Central Nervous System

Central Nervous System

Elizabeth J. Cochran 19 Central Nervous System Astrocytic Tumors Ependymal Tumors Diffuse Astrocytoma, Anaplastic Astrocytoma, Gliomatosis Cerebr...

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Elizabeth J. Cochran

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Central Nervous System

Astrocytic Tumors

Ependymal Tumors

Diffuse Astrocytoma, Anaplastic Astrocytoma, Gliomatosis Cerebri, Glioneuronal Tumor with Neuropil-like Islands, Gliosarcoma, and Glioblastoma Multiforme (WHO Grades II, III, IV)  988 Pilocytic Astrocytoma (WHO Grade I)  992 Pilomyxoid Astrocytoma (WHO Grade II)  993 Pleomorphic Xanthoastrocytoma (WHO Grade II)  994 Subependymal Giant Cell Astrocytoma (WHO Grade I)  995

Ependymoma (WHO Grade II) and Anaplastic Ependymoma (WHO Grade III)  999 Myxopapillary Ependymoma (WHO Grade I)  1000 Subependymoma (WHO Grade I)  1001

Oligodendroglial Tumors Oligodendroglioma (WHO Grade II) and Anaplastic Oligodendroglioma (WHO Grade III)  996

Mixed Gliomas Oligodendroglioma and Astrocytoma (WHO Grade II), Anaplastic Oligodendroglioma and Astrocytoma (WHO Grade III), and Glioblastoma Multiforme with Oligodendroglial Features (WHO Grade IV)  998

Other Neuroepithelial Tumors Astroblastoma (No WHO Grade at Present)  1002 Chordoid Glioma (WHO Grade II)  1003 Angiocentric Glioma (WHO Grade I)  1003

Neuronal and Glioneuronal Neoplasms Gangliocytoma (WHO Grade I) and Ganglioglioma (WHO Grades II and III)  1004 Dysembryoplastic Neuroepithelial Tumor (WHO Grade I)  1006 Central and Extraventricular Neurocytoma (WHO Grade II)  1007 Papillary Glioneuronal Tumor (No WHO Grade at Present)  1008 Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle (WHO Grade I)  1009 Paraganglioma of the Spinal Cord (WHO Grade I)  1009 987

988  Differential Diagnosis in Surgical Pathology

Embryonal Tumors Medulloblastoma (WHO Grade IV)  1010 Supratentorial Primitive Neuroectodermal Neoplasms (Neuroblastoma, Ganglioneuroblastoma, Ependymoblastoma, Medulloepithelioma) (WHO Grade IV)  1012 Atypical Teratoid/Rhabdoid Tumor (WHO Grade IV)  1013

Choroid Plexus Tumors Choroid Plexus Papilloma (WHO Grade I), Atypical Choroid Plexus Papilloma (WHO Grade II), and Choroid Plexus Carcinoma (WHO Grade III)  1014

Pineal Parenchymal Tumors Pineocytoma (WHO Grade I) and Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grades II and III)  1015 Pineoblastoma (WHO Grade IV)  1016 Papillary Tumor of the Pineal Region (WHO Grades II and III)  1016

Other Neoplasms and Related Entities Peripheral Nerve Sheath Tumors  1017

Meningioma (WHO Grade I), Atypical Meningioma (WHO Grade II), and Anaplastic Meningioma (WHO Grade III)  1020 Hemangiopericytoma (WHO Grade II) and Anaplastic Hemangiopericytoma (WHO Grade III)  1022 Hemangioblastoma (WHO Grade I)  1023 Malignant Lymphoma (Non-Hodgkin and Hodgkin)  1024 Germ Cell Tumors  1026 Neuraxial Cysts: Rathke Cleft Cyst, Colloid Cyst, and Enterogenous Cyst  1026 Pituitary Adenoma (Including Typical and Atypical Adenomas), Pituitary Carcinoma, and Pituitary Hyperplasia  1028 Pituicytoma (WHO Grade I)  1030 Craniopharyngioma (WHO Grade I)  1031 Chordoma  1032 Secondary Tumors  1033

Non-neoplastic Conditions Vascular Malformations  1035 Cerebral Infarction and Intracerebral Hematomas  1036 Vasculitis  1038 Brain Abscess  1040 Encephalitis and Meningoencephalitis  1041 Progressive Multifocal Leukoencephalopathy  1044 Demyelinating Diseases  1045 Dementia  1047

Astrocytic Tumors Diffuse Astrocytoma, Anaplastic Astrocytoma, Gliomatosis Cerebri, Glioneuronal Tumor with Neuropil-like Islands, Gliosarcoma, and Glioblastoma Multiforme (WHO Grades II, III, IV) Clinical Features Account for 33% of all primary brain tumors and about 75% of diffuse gliomas ● Produce neurologic findings, including seizures; symptoms are related to mass effect, or focal ●

neurologic deficits are related to the location of the tumor ● Computed tomography (CT) scans show an ill-defined area of low density ● Low-grade astrocytomas do not show contrast enhancement; higher-grade tumors, including anaplastic astrocytomas, gliosarcoma, and glioblastoma multiforme (GBM), typically enhance and frequently show ring enhancement ● Gliomatosis cerebri shows diffuse enlargement of involved areas without a focal mass identifiable (T1 hypointensity, T2 hyperintensity); no enhancement

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A

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Figure 19-1.  A, Low-grade astrocytoma. Cellular infiltrate of neoplastic astrocytes showing nuclear enlargement, nuclear membrane irregularity, and slight hyperchromasia. B, Anaplastic astrocytoma. Highly cellular tumor composed of neoplastic astrocytes with moderate nuclear pleomorphism, hyperchromatism, nuclear membrane irregularity, and mitoses. C, Glioblastoma multiforme (GBM). Notice the prominent area of necrosis with pseudopalisading. D, GBM. Neoplastic astrocytes surrounding endothelial proliferation (glial fibrillary acidic protein stain).

Astrocytoma occurs commonly in cerebral hemispheres in adults (mean age, 30 to 40 years) and in the brain stem in children; occasionally occur in cerebellum or spinal cord ● Anaplastic astrocytoma is typically found in adults (mean age, 45 years); pontine lesions are more common in children ● Gliomatosis cerebri — Glioma, usually astrocytic, which involves at least three cerebral lobes of the brain; usually bilateral involvement and without defined focal mass identifiable — Peak occurrence between ages 40 and 50 years — Wide-ranging signs and symptoms; generalized cognitive impairment, often without focal neurologic deficits ● GBM — Most frequently occurring brain tumor; up to 15% of all intracranial neoplasms and up to 75% of all astrocytic neoplasms — Overall, usually occurs in individuals between ages 45 and 75 years (80% occur in those older than 50 years); most commonly involves the cerebral hemispheres — Usually affects the brain stem in children ●

— Primary glioblastoma occurs de novo as a grade IV neoplasm ◆ Most GBMs are primary and have a short (<3 months) clinical history ◆ Usually occur at older ages (mean age, 62 years) — Secondary glioblastomas occur in the setting of a previously diagnosed grade II or III astrocytoma ◆ Mean age of occurrence is 45 years Gross Pathology ● Low-grade tumors have a variable gross appearance ranging from subtle, barely visible lesions to large, soft, gelatinous, gray-white ill-defined masses that blur the gray-white border and expand the cortex and white matter ● GBMs are typically large and often involve more than one lobe — Extension across the corpus callosum results in involvement of both hemispheres (butterfly glioma) — Hemorrhage and large areas of necrosis are characteristic ● Gliomatosis cerebri: diffuse enlargement of affected brain regions; usually, no distinct mass is seen

990  Differential Diagnosis in Surgical Pathology

Giant cell GBMs and gliosarcoma may each be sharply circumscribed and firm owing to presence of connective tissue components



Histopathology ❚ Astrocytoma (WHO grade II) ● Hypercellular (relative to normal brain), infiltrative, ill-defined lesions typically centered in the white matter or less commonly the cerebral cortex ● Presence of a single mitosis should not prompt designation as an anaplastic astrocytoma ● Sample size is important in this determination; a small sample with a mitosis should suggest an anaplastic designation, but a single mitosis in a large resection should not prompt a higher-grade diagnosis ❚ Fibrillary astrocytomas: most common type ● Neoplastic astrocytes are slightly pleomorphic and enlarged, with hyperchromatic angular cigar-shaped nuclei ● Cytoplasm is often not visible, or scant asymmetrical cell processes are evident ● Loose fibrillary glial matrix is present in more cellular areas ❚ Protoplasmic astrocytomas: rare variant of low-grade astrocytoma ● Nuclei are round to oval, and fibrillary processes are not evident ● Cells reside in loose mucoid matrix with prominent microcysts ❚ Gemistocytic astrocytoma ● Neoplastic astrocytes have large cell bodies with abundant eosinophilic cytoplasm and short fibrillary processes and eccentric nuclei ● Presence of at least 20% of gemistocytes is necessary for this designation ● This subtype has a high tendency to progress to anaplastic astrocytoma ● Mitotic figures are typically scant or absent ❚ Anaplastic astrocytoma (WHO grade III) ● Tumor shows higher cellularity, increased nuclear pleomorphism, and hyperchromasia ● Mitotic figures are present (see previous discussion of mitoses in astrocytoma) ❚ Gliomatosis cerebri (WHO grade III) ● Growth pattern of diffuse glioma, most often astrocytoma, but may be mixed or oligodendroglioma ● Astrocytic cells often contain elongated nuclei (may be confused with microglia) ● Mitoses are usually sparse; endothelial proliferation and necrosis are absent ● With longer survival, autopsy may show focal areas of higher grade (glioblastoma) ❚ Glioneuronal tumor with neuropil-like islands (WHO grade II or III) ● Fibrillary or gemistocytic astrocytic components alternate with islands of neuropil-like tissue

containing neurocytic cells, frequently peripherally ringing the neuropil islands ● Ganglion cells may also be present ● Usually behaves in an aggressive and malignant fashion ❚ GBM (WHO grade IV) ● Infiltrative, highly cellular tumor with a wide range of abnormal cytology ● Most often present, at least focally, are cells with hyperchromatic, pleomorphic nuclei and ill-defined fibrillary cytoplasm ● The following may also be seen: small cells (primitive appearing), multinucleated cells, giant cells, lipidized cells, granular cells, and epithelioid change ● Numerous mitotic figures are always present ● Rarely, metaplastic elements are present, including squamous or adenoid differentiation, bone, or cartilage ● Required for diagnosis of GBM — Abundant vascular endothelial cell proliferation or areas of necrosis with or without pseudopalisading ❚ Variants of glioblastoma ● Giant cell glioblastoma (WHO grade IV) — Large, bizarre cells with markedly pleomorphic nuclei and multinucleation — May have increased reticulin network and appear more circumscribed ● Gliosarcoma (WHO grade IV) — Defined by the presence of a sarcomatous component in addition to a malignant astrocytic component of the neoplasm — Astrocytic component is high grade and may occasionally display adenoid or squamous metaplasia — Sarcomatous component shows histology suggesting fibrosarcoma or malignant fibrous histiocytoma most frequently ● Small cell astrocytoma (WHO grade III or IV) — Monomorphous oval nuclei, mild nuclear hyperchromasia, occasional small nucleoli, scant cytoplasm, many mitoses — Endothelial proliferation or pseudopalisading necrosis may be present (if present, grade IV; if absent, grade III) — May exhibit architectural features causing confusion with oligodendroglioma, such as chicken-wire vasculature, clear halos, perineuronal satellitosis, and calcifications Special Stains and Immunohistochemistry ● Glial fibrillary acidic protein (GFAP) positive in grade II; higher-grade tumors are highly variable in expression ● Mib-1 (Ki-67): labeling index is low in low-grade astrocytomas (<5%) and high in anaplastic

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astrocytomas (5% to 10%) and glioblastomas (15% to 20%) ● Cytokeratin: may see cross-reactivity with AE1/AE3 cytokeratin antibody ● Epithelial membrane antigen (EMA) typically negative ● Positive for TP53; may help to identify a low-grade astrocytoma from reactive astrocytosis and from a pilocytic astrocytoma ● Reticulin highlights mesenchymal and sarcomatous components in gliosarcoma and desmoplastic component in giant cell GBM ● Periodic acid–Schiff (PAS) positive in granular cell change Other Techniques for Diagnosis ● Electron microscopy — Astrocytes show cytoplasmic intermediate filaments and cell processes; poorly formed cell junctions may be seen ● Cytogenetics — TP53 mutation: 59% of astrocytomas, 53% of anaplastic astrocytomas, 65% of secondary glioblastomas, 84% of giant cell GBMs, and 28% of primary glioblastomas — Loss of heterozygosity of chromosome 10q: 35% to 60% of anaplastic astrocytomas, and about equal frequencies in primary and secondary glioblastomas (60% to 70%) — PTEN mutation: 4% of secondary GBMs, 32% of primary GBMs, and 33% of giant cell GBMs — EGFR gene amplification, 8% of secondary glioblastomas, 5% of giant cell GBMs, and 36% of primary glioblastomas — Small-cell subtype: high frequency of EGFR amplification Differential Diagnosis ❚ Metastasis (metastatic carcinoma or metastatic melanoma) ● Metastatic carcinoma: cytokeratin and EMA positive ● Metastatic melanoma: S-100 and HMB-45 typically positive ● GFAP negative ❚ Lymphoma ● May show radiologic findings similar to those in GBM ● Typically located in periventricular regions ● Angiocentric distribution ● Leukocyte common antigen (LCA) positive; most are of B-cell lineage (CD20 positive) ❚ Reactive astrocytosis ● Small cystlike spaces are not typically seen in reactive processes ● Cellularity is not as high as in astrocytomas ● Reactive astrocytes lack hyperchromatic and pleomorphic nuclei ● More regular arrangement of cells

❚ Oligodendroglioma ● Cells show cytologic features of oligodendrocytes, including perinuclear halos ● Composed of uniform round cells with minimal cytologic atypia ● Negative for GFAP ● Characteristic genetic profile: deletions of chromosomes 1p and 19q ❚ Demyelinating diseases ● Characteristically have numerous foamy macrophages and inflammatory cells ● Areas of demyelination may be identified with myelin stains Pearls ● Patients with well-differentiated diffuse astrocytomas may be treated with surgery, radiation, or both; most patients die of the disease within 10 years; progression to a high-grade tumor commonly occurs (secondary GBM) ● Anaplastic astrocytoma may be treated with surgery and radiation; patients typically die in 2 to 3 years ● GBM is a highly aggressive tumor with a poor outcome; death usually results within 1 year; younger patients may have a slightly better outcome ● Astrocytomas of the brain stem occur most commonly in the first decade in the ventral pons, encasing the basilar artery and associated with a poor prognosis Selected References Edgar M, Rosenblum MK: Mixed glioneuronal tumors, recently described entities. Arch Pathol Lab Med 131:228-233, 2007. Takei H, Bhattacharjee MB, Rivera A, et al: New immunohis­ tochemical markers in the evaluation of central nervous system tumors: A review of seven selected adult and pediatric brain tumors. Arch Pathol Lab Med 131:234-241, 2007. von Deimling A, Burger PC, Nakazato Y, et al: Diffuse astrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 25-29. Kleihues P, Burger PC, Rosenblum MK, et al: Anaplastic astrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 30-32. Kleihues P, Burger PC, Aldape KD, et al: Glioblastoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 33-49. Fuller GN, Kros JM: Gliomatosis cerebri. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 50-52. Perry A, Aldape KD, George DH, Burger PC. Small cell astrocytoma: An aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma. Cancer 101:2318-2326, 2004.

