Neuropathology Tumors

Neuroepithelial neoplasms displaying neuronal features

Ganglion cell neoplasms

Usually present in the first three decades with epilepsyhave predilection for the temporal lobe
frequently cause complex partial seizures
often form a cyst with a mural nodule
are associated with congenital abnormalities in 5% of cases
Macroscopically appear firm and gray, frequently contain flecks of calcification and cysts.
Microscopically look like large neurons.

Gangliocytomas: admixed regions of large and small cells with round vesicular nuclei, prominent nucleoli, and basophilic nissl substnace. with occasional double nuclei.
Gangliogliomas contain neoplastic glial cells which may greatly outnomber the ganglion cells.
Ganglioneuroblastoma: small round cells with a high nuclear: cytoplasmic ratio and nuclear hyperchromasia are combined with ganglion cells in the ganglioneuroblasmoa: Mitoses and apoptosis are usually idenfiable among the small cells. Recognition of the embryonal elements is importnat because their presence confers a much poorer prognosis.
Differential diagnosis

Gliomas that diffusely invade the gray matter or from other neuroepithelial neoplasms that contain large cells with prominent nucleoli.
are neoplastic ganglion cell present? look for a disorderly array of neuron-like cells with double nuclei.
Not all neuronal like cells are neuronal!!: giant cell glioblastoma, pleomorphic xanthoastrocytoma, and subependymal giant cell astrocytoma of tuberous sclerosis may appear as such, but immunophenotypically are different in their staining for GFAP vs. neurofilament and synaptophysisn.
the presence of mitoses indicates anaplastic transofrmation vs. anaplastic astrocytoma.

Desmoplastic infantile gangioglioma (DIGG)

Usually presents in infants under 1 year of age
Usually a large superficial neoplasm of the cerebrum
Usually associated with a cyst

Central neurocytoma

are midline neoplasms located predominantly in the vicinity of the septum pellucidum
cause hydrocephalus
are usually present in young adults
grossly appear well circumscribed, midline, extending into the ventricles.

Paraganglioma of the filum terminale

Microsopically appear similar to myxopapillary ependymomas, but are distinguished by immunohistochemistry which identifies ependymomas with GFAP and paragangliomas as synaptophysin and chromogranin positive.
Electron microscopy reveals dense core granules.
Shares many features of other extra-adrenal paragangliomas.
Clincal presentation: often with sciatica.

Dysembryoplastic neuroepithelial tumor (DNT)

Located usually in the temporal lobe.
presents in children and young adults
usually with simple or complex partial seizures which may become intractible.
Macroscopically appears a mixed population of neuroepithelial cells and display a distinctive multinodular architecture.
Histologic hallmarks are glial nodules and masses of oligodendrocyte-like cells (OLCs)

Dysplastic gangliocytoma of the cerebellum

usually presents with raised intracranial pressure in young adults
associated with megaencephaly, polydactyly, Cowden's syndrome (multiple hamartoma-neoplasia syndrome) and multiple cutaneous schwannomas.
AKA Lhermitte-Duclos disease

Hypothalamic neuronal hamartoma

Embryonal neuroepithelial neoplasms of the CNS

Medulloblastoma

represents about 5% of intracranial neoplasms
represents about 25% of childhood CNS neoplasm
represents about 90% of childhood CNS PNET.
50% occur in patients less than 10 years of age.
generally arises from the vermis and fills the fourth ventricle
may be located laterally in the posterior fossa
may spread through CSF pathways

Genetic aspects

nearly all are sporadic
allelic losses in 17P in 50%
Allelic loss on 9q in a few. especially desmoplastic meulloblastomas
N-Myc is not amplified

Syndromes associated with medulloblastomas

Gorlin's (basal cell nevus) syndrome: which is characterized by basal cell carcinomas ovarian fibromas and developmental defects shows autosomal dominant inheritance, and has medulloblasmoas in 3-5% of patinets. The syndrome occurs in 1-2% of patients with medulloblastomas. The genes is localized to chromosome 9q31
Turco't syndrome: includes medulloblastmoa, astrocytic neoplasms, familial polypposis and colonic carconoma.

Microscopic appearance

PNET: in general show undifferentiated cells with hyperchromatic nuclei and sparse cytoplasm. Typically small and round, the nuclei may measure up to 20 microns or more in diameter and hve ocntours that are focally flattened or even slightly indented. No morphologic or immunohitochemical evidence of neuronal or glial differentiation, and ultrastructural examination supports the view that most cells inthe PNET are undifferentiated. Mitoses and apoptoci bodies are plentiful in regions where the N:C ratio is high.
Neuronal differentiation may take the form of rosettes that lack a central canal or capillry (Homer-Wright rosettes). Small neurons or ganglion cells are rare. Immunoreactivity to GFAP, synaptophysin may occur rarely.

