
• No mutation in IDH1 and IDH2

Cystic

Mural nodule in the wall of the cyst

If solid, usually well circumscribed

Bipolar cells with long, thin “hairlike” processes

GFAP-positive

Rosenthal fibers, eosinophilic granular bodies, and microcysts are often present

Necrosis and mitoses are very rare

Diffuse Astrocytomas

• 80% of adult gliomas
• Fourth-sixth decades of life
• Usually in the cerebral hemispheres
• Presenting signs and symptoms
  • Seizures
  • Headaches
  • focal neurologic deficits related to the anatomic site of involvement
• Spectrum of histologic differentiation that correlates well with clinical course and outcome
  • well-differentiated astrocytoma (grade II/IV)
  • anaplastic astrocytoma (grade III/IV)
  • glioblastoma (grade IV/IV)

Infiltrating pontine glioma (astrocytoma)

Autopsy Pathology: A Manual and Atlas

Diffusely infiltrating astrocytoma

Autopsy Pathology: A Manual and Atlas

Well-differentiated astrocytomas are poorly defined, gray, infiltrative tumors that expand and distort the invaded brain without forming a discrete mass

Robbins Basic Pathology

Infiltration beyond the grossly evident margins is always present

Cut surface of the tumor is either firm or soft and gelatinous

Cystic degeneration may be seen

Robbins Basic Pathology

Clinical Neuropathology Text and Color Atlas

Practical Surgical Neuropathology

Brain Tumor Pathol (2011) 28:177–183

• Well-differentiated astrocytomas can be static for several years
  • When progress; the mean survival is more than 5 years
• Rapid clinical deterioration, correlates with the appearance of anaplastic features and more rapid tumor growth
• Tumors increase in grade
  • well-differentiated → anaplastic astrocytoma → glioblastoma
• Once the histologic features of glioblastoma appear, the prognosis is very poor
• Resection, radiotherapy, and chemotherapy median survival is 15 months

Brain Tumor Pathol (2011) 28:177–183

Defects in tricyclic carbon cycle

Isocitrate dehydrogenase mutations cause accumulation of byproducts

Most important discovery in malignant CNS tumors

Cancer Cell. 2010 Jan 19;17(1):7-9

N Engl J Med 2009;360:765-73.

Well-differentiated astrocytomas

Mild to moderate increase in the number of glial cell nuclei

Variable nuclear pleomorphism

Intervening feltwork of fine, glial fibrillary acidic protein (GFAP)-positive astrocytic cell processes that give the background a fibrillary appearance

Transition between neoplastic and normal tissue is indistinct

Tumor cells can be seen infiltrating normal tissue many centimeters from the main lesion

Anaplastic astrocytomas, Grade III

More densely cellular

Greater nuclear pleomorphism

Mitotic figures

Practical Surgical Neuropathology

Glioblastoma, Grade IV

Loss-of-function mutations in the p53 and Rb tumor suppressor pathways

Gain-of-function mutations in the oncogenic PI3K pathways

Mutations that alter the enzymatic activity of two isoforms of the metabolic enzyme isocitrate dehydrogenase (IDH1 and IDH2) are common in lower-grade astrocytomas

Immunostaining for the mutated form of IDH1 has become an important diagnostic tool in evaluating biopsy specimens for the presence of low-grade astrocytoma

Glioblastoma

• Appearance similar to that of anaplastic astrocytoma AND
• Necrosis
  • pseudopalisading nuclei
• Vascular proliferation
  • Microvascular proliferation
  • Vascular endothelial proliferation
  • Glomeruloid vascular proliferation

Glioblastoma

Necrotic, hemorrhagic, infiltrating mass

• Variation in the gross appearance of the tumor from region to region is characteristic:
• Firm and white
• Soft and yellow
  • Necrosis
• cystic degeneration and hemorrhage

Robbins Basic Pathology

Glioblastoma multiforme

Autopsy Pathology: A Manual and Atlas

Glioblastoma

densely cellular tumor with necrosis and pseudopalisading of tumor cell nuclei

Robbins Basic Pathology

Clinical Neuropathology Text and Color Atlas

Practical Surgical Neuropathology

Practical Surgical Neuropathology

OLIGODENDROGLIOMA

Oligodendroglioma

• 5-15% of gliomas
• Fourth-fifth decades
• Several years neurologic complaints, often seizures
• Mostly in the cerebral hemispheres
  • Frontal or temporal lobes