992  Differential Diagnosis in Surgical Pathology

Pilocytic Astrocytoma (WHO Grade I)

Neoplastic astrocytes are usually piloid and have uniform nuclei with minimal pleomorphism ● Multinucleated giant cells are commonly seen ● Mitotic activity is rare; more frequently seen in tumors of infants ● Vascular proliferation and areas of hyalinization are common features ● Focal areas of calcification may be seen, but necrosis is uncommon ● Although grossly circumscribed, the tumor may have microscopic infiltration into adjacent brain tissue ● Occasionally hypercellular tumors with increased pleomorphism and multinucleation (features associated with long-standing lesions) are seen ●

Clinical Features Occurs predominantly in children and young adults; usually presents in the first two decades ● Most common glioma in children ● Most frequently occurs in the cerebellum; may be seen in the optic nerve, third ventricle, hypothalamus, brain stem, cerebral hemispheres, or thalamus ● When arising in the brain stem, it is usually exophytic dorsally or extends into the cerebellopontine angle ● Patients can present with either focal or nonlocalized neurologic deficits or symptoms of increased intracranial pressure; may present with seizures ●

Special Stains and Immunohistochemistry ● GFAP positive ● Negative for TP53 ● Mib-1 labeling index ranges from 0% to 4% (mean, 1%)

Gross Pathology ● Typically well-circumscribed, soft, gray, discrete tumors ● Cyst formation in about 50% of cases

Other Techniques for Diagnosis ● Electron microscopy: pilocytic astrocytes show abundant intermediate filaments; eosinophilic granular bodies contain intermediate filaments, osmiophilic granules, and myelin figures ● Cytogenetics: gains are seen most often in chromosomes 5 and 7

Histopathology ● Most commonly demonstrates a biphasic pattern consisting of pilocytic areas and microcystic components — Loose, microcystic areas typically contain eosinophilic granular bodies or protein droplets — Pilocytic component shows elongated cells with densely packed fibrillary cytoplasm and Rosenthal fibers (tapered, eosinophilic, corkscrew-shaped hyaline structures); Rosenthal fibers are not always seen or necessary for diagnosis ● A diffuse variant of pilocytic astrocytomas having a dense fibrillary component and lacking microcystic areas has been described and has a good prognosis

Differential Diagnosis ❚ Diffuse astrocytoma ● Typically lack circumscription and contrast enhancement ● Tissue infiltration and malignant behavior are much more common ● Usually lacks biphasic pattern, Rosenthal fibers, and eosinophilic granular bodies

A

B

Figure 19-2.  Pilocytic astrocytoma. A, Classic architecture of densely fibrillated areas alternating with microcystic areas. B, Diffuse pilocytic astrocytoma consisting only of densely packed elongated cells. Rosenthal fibers are also present.

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❚ Pleomorphic xanthoastrocytoma ● Lacks biphasic pattern ● Typically more cellular and has increased nuclear pleomorphism ● Xanthomatous cells are not seen in pilocytic astrocytoma ❚ Ganglion cell tumors ● Show clustered atypical neurons, which are immunohistochemically positive with neuronal markers ❚ Hemangioblastoma ● Also associated with cyst formation ● Highly vascular with abundant reticulin formation ● Contains foamy cells filled with lipid Pearls ● Important to distinguish pilocytic astrocytomas from fibrillary or diffuse astrocytomas because treatment and prognosis are different ● Typically cured by complete resection; overall prognosis is excellent ● Rare tumors have an aggressive clinical course, and transformation to glioblastoma has been reported Selected References Scheithauer BW, Hawkins C, Tihan T, et al: Pilocytic astrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 14-20. Tihan T, Davis R, Elowitz E, et al: Practical value of Ki-67 and p53 labeling indexes in stereotactic biopsies of diffuse and pilocytic astrocytomas. Arch Pathol Lab Med 124:108-113, 2000. Tomlinson FH, Scheithauer BW, Hayostek CJ, et al: The significance of atypia and histologic malignancy in pilocytic astrocytomas of the cerebellum: A clinicopathologic and flow cytometric study. J Child Neurol 9:301-310, 1994.

Pilomyxoid Astrocytoma (WHO Grade II) Clinical Features ● Considered a variant of pilocytic astrocytoma ● Occurs in infants and young children (mean age, 18 months) and involves the chiasm and hypothalamus most often ● Has been reported in temporal lobe, thalamus, posterior fossa, and spinal cord ● Presenting symptoms may be nonlocalizing: failure to thrive, developmental delay, vomiting and feeding difficulties, generalized weakness, and altered levels of consciousness ● Focal neurologic symptoms also occur: visual disturbances and endocrine dysfunction ● Tendency to disseminate through cerebrospinal fluid and to recur

Gross Pathology Myxoid ill-defined mass



Histopathology ● Monomorphous, hypercellular, compact small bipolar cells set in a myxoid and fibrillary background ● An angiocentric pattern of arrangement of cells suggestive of perivascular pseudorosettes is often evident ● Limited peripheral parenchymal involvement ● Rare nuclear pleomorphism ● Usually lacks Rosenthal fibers and eosinophilic granular bodies ● Mitotic figures may be present ● Vascular proliferation and necrosis reported in some cases Special Stains and Immunohistochemistry ● GFAP: diffuse positivity ● Vimentin positive ● Neuronal markers: negative ● Mib-1 labeling index ranges from 2% to 20% Other Techniques for Diagnosis ● Cytogenetics: only rare case reports Differential Diagnosis ❚ Pilocytic astrocytoma ● Occurs also in the chiasm and hypothalamus ● Rosenthal fibers and eosinophilic granular bodies present ● Biphasic architecture Pearls ● Report of transition of a pilomyxoid astrocytoma to a pilocytic astrocytoma supports a close relationship between these two entities ● Pilomyxoid astrocytoma is locally aggressive with a tendency to recur (76%) and disseminate through the cerebrospinal fluid (14%); overall survival is 63 months ● Focal areas of pilomyxoid features in an otherwise typical pilocytic astrocytoma do not indicate a diagnosis of pilomyxoid astrocytoma Selected References Brat DJ, Scheithauer BW, Fuller GN, Tihan T. Newly codified glial neoplasms of the 2007 WHO Classification of Tumours of the Central Nervous System: Angiocentric glioma, pilomyxoid astrocytoma and pituicytoma. Brain Pathol 17:319-324, 2007. Ceppa EP, Bouffet E, Griebel R, Robinson C: The pilomyxoid astrocytoma and its relationship to pilocytic astrocytoma: Report of a case and a critical review of the entity. J Neurooncol 81:191-196, 2007. Komotar RJ, Mocco J, Jones JE, et al: Pilomyxoid astrocytoma: diagnosis, prognosis, and management. Neurosurg Focus 18:E7, 2005.

994  Differential Diagnosis in Surgical Pathology

Tihan T, Fisher PG, Kepner JL, et al: Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropath Exp Neurol 58:1061-1068, 1999.

Pleomorphic Xanthoastrocytoma (WHO Grade II) Clinical Features Rare astrocytic neoplasm usually found in children and young adults (66% are younger than 18 years) ● Superficial location in the cerebral hemisphere (most frequently temporal lobe) often involving the meninges; rare involvement of the deep gray matter, cerebellum, spinal cord, sella, suprasellar region, and retina ● Patients present typically with long history of seizures and occasional headaches; seldom with focal neurologic signs ● CT and magnetic resonance imaging (MRI) show a well-defined enhancing mass, adjacent to the meninges, that is solid or cystic with a mural nodule ●

Gross Pathology ● Well-defined, cystic mass with a mural nodule or a solid mass ● Often attached to the meninges; may spread along brain surface Histopathology ● Varied histologic pattern ranging from single or multinucleated giant cells to irregular spindle cells showing intracellular lipid accumulation (xanthomatous change) ● Reticulin network surrounding individual tumor cells; desmoplasia often present

Figure 19-3.  Pleomorphic xanthoastrocytoma. Infiltrate of neoplastic astrocytic cells with marked nuclear pleomorphism and xanthomatous changes. Eosinophilic granular bodies are present.

Patchy lymphocytic infiltrates often seen Variable degrees of vascular sclerosis ● Eosinophilic granular bodies or protein droplets prominent ● Usually absent or inconspicuous mitotic activity and necrosis ● When numerous mitoses (≥5 mitoses/10 high-power fields [hpf]) and necrosis are present, high rates of recurrence are seen (pleomorphic xanthoastrocytoma with anaplastic features) ● Neuronal differentiation may be present ● ●

Special Stains and Immunohistochemistry ● GFAP, S-100 protein, and CD34 positive ● Reticulin highlights fibrous network surrounding tumor cells ● Synaptophysin and neurofilament variably positive ● Mib-1 labeling index: less than 1% Other Techniques for Diagnosis ● Electron microscopy: cells typically show abundant intermediate filaments, lysosomes, lipid droplets, basal lamina, and secondary lysosomes ● About 20% show ultrastructural features indicating neuronal differentiation: microtubules, dense core granules, and clear vesicles ● Cytogenetic analyses: gains of chromosomes 3 and 7 and alterations of chromosome 1 Differential Diagnosis ❚ Glioblastoma ● Important distinction from pleomorphic xanthoastro­ cytoma because of poor prognosis associated with glioblastoma ● Most lack reticulin investment and eosinophilic granular bodies ● Usually not cystic with mural nodules; always a high mitotic index and endothelial proliferation or necrosis ❚ Pilocytic astrocytoma ● Biphasic pattern is characteristic ● Rosenthal fibers are commonly found ● Usually less cellular and without xanthomatous changes ❚ Ganglion cell tumors ● Atypical neurons that are positive for neuronal markers (synaptophysin and neurofilament) are a defining feature ● Usually lack xanthomatous changes Pearls ● Surgical resection is usually sufficient to control tumor ● Subtotally resected and recurrent tumors have been treated with radiation, with unclear results ● These tumors are hypothesized to arise from subpial astrocytes and often display neuronal differentiation

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Selected References Giannini C, Paulus W, Louis DN, Liberski P: Pleomorphic xanthoastrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 22-24. McClendon RE, Gray L, Shah LM, Friedman AH: Pleomorphic xanthoastrocytoma. In McClendon RE, Rosenblum MK, Bigner DD (eds): Russell and Rubenstein’s Pathology of Tumors of the Nervous System. New York, Oxford, 2006. Giannini C, Scheithauer BW, Lopes MBS, et al: Immunophenotype of pleomorphic xanthoastrocytoma. Am J Surg Pathol 26:479-485, 2002. Kepes JJ: Pleomorphic xanthoastrocytoma: The birth of a diagnosis and a concept. Brain Pathol 3:269-274, 1993.

Subependymal Giant Cell Astrocytoma (WHO Grade I) Clinical Features Most common neoplastic process involving the brain in patients with tuberous sclerosis — Tuberous sclerosis is an autosomal dominant disorder with markedly variable penetrance and an incidence between 1 per 9000 and 1 per 10,000 births — Central nervous system (CNS) abnormalities include cortical hamartomas (tubers), subcortical glioneuronal hamartomas, subependymal glial nodules, subependymal giant cell astrocytoma (SEGA); other organs affected are skin, eyes, kidney, and heart — Neurologic symptoms in tuberous sclerosis usually occur shortly after birth and include seizures and infantile spasms; cognitive disability and autism may become evident at older ages



— Caused by mutation in two genes: TSC1 (encoding hamartin) on chromosome 9 and TSC2 (encoding tuberin) on chromosome 16 ● SEGA rarely occurs without association with tuberous sclerosis — Occurs in 10% of persons with tuberous sclerosis — Usually develops during childhood or adolescence — Clinical symptoms are usually secondary to obstructive hydrocephalus and occur when large SEGAs block cerebrospinal fluid (CSF) flow Gross Pathology ● Typically an exophytic, solid, fleshy, well-defined, tan mass arising in the wall of the lateral ventricle Histopathology ● Variable cellular morphology, including — Polygonal cells with abundant eosinophilic cytoplasm suggestive of gemistocytic astrocytes — Spindle-shaped cells with fibrillary cytoplasm forming streams and bundles — Large pleomorphic cells with nuclei exhibiting prominent nucleoli, suggestive of neuronal differentiation (sometimes multinucleated) — Focal microcalcifications and scattered mast cells are common features — Ill-defined pseudorosette formation may be seen — Variable mitotic activity — Vascular proliferation and necrosis are uncommon — High-grade cytologic features do not appear to impose an adverse clinical course Special Stains and Immunohistochemistry ● GFAP, S-100 protein, synaptophysin, and neurofilament positive ● Class III β-tubulin and neuropeptides (somatostatin and met-enkephalin) positive ● Mib-1 (Ki-67): few positive cells (low proliferative index) Other Techniques for Diagnosis ● Cytogenetics: associated with abnormalities involving long arm of chromosome 9 (TSC1) and short arm of chromosome 16 (TSC2)

Figure 19-4.  Subependymal giant cell astrocytoma. Infiltrate of astrocytic-appearing cells with abundant, frequently spindled eosinophilic cytoplasm. Prominent nucleoli are frequent.

Differential Diagnosis ❚ Gemistocytic astrocytoma ● May be confused because both lesions contain astrocytic cells with abundant pink glassy cytoplasm ● Intraparenchymal tumor rather than an exophytic intraventricular mass ● Typically shows an infiltrative architecture ● No mast cell infiltrate and microcalcifications

996  Differential Diagnosis in Surgical Pathology

❚ Subependymal glial nodule ● Considered to be a precursor to SEGA ● More frequently calcified than SEGA ● Usually asymptomatic; shows no growth on serial brain scans ● Histologically identical to SEGA Pearls ● Debate still exists as to whether SEGAs can occur outside the setting of tuberous sclerosis ● Believed to be an astrocytic neoplasm; however, studies have shown that many tumors show a more glioneuronal phenotype ● Tumors occasionally recur, but unlike gemistocytic astrocytoma, no malignant transformation has been shown, although local invasion has been reported ● Only about 50% of tuberous sclerosis patients have a positive family history, suggesting a high rate of spontaneous mutation

A

Selected References Lopes MBS, Wiestler OD, Stemmer-Rachamimov AO, Sharma MC: Tuberous sclerosis complex and subependymal giant cell astrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 218221. Goh S, Butler W, Thiele EA: Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63:1457-1461, 2004. Burger PC, Scheithauer BW, Vogel FS: The brain: Tumors. In Surgical Pathology of the Nervous System and Its Coverings, 4th ed. New York, Churchill Livingston, 2002, pp 220-223.

Oligodendroglial Tumors Oligodendroglioma (WHO Grade II) and Anaplastic Oligodendroglioma (WHO Grade III) Clinical Features ● Reported to represent between 12% and 20% of all infiltrating gliomas ● Typically occurs in adults (peak, fifth and sixth decades) ● Patients present with a long history of progressively worsening neurologic symptoms ● Commonly cause severe headache and epileptic seizures ● CT and MRI show a well-defined mass, often with calcifications Gross Pathology ● Typically white-matter tumors; infiltration into the cortex is common, and infiltration into leptomeninges may be seen ● Soft, ill-defined, gray-pink tumors

B Figure 19-5.  A, Low-grade oligodendroglioma. Moderately cellular tumor composed of cells with round hyperchromatic nuclei and clear cytoplasm, giving the characteristic fried-egg appearance. B, Anaplastic oligodendroglioma. Notice the mitoses, high cellularity, nuclear enlargement, and hyperchromatism.