Differential diagnosis

unlike a medulloblasmtoma, an ependymoma usually arises from the floor of the fourth venticle and show widespread pseudorosettes and GFAP immunoreactivity byt does not show focal immunoreactivity for synatpophysisn
unlike medulloblasoma, a GB of the cerebellum contains many astrocytic morphophenotype, and no focal immunoreactivyt for synaptotphysisn

Collin's rule for PNET

States that the period of risk for recurrence - the ghild's age at diagnosis + 9 more months.
applies to over 95% of children under 8 y of age with a medulloblastoma provided the neoplasm appears to have been eradicated by surgery and XRT.

Variants of medulloblastoma

desmoplastic medulloblastoma
medullomyoblastoma
melanotic medulloblastoma.
pleomorphic large cell variant.

Ependymoblastoma

extremely rare
nearly always presents in less than 5 years of age
can be congenital
can affect any level of the CNS
poor prognosis
microscopic appearance

rosette of mainly undifferntiated small cells, with hyperchormatic nuclei that surround a circular or elongated lumen. Different from pseudorosettes of ependymomas in that glomeruloid capillary endothelial proliferation is not seen here.

Neuroblastoma

frequency: very rare
age: under 20 years
survival: median 4 years
location: usually supratentorial
Microscopic appearance: small cells with sparse cytoplasm, hyperchormatic nuclei and a high mitotic count. hoer-wright rosetts and scatterered immunoreactivity for neurofilament protien, class III beta tubulin, and synaptophysisn.

Medulloepithelioma

frequency: extremely rare
age: almost always <5, and most < 1
can be congenital
shows no bias towards either sex
genearlly a deep seated supratentorial mass
median survival 8 months.
Microscopic appearance
papillary architecture
tubules of cells with hyperchromatic nuclei mimicking a primitive neural tube

Neoplasms of the pineal gland

Clinical presentation:

Rased intracranial pressure symptoms
brain sem compresion, producing Parinauds' syndrome, other gaze palsies, nystagmus, ataxia or long ract signs.
endocrine dysfunction related to hydrocephalus and rarely to neoplastic infiltration of the hypothalamus.

Pineocytic neoplasms

Breakdown
40% pineocytomas
40% pineoblastomas
20% mixed or intermediate

Age:

mostly 3rd or 4th decade
pineoblastomas usu 2nd decade
pineocytomas usu 4th decade

Sex: M=F
In children, rare association of pineoblastomas with bilateral retinoblastomas.
Microscopic appearances

pineocytomas:.

pineocytomatous rosettes
usually elongated in shape
immunostaining is positive for neurofilament
mixed pineocytic or intermediate
groups of small , rapidly proliferating cells in a neoplasm which otherwise has the architecture and cytology of a pineocytoma. The small, "blas" cells confer the behavioral properties of a pineoblastoma
lacks teh well differentiated features of a pineocytoma such as the pseudorosettes.

pineoblastoma

resembles the medulloblastoma
may have homer-wright rosettes or flexner-Winterstiener rosettes but no pineocytomatous rosettes.

Pineal cyst

common finding at necropsy, rarely symptomatic. Microscopic appearances show rosenthal fibers, surrounding pineal gland may appear compressed.

Primary CNS Germ cell neoplasms

Breakdown

50% germinomas
20% teratomas
25% mixed
5% pure non teratomatous non germinomatous

75% under age 10-20years. 95% under 33 years
Germinomas most commonly occur around puberty

M>F 2:1 for GCT in the pineal region

presenting clinical features. DI
mixed GCT may transofrm into a symptomatic tertoma if XRT or chemo is used to treat based on raised markers.
Germinomas

macroscopic appearance

soft friable well-circumscribed

microscopically

same histoligic features as ovarian dysgerminomas and testicular seminomas. Groups of plump round neoplastic cells with prominent nucleoli are surrounded by aggregates of reactive T lymphocytes. The neoplastic cells often have clear glycogen-rich cytoplasm.
plasmalemmal placental alkaline phosphatase immunoreactivity of large cells is characterisitic.

Embryonal carinoma, yolk sac, and choriocarcinoma

These are rare, markers beta HCG and AFP in CSF requires search
embryonal carcinoma: sheets of large moderately peomorphic cells with a glandular cribriform papillary or solid arrangement. Clear cytoplasm may be a feature of some cells. Mitoses and necrosis are evident. Immunohistochemistry reveals scattered reactivity for low MW cytokeratins. Cells may occasionally label with antibodies to placental alkaline phosphatase, beta HCG and AFP.