Oligodendroglioma tumor cells have round nuclei, often with a cytoplasmic halo

Blood vessels in the background are thin and can form an interlacing pattern

Robbins Basic Pathology

• Better prognosis than that for patients with astrocytomas of similar grade
• Treatment with surgery, chemotherapy, and radiotherapy yields
  • average survival of 10-20 years, well-differentiated (WHO grade II)
  • 5-10 years for anaplastic (WHO grade III) oligodendrogliomas

Deletions of chromosomes 1p and 19q

1p and 19q loss typically occur together

Tumors with deletions of 1p and 19q are usually highly responsive to chemotherapy and radiotherapy

Well-differentiated oligodendrogliomas(WHO grade II/IV)

• Infiltrative tumors
• Gelatinous, gray masses
• May show cysts, focal hemorrhage, and calcification
• Sheets of regular cells
  • spherical nuclei containing finely granular-appearing chromatin (similar to that in normal oligodendrocytes)
  • surrounded by a clear halo of cytoplasm
• Delicate network of anastomosing capillaries
• Calcification
  • present in 90% of these tumors
  • ranges in extent from microscopic foci to massive depositions
• Mitotic activity usually is difficult to detect

Anaplastic oligodendroglioma (WHO grade III/IV)

More aggressive subtype

Higher cell density

Nuclear anaplasia

Mitotic activity

EPENDYMOMA

Ependymoma

• Arise next to
  • the ependyma-lined ventricular system
  • central canal of the spinal cord
• First 2 decades of life
  • fourth ventricle
  • 5-10% of the primary brain tumors in this age group
• Adults
  • spinal cord is their most common location
  • frequent in the setting of neurofibromatosis type 2
• The clinical outcome for completely resected supratentorial and spinal ependymomas is better than for those in the posterior fossa

Fourth ventricle

Solid or papillary masses

Extending from the ventricular floor

• Cells with regular, round to oval nuclei and abundant granular chromatin
• Between the nuclei a variably dense fibrillary background
• Round or elongated structures
  • rosettes, canals
  • resemble the embryologic ependymal canal
• Long, delicate processes extending into a lumen
• Perivascular pseudorosettes
  • tumor cells are arranged around vessels with an intervening zone containing thin ependymal processes

Anaplastic ependymoma

Increased cell density

High mitotic rates

Necrosis

Less evident ependymal differentiation

Robbins Basic Pathology

NEURONAL TUMORS

Neuronal Tumors

Central neurocytoma

Low-grade neoplasm

Within and adjacent to the ventricular system

Most commonly the lateral or third ventricles

Evenly spaced, round, uniform nuclei

Islands of neuropil

Ganglioglioma

• Manifest with seizures
• Slow-growing
• Mixed tumor
  • glial elements
    • low-grade astrocytoma
  • mature-appearing neurons
• Glial component occasionally becomes anaplastic
  • then progresses rapidly

Dysembryoplastic neuroepithelial tumor (DNET)

• Low-grade childhood tumor
• Grows slowly
• Relatively good prognosis after resection
• Often manifests as a seizure disorder
• Typically located in the superficial temporal lobe
• Consists of small round neuronal cells
  • arranged in columns
  • around central cores of processes
• Typically form multiple discrete intracortical nodules
  • myxoid background
• Well-differentiated “floating” neurons within pools of mucopolysaccharide-rich myxoid fluid

EMBRYONAL (PRIMITIVE) NEOPLASMS

Embryonal (Primitive) Neoplasms

• Neuroectodermal origin
• Primitive “small round cell” appearance
  • reminiscent of normal progenitor cells encountered in the developing CNS
• Differentiation is often limited
• May progress along multiple lineages

Medulloblastoma

• Most common Embryonal (Primitive) Neoplasm
• 20% of pediatric brain tumors
• Cerebellum
• Neuronal and glial markers are nearly always expressed
• Highly malignant
  • Prognosis for untreated patients is dismal
  • Exquisitely radiosensitive
  • Total excision, chemotherapy, and irradiation, the 5-year survival rate may be as high as 75%
• Primitive neuroectodermal tumors (PNETs)
  • Tumors of similar histologic type and a poor degree of differentiation elsewhere in the nervous system