Mucoid degeneration with a gelatinous appearance may be seen ● Cyst formation and focal intratumoral hemorrhage are common ●

Histopathology ❚ Oligodendroglioma ● Low to moderately cellular tumor composed of cells with round nuclei that are larger than normal oligodendrocytes and show atypia; nuclei are hyperchromatic and may appear lobate (cytologic features are well demonstrated with smear preparations) ● Formalin-fixed, paraffin-embedded tissue often causes the tumor cells to swell, resulting in an enlarged cell with well-defined cell membranes and clear cytoplasm; fried-egg appearance (not seen on smear preparations, frozen sections, or quickly fixed tissue) ● Few glial fibrillary processes are seen

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Two morphologic variants of oligodendroglial cells may also be present — Minigemistocytes or microgemistocytes, exhibiting small pools of eosinophilic cytoplasm — Gliofibrillary oligodendrocytes, exhibiting paranuclear eosinophilic fibrils ● A dense network of branching capillaries (chickenwire appearance) is seen throughout tumor ● Mitotic activity is usually low ● Microcalcifications and mucoid and microcystic degeneration are helpful diagnostic features ● Focal hemorrhage is commonly seen ● Cortex is often involved; perinuclear satellitosis is often present ❚ Anaplastic oligodendroglioma ● Same cytologic features described previously but with increased nuclear atypia and cellular pleomorphism while retaining round nuclear outlines ● Increased cellularity is evident ● Mitotic activity is marked (minimum of 6 mitoses/10 hpf) ● Endothelial vascular proliferation has been shown in several studies to correlate with aggressive behavior and poor prognosis ● Presence of geographic necrosis (with or without pseudopalisading) has also been found to correlate with aggressive behavior and poor prognosis but is not an independent prognostic factor in all studies ❚ Oligodendroglioma with neurocytic differentiation ● Foci of Homer-Wright rosettes and perivascular pseudorosettes associated with small round dark nuclei (reminiscent of internal granular cell layer neurons) have been reported in otherwise typical oligodendrogliomas ●

Special Stains and Immunohistochemistry ● GFAP positive in reactive astrocytes; GFAP also positive in gliofibrillary oligodendrocytes and minigemistocytes ● Synaptophysin, Neu-N, and neurofilament negative except in rare specimen with foci of neurocytic differentiation ● Cytokeratin negative ● Mib-1: disease-free survival is significantly shorter in patients with a labeling index of more than 5% compared with patients with a labeling index of less than 5% Other Techniques for Diagnosis ● Electron microscopy: presence of microtubules ● Cytogenetics: losses of 1p and 19q are almost always found together in oligodendrogliomas (50% to 80%) Differential Diagnosis ❚ Diffuse astrocytoma ● Tumor cells have greater nuclear irregularity and pleomorphism, no perinuclear halos, and fibrillary cytoplasm

GFAP positive TP53 mutations; no losses of chromosomes 1p and 19q ❚ Small cell variant of anaplastic astrocytoma and glioblastoma ● Cytologically monotonous, but oval, not round, nuclei ● Numerous mitoses, pseudopalisading necrosis, vascular proliferation ● GFAP positive cytoplasmic processes ● No loss of chromosomes 1p and19q ● Amplification of EGFR and EGFRvIII, loss of chromosome 10q ❚ Central neurocytoma ● Usually within the ventricle attached to the septum pellucidum ● Well circumscribed without infiltrative borders, neurocytic rosettes ● Positive for synaptophysin ❚ Dysembryoplastic neuroepithelial tumor (DNET) ● Usually found in younger individuals with a long history of seizures ● Most are located in the temporal lobe ● Histologically consists of a glioneuronal element, glial nodules, and cortical dysplasia ❚ Clear cell ependymoma ● Usually affects younger individuals ● Forms perivascular pseudorosettes consisting of cells with elongated, tapering processes and ependymal rosettes and canals ● GFAP positive ❚ Pilocytic astrocytoma ● Affects children usually ● Cerebellar location, but also in hypothalamus, optic nerve, and brain stem ● Elongated cells with prominent fibrillary cytoplasm ● GFAP positive ● ●

Pearls ● Loss of 1p and 19q is a strong predictor of response to chemotherapy (procarbazine, lomustine, vincristine [PCV] and temozolomide), possibly radiation therapy, and long survival in low- and high-grade oligodendrogliomas ● Combined loss of 1p and 19q is rare in other gliomas ● Testing for deletions of 1p and 19q may be indicated to help in diagnostic classification when a glioma does not clearly show morphologic features allowing definitive designation as oligodendroglioma ● Overall, patients have a survival time of 3 to 5 years for all oligodendrogliomas ● Other factors associated with increased survival: younger age, frontal location, complete surgical removal, and radiation ● Most patients with anaplastic oligodendroglioma die of local recurrence; CSF dissemination or systemic metastases occur rarely

998  Differential Diagnosis in Surgical Pathology

Selected References Aldape K, Burger PC, Perry A: Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med 131:242-251, 2007. Perry A, Scheithauer BW, Macaulay RJB, et al: Oligodendrogliomas with neurocytic differentiation: A report of four cases with diagnostic and histogenetic implications. J Neuropathol Exp Neurol 61:947-955, 2002. Giannini C, Scheithauer BW, Weaver AL, et al: Oligodendrogliomas: Reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol 60:248-262, 2001. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473-1479, 1998.

Mixed Gliomas Oligodendroglioma and Astrocytoma (WHO Grade II), Anaplastic Oligodendroglioma and Astrocytoma (WHO Grade III), and Glioblastoma Multiforme with Oligodendroglial Features (WHO Grade IV) Clinical Features Account for 5% to 10% of gliomas Clinical signs and symptoms at presentation are similar to those seen in pure gliomas

● ●

Gross Pathology ● Gross features similar to those seen with pure gliomas Histopathology ● May exhibit distinct areas of astrocytic and oligodendroglial differentiation or have intermingled astrocytic and oligodendroglial cells ● Percentages of each glial component necessary to qualify the glioma as mixed are not universally agreed on ❚ Oligodendroglioma and astrocytoma (WHO grade II) ● Low to moderate cellularity and cytologic atypia ● Rare mitotic figures ❚ Anaplastic oligodendroglioma and astrocytoma (WHO grade III) ● Higher cellularity and increased cytologic atypia ● Abundant mitotic activity ● Endothelial proliferation ● Anaplastic features may be present in either glial component ❚ Glioblastoma multiforme with oligodendroglial features (WHO grade IV) ● Recent study has found that the presence of necrosis with or without pseudopalisading is associated with a worse prognosis than an anaplastic oligoastrocytoma without necrosis, and suggested use of designation GBM with oligodendroglial features

Special Stains and Immunohistochemistry See “Special Stains and Immunohistochemistry” for astrocytomas and oligodendrogliomas



Other Techniques for Diagnosis ● Cytogenetics — Mixed tumors usually exhibit homogeneous genetic profiles — Analysis of oligoastrocytomas suggests two distinct genetic subsets ◆ Mutation in TP53 gene or loss of heterozygosity of 17p indicates relationship to astrocytomas ◆ Loss of heterozygosity of 1p and 19q indicates genetic resemblance to oligodendrogliomas (reported in 20% to30% of oligoastrocytomas) Differential Diagnosis ❚ Pure astrocytoma ● Consists of only a neoplastic astrocytic component ● Lacks unequivocal neoplasia in other glial cell line ❚ Pure oligodendroglioma ● Consists of only a neoplastic oligodendroglial component ● Lacks unequivocal neoplasia in other glial cell line Pearls ● The prognosis in this neoplasm is still better than that of a GBM without an oligodendroglioma component, independent of 1p and 19q deletion status ● Some studies show that oligoastrocytomas and pure oligodendrogliomas respond similarly to chemotherapy and show no significant differences in survival; in addition, it has been reported that patients with pure oligodendrogliomas or oligoastrocytomas do better than those with pure astrocytomas ● Combined loss of 1p and 19q is associated with improved survival in oligoastrocytomas compared with oligoastrocytomas without deletions of 1p and 19q Selected References Von Deimling A, Reifenberger G, Kros JM, et al: Oligoastrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 63-65. Von Deimling A, Reifenberger G, Kros JM, et al: Anaplastic oligoastrocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 66-67. Miller CR, Dunham CP, Scheithauer BW, Perry A: Significance of necrosis in grading of oligodendroglial neoplasms: A clinicopathologic and genetic study of newly diagnosed highgrade gliomas. J Clin Oncol 24:5419-5426, 2006. Perl A, Fuller CE, Banerjee R, et al: Ancillary FISH analysis for 1p and 19q status: Preliminary observations in 287 gliomas and oligodendroglioma mimics. Front Biosci 8:a1-a9, 2003.

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Ependymal Tumors Ependymoma (WHO Grade II) and Anaplastic Ependymoma (WHO Grade III) Clinical Features Typically occur in children and young adults Account for about 3% to 9% of all neuroepithelial tumors; most frequent neuroepithelial tumors of the spinal cord (50% to 60% of spinal gliomas) ● Occur at any site along the ventricular system; most commonly in the fourth ventricle and spinal cord, followed by the lateral ventricles ● Tumors in children are more commonly in the infratentorial region at a mean age of 6.4 years ● In adults, spinal tumors present between the ages of 30 and 40 years ● Patients often present with symptoms of hydrocephalus, including nausea, vomiting, and headache; patients occasionally develop seizures ● Posterior fossa tumors may cause visual disturbances or cerebellar ataxia ● ●

Gross Pathology ● Soft gray-pink tumors that may be solid or cystic ● Areas of hemorrhage or necrosis may be present ● Typically protrude from the ventricular lining and fill the ventricular lumen; well demarcated, but may invade the adjacent brain parenchyma Histopathology ❚ Ependymoma ● Cellular tumors composed of monomorphic cells with round to oval hyperchromatic nuclei and long fibrillary cell processes ● Characteristically form perivascular pseudorosettes and true rosettes ● Perivascular pseudorosettes consist of tumor cells radially arranged around blood vessels ● True ependymal rosettes consist of columnar cells radially arranged around a central lumen; not present in most ependymomas ● Calcification, as well as metaplastic cartilage or bone, may be seen ● Necrosis without pseudopalisading may be present in ependymoma, grade II ❚ Ependymoma variants ● Cellular ependymoma (WHO grade II) — Increased cellularity without appreciable increase in mitotic rate or other features associated with anaplasia — Increased occurrence in extraventricular sites ● Papillary ependymoma (WHO grade II) — Extensive papillary formations ● Clear cell ependymoma — Cells exhibit round nuclei and perinuclear halos — Anaplastic histologic features are often present

A

B

C Figure 19-6.  Ependymoma. A, Low-power view shows a moderately cellular glial tumor with classic perivascular pseudorosettes. B, Highpower view shows classic ependymal rosettes. Notice glial cells radially arranged to form a canal (phosphotungstic acid–hematoxylin stain). C, Myxopapillary ependymoma. Glial cells exhibiting perivascular arrangement with abundant interposed mucin deposition.

— Occur more frequently in supratentorial compartment than in infratentorial compartment ● Tanycytic ependymoma (WHO grade II) — Occur more commonly in spinal cord — Composed of elongated spindled glial cells forming fascicles — Ependymal rosettes often not present; perivascular pseudorosettes may be ill-defined

1000  Differential Diagnosis in Surgical Pathology

❚ Anaplastic ependymoma ● Morphologic criteria that consistently correlate with prognosis are not well established ● Increased cellularity and increased mitotic activity ● Often endothelial proliferation and necrosis with pseudopalisading ● Perivascular pseudorosettes persist Special Stains and Immunohistochemistry ● GFAP: marked cytoplasmic immunoreactivity, especially prominent in the perivascular pseudorosettes ● Cytokeratin: AE1/AE3 immunoreactivity present in most ependymomas; focal and variably strong positivity with other keratin antibodies ● EMA: dotlike cytoplasmic immunoreactivity present in most neoplastic cells ● CD99: diffuse and dotlike cytoplasmic immunoreactivity with accentuation at membrane surface ● Mib-1 labeling index in more than 5% associated with decreased survival Other Techniques for Diagnosis ● Electron microscopy: cells show polarity with wellformed terminal bars; typically have surface microvilli, cilia, intercellular junctions (zonula adherens), and blepharoplasts ● Cytogenetics: chromosome 22 deletions involving NF2 tumor suppressor gene (member of protein 4.1 family) are most common; clear cell ependymomas have been reported to exhibit losses on chromosome 18 Differential Diagnosis ❚ Metastatic adenocarcinoma ● Morphology more consistently epithelial ● Cytokeratin positivity specific for site of origin; less likely positive in ependymoma ❚ Fibrillary or diffuse astrocytoma ● Poorly defined infiltrative tumor ● Lacks rosette formation ● EMA typically negative ❚ Astroblastoma ● Rare tumor ● Located away from the ventricle ● Shows marked and diffuse vascular sclerosis ● Tumor cells have short, broad processes ● Lacks true rosette formation ❚ Choroid plexus papilloma or carcinoma ● Papillary architecture and no rosette formation ● Negative or only focally positive for GFAP ● Carcinomas have a loose papillary architecture and consist of sheets of pleomorphic cells with a high mitotic rate; extensive necrosis is common

Figure 19-7.  Choroid plexus papilloma. Columnar epithelium overlying classic papillary architecture with central fibrovascular core.

Pearls Complete surgical resection may offer long survival time; many eventually recur, and death often results ● Patients with spinal ependymomas do much better because complete surgical resection is more feasible ● May occasionally occur in the deep white matter away from the ventricle ●

Selected References Kurt E, Zheng POP, Hop WCJ, et al: Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 106:388-395, 2006. Rajaram V, Gutmann DH, Prasad SK, et al: Alterations of protein 4.1 family members in ependymomas: A study of 84 cases. Mod Pathol 18:991-997, 2005. Kawano N, Yasui Y, Utsuki S, et al: Light microscopic demonstration of the microlumen of ependymoma: A study of the usefulness of antigen retrieval for epithelial membrane antigen (EMA) immunostaining. Brain Tumor Pathol 21:1721, 2004. Foulade M, Helton K, Dalton J, et al: Clear cell ependymoma: A clinicopathologic and radiographic analysis of 10 patients. Cancer 98:2232-2244, 2003.

Myxopapillary Ependymoma (WHO Grade I) Clinical Features ● Represents about 10% to 13% of all ependymomas ● Typically presents in young adults at an average age of 36 years ● Occurs more frequently in males (2.5:1) ● Occurs almost exclusively in the conus-cauda-filum terminale region ● Also reported in subcutaneous tissue overlying the sacrococcyx, and in the presacral and postsacral regions ● Rarely occurs outside of this region (fourth or lateral ventricles, brain parenchyma)

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Signs and symptoms include low back pain, sciatica, and focal neurologic deficits referable to the tumor location



Gross Pathology ● Lobulated, circumscribed, soft gray tumors in the filum terminale or attached to nerve roots Histopathology ● Composed of papillae lined by monotonous elongated or columnar cells surrounding a central vascular core ● Occasionally fascicular architecture is present ● Abundant perivascular mucin pools and a fibrillary background Special Stains and Immunohistochemistry ● GFAP, vimentin, and S-100 protein positive ● PAS and Alcian blue highlight perivascular mucin ● Cytokeratin negative ● Mib-1: low Other Techniques for Diagnosis ● Ultrastructural examination shows collagen-rich stroma, cells with basal lamina, and cellular interdigitation Differential Diagnosis ❚ Metastatic adenocarcinoma (mucin secreting) ● Rarely involves the filum terminale ● Consists of pleomorphic tumor cells with high mitotic rate ● Hemorrhage and necrosis are typical ● Strong cytokeratin positivity ❚ Chordoma ● Characterized by a lobular architecture with cords of epithelial and physaliphorous cells ● Lacks papillary architecture and fibrillary background ● GFAP negative ❚ Schwannoma ● Abundant reticulin ● GFAP negative ❚ Paraganglioma ● Morphologic features of neuroendocrine differentiation ● Immunoreactive for neuroendocrine markers Pearls ● Typically slow-growing tumors with a favorable prognosis ● Treatment includes surgical resection and radiation therapy for incompletely excised tumors ● Survival is excellent following complete resection; slightly lower survival rate for incompletely excised lesions ● Tumors occurring in soft tissues have been associated with aggressive behavior and metastases

Selected References McLendon RE, Rosenblum MK, Schiffer D, Wiestler OD: Myxopapillary ependymoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp. 72-73. Ng, HK: Ependymoma, subependymoma, and myxopapillary ependymoma. In McLendon RE, Rosenblum MK, Bigner DD (eds): Russell & Rubinstein’s Pathology of Tumors of the Nervous System, 7th ed. New York, Oxford University Press, 2006, pp 201-221. Prayson RA: Myxopapillary ependymomas: A clinicopathologic study of 14 cases including MIB-1 and p53 immunoreactivity. Mod Pathol 10:304-310, 1997.