Yolk sac tumor: Loose or lacy pattern with Schiller-Duval and eosinophilic bodies The eosinophilic bodies are PA positive and often contain AFP
Choriocarcinoma: conatin syncytiotrophoblastic giant cells and cytotrophoblastic elements that show a bilaminar pattern. Foci of hemorrhage and necrosisis are usual. Synctytiotrophoblasts are immunoreactive for beta HCG.
Teratomas

Differntiated teratomas are well circumscribed and usually have a lobulated or partly cystic appearnce. Usually contain all three embryonic cell lines endodemr, mesoderm ectoderm.

Choroid plexus neoplasms

Frequency:

0.5 % of CNS neoplasms
of 3% of childhood CNS neoplasms
may be congenital

wide rande but over 50% are < 2y

Location

predominantly lateral ventricles in children
nearly always 4th ventricle in adults

clinical presentation

usually with hydrocephalic signs due to blocked CSF drainage pathways and increased CSF production

Genetic factors

have been reported with Li-Fraumeni and von Hippel-Linau syndromes
rarely contain p53 mutations
induced in mice by SV40 large T antigen.

Macroscopic appearance

Highly vascular: contain foci of hemorrhage
CP well circumscribed. CPC invasive

Microscopic appearance

CPP vs normal CP: is dinguished from normal CP on architectural and cytologic grounds
is dintinguished from papillary ependymomas by a prominent PAS-postiive basement membrane beneath the epithelium, widespread immunolabeling with cytokeratin antibodies, only scanty focal GFAP immunoreactivyt and the absence of pseudorosettes

CPC is distinguished from others (medulloepitheilioma, anaplastic ependymoma, embryonal carcinoma, and metastatic papillary carcinoma) by its staining for cytokeratin.

Primary CNS lymphomas

A word about primary lymphomas

Non-hodgkin's lymphomas
>80% are large B cell lymphomas that are conifened to the CNS
Most involve the cerebrum but about 10% originate in the cerebellum and a few from the brainstem or spinal cord.
Their behavior, response to treatment aer different from other systemic diffuse large B-cell lymphomas.

Secondary lymphomas

By far more common than PCNSL
5-10% of systemic lymphomas involve the CNS, often occupying the subarachnoid space. Leukemias share this predilection for the meninges.

Condtions associated with PCNSL

Primary immunodeficiency syndromes

Wiskott-Aldrich syndrome
X-linked lymphoproliferative syndrome
SCID
Ataxia-telangiectasia

Secondary immunodeficiency syndromes

HIV infection
Immunosuppresive therapy
Hodgkin's disease

Other disorders

autoimmune disorders such as Sjogren's syndrome, sle, RA
EBV is implicated in all PCNSL in all immunocompromised patients and 15-20% of immunocompetent patients

Epidemiologic and clinical aspects

PCNSL accounts for 2-3% of intracranial neoplasms
PCNSL accounts for approximately 1% of NHL
incidence in both immunocompetent and immunocompromised has increased since 1985
peak incidence in immunocompetent is 6th and 7th decade and in immunocompromised 4th.
M:F 3:2
T cell usually a younger age group than B cell
Presenting symptoms can be a space-occupying lesion causing raised intracranial pressure, focal neurologic defict, or epilepsy.
Angiotropic large-cell lymphoma presents with fluctuating confusion, TIAs or a rapid dementia
PCNSL is evident as irregular sometimes multifocal, contrast enhancing masses on CT or MRI
In immunocompromised patients, the radiologic appearance may mimic high grade glioma or toxoplasmosis
survival does not correlate with histologic features.

Macroscopic appearance

multifocal, well demarcated despite microscopic infiltration of surrounding tissue.

Microscopic appearance

characterized by sheets of lymphoma cells separated by areas of necrosis. Tend to invade the walls of small cerebral blood vessels and accumulate in the perivascular apaces. Produces a characterisitc lacy pattern of reduplicated perivascular reticulin.
Polymorphous diffuse large B cell lymphomas account for more than 80% of PCNSLs. They contain cells resembling centroblasts, and immunoblasts which are mixed with smaller cells, including reactive T cell
<10 % of PCNSL are B cell lymphomas with lymphocytic or lymphoplamacytoid cytology
T cell pCNSL is very rare.
the rare CNS agiotropic lymphoma usually a large B cell lymphoma, fill the lumina of small cerebral vessels and invade the surrounding parancyma in only a few places. tend to cause vascular occlusion and hemorrhagic infarcts. Most are systemic lymphomas that preferentially affect the CNS and skin.