Located in the midline of the cerebellum

Lateral tumors occur more often in adults

Often well circumscribed, gray, and friable

May extend to the surface of the cerebellar folia and involve the leptomeninges

Robbins Basic Pathology

Autopsy Pathology: A Manual and Atlas

Extremely cellular

Sheets of anaplastic (small blue) cells

Small, with little cytoplasm

Hyperchromatic nuclei

Abundant mitosis

Robbins Basic Pathology

Focal neuronal differentiation

Homer Wright or neuroblastic rosette

Resembles the rosettes in neuroblastomas

Primitive tumor cells surrounding central neuropil

-delicate pink material formed by neuronal processes

Genetic of medulloblastoma

• Morphologically similar tumors commonly exhibit distinct alterations
• There is a relationship between the underlying mutations and outcome
• MYC amplification
  • associated with poor outcomes
• WNT signaling pathway
  • have a more favorable course
• Sonic hedgehog (shh) pathway
  • has a critical role in tumorigenesis but an uncertain relationship to outcome

LYMPHOMAS

Primary CNS Lymphoma

• Mostly diffuse large B cell lymphoma
• 2% of extranodal lymphomas
• 1% of intracranial tumors
• Most common CNS neoplasm in immunosuppressed persons
  • nearly always positive for the oncogenic Epstein-Barr virus
• Nonimmunosuppressed populations
  • age spectrum is relatively wide
  • incidence increasing >60 years of age
• Aggressive disease
  • relatively poor response to chemotherapy compared with peripheral lymphomas
• Multiple tumor nodules within the brain parenchyma
• Involvement outside of the CNS is an uncommon late complication
• Lymphoma originating outside the CNS rarely spreads to the brain parenchyma
  • when it happens, within the CSF or involvement of the meninges
• Often involve deep gray structures
• Also white matter and the cortex
• Periventricular spread is common
• Relatively well defined as compared with glial neoplasms
  • not as discrete as metastases
• EBV-associated tumors
  • extensive areas of necrosis
• Nearly always aggressive large B-cell lymphomas
  • rarely other histologic types
• Malignant cells accumulate around blood vessels
• Infiltrate the surrounding brain parenchyma

GERM CELL TUMORS

Primary brain germ cell tumors

• Occur along the midline
  • Most commonly in the pineal and the suprasellar regions
• 0.2-1% of brain tumors in European
• 10% of brain tumors in Japanese
• Young
  • 90%, during the first 2 decades of life
• Pineal region show a strong male predominance
• Germinoma
  • Most common primary CNS germ cell tumor
  • resembles testicular seminoma
• Metastatic gonadal germ cell tumors also occur

MENINGIOMA

Meningioma

• Predominantly benign tumors
• Arise from arachnoid meningothelial cells
• Usually occur in adults
• Often attached to the dura
• Found along any of the external surfaces of the brain
• Within the ventricular system
  • arise from the stromal arachnoid cells of the choroid plexus
• Sympotoms
  • vague nonlocalizing symptoms
  • focal findings compression of adjacent brain
• Most meningiomas are easily separable from underlying brain
  • some tumors infiltrate the brain
  • increased risk of recurrence
• Overall prognosis
  • lesion size and location
  • surgical accessibility
  • histologic grade
• Neurofibromatosis type 2 (NF2)
  • Multiple meningiomas
  • eighth-nerve schwannomas
  • glial tumors
• Half of meningiomas not associated with NF2
  • acquired loss-of-function mutations in the NF2 TSG on 22q
• Mutations found in all grades of meningioma
  • involved with tumor initiation
• Mutations in NF2 are more common in:
  • fibroblastic, transitional, and psammomatous growth pattern

Meningioma

WHO grade I/IV

well-defined dura-based masses

compress the brain but do not invade it

Extension into the overlying bone may be present

Robbins Basic Pathology

Parasagittal meningioma

Autopsy Pathology: A Manual and Atlas

Intraosseous meningioma

Autopsy Pathology: A Manual and Atlas

Histologic patterns of Meningioma

• Syncytial
  • whorled clusters of cells without visible cell membranes that sit in tight groups
• Fibroblastic
  • elongated cells and abundant collagen deposition between them
• Transitional
  • shares features of the syncytial and fibroblastic types
• Psammomatous
  • numerous psammoma bodies
• Secretory
  • gland-like PAS-positive eosinophilic secretions known as pseudopsammoma bodies

Robbins Basic Pathology

Atypical meningiomas(WHO grade II/IV)

prominent nucleoli

increased cellularity

pattern-less growth

higher mitotic rate

More aggressive local growth

Higher rate of recurrence

Require therapy in addition to surgery

Anaplastic (malignant) meningiomas(WHO grade III/IV)

Highly aggressive tumors

May resemble a high-grade sarcoma or carcinoma

usually some histologic evidence of a meningothelial cell origin

METASTATIC TUMORS

Metastatic Tumors

Mostly carcinomas

1/4-1/2 of intracranial tumors

Most common primary sites

Lung, breast, skin (melanoma), kidney, and gastrointestinal tract

Form sharply demarcated masses

Often at the gray-white junction, and elicit edema

The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis

Direct and localized effects

##

Metastatic spread of brain tumors to other regions of the body is rare

Brain is not protected against spread of distant tumors

Carcinomas are the dominant type of systemic tumors that metastasize to the nervous system