Subependymoma (WHO Grade I) Clinical Features Most frequently found in adult males (male-to-female ratio, 4:1) ● Most occur in the fourth (50% to 60%) or lateral (40% to 50%) ventricles; less commonly in the spinal cord ● Many are found incidentally at autopsy, but some cause symptoms, usually related to increased intracranial pressure due to obstruction of the ventricular system ● Symptoms related to mass effect may also be seen (focal neurologic signs, seizures) ●

Gross Pathology ● Firm, tan-white, polypoid nodules of varying size ● Arise from the lining of the ventricle or from the septum pellucidum and protrude in the ventricular lumen; usually well circumscribed ● Focal hemorrhage, calcifications, and cystic changes may be present Histopathology ● Characterized by clusters of monomorphic tumor cells (resembling normal ependymal cells) in a dense fibrillary matrix of glial cell processes ● Microcystic architecture is a common feature ● Small blood vessel proliferation or focal hemorrhage may be seen within the tumor ● Mitotic activity is rare to absent ● Ependymal pseudorosettes may be seen but are not a typical finding; true rosettes are rare ● Microcalcifications are common ● Microcysts filled with basophilic amorphous material are common Special Stains and Immunohistochemistry ● GFAP positive, but may be variable in extent ● S-100 protein diffusely positive ● Mib-1: usually less than 1%

1002  Differential Diagnosis in Surgical Pathology

Other Techniques for Diagnosis Typically have a normal karyotype Ultrastructural examination shows features typical of ependymal cells (surface microvilli, intercellular junctions, and cilia)

● ●

Differential Diagnosis ❚ Ependymoma ● Generally found in younger individuals ● Usually symptomatic, producing hydrocephalus, visual disturbances, or cerebellar ataxia ● More cellular and characterized by rosette and prominent pseudorosette formation Pearls ● For symptomatic lesions, surgical resection is the treatment of choice and is often curative ● Tumors showing both ependymal and subependymal features are generally classified as ependymomas ● Believed to arise from subependymal glial cells (tanycytes) or astrocytes of the subependymal plate; may be a hamartomatous proliferation Selected References McLendon RE, Schiffer D, Rosenblum MK, Wiestler OD: Subependymoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 70-71. Ragel BT, Osborn AG, Whang K, et al: Subependymomas: An analysis of clinical and imaging features. Neurosurgery 58:881-890, 2006. Brown DF, Rushing EJ: Subependymomas: Clinicopathological study of 14 tumors. Arch Pathol Lab Med 123:873, 1999.

Other Neuroepithelial Tumors Astroblastoma (No WHO Grade at Present) Clinical Features ● Rare neoplasm occurring most frequently in children and young adults; uncommon in older adults; one study has noted a female predominance ● Patients typically present with symptoms of mass effect; may have focal neurologic deficits, headache, or seizures ● Most often located near or at the surface of the cerebral hemispheres; may arise in the corpus callosum, cerebellum, optic nerves, brain stem, or cauda equina ● MRI shows a well-defined, contrast-enhancing mass with solid or cystic components; the solid component has a characteristic bubbly appearance and little associated T2 hyperintensity

Gross Pathology Small cyst formation and focal necrosis may be seen, especially in larger tumors



Histopathology ● Key feature is the astroblastic pseudorosette composed of broad, nontapering, nonfibrillar processes that radiate toward a central blood vessel ● Depending on the tumor grade, cells may be monomorphic with inconspicuous nucleoli or show pleomorphic, hyperchromatic nuclei with obvious nucleoli ● Marked perivascular hyalinization is characteristic and may coalesce to occupy extensive areas ● Typically noninfiltrative interface with surrounding brain tissue ● Low grade — Uniform distribution of perivascular pseudo­ rosettes — Low mitotic activity (mean, 1 mitosis/10 hpf) — Minimal cellular pleomorphism — No vascular proliferation or necrosis with pseudopalisading ● High grade — Increased cellularity (focal or multifocal) — High mitotic rate (>5 mitoses/10 hpf) — Nuclear anaplasia — Vascular proliferation and necrosis with pseudopalisading Special Stains and Immunohistochemistry ● GFAP, S-100, and vimentin: strong immunoreactivity ● EMA: focal membranous immunoreactivity ● Cytokeratin (low molecular weight): variable ● Mib-1 index: low grade, 3%; high grade, 15% Other Techniques for Diagnosis ● Electron microscopy: tumor cells contain abundant intermediate filaments and exhibit microvilli, poorly developed intercellular junctions, and rare cilia ● In comparative genomic hybridization studies, most frequently found was gain of chromosome arm 20q, and slightly less frequent was gain of chromosome 19 Differential Diagnosis ❚ Ependymoma ● Most are infratentorial and within or close to a ventricle ● Lacks vascular hyalinization ● Shows formation of true rosettes ● Cells have elongated fibrillary processes and fibrillary background ❚ Angiocentric glioma ● In contrast to astroblastoma, angiocentric gliomas are infiltrating lesions composed of piloid cells that exhibit circumferential arrangements of neoplastic cells around vessels in addition to radial arrangements (as seen in astroblastomas)

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❚ Papillary meningioma ● Contain distinct areas of meningothelial differentiation ● Characteristically EMA positive ● GFAP negative Pearls ● Cell of origin is debated because astroblastomas exhibit features of both astrocytes and ependymal cells; they are suggested to be of tanycytic derivation ● Complete resection typically results in long-term survival ● Focal astroblastic features may be seen in low-grade and high-grade astrocytomas Selected References Port JD, Brat DJ, Burger PC, Pomper MG: Astroblastoma: Radiologic-pathologic correlation and distinction from ependymoma. Am J Neuroradiol 23:243-247, 2002. Brat DJ, Hirose Y, Cohen KJ, et al: Astroblastoma: Clinicopathologic features and chromosomal abnormalities defined by comparative genomic hybridization. Brain Pathol 10:342-352, 2000.

Chordoid Glioma (WHO Grade II) Clinical Features ● Uncommon glioma arising in region of third ventricle ● Mean age, 46 years; range, 12 to 70 years ● Females affected more than males ● Signs and symptoms usually secondary to obstructive hydrocephalus; reported symptoms include headache, weight loss, endocrine disturbances, autonomic disturbances, psychosis, and focal neurologic deficits Gross Pathology ● Well-circumscribed, fusiform, ovoid shape containing cysts; may be attached to the hypothalamus Histopathology ● Cords and clusters of epithelioid cells, myxoid and mucinous background ● Neoplastic cells have abundant eosinophilic cytoplasm, round to oval nuclei, and inconspicuous nucleoli ● Sparse to abundant lymphoplasmacytic infiltrates with Russell bodies ● Rare mitotic figures, no necrosis, and endothelial proliferation ● Does not infiltrate into surrounding brain, but Rosenthal fibers are present in adjacent brain Special Stains and Immunohistochemistry ● PAS and Alcian blue positive background ● GFAP and vimentin: strong diffuse immunoreactivity ● CD34, EMA, and cytokeratin: focal positivity

E-cadherin, neuron-specific enolase (NSE), neurofilament, and S-100: variable positivity ● Synaptophysin and desmin negative ● Mib-1 labeling index: generally less than 2% ●

Other Techniques for Diagnosis ● Electron microscopy: abundant intermediate filaments in cytoplasm, microvilli, focal basal lamina, and hemidesmosomes Differential Diagnosis ❚ Chordoma ● Limited cytokeratin immunoreactivity in chordoid glioma, compared with diffuse and strong reactivity in chordoma ● Physaliferous cells characteristic ❚ Chordoid meningioma ● Presence of whorls and psammoma bodies, nuclear pseudoinclusions ● No immunoreactivity for GFAP; usually positive for EMA ● Both may have inflammatory infiltrates Pearls ● Gross total resection is optimal treatment, but adherence to hypothalamus may prevent complete resection and lead to significant morbidity and poor outcome ● Cell of origin is hypothesized to originate from tanycytes (glial progenitor cells with astrocytic and ependymal features) found in circumventricular organs (lamina terminalis in anterior third ventricular wall) ● Metaplastic elements have been reported (chondroid) Selected References Buccoliero AM, Caldarella A, Gallina P, et al: Chordoid glioma: Clinicopathologic profile and differential diagnosis of an uncommon tumor. Arch Pathol Lab Med 128:e141-145, 2004. Cenacchi G, Roncaroli F, Cerasoli S, et al: Chordoid glioma of the third ventricle: An ultrastructural study of three cases with a histogenetic hypothesis. Am J Surg Pathol 25:401-405, 2001. Brat DJ, Scheithauer BW, Stugaitis SM, et al: Third ventricular chordoid glioma: A distinct clinicopathologic entity. J Neuropathol Exper Neurol 57:283-290, 1998.

Angiocentric Glioma (WHO Grade I) Clinical Features ● Slow-growing glioma ● Reported in patients ranging in age from 2 to 70 years, but occurs most commonly in childhood and adolescence ● Long-standing history of seizures is common

1004  Differential Diagnosis in Surgical Pathology

Occurs in cerebrum, most often frontoparietal lobe; also temporal lobe



Gross Pathology ● Not yet described Histopathology ● Superficial cortical location with subpial accumulation ● Infiltration of surrounding parenchyma ● Monomorphous slender bipolar cells with angiocentricity ● Circumferential (more common) or radial arrangements around vessels of all sizes ● Occasional fascicular architecture ● Rare mitoses Special Stains and Immunohistochemistry ● GFAP: variable degrees of positivity, often around vessels ● S-100 and vimentin positive ● EMA surface and paranuclear dotlike positivity ● Neu-N, chromogranin, and synaptophysin negative ● Mib-1 index: 1% to 5% Other Techniques for Diagnosis ● Ultrastructure: perivascular cells contain cytoplasmic intermediate filaments and exhibit basement membrane; cell junctions and microvilli are described ● Cytogenetics: not yet fully studied; gains of chromosome 11 described Differential Diagnosis ❚ Astrocytoma ● Lacks monomorphic nuclear appearance of angiocentric glioma ● No angiocentricity ❚ Pilocytic astrocytoma ● Not infiltrative ● EMA negative ❚ Pilomyxoid astrocytoma ● Mucinous and myxoid background ● Usual location in hypothalamus ● Contrast enhancing ● Occurs in very young ❚ Ependymoma ● Usually in or adjacent to a ventricle ● Exhibits only radially arranged perivascular pseudorosettes and ependymal rosettes ❚ Astroblastoma ● Radially arranged perivascular pseudorosettes with marked vessel sclerosis Pearls ● Newly described entity ● Surgical excision is usually curative

Selected References Brat DJ, Scheithauer BW, Fuller GN, Tihan T: Newly codified glial neoplasms of the 2007 WHO classification of tumors of the central nervous system: Angiocentric glioma, pilomyxoid astrocytoma, and pituicytoma. Brain Pathol 17:319-324, 2007. Wang M, Tihan T, Fojiani AM, et al: Monomorphous angiocentric glioma: A distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropath Exp Neurol 64:875-881, 2005.

Neuronal and Glioneuronal Neoplasms Gangliocytoma (WHO Grade I) and Ganglioglioma (WHO Grades II and III) Clinical Features Gangliocytomas are WHO grade I Most gangliogliomas are WHO grade I; criteria for grade II gangliogliomas are not yet established ● Anaplastic gangliogliomas are uncommon (WHO grade III) ● Low incidence (1.3% of all brain tumors), but is the most common neoplasm in patients with chronic intractable focal epilepsy ● Typically supratentorial and usually involves the temporal lobe (70%) ● Most present in the first three decades; may be found in all ages ● CT and MRI usually show a complex solid or cystic mass; often with calcification ● ●

Gross Pathology ● Well-circumscribed gray granular mass that is variably solid and cystic; mural nodule within the cystic component often seen ● May extend into the leptomeninges and subarachnoid space ● Extensive calcification, hemorrhage, or necrosis may be seen

Figure 19-8.  Ganglioglioma. Mixed glial-neuronal neoplasm composed of neoplastic astrocytes intermixed with atypical clustered ganglion cells.