Peripheral nerve sheath neoplasms

Nearly all cranial nerve sheath neoplasms and most peripheral nerve sheath tumors inthe spinal canal are schwannomas. All three groups are associated with neurofibromatosis (NF).
The commonest neoplasm of the cerebellopontine angle is a schwannoma of the vestibulocochlear nerve.
Schwannomas (85%), meningioma (10%) Others (cholesteatoma, glioma, medulloblastoma, metastatic carcinoma, paraganglionoma, hemangioma) 5%.
Histologic features to distinguish from fibrobalstic meningioma and astrocytoma are : the reticulin pattern, which surrounds each cell to form a dense pattern in schwannomas, GFAP negative in schwanommas, and are uniformly S-100 positive, and a pericellular basal lamina without inermediate filaments of astrocytes and desmosomes of meningiomas on ultrasturural exam.
The relation of schwannoma and neurofibromas with respect to the associated nerve is important: Schwannomas grow outside of the nerve whereas the neurofibroma incorporates the axons.

Schwannomas

Macroscopic appearance: nodular ruberry tissue, capsulated with nerve adjacent to the mass
Microscopic appearance:

Antoni A: spinle-shaped cells with rod-shaped nuclei and dense pericelluar reticulin are arnaged in compact intertwinng fascicles
Antoni B: stellate or spindle shaped cells with smaller, more hyperchormatic nuclei, tenuous cytoplasmic processes and scanty surrounding reticulin are loosely arranged in a myxoid stroma.
Verocay bodies: sequential nuclear palisades separated by an anuclear area.

Neurofibromas

Macroscopic appearance

solitary intraneural neurofibromas are usually oval gray or tan-colored neoplasm with a smooth shiny surface covered by a delicate pseudocapsule.

Microscopic appearance

wavy serpentine nuclei.
mixed cell population

Malignant nerve sheath tumors

Macroscopic appearance
Microscopic appearance

Neurofibromatosis 1 (NF1)

Genetics

Chromosome 17q11
autosomal dominant inheritance with almost complete penetrance
about 50% present as new mutations

Prevalence 1:3000
Gene product is neurofibromin which is a guanosine triphosphatase-activating protein
Neoplasms associated with NF1

Neurofibromas
Malignant nerve sheath tumors
Optic nerve gliomas
Rhabdomyosarcomas
Pheochromocytomas
Carcinoid tumors
NOTE: plexiform schwannomas is NOT associated with NF1 mutations.

Clincal diagnostic criteria

Two or more of the following:

At least two solitary neurofibromas or one plexiform neurofibroma
At least 6 cafe-au-lait spots larger than 5 mm diameter prepubertal and larger than 15 mm post pubertal
At least 2 Lisch noduels
Optic glioma (pilocytic astrocytoma)
Osseous lesions (sphenoid dysplasia, pseudoarthrosis, or spinal deformity)
Axillary freckling
A family history of a first degree relative with NF1 fulfilling the above criteria.

Neurofibromatosis 2 (NF2)

Genetics

Chromosome 22q12
Autosomal dominance with high penetrance
Approximately 50% present as new mutations

Prevalence 1:40,000
Gene product: Merlin, associated with membrane and cytoskeletal structures
Neoplasms associated with NF2

Schwannomas
Neurofibromas
Ependymomas
Other gliomas
Meningiomas (may be multiple)
NOTE: plexiform neurofibromas are not found in NF2 and association with MNSTs is very rare.

Clinical diagnostic criteria

One of the four clinical presentations

Bilateral vestibular schwannomas
First degree relative with NF2 plus one vestibular nerve schwannoma
First degree relative with NF2 plus two of the following

meningioma
schwannoma
glioma
nerfibroma
posterior subcapsular lens opacity

Two of the following

unilateral vestibular nerve schwannoma
multiple meningiomas
multiple schwannomas
glioma
neurofibroma
posterior subcapsular lens opacity
cerebral calcification

Genetic aspects of Nerve sheath neoplasms

MNST and NF1

30-50% of MNST are associated with NF1
For NF1 patients, the lifetime risk of developing MNST is 2%
Approximately 5-10% of plexiform neurofibromas in patients with NF1 progress to MNST.

Schwannomas and NF2

Patients iwth NF2 may have bilateral vestibular schwannomas
Sporadic schwannomas fequently show NF2 gene mutations plus allelic loss on the other chromosome

Carney's complex

Autosomal dominant syndrome comprises melanotic schwannomas, spotty pigmentation, cardiac or skin myxomas, and endocrine overactivity (Cushing's or acromegaly)

CNS Schwannomas

Cranial schwannomas

constitute 8% if intracranial neoplasms
are most common in the 5th and 6th decades
arise predominatly from the vestibular branch of the eighth cranial nerve
sometimes encroach upon the vestibular ganglion
sometimes occur on the CN V

Spinal schwannomas

predominantly arise from sensory nerve roots
are most common in the lumbosacral region
are mainly intradural and extramedullary
adopt a dumb-bell shape as they grow through the vertebral foramen
may be multiple in NF2