Metastatic melanoma

Metastatic lesions are distinguished grossly from most primary central nervous system tumors by their multicentricity and well-demarcated margins

The dark color of the tumor nodules in this specimen is due to the presence of melanin

Robbins Basic Pathology

Paraneoplastic syndromes

• Subacute cerebellar degeneration
  • result in ataxia
  • destruction of Purkinje cells, gliosis, and a mild inflammatory infiltrate
• Limbic encephalitis
  • subacute dementia
  • perivascular inflammatory cells, microglial nodules, some neuronal loss, and gliosis, all centered in the medial temporal lobe
• Subacute sensory neuropathy
  • altered pain sensation
  • loss of sensory neurons from dorsal root ganglia, in association with inflammation
• Syndrome of rapid-onset psychosis, catatonia, epilepsy, and coma
  • associated with ovarian teratoma
  • antibodies against the N-methyl-d-aspartate (NMDA) receptor

FAMILIAL TUMOR SYNDROMES

Tuberous Sclerosis (TSC)

• Autosomal dominant
• Development of hamartomas and benign neoplasms involving the brain and other tissues
• CNS hamartomas
  • cortical tubers
  • subependymal hamartomas
  • tumefactive form known as subependymal giant cell astrocytoma
• Proximity to the foramen of Monro
  • present acutely with obstructive hydrocephalus
  • requires surgical intervention and/or therapy with an mTOR inhibitor
• Seizures
  • associated with cortical tubers
  • difficult to control with antiepileptic drugs
• Extracerebral lesions
  • renal angiomyolipomas
  • retinal glial hamartomas
  • pulmonary lymphangiomyomatosis
  • cardiac rhabdomyomas
  • Cysts
    • liver, kidneys, and pancreas
  • Cutaneous lesions
    • angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas
• TSC1
  • encodes hamartin
• TSC2
  • encodes tuberin
• Two TSC proteins form a dimeric complex
  • negatively regulates mTOR, a kinase that “senses” the cell’s nutrient status and regulates cellular metabolism
• Loss of either protein leads to increased mTOR activity
  • Disrupts nutritional signaling and increases cell growth
• Cortical hamartomas
• Firmer than normal cortex
• Likened in appearance to potatoes
  • “tubers”
• Composed of haphazardly arranged large neurons
• Lack the normal cortical laminar architecture
• Cells exhibit a mixture of glial and neuronal features
  • large vesicular nuclei with nucleoli (like neurons)
  • abundant eosinophilic cytoplasm (like gemistocytic astrocytes)
  • Similar cells are present in the subependymal nodules

von Hippel–Lindau Disease

• Autosomal dominant disorder
• Hemangioblastoma
  • cerebellar hemispheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots
• Cysts
  • pancreas, liver, and kidneys
• Renal cell carcinoma
• Frequency is 1/30,000-40,000
• Therapy is directed at the symptomatic neoplasms
  • surgical resection of cerebellar tumors and laser ablation of retinal tumors
• Tumor suppressor VHL
• Encodes a protein that is part of a ubiquitin-ligase complex
• Targets the transcription factor hypoxia-inducible factor (HIF) for degradation
• Lost all VHL protein function
• Express high levels of HIF
• Expression of VEGF, various growth factors
• Expression of erythropoietin
  • paraneoplastic polycythemia
• Cerebellar capillary hemangioblastoma
  • Highly vascular neoplasm
  • Mural nodule
  • Large, fluid-filled cyst
  • Numerous capillary-sized or somewhat larger thin-walled vessels
  • Intervening stromal cells with vacuolated, lightly PAS-positive, lipid-rich cytoplasm

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Distribution of CNS Tumors

**A pilocytic astrocytoma of the cerebellum in a child. **

Glioma of the brainstem – pilocytic astrocytoma

GBM. Note the prominent vascularity as well as the area of necrosis at the left with neoplastic cells palisading around it (pseudopalisading necrosis*).

Here is an ependymoma arising from the ependymal lining of the fourth ventricle above the brainstem and bulging toward the cerebellum.

This horizontal (CT scan) section of the brain reveals a large ependymoma of the fourth ventricle.

Irregular posterior fossa mass (medulloblastoma) - near the midline of the cerebellum and extending into the fourth ventricle above the brainstem