Central Nervous System  1005

Histopathology ❚ Gangliocytoma ● Composed entirely of neurons forming ill-defined groups ● Often exhibits cytologic atypia ❚ Ganglioglioma ● Tumor composed of atypical ganglion cells as well as a neoplastic glial component ● Neoplastic neurons are characterized by haphazard clustering, lack of orderly distribution, and, often, an abnormal location (in white matter) ● Abnormal neurons may be small or large; often they are binucleated and have large nuclei and prominent nucleoli ● Variably cellular glial component most commonly consisting of a neoplastic astrocytic population; oligodendroglial foci are rarely seen ● Astrocytic component may be pilocytic with Rosenthal fibers and eosinophilic granular bodies ● Atypical glial cells with large, bizarre, hyperchromatic nuclei with intranuclear cytoplasmic inclusions may be seen ● Tumor cells may be located in a reticulin-rich stroma ● Foci of perivascular chronic inflammation is common histologic feature ● Microcalcifications are often present ● Microcystic cavities may be present ● Mitotic figures are rare ● Atypical ganglioglioma (WHO grade II): increased cellularity and mitoses in the astrocytic component ● Anaplastic ganglioglioma (WHO grade III): further increased mitotic activity in the astrocytic component Special Stains and Immunohistochemistry ● Synaptophysin, S-100 protein, NSE, and Neu-N: neurons are positive ● Neurofilament: neurons may be positive ● Silver stain (Bielschowsky) highlights cell processes of ganglion cells ● CD 34: neuronal component is positive ● GFAP: astrocytic component is positive ● Mib-1: low index (<3%) in typical ganglioglioma (grade I); elevated in atypical (grade II) and anaplastic (grade III) gangliogliomas Other Techniques for Diagnosis ● Electron microscopy: neurons contain dense-core neurosecretory granules and occasionally exhibit synapses ● Cytogenetic analyses: gangliogliomas; gains of chromosome 7 are most often found, and TSC2 gene mutation is reported in glial component Differential Diagnosis ❚ Variants of ganglioglioma ● Desmoplastic infantile ganglioglioma and astrocytoma, WHO grade I

— Most occur before 2 years of age — Large cystic masses, superficially located, most often occurring in frontal and parietal lobes, may involve more than one lobe — Dense fibrotic masses — Fibrous stroma with intermixed clusters or scattered astrocytes — Eosinophilic granular bodies and Rosenthal fibers — Ganglion cells and small neurocytic cells present in desmoplastic infantile ganglioglioma but may be sparse ● Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos) — Benign cellular proliferation of dysplastic ganglion cells — Diffusely enlarged cerebellar folia secondary to ganglion cells that enlarge and distort the molecular and internal granular cell layers — Pathognomic of Cowden disease ❚ Pilocytic astrocytoma ● Similar radiographic findings ● Biphasic tumor consisting of pilocytic areas and a microcystic background ● Lacks clusters of atypical neurons ❚ DNET ● Both tumors show similar clinical picture ● Composed of a multinodular architecture with a mucoid collagenous background ● Neurons in DNET are typically normal; lacks clustering of pleomorphic neurons ❚ Fibrillary or diffuse astrocytoma ● Entrapped non-neoplastic neurons may suggest ganglioglioma ● Tumor cells are negative for neuronal markers; positive for GFAP ● Mib-1 index: higher in astrocytomas than gangliogliomas ❚ Pleomorphic xanthoastrocytoma ● Pleomorphic, xanthomatous cells characterize the neoplasm ● Exhibits both CD34 and GFAP positivity ● Usually lacks a neuronal component Pearls ● Surgical resection for gangliocytoma and ganglioglioma is usually curative; no radiation or chemotherapy is needed ● Eosinophilic granular bodies are evidence of chronicity and slow growth; they are not diagnostic of gangliogliomas and may be seen in pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and other low-grade astrocytomas ● Malignant transformation of the glial cells is extremely rare (anaplastic ganglioglioma)

1006  Differential Diagnosis in Surgical Pathology

Ganglion cells may be difficult to appreciate on frozen section; patient age, radiographic findings, and clinical history are helpful



Selected References Becker AJ, Wiestler OD, Figarella-Branger D, Blumcke I: Ganglioglioma and gangliocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 103-105. Blumcke I, Wiestler OD: Gangliogliomas: An intriguing tumor entity associated with focal epilepsies. J Neuropathol Exper Neurol 61:575-584, 2002. McLendon RE, Provenzale J: Glioneuronal tumors of the central nervous system. Brain Tumor Pathol 19:51-58, 2002. Prayson RA, Khajavi K, Comair YG: Cortical architecture abnormalities and MIB-1 immunoreactivity in gangliogliomas: A study of 60 patients with intracranial tumors. J Neuropathol Exper Neurol 54:513-520, 1995.

Dysembryoplastic Neuroepithelial Tumor (WHO Grade I) Clinical Features ● Typically found in the first decade in the setting of drug-resistant epilepsy ● Occurs most often in the temporal lobe cortex; also reported in frontal, parietal, and occipital cortexes and selected infratentorial areas Gross Pathology ● May be well defined or poorly demarcated ● Variable size; most measure a few centimeters ● Gyral expansion with vague multinodular formation and mucoid viscous appearance

Figure 19-9.  Dysembryoplastic neuroepithelial tumor. Neurons floating in a mucoid matrix with oligodendroglial-like cells.

Small cyst formation often seen Distortion of the overlying skull may be present

● ●

Histopathology ● Cortical, multinodular, microcystic, mucoid tumor ● Three classic histologic features — Glioneuronal element (“specific component”) ◆ Oligodendroglial-like cells and normalappearing neurons floating in mucin-rich spaces ◆ Up to 50% of DNETs lack this element — Glial nodules ◆ Aggregates of oligodendroglial-like cells mixed with astrocytes resembling an oligoastro­ cytoma — Cortical dysplasia ◆ Architectural disarray with loss of normal laminations ● Presence of the nodular architecture in association with the glioneuronal element is sufficient to make a diagnosis of DNET ● Eosinophilic granular bodies may be present ● Endothelial proliferation may be present Special Stains and Immunohistochemistry ● Synaptophysin, NSE, and Neu-N highlight neuronal component ● GFAP stains astrocytic component ● S-100 protein stains oligodendroglial-like cells ● Alcian blue highlights mucoid background (acid mucopolysaccharide) ● Mib-1: usually low labeling index, but up to 8% reported Other Techniques for Diagnosis ● Ultrastructure — Oligodendroglial-like cells in the glial nodules or specific glial neuronal component have round or oval nuclei and scant cytoplasm with short processes — Cytoplasm contains mitochondria, free ribosomes, rough endoplasmic reticulum, and lysosomes — Occasional astrocytic (intermediate filaments) and neuronal differentiation (dense core granules) are seen ● Cytogenetics: do not exhibit loss of chromosome arms 1p and 19q (three cases studied) Differential Diagnosis ❚ Ganglioglioma ● Dominant feature is bizarre, pleomorphic, or binucleate neurons ● Shows a neoplastic glial component in addition to the abnormal neurons ● Lacks multinodular architecture ● Typically shows perivascular lymphoid infiltrate and may have abundant collagenous stroma

Central Nervous System  1007

❚ Oligodendroglioma ● Lacks distinct multinodular architecture ● No glioneuronal element ● Difficult to distinguish from DNET in small biopsies ❚ Oligoastrocytoma ● Lacks distinct multinodular architecture ● No glioneuronal element ❚ Pilocytic astrocytoma ● Composed of biphasic dense and loose piloid astrocytes without floating neurons or associated cortical dysplasia Pearls ● Histogenesis is currently unknown; may be hamartomatous rather than neoplastic ● Surgical resection is reserved for patients with intractable seizures ● Most patients remain seizure free and without tumor recurrence after resection ● Recurrence is rare, and there are only two case reports of malignant transformation Selected References Daumas-Duport C, Pietsch T, Hawkins C, Shankar SK: Dysembryoplastic neuroepithelial tumor. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 99-102. Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, et al: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Report of 39 cases. Exp Clin Studies 23:545-556, 1988.

Central and Extraventricular Neurocytoma (WHO Grade II) Clinical Features ● Incidence is 0.25% to 0.50% of all brain tumors ● Typically occurs in young adults (ages 20 to 40 years) ● Central neurocytoma: intraventricular tumors are usually found in the lateral or third ventricles, adjacent to the foramen of Monro — Extraventricular neurocytomas occur in parenchyma, away from the ventricular system; reported in cerebrum, cerebellum, midbrain, and spinal cord — Central neurocytomas present with signs of increased intracranial pressure including headache, nausea, vomiting, seizures, visual disturbance, and papilledema — CT and MRI characteristically show a heterogeneously contrast-enhancing, partially calcified intraventricular (or in extraventricular lesions, parenchymal) mass; cysts and calcification are common

Figure 19-10.  Central neurocytoma. The neoplasm is composed of a monotonous population of small round cells with a fine chromatin pattern and occasional nuclei-free islands suggesting neuropil.

Cerebellar liponeurocytoma — Rare low-grade (WHO grade II) neoplasm composed of neurocytes with focal lipomatous differentiation — Mean age of occurrence, 50 years



Gross Pathology ● Well-circumscribed, lobulated tumor ● Typically, infiltration into the surrounding brain parenchyma is not seen ● Often hemorrhagic, focally calcified, and cystic ● Cerebellar liponeurocytoma: usually in cerebellar hemispheres Histopathology ❚ Central neurocytomas ● Hypercellular tumor composed of diffuse sheets of monotonous uniform cells punctuated by anuclear areas composed of a fibrillar matrix, reminiscent of neuropil ● Perivascular clearing composed of cell processes resembling ependymal pseudorosettes may be seen ● A delicate vascular stroma and microcalcifications are often present ● Nuclei have regular outlines with delicate chromatin and small inconspicuous nucleoli ● Mitotic activity, endothelial proliferation, and necrosis are rare ● Rare cases exhibit ganglion cells ❚ Atypical neurocytomas ● Defined by elevation of Mib-1 index (>2%) with or without the presence of endothelial proliferation, necrosis, and increased atypia ❚ Extraventricular neurocytomas ● Cytologically very similar to central neurocytomas ● Architectural pattern is more varied, such as clusters, ribbons, or rosettes, in addition to sheets

1008  Differential Diagnosis in Surgical Pathology

Higher degree of ganglionic differentiation and possibly glial differentiation ❚ Cerebellar liponeurocytoma ● Composed of neurocytes, some showing lipidization ●

Special Stains and Immunohistochemistry ● Synaptophysin: diffusely positive ● NSE and Neu-N positive ● Chromogranin and neurofilament usually negative ● GFAP negative in central neurocytomas; variable in extraventricular neurocytomas ● Mib-1 index: less than 2% in typical neurocytomas; more than 2% shortens recurrence-free survival ● Cerebellar liponeurocytoma: in addition to neuronal markers, focal GFAP positivity is often present Other Techniques for Diagnosis ● Cytogenetic analyses: gains at 2p, 10q, and 18q; frequent deletions of both arms of 17 and small deletions in 1p Differential Diagnosis ❚ Oligodendroglioma ● Poorly circumscribed with an infiltrative border ● Typically not located in the ventricle ● Lacks salt-and-pepper nuclei, neuropil islands, and ganglion cell differentiation ● Synaptophysin negative ❚ Ependymoma (especially clear cell variant) ● Cells have long fibrillary processes ● Characteristically shows true rosettes ● Typically protrudes from ventricular lining ● GFAP positive and synaptophysin negative ❚ Neuroblastoma (primitive neuroectodermal tumor) ● Hyperchromatic atypical cells with frequent mitoses ● Lack of fine chromatin and neuropil islands ● Intraparenchymal with tendency to seed neuraxis ● Immunohistochemical profiles are the same Pearls ● Most are slow-growing tumors that are essentially cured by surgical resection; associated with an excellent prognosis ● Recurrence is associated with subtotal resection, atypical histology, and elevated Mib-1 proliferation index Selected References Figarella-Branger D, Soylemezoglu F, Burger PC: Central neurocytoma and extraventricular neurocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 106-109. Kleihues P, Chimelli L, Giangaspero F, Ohgaki H: Cerebellar liponeurocytoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 110-112.

Giangaspero F, Cenacchi G, Losi L, et al: Extraventricular neoplasms with neurocytoma features. Am J Surg Pathol 21:206-212, 1997.

Papillary Glioneuronal Tumor (No WHO Grade at Present) Clinical Features Generally behave as grade I Rare neoplasm; wide age range, from 4 to 75 years (mean age, 23 years) ● Seizures, headaches, visual disturbances, language or gait disturbances, and mood changes have been reported as presenting symptoms ● Occurs in cerebral parenchyma, most commonly in frontal and temporal lobes ● MRI shows well-circumscribed solid and cystic masses with contrast enhancement; may have a cyst with a mural nodule ● ●

Gross Pathology ● Well-circumscribed solid and cystic mass, may have a mural nodule in a cyst Histopathology ● Architecturally composed of pseudopapillae and solid areas ● Pseudopapillae exhibit pseudostratified, small cuboidal cells without atypia around hyalinized vessels ● Solid areas contain mixtures of neurocytes and ganglion cells and cells intermediate between the two within a fibrillar or basophilic mucoid matrix ● Rosenthal fibers, calcification, and old hemorrhage are seen ● Mitoses are rare or absent ● No endothelial proliferation or necrosis Special Stains and Immunohistochemistry ● GFAP: cells of pseudopapillae positive ● Synaptophysin: cells from solid areas (neurocytes and ganglion cells) positive ● Neu-N: cells from solid areas (neurocytes and ganglion cells) positive ● Neurofilament: cells from solid areas and ganglion cells positive ● Chromogranin: cells from solid areas (neurocytes and ganglion cells) negative ● Mib-1 index: range, 1% to 3% Other Techniques for Diagnosis ● Ultrastructural examination: pseudopapillae lining cells show astrocytic features with intermediate filaments; solid area cells show neuronal features such as microtubules, dense core, and clear vesicles and occasionally synaptic junctions ● Cytogenetic analyses: no definitive studies at present

Central Nervous System  1009

Differential Diagnosis ❚ Papillary ependymoma ● Lacks solid component exhibiting neuronal elements ❚ Papillary meningioma ● EMA positive ● GFAP negative ● Synaptophysin and Neu-N negative ❚ Choroid plexus papillomas ● Papillary formations not consistently GFAP positive ● Lacks solid areas composed of neuronal elements ❚ Metastatic papillary adenocarcinoma ● Cytokeratin positive ● GFAP, synaptophysin, and Neu-N negative ❚ Astroblastoma ● Lacks neuronal elements Pearls ● Good prognosis ● No reports of recurrence after gross total resection Selected References Atri S, Sharma MC, Sarkar C, et al: Papillary glioneuronal tumor: A report of a rare case and review of the literature. Child Nerv Syst 23:349-353, 2007. Edgar M, Rosenblum MK: Mixed glioneuronal tumors, recently described entities. Arch Pathol Lab Med 131:228-233, 2007. Komori T, Scheithauer BW, Anthony DC, et al: Papillary glioneuronal tumor: A new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 22:1171-1183, 1998.

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle (WHO Grade I) Clinical Features ● Rare neoplasm occurring at mean age of 32 years (range, 12 to 59 years) ● Women affected more than men ● Signs and symptoms secondary to obstructive hydrocephalus, ataxia, visual disturbances, and vertigo Gross Pathology ● Soft, gelatinous, well demarcated Histopathology ● Composed of neurocytic and glial cells ● Neurocytic component exhibits small round nuclei and scant cytoplasm and forms perivascular pseudorosettes and Homer-Wright rosettes, often accompanied by a microcystic, myxoid background; rarely, ganglion cells may be seen ● Glial component exhibits piloid and spindle-shaped cells, may be more extensive than the neuronal component ● Rosenthal fibers and eosinophilic granular bodies may be seen

Degenerative changes are often seen consisting of sclerotic vessels, collagen, calcifications, and hemosiderin-laden macrophages ● Endothelial proliferation may be seen ● Mitoses are rare ● Well-defined tumor-parenchyma interface ●

Special Stains and Immunohistochemistry ● Synaptophysin: positive granular staining of neurocytic component ● NSE positive in neurocytic component ● GFAP and S-100 positive in glial component ● Mib-1 index: less than 3% Other Techniques for Diagnosis ● Ultrastructure: glial component has bundles of intermediate filaments; neurocytic component exhibits cells with small round nuclei, ribosomes, and rough endoplasmic reticulum; Golgi apparatus, sparse dense core granules, and microtubules in the rosette formations ● Occasional presynaptic specializations Differential Diagnosis ❚ Pilocytic astrocytoma ● Usually occurs in younger individuals ● Lacks neurocytic component and Homer-Wright rosettes ❚ Central neurocytoma ● Does not have a biphasic appearance with the piloid astrocytic component alternating with the neurocytic component ❚ Papillary glioneuronal neoplasm ● More often occurs in cerebrum rather than fourth ventricle ● Does not display Homer-Wright rosettes ● Exhibits papillary architecture formed by astrocytic cells Pearls ● Indolent growth ● Multifocal tumor nodules have been reported Selected References Edgar M, Rosenblum MK: Mixed glioneuronal tumors, recently described entities. Arch Pathol Lab Med 31:228-233, 2007. Komori T, Scheithauer BW, Hirose T: A rosette-forming glioneuronal tumor of the fourth ventricle: Infratentorial form of dysembryoplastic neuroepithelial tumor? Am J Surg Pathol 26:582-591, 2002.

Paraganglioma of the Spinal Cord (WHO Grade I) Clinical Features ● Benign, encapsulated neoplasm arising from neural crest cells, occurring in cauda equina and filum terminale

1010  Differential Diagnosis in Surgical Pathology

Constitutes 3.5% of all neoplasms in this location Mean age of occurrence is 48 years ● Patients most commonly present with back pain or sciatica and urinary or fecal incontinence; sensory or motor deficits are less common; symptoms secondary to hormonal manifestations are uncommon

Recurrence may occur with subtotal resection Subarachnoid space dissemination reported ● Morphologic criteria to distinguish between benign and aggressive tumors not described Selected References

Gross Pathology ● Most are intradural and encapsulated (80%) ● Red-brown soft tissue; may contain cysts ● Usually attached to filum terminale

Pytel P, Krausz T, Wollmann R, Utset MF: Ganglioneuromatous paraganglioma of the cauda equina: A pathological case study. Hum Pathol 36:444-446, 2005. Miliaras GC, Kyritsis AP, Polyzoidis KS: Cauda equina paraganglioma: A review. J Neurooncol 65:177-190, 2003.









Histopathology ● Nests (Zellballen) of small uniform cells surrounded by sustentacular cells ● Delicate vascular network (organoid pattern) ● Cells are polygonal or columnar with round nuclei and fine chromatin and granular eosinophilic cytoplasm ● Perivascular pseudorosette formation may occur ● Mitoses and necrosis are infrequent ● Ganglion cell differentiation present in up to 45% ● Divergent differentiation is reported (homologous or heterologous components) ● Melanotic and oncocytic variants have been described Special Stains and Immunohistochemistry ● Chromogranin, synaptophysin, and NSE positive ● Neurofilament: variable staining ● GFAP and cytokeratin negative ● Sustentacular cells: S-100 and GFAP positive ● Mib-1 index: low Other Techniques for Diagnosis ● Ultrastructure: cytoplasmic dense core secretory granules and intermediate filaments ● Cytogenetics — Mutations in succinic dehydrogenase genes (part of mitochondrial complex II) — Associated with the following autosomal dominant syndromes: von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type II (MEN II), and neurofibromatosis type 1 (NF1)

Embryonal Tumors Medulloblastoma (WHO Grade IV) Clinical Features ● Malignant neoplasm of cerebellum composed of primitive cells usually with neuronal differentiation ● Most occur before 16 years of age (peak, 17 years) ● May occur in adulthood; most often between 21 and 40 years ● Symptoms include signs of cerebellar dysfunction (gait abnormalities, ataxia) or increased intracranial pressure Gross Pathology ● Most occur in vermis and may bulge into or fill the fourth ventricle ● Involvement of the hemispheres is more common in older individuals ● Hemispheric lesions are more likely desmoplastic ● Solid, variably demarcated (from well to poorly defined), homogeneous mass

Differential Diagnosis ❚ Ependymoma ● GFAP positive ● Fibrillary pattern with perivascular pseudorosettes and ependymal rosettes ❚ Metastatic carcinoma ● Cytologically anaplastic, lacking organoid pattern of uniform cells ● Not encapsulated Pearls ● Most are slow growing and curable with complete resection

Figure 19-11.  Medulloblastoma. Highly cellular tumor, spreading in the subarachnoid space, composed of small cells with carrot-shaped nuclei and indistinct cytoplasm forming Homer-Wright rosettes.

Central Nervous System  1011

Histopathology Highly cellular tumor composed of undifferentiated cells with variable growth patterns ● Classically consists of small, round to carrot-shaped uniform cells with hyperchromatic nuclei and wispy cytoplasm, often with distinct fibrillary background composed of cell processes ● Homer-Wright rosettes may be seen (40%) but are often absent ● High mitotic rate is common ● Individual cell and small areas of necrosis are frequently present ● Distinct streaming (single-filing) or palisading of tumor cells is often seen ● Morphologic subtypes — Nodular and desmoplastic medulloblastoma (previously called cerebellar neuroblastoma) ◆ Pale nodular areas lacking reticulin are surrounded by hypercellular sheets containing abundant reticulin ◆ Nodules contain cells with neuronal maturation, and often a fibrillary matrix is present ◆ Surrounding cells are more primitive and have high mitotic rates — Medulloblastoma with extensive nodularity ◆ Large pale areas composed of neurocytic cells and neuropil with scant internodular component — Large cell and anaplastic medulloblastoma ◆ Anaplastic changes are the presence of marked nuclear pleomorphism, cell wrapping and molding, high mitotic and Mib-1 indexes, and abundant apoptosis ◆ Large cell changes are defined by cells with large round nuclei with prominent nucleoli, abundant mitoses, and apoptosis ◆ Often, both large cells and anaplastic changes are found in the same neoplasm — Medullomyoblastoma ◆ Rhabdomyoblastic differentiation is present ◆ Spindle cells or globular cells that are positive for desmin, actin, or myoglobin — Melanotic medulloblastoma ◆ Contains cells with melanin pigment ◆ May also see ill-defined tubules or papillary formations ●

Special Stains and Immunohistochemistry ● Synaptophysin, microtubule-associated protein 2, neurofilament (low- and intermediate-molecularweight), vimentin, NSE positive ● Cytokeratin negative ● GFAP may show focal positivity in tumors with astrocytic differentiation or may represent entrapped astrocytes ● Mib-1 index: more than 20%

Other Techniques for Diagnosis Electron microscopy: undifferentiated neuroepithelial cells with scant cytoplasm and few organelles; may show prominent cytoplasmic processes ● More differentiated neoplasms have microtubules, dense core vesicles, and synapses ● Cytogenetics: isochromosome 17q (30% to 40%) ●

Differential Diagnosis ❚ Atypical teratoid/rhabdoid tumor ● Usually in children younger than 2 years ● Presence of rhabdoid cells ● Unique immunohistochemical profile positive for EMA, vimentin, SMA, cytokeratin, and synaptophysin; negative Ini protein antibody ● hSNF4/INI1 deletion or mutation (found in 85%) ❚ Peripheral primitive neuroectodermal tumor (PNET) and extraosseous Ewing sarcoma of the craniospinal vault ● Morphologically indistinguishable from medulloblastoma and supratentorial PNET ● CD99: membranous staining ● EWS-FLI1 fusion gene detectable by fluorescent in situ hybridization (FISH) ❚ Ependymoma ● Generally less cellular, and cells have more cytoplasm; infrequent mitotic activity ● Form perivascular pseudorosettes and ependymal rosettes ● GFAP positive ● Synaptophysin and chromogranin negative ❚ Pilocytic astrocytoma ● Similar location and age range ● Less cellular tumor consisting of biphasic pattern with elongated astrocytic areas (piloid) and a microcystic architecture ● GFAP diffusely positive ● Synaptophysin and chromogranin negative ❚ Lymphoma and leukemia ● History of lymphoma and leukemia is often known ● Lack nodular architecture and rosette formation ● Lymphomatous infiltrate is positive for LCA (CD45) and, if B-cell type, CD20 ❚ Metastatic neuroendocrine carcinoma ● Typically found in older individuals ● Lacks rosette formation ● Positive for cytokeratin Pearls ● Propensity for leptomeningeal dissemination ● Surgical resection with craniospinal radiation is the typical treatment ● Negative prognostic factors: incomplete surgical resection, large cell and anaplastic subtype, isochromosome 17q, loss of 17p, or amplification of MYCC or MYCN ● Good prognostic factor: presence of extensive nodularity

1012  Differential Diagnosis in Surgical Pathology

Selected References Kazmi SA, Perry A, Pressey JG, et al: Primary Ewing sarcoma of the brain: A case report and literature review. Diagn Mol Pathol 16:108-111, 2007. Giangaspero F, Wellek S, Masuoka J, et al: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112:5-12, 2006. McManamy CS, Lamont JM, Taylor RE, et al: Morphophenotypic variation predicts clinical behavior in childhood nondesmoplastic medulloblastomas. J Neuropath Exp Neurol 62:627-632, 2003. Eberhart CG, Kepner JL, Goldthwaithe PT, et al: Histopathologic grading of medulloblastomas. Cancer 94:552-560, 2002.

Supratentorial Primitive Neuroectodermal Neoplasms (Neuroblastoma, Ganglioneuroblastoma, Ependymoblastoma, Medulloepithelioma) (WHO Grade IV) Clinical Features Neoplasms of primitive neuroepithelial cells occurring in hemispheres, brain stem, or spinal cord ● May display differentiation along neuronal (neuroblastoma, ganglioneuroblastoma), astrocytic, ependymal (ependymoblastoma), or mesenchymal lines (medulloepithelioma) ● Mean age of presentation is 5.5 years (range, 4 to 20 years) ● Signs and symptoms are referable to the site of the mass lesion ●

Gross Pathology ● Appear as a well-circumscribed, tan-gray, homo­ geneous mass ● Small cyst formation and calcification are common ● Hemorrhage and necrosis may be present ● Ependymoblastoma and medulloepithelioma usually arise close to the ventricles ● Medulloepitheliomas are often massive lesions with abundant necrosis and hemorrhage Histopathology ● Hypercellular tumors that appear well circumscribed but are infiltrative ● Homer-Wright rosettes are often present, but poorly formed pseudorosettes consisting of perivascular anuclear zones showing loose fibrillary processes are more common ● Presence of fibrous connective tissue stroma will produce a lobular pattern; this is most prominent when leptomeninges are invaded (desmoplastic form) ● The tumor cells are usually small (round to carrot shaped) and have monomorphic but hyperchromatic nuclei and inconspicuous nucleoli; a moderate degree of nuclear pleomorphism occasionally seen ● Neuronal differentiation is seen in 25% to 50% of cases involving the brain

❚ Ganglioneuroblastoma ● Cells will have larger nuclei, vesicular chromatin, nucleoli, and more abundant fibrillar cytoplasm ● Mitotic activity is variable (usually numerous) ❚ Medulloepithelioma ● Papillary or trabecular pattern ● May display differentiation along neural, glial, and mesenchymal lines ❚ Ependymoblastoma ● Distinguished by multilayered rosettes in a background of primitive cells (true rosettes consisting of stratified, small, mitotically active cells with basally oriented nuclei radially arranged around a central lumen) Special Stains and Immunohistochemistry ❚ Ganglioneuroblastoma and neuroblastoma ● Synaptophysin and S-100 positive ● NSE and neurofilament positive ● Cytokeratin negative ● Mib-1 index: markedly variable, 0% to 85% ❚ Ependymoblastoma ● GFAP positive ● Cytokeratin positive ❚ Medulloepithelioma ● Nestin and vimentin positive ● EMA, cytokeratin, and NF variably positive ● GFAP and S-100 negative Other Techniques for Diagnosis ● Electron microscopy: tumor cells have microtubules within bipolar processes; typically few neurosecretory granules and sparse cytoplasmic organelles ● Cytogenetics: variable chromosomal losses and gains Differential Diagnosis ❚ Central neurocytoma ● Located within the lateral or third ventricle ● Lacks distinct rosette formation ● Cells are uniform and have low mitotic activity ❚ Peripheral PNET and extra-osseus Ewing sarcoma of the craniospinal vault ● Morphologically indistinguishable from medulloblastoma and supratentorial PNET ● CD99: membranous staining ● EWS-FLI1 fusion gene detectable by FISH ❚ Metastatic neuroendocrine carcinoma ● Typically found in older individuals ● Lacks rosette formation ● Positive for cytokeratin ❚ Desmoplastic infantile ganglioglioma ● Large cystic masses in infancy (usually younger than 18 months) ● Typically involves frontal and parietal lobes

Central Nervous System  1013

Usually involves leptomeninges, prominent collagenous stroma ● Divergent differentiation along astrocytic and neuronal lines ● Composed of GFAP-positive spindle cells and often inconspicuous ganglion cells ●

Pearls ● Children younger than 2 years have a poorer prognosis than those older than 2 years ● Cerebrospinal pathway seeding does occur, and metastases outside the CNS have been reported ● Ependymoblastoma: particularly poor prognosis; death occurs in less than 6 months Selected References McLendon RE, Judkins AR, Egerhart CG, et al: Central nervous system primitive neuroectodermal tumors. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 141-146. McLendon RE, Provenzale J: Glioneuronal tumors of the central nervous system. Brain Tumor Pathol 19:51-58, 2002. Molloy PT, Yachnis AT, Rorke LB, et al. Central nervous system medulloepithelioma: A series of eight cases including two arising in the pons. J Neurosurg 84:430-436, 1996. Dorsay TA, Rovira MJ, Ho VB, Kelly J: Ependymoblastoma: MR presentation. A case report and review of the literature. Pediatr Radiol 25:433-435, 1995.

Atypical Teratoid/Rhabdoid Tumor (WHO Grade IV) Clinical Features ● Rare malignant neoplasm occurring most commonly in children younger than 3 years ● About 50% of cases occur in the posterior fossa, with a predilection for the cerebellopontine angle; other reported sites include suprasellar region, pineal region, cerebrum, and spinal cord ● May be intra-axial or extra-axial, with predilection for leptomeningeal dissemination ● Symptoms may be nonlocalizing, consisting of lethargy, vomiting, and failure to thrive; in posterior fossa tumors, focal signs are usually cranial nerve palsies Gross Pathology ● Gray-white tissue with necrosis and hemorrhage Histopathology ● Sheets or nests of large cells, each with a round nucleus, prominent nucleolus, plump cell body with homogeneous cytoplasm, or a dense round distinct cytoplasmic inclusion (rhabdoid cells)

Frequently co-occurrence of foci or sheets of primitive neuroectodermal neoplastic cells, most often a minority component ● An epithelial (adenomatous or papillary pattern) or mesenchymal (loosely packed spindle cells) neoplastic component may also be present (about 33%) ● Epithelial component is least common ● Abundant mitoses and necrosis ● Leptomeningeal spread may be evident on the surface of the cerebellum ●

Special Stains and Immunohistochemistry ● EMA, vimentin, and smooth muscle actin positive ● GFAP, synaptophysin, and cytokeratin (highand low-molecular-weight cocktail) frequently positive ● Neurofilament, chromogranin, S-100, desmin, and HMB-45 may be positive ● Ini negative ● Mib-1 index: more than 50% Other Techniques for Diagnosis ● Ultrastructure: rhabdoid cell cytoplasm contains bundles of intermediate filaments ● Cytogenetics: hSNF4/INI1 deletion or mutation (found in 85%) Differential Diagnosis ❚ Medulloblastoma ● Rhabdoid cells not seen, EMA negative, Ini positive ❚ Choroid plexus carcinoma ● Not usually in posterior fossa; cytokeratin positive, EMA negative Pearls ● Resistant to standard therapy for primitive neuroectodermal neoplasms; mean survival time is 10 to 15 months ● Presence of rhabdoid cells is not diagnostic of atypical teratoid/rhabdoid tumor ● Immunohistochemistry and evaluation for the presence of a mutation of the hSNF5/INI1 gene should be performed ● Seeding of the subarachnoid space is common Selected References Bambakidis NC, Robinson S, Cohen M, Cohen AR: Atypical teratoid/rhabdoid tumors of the central nervous system: Clinical, radiographic and pathologic features. Pediatr Neurosurg 37:64-70, 2002. Packer RJ, Biegel JA, Blaney S, et al: Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24:337-342, 2002. Rorke LB, Packer RJ, Biegel JA: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85:56-65, 1996.

1014  Differential Diagnosis in Surgical Pathology

Choroid Plexus Tumors Choroid Plexus Papilloma (WHO Grade I), Atypical Choroid Plexus Papilloma (WHO Grade II), and Choroid Plexus Carcinoma (WHO Grade III) Clinical Features Choroid plexus papillomas (WHO grade I) — Slow-growing benign tumors accounting for less than 1% of brain tumors — Characteristically found in the fourth ventricle (40%), lateral ventricle (50%), or third ventricle (5%) or at the cerebellopontine angle — Commonly found in the first and second decades (50% found before age 20); more often occur in the lateral ventricles when in young individuals and in the fourth ventricle in adults ● Choroid plexus carcinomas (WHO grade III) — Typically occur in patients younger than 10 years; rare in adults — Most carcinomas affecting the choroid plexus in adults represent metastatic carcinomas ● Patients often present with signs and symptoms secondary to hydrocephalus owing to the overproduction of cerebrospinal fluid or obstruction ●

Gross Pathology ● Well-demarcated, pedunculated, or cauliflower-like masses ● Papillomas do not invade into the adjacent tissue ● Carcinomas characteristically invade the surrounding tissue and are often necrotic and hemorrhagic Histopathology ❚ Choroid plexus papilloma ● Papillary architecture is composed of a single orderly layer of columnar cells surrounding a distinct fibrovascular core ● A mild degree of nuclear stratification, crowding of the nuclei, focal necrosis, and nuclear atypia may be seen ● Stromal calcifications; may see metaplastic bone or cartilage ● Mitotic activity is typically minimal ● Small foci of ependymal differentiation may be seen ❚ Atypical choroid plexus papilloma ● Defined by increase in mitoses (≥2 mitoses/10 randomly selected hpf) ● Hypercellularity, nuclear pleomorphism, solid growth pattern, and necrosis may also be present ❚ Choroid plexus carcinoma ● Typically show a loose papillary architecture consisting of sheets of pleomorphic cells ● Extensive necrosis and high mitotic activity (>5 mitoses/hpf) ● Brain invasion

Special Stains and Immunohistochemistry S-100 protein positive (more uniform in papillomas than in carcinomas) ● Cytokeratin 8 and 18, vimentin positive ● Transthyretin (prealbumin): approximately 70% are positive ● GFAP: papillomas may be focally positive; carcinomas typically negative ● EMA variable to negative ● Carcinoembryonic antigen (CEA) usually negative ● Ini protein positive ● Synaptophysin variable positivity ● Mib-1 index: range in papillomas is 2% to 5%; range in carcinomas is 14% to 18% ●

Other Techniques for Diagnosis ● Electron microscopy: cells of both papillomas and carcinomas typically show cilia, microvilli, basement membrane, and desmosomes ● Cytogenetics — Inactivating mutation of the hSNF5/INI1 gene has been reported in several series of choroid plexus carcinomas and in one series of papillomas — A variety of other cytogenetic abnormalities have been described in choroid plexus papillomas and carcinomas Differential Diagnosis ❚ Normal choroid plexus ● Apical hobnail cuboidal cells instead of crowded, more columnar cells with some atypia are present in normal choroid plexus ❚ Metastatic carcinoma ● Usually found in older adults ● Not usually associated with the ventricle ● Typically positive for EMA and often also for CEA ● Usually negative for S-100 protein and GFAP ❚ Ependymoma (especially papillary subtype) ● Intraventricular location is common for both tumors ● Solid nonpapillary areas may be evident with both perivascular pseudorosette and true rosette formation ● GFAP positive; usually more diffuse than in choroid plexus neoplasms ❚ Atypical teratoid and rhabdoid tumors ● Important part of differential diagnosis in children with posterior fossa tumors ● Epithelial areas form part, not all, of the neoplasm ● Rhabdoid cells and primitive neuroectodermal cell components are also present ● Ini protein negative Pearls ● GFAP positivity demonstrates that choroid plexus tumors may show ependymal differentiation ● In choroid plexus papilloma, overall prognosis is good with surgical resection, but incompletely resected tumors may occasionally recur

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Leptomeningeal spread may occur in both papillomas and carcinomas but is rare in papillomas ● Choroid plexus carcinoma has an overall poor prognosis — Brain invasion and cerebrospinal fluid spread is typically seen — Systemic metastases are rarely seen ●

Selected References Paulus W, Brandner S: Choroid plexus tumors. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 82-85. Krishnan S, Brown PD, Scheithauer BW, et al: Choroid plexus papillomas: A single institutional experience. J Neurooncol 68:49-55, 2004. Gessi M, Giangaspero F, Pietsch T: Atypical teratoid/rhabdoid tumors and choroid plexus tumors: When genetics “surprise” pathology. Brain Pathol 13:409-414, 2003.

Pineal Parenchymal Tumors Pineocytoma (WHO Grade I) and Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grades II and III) Clinical Features ● Rare tumors accounting for less than 1% of all intracranial neoplasms ● Typically occur in adults ● Localized to the region of the pineal gland and surrounding structures, may extend into the third ventricle and compress the colliculi and cerebral aqueduct ● Variable clinical presentation: ophthalmologic dysfunction, mental status changes, and symptoms related to increased intracranial pressure or endocrine abnormalities ● Computed tomography shows a round, homogeneous, contrast-enhancing mass Gross Pathology ● Well-circumscribed tumor typically less than 3 cm in diameter ● Gray-tan homogeneous tumor often with small cyst formation ● Small areas of hemorrhage may be present ● Necrosis is not a typical finding Histopathology ❚ Pineocytoma ● Sheets of tumor cells without a distinct pattern or an irregular lobular arrangement with large aggregates of tumor cells separated by fibrous septa ● Small and uniform cells with hyperchromatic nuclei, finely granular chromatin, inconspicuous nucleoli, and eosinophilic cytoplasmic processes

Forms large (pineocytomatous) rosettes with abundant fibrillary cell processes in the center, sometimes with cytoplasmic club-shaped terminal expansion; may or may not be centered around blood vessels ● Calcification may be present ● Ganglion cells and multinucleated giant cells are occasionally seen ● Mitotic activity is minimal, and necrosis is not seen ❚ Pineal parenchymal tumor of intermediate differentiation ● Diffuse or lobulated tumors of moderate cellularity ● Mild to moderate nuclear atypia and sparse to moderately frequent mitoses ●

Special Stains and Immunohistochemistry ● Synaptophysin, chromogranin, NSE, and S-100 protein positive ● Retinal S antigen and rhodopsin positive ● GFAP highlights background residual reactive astrocytes ● Mib-1 labeling index — Pineocytoma: low — Pineal parenchymal tumor of intermediate differentiation: 3% to 10% Other Techniques for Diagnosis ● Electron microscopy: cells have oval nuclei and cytoplasm containing numerous organelles, including smooth and rough endoplasmic reticulum, Golgi complexes, mitochondria, lysosomes, intermediate filaments, microtubules, synapse-like junctions, and membrane-bound electron-dense granules; cell processes are typically prominent ● Cytogenetic analyses — Pineocytomas: show loss of all or part of chromosomes 22, 11, and 12 — Pineal parenchymal tumor of intermediate differentiation: abnormalities on chromosomes 4, 12, and 22 Differential Diagnosis ❚ Normal pineal gland ● Normal lobular architecture is a helpful distinguishing feature ● May show irregular calcifications ❚ Pineal cyst ● Radiographically shows a distinct cystic structure ● Rarely symptomatic; mean age of symptomatic occurrence is 30 years ● Women are affected more than men ● Lacks large rosettes typically seen in pineocytoma ● Consists of a glial-lined cavity surrounded by reactive glial tissue ❚ Pineoblastoma ● Occurs typically in young individuals ● Shows well-formed, small perivascular rosettes ● Consists of undifferentiated, monomorphic, small round blue cells

1016  Differential Diagnosis in Surgical Pathology

❚ Astrocytoma ● Lacks lobular architecture and rosettes ● GFAP positive ● Synaptophysin negative Pearls ● Pineocytoma — Slow-growing neoplasm with excellent prognosis; metastases are not reported with these tumors — Treatment consists of conservative surgery after the development of symptoms ● Five-year survival rate for pineal parenchymal tumor of intermediate differentiation ranges from 39% to 74% ● Factors associated with improved survival are presence of neurofilament immunoreactivity, low mitoses, and absence of necrosis Selected References Hirato J, Nakazato Y: Pathology of pineal region tumors. J Neurooncol 54:239-249, 2001. Jouvet A, Sainte-Pierre G, Fauchon F, et al: Pineal parenchymal tumors: A correlation of histological features with prognosis in 66 cases. Brain Pathol 10:49-60, 2000. Taylor MD, Mainprize TG, Squire JA, Rutka JT: Molecular genetics of pineal region neoplasms. J Neurooncol 54:219238, 2001.

Pineoblastoma (WHO Grade IV) Clinical Features ● Constitute 45% of all pineal tumors ● Typically found in children within the first two decades ● Variable clinical presentation: ophthalmologic dysfunction; mental status changes, symptoms related to increased intracranial pressure, or endocrine abnormalities ● CT and MRI show a large, lobulated, poorly defined, contrast-enhancing mass Gross Pathology ● Poorly defined soft, friable mass with hemorrhage and necrosis ● Infiltration into adjacent brain parenchyma and meninges is common Histopathology ● Highly cellular neoplasm composed of primitive poorly differentiated tumor cells ● Diffuse sheets of neoplastic cells with focal rosette formation ● Round or oval hyperchromatic nuclei, typically with single nucleoli, scant cytoplasm, and indistinct cell borders ● Homer-Wright rosettes or, less commonly, FlexnerWintersteiner true rosettes

Mitotic activity is often prominent; hemorrhage and necrosis are common



Special Stains and Immunohistochemistry ● Synaptophysin positive, diffuse, or dotlike ● Chromogranin and NSE positive ● Retinal S antigen positive ● GFAP typically negative Other Techniques for Diagnosis ● Cytogenetic analyses: patients with germline mutations in Rb gene (chromosome 13q14) are predisposed to tumor occurrence as part of trilateral retinoblastoma disease ● This mutation has not been reported in sporadic pineoblastomas Differential Diagnosis ❚ Pineocytoma and pineal parenchymal tumor of intermediate differentiation ● Pineocytomas have better-differentiated cells with more abundant cytoplasm and pineocytomatous rosettes ● Pineal parenchymal tumors of intermediate differentiation have moderate cellularity, less atypia, and fewer mitosis Pearls ● Aggressive tumor typically with craniospinal seeding; rare extracranial metastases Selected References Nakazato Y, Jouvet A, Scheithauer BW: Pineoblastoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 126-127. Hirato J, Nakazato Y: Pathology of pineal region tumors. J Neurooncol 54:239-249, 2001. Taylor MD, Mainprize TG, Squire JA, Rutka JT: Molecular genetics of pineal region neoplasms. J Neurooncol 54:219238, 2001.

Papillary Tumor of the Pineal Region (WHO Grades II and III) Clinical Features ● Wide age range (5 to 66 years); mean, 32 years ● Presentation is usually with headache due to obstructive hydrocephalus, without focal neurologic signs ● MRI shows a well-circumscribed T1-hypointense, T2hyperintense enhancing mass in the pineal region, ranging in size from 1.7 to 5 cm Gross Pathology ● Well-circumscribed, usually solid

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Histopathology Papillary architecture with perivascular pseudorosettes; ependymal rosettes have been reported ● Cells are cuboidal to columnar and have well-defined cytoplasm ● Necrosis is usually present; mitoses are sparse, and vascular proliferation is not usually present ●

Special Stains and Immunohistochemistry ● Cytokeratin (AE1/AE3, CAM5.2, CK18) and S-100 positive ● GFAP: focal positivity ● Synaptophysin, chromogranin, and NSE weakly and focally positive ● EMA variably positive ● Mib-1 labeling index: 4% to 5% Other Techniques for Diagnosis ● Ultrastructure: microvilli, zipper-like junctions, abundant rough endoplasmic reticulum, dilated cisternae, annulatae lamellae, dense core vesicles, and microtubules ● Cytogenetics: most commonly found are losses of chromosomes 10 and 22q and gain of chromosome 4 Differential Diagnosis ❚ Choroid plexus papilloma ● Distinctly epithelial morphology and well-defined papillary formations ● No ependymal rosettes ● Usually no necrosis ❚ Ependymoma ● Fibrillary cytoplasm ● GFAP: prominent perivascular pseudorosette positivity ● EMA: consistent dotlike positivity ● Cytokeratin: focally positive

Other Neoplasms and Related Entities Peripheral Nerve Sheath Tumors Clinical Features ❚ Schwannoma (WHO grade I) ● Benign tumor composed of Schwann cells; also called neurilemmoma ● Found in all ages, most commonly in the fourth through sixth decades ● Most commonly involves peripheral nerves in skin and subcutaneous tissues of the head and neck region and flexor surfaces of extremities ● Accounts for about 10% of intracranial tumors (usually arises from sensory cranial nerves, most often eighth cranial nerve) and about 30% of spinal tumors ● Associated with neurofibromatosis type 2 (NF2) (bilateral vestibular schwannomas)

A

Pearls ● Newly defined entity ● Tumor recurrence and progression is frequent (72%) and is associated with incomplete resection and increased mitoses Selected References Boco T, Aalaei S, Musacchio M, et al: Papillary tumor of the pineal region. Neuropathology 28:87-92, 2008. Fèvre-Montange M, Hasselblatt M, Figarella-Branger D, et al: Prognosis and histopathologic features in papillary tumors of the pineal region: A retrospective multicenter study of 31 cases. J Neuropathol Exp Neurol 65:1004-1011, 2006. Jouvet A, Fauchon F, Liberski P, et al: Papillary tumor of the pineal region. Am J Surg Pathol 27:505-512, 2003.

B Figure 19-12.  A, Schwannoma. Compact spindle cells (Antoni A tissue) and Verocay bodies. B, Neurofibroma. Sparsely cellular proliferation of spindle cells with wavy nuclei and cytoplasmic processes.

1018  Differential Diagnosis in Surgical Pathology

Peripheral tumors typically present as asymptomatic masses; spinal tumors often present with radicular pain or signs of spinal cord compression; tumors of cranial nerve VIII cause hearing difficulties, tinnitus, or facial paresthesias ❚ Neurofibroma (WHO grade I) ● Common benign tumor composed of Schwann cells, fibroblasts, and perineural cells ● Occur sporadically most frequently but also associated with NF1 ● Multiple subtypes — Localized cutaneous neurofibroma: most common subtype, usually solitary and not associated with NF; cases associated with NF1 are often multiple — Diffuse cutaneous neurofibroma: uncommon, occurs primarily in children and young adults, forms large, ill-defined plaques — Localized intracranial neurofibroma: causes segmental, fusiform enlargement of the nerve; multiple lesions occur primarily in a background of NF1 — Plexiform neurofibroma: transformation of multiple fascicles of nerve into neurofibroma with preservation of normal anatomic configuration, affecting larger nerves or a nerve plexus and occurring almost exclusively in patients with NF1 — Massive soft tissue neurofibroma: the least common variant found in patients with NF1, typically massive tumors resulting in marked enlargement of the affected extremity or regional soft tissue ❚ Malignant peripheral nerve sheath tumor (MPNST) (WHO grade II, III, or IV) ● May arise from Schwann cells, fibroblasts, or perineural cells ● Most present as mass lesions in association with medium to large peripheral nerves of the extremities ● Intracranial lesions usually involve the vagus or vestibular nerves ● About 50% are associated with NF1 ● Tumors occur most commonly in third to sixth decades, but earlier in association with NF1 ❚ Perineurioma (WHO grade I, II, or III) ● Present in teens or young adulthood with muscle weakness in distribution of a peripheral nerve or as mass lesion in deep soft tissue ● Several types described with varying presentations — Extraneural soft tissue perineurioma: subcutaneous tissues of trunk and limbs; painless mass, in children or adults — Sclerosing perineurioma: hands of young adult men — Reticular perineurioma: in upper limbs of women (31 to 61 years) — Intraneural perineurioma: in children and young adults, in extremities ●

Gross Pathology ❚ Schwannoma ● Typically solitary, encapsulated, round to oval mass measuring up to 10 cm (multiple lesions are seen in NF) ● Cut surface shows firm, tan-white to bright-yellow, glistening tissue ● Small cyst formation and focal hemorrhage may be seen (cysts are typically absent in cellular schwannomas) ● Nerve is often identified ❚ Neurofibroma ● Solid, tan-white, soft to mucoid tumors surrounded by a thin capsule ● Tumor incorporates the nerve, so no nerve is typically identified ❚ Plexiform neurofibroma ● Typically forms a complex tangle of enlarged nerves resembling a bag of worms ❚ Malignant peripheral nerve sheath tumor ● Large infiltrative, nonencapsulated mass with a fleshy, tan cut surface ● Hemorrhage and necrosis are common ❚ Perineurioma ● Circumscribed and firm; intraneural subtype is associated with peripheral nerve Histopathology ❚ Schwannoma ● Shows biphasic pattern alternating between highly cellular, compact areas and loose, spongy areas of low cellularity ● Compact, cellular areas are termed Antoni A and consist of interlacing fascicles of elongated, regular spindle cells with long, pencil-shaped nuclei ● Sparsely cellular areas consisting of loose, spongy tissue with small, uniform cells termed Antoni B ● Tumors showing marked nuclear pleomorphism, hyperchromasia (degenerative atypia), and thick, hyalinized blood vessels are called ancient schwannomas ● Areas of nuclear palisading with nuclei arranged in linear stacks are called Verocay bodies; more commonly seen in spinal schwannomas ● Axons may be seen at the periphery of the tumor ● Mitotic activity is minimal ● Perivascular whorls resembling meningioma may occasionally be seen ● Vessels are often hyalinized, and foci of lipid-laden macrophages may be present ● Two subtypes — Cellular schwannoma ◆ Increased likelihood of recurrence, but lacks ability to metastasize ◆ Highly cellular, consisting predominantly of Antoni A areas

Central Nervous System  1019 ◆

Variable mitotic activity; typically show 1 to 4 mitoses/10 hpf ◆ Frequent capsular, subcapsular, and perivascular lymphocytic infiltrates ◆ Small foci of necrosis may be seen — Melanotic schwannoma ◆ Usually grossly pigmented and contains Schwann cells with melanosomes ◆ About 10% behave more aggressively than the nonmelanotic schwannomas ❚ Neurofibroma ● Typically hypocellular tumor consisting of interlacing fascicles of elongated spindle cells with wavy nuclei; minimal nuclear pleomorphism is typical ● Background shows variable degrees of mucopolysaccharide matrix, collagen, and reticulin ● Minimal mitotic activity ● Plexiform neurofibroma: consists of multiple hypocellular, pale fascicles of spindle cells ● Mucinous or myxoid background ❚ Malignant peripheral nerve sheath tumor ● Highly cellular tumors with moderate to marked nuclear pleomorphism (sarcomatous appearance) ● High mitotic rate (more than 5/10 hpf) ● Areas of geographic necrosis may be seen ● Greatly variable morphology, but often spindle cells forming a herringbone or fascicular pattern are seen ● Up to 20% of cases show unusual histologic features, including epithelioid cells and divergent mesenchymal or glandular differentiation ❚ Perineurioma ● Extraneural and sclerosing subtypes: vary from spindle-shaped elongated cells to epithelioid; variable architectural patterns, including whorling, lamellar, and storiform ● Reticular subtype: prominent myxoid stroma, netlike growth pattern ● Intraneural subtype: spindle cells arranged in pseudo onion-bulb arrangement around axons and Schwann cells Special Stains and Immunohistochemistry ❚ Schwannomas ● S-100 positive ● GFAP: variable focal positivity ● Collagen IV and laminin positive ❚ Neurofibroma ● S-100 positive ● Collagen IV, laminin variable ● EMA: few positive cells ❚ Perineurioma ● EMA positive ● Collagen IV, laminin positive ● Claudin-1, GLUT1 positive

S-100 negative Mib-1 index: ranges from 5% to 15% ❚ MPNST ● S-100 positive in up to 70%, but higher-grade lesions show less positivity ● Mib-1 index: ranges from 5% to 65% ● ●

Other Techniques for Diagnosis ❚ Conventional and cellular schwannoma ● Electron microscopy: well-differentiated, elongated cells with long cytoplasmic processes surrounded by a complete basal lamina; characteristically shows intercellular long-spacing collagen (Luse bodies) ● Cytogenetics: loss of the NF2 gene product on chromosome 22 (also called Merlin) in 60% ❚ Neurofibroma ● Electron microscopy: mixture of cells including Schwann cells and perineurial cells ● Cytogenetics: plexiform subtype associated with NF1; sporadic neurofibromas commonly also have mutations in the NF1 gene ❚ MPNST ● Electron microscopy: poorly differentiated cells showing nuclear pleomorphism and an incomplete basement membrane; usually no Luse bodies ● Cytogenetics: 50% associated with NF1 ❚ Perineurioma ● Electron microscopy: elongated cells and nuclei, delicate chromatin, pinocytotic vesicles, basal lamina, and tight junctions ● Cytogenetics: loss of chromosome 22 or 22q Differential Diagnosis ❚ Meningioma ● Often shows prominent whorled pattern and psammoma bodies ● Rare in lumbosacral region (common site for schwannomas) ● Negative or faint staining for S-100 protein ● Positive staining for EMA (70%) Pearls ● Large neurofibromas associated with NF and plexiform neurofibromas have an increased potential for malignant transformation (MPNST) ● Multiple schwannomas may be seen in various syndromes (schwannomatosis, NF); isolated bilateral schwannomas of cranial nerve VIII are pathognomonic of NF2 ● MPNSTs are high-grade, aggressive tumors with tendency to recur and metastasize (often metastasize to lung) ● EMA positivity in perineuriomas may be faint and difficult to see because of thin processes ● Perineuriomas are usually cured with complete resection, but rare malignant cases are reported

1020  Differential Diagnosis in Surgical Pathology

Selected References Macarenco RS, Ellinger F, Oliveira AM: Perineurioma: A distinctive and underrecognized peripheral nerve sheath neoplasm. Arch Pathol Lab Med 31:625-636, 2007. Scheithauer BW, Louis DN, Hunter S, et al: Tumors of the cranial and paraspinal nerves. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 151-162. Scheithauer BW, Woodruff JM, Erlandson RA: Tumors of the peripheral nervous system. Atlas of Tumor Pathology, 3rd Series, Fascicle 24. Bethesda, MD, Armed Forces Institute of Pathology, 1999.

Meningioma (WHO Grade I), Atypical Meningioma (WHO Grade II), and Anaplastic Meningioma (WHO Grade III) Clinical Features Common tumor accounting for 24% to 30% of all primary intracranial neoplasms ● Typically found in middle-aged adults; occasionally seen in children ● More commonly occurs in females (3:2); intraspinal tumors show a 10:1 female-to-male ratio ● About 90% of tumors are intracranial ● Patients usually present with symptoms related to an enlarging intracranial mass or increased intracranial pressure; may have focal neurologic deficits or rarely seizures ● CT and MRI show dura-based, richly vascular, contrast-enhancing, well-defined masses; clusters of calcifications may be seen ● Rarely arises from the optic nerve, causing visual symptoms, or within the spinal cord, causing radicular pain; may also rarely involve the ventricular system ●

Figure 19-13.  Meningioma. Syncytial pattern of neoplastic cells displaying a classic meningothelial appearance with round to oval nuclei. Several whorls are present.

Gross Pathology Firm, well-defined, tan-white tumor often showing attachment to a segment of dura; may show a yellow or gelatinous cut surface owing to lipid or mucin accumulation ● Frequent infiltration of bone and scalp ● Frequently causes hyperostosis of skull ● Calcification is commonly seen ● Atypical or anaplastic meningioma — Typically causes considerable cerebral edema — Brain invasion is frequently present ●

Histopathology ● Extremely diverse tumor with numerous histologic variants ❚ Classic meningioma (WHO grade I) ● Syncytial, fibrous, and transitional variants (transitional variant is most common): syncytial pattern is created by sheets of tumor cells that have indistinct cell borders; fibrous meningiomas show elongated cells in a collagenous background; transitional meningiomas show a pattern that is intermediate between the syncytial and fibrous types or composed of a mixture of syncytial and fibrous patterns — Neoplastic cells are arranged in a whorled or lobulated architecture — Tumor cells have a meningothelial appearance with round to oval nuclei, dispersed chromatin, inconspicuous nucleoli, and eosinophilic cytoplasm — Prominent round intranuclear inclusions are typical — Psammoma bodies are often noted throughout the tumor; less commonly seen in pure fibrous types — Focal nuclear pleomorphism is often present — Scattered mitotic figures may be seen ● Other variants — Psammomatous meningioma (WHO grade I) ◆ Shows abundant psammoma bodies throughout the tumor — Secretory meningioma (WHO grade I) ◆ Cytoplasm contains round, eosinophilic, hyaline structures resembling psammoma bodies (pseudopsammoma bodies) ◆ Structures are PAS positive and diastase resistant — Microcystic meningioma (WHO grade I) ◆ Consists of a delicate, microcystic architecture with cystic spaces filled with clear fluid ◆ Often shows greater degree of cytologic atypia or areas of xanthomatous cells with vacuolated cytoplasm — Lymphoplasmacytic meningioma (WHO grade I) ◆ Shows a pronounced lymphoplasmacytic response

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— Metaplastic meningioma (WHO grade I) ◆ Metaplastic areas may consist of myxoid, chordoid, osteoblastic, lipoblastic, or xanthomatous differentiation — Angiomatous meningioma (WHO grade I) ◆ Abundant vessels with sparse meningothelial cells ◆ Vessels are usually hyalinized, and degenerative nuclear atypia is common ● Prognostically important variants — Chordoid meningioma (WHO grade II) ◆ Rare variant ◆ Consists of small groups or cords of epithelioid cells in a mucin-rich background (resembles a chordoma) — Clear cell meningioma (WHO grade II) ◆ Composed of cells with clear cytoplasm ◆ Cytoplasm contains glycogen (PAS positive) ◆ Suggestion of aggressive growth and high recurrence rates — Papillary meningioma (WHO grade III) ◆ Typically occurs in younger individuals ◆ Tumor cells arranged around blood vessels resembling ependymoma-like pseudorosettes ◆ Aggressive clinical course (55% recurrence rate; 20% metastasis rate) — Rhabdoid meningioma (WHO grade III) ◆ Tumor may exhibit exclusively rhabdoid cellular morphology, but more commonly presents mixed with rhabdoid cells and typical meningioma cells ◆ Rhabdoid cells have eccentric nuclei and hyaline paranuclear inclusions ◆ Reported cases have high Mib-1 index and many mitoses, which have been associated with a high rate of recurrence and aggressive growth ❚ Atypical meningioma (WHO grade II) ● Exhibits increased mitoses (≥4 mitoses/10 hpf), brain invasion, or the presence of at least three of following four microscopic features: tumor showing sheetlike growth pattern, nuclei with macronucleoli, hypercellularity, and small cell formation or spontaneous necrosis ❚ Anaplastic meningioma (WHO grade III) ● Exhibits focal or diffuse loss of meningothelial differentiation at the light microscopic level (areas showing sarcomatous, carcinomatous, or melanomalike appearance) or marked elevation in mitotic rate (≥20 mitoses/10 hpf) Special Stains and Immunohistochemistry ● EMA, claudin-1: most are positive ● S-100 protein: occasionally positive; fibrous meningiomas: 80% are positive ● Cytokeratin: usually negative; secretory meningiomas usually positive

GFAP negative Mib-1: labeling index correlates with grade and recurrence rate; in general, an index greater than 4% is associated with increased recurrence; mean values of Mib-1 index: benign, 3.8%; atypical, 7.2%; anaplastic, 14.7% ● CD34: 60% of fibrous meningiomas are positive ● Progesterone receptor: variably positive; less likely to be positive in atypical or anaplastic meningiomas ● ●

Other Techniques for Diagnosis ● Electron microscopy: cells have nuclei with interdigitating, irregular membranes, desmosomes, and intranuclear cytoplasmic inclusions ● Cytogenetics — Monosomy 22 is most commonly found — With increasing grade, cytogenetic abnormalities increase; most often found are abnormalities of chromosomes 1, 6, 10, 14, and 18 — Meningiomas are found in NF2 (NF2 locus on chromosome 22q), and mutations in the NF2 gene are found in 60% of sporadic meningiomas Differential Diagnosis ❚ Schwannoma ● Biphasic tumor consisting of highly cellular areas (Antoni A) admixed with loose spongy areas of lower cellularity (Antoni B) ● Usually lacks distinct whorled architecture and psammoma bodies ● Typically found in posterior fossa or spinal cord ● S-100 protein and EMA usually positive ❚ Ependymoma ● Located within the ventricle; not usually associated with the meninges ● Typically occurs in children or young adults ● Cells have long fibrillary processes ● Rosettes are commonly seen ● GFAP positive ❚ Meningeal hyperplasia ● Single or multiple foci of meningothelial cells (more than 10 cell layers thick) ● Usually associated with a predisposing factor (hemorrhage, chronic renal failure, trauma) ● Discontinuous growth pattern and no invasion or adjacent tissue ❚ Hemangiopericytoma ● Contains numerous variably sized, slitlike and staghorn vessels ● No psammoma bodies ● Negative for EMA, and patchy, weak positivity for CD34 ❚ Solitary fibrous tumor ● Shows hemangiopericytoma-like vascular pattern ● CD34 positive

1022  Differential Diagnosis in Surgical Pathology

Pearls Treatment is complete surgical resection; typically offers an excellent prognosis with classic meningiomas ● Radiation therapy has been shown to be beneficial in recurrent or unresectable tumors ● Benign meningiomas have a recurrence rate of up to 25%; atypical meningiomas are associated with a 29% to 52% recurrence rate; anaplastic meningiomas have recurrence rate range of 50% to 94% ●

Selected References Nakasu S, Li DH, Okabe H, et al: Significance of MIB-1 staining indices in meningiomas. Am J Surg Pathol 25:472-478, 2001. Perry A, Scheithauer BW, Stafford SL, et al: “Malignancy” in meningiomas: A clinicopathologic study of 116 patients with grading implications. Cancer 85:2046-2056, 1999. Perry A, Stafford SL, Scheithauer BW, et al: Meningioma grading: An analysis of histologic parameters. Am J Surg Pathol 21:1455-1465, 1997. Perry A, Scheithauer BW, Nascimento AG: The immunophenotypic spectrum of meningeal hemangiopericytoma: A comparison with fibrous meningioma and solitary fibrous tumor of meninges. Am J Surg Pathol 21:1354-1360, 1997.

Hemangiopericytoma (WHO Grade II) and Anaplastic Hemangiopericytoma (WHO Grade III) Clinical Features ● Dura-based sarcoma accounts for less than 1% of all CNS tumors ● Typically associated with meninges and located within the cranial rather than the spinal compartment ● Most originate in the meninges and often mimic meningiomas

Usually found in adults; no sex predilection Most patients present with headache and focal neurologic deficits ● CT and MRI show a diffusely enhancing, sharply defined lesion with dural attachment suggestive of meningioma; bone destruction may be seen ● ●

Gross Pathology ● Typically forms a discrete, lobulated, tan-gray, fleshy mass ● May show invasive architecture with destruction of adjacent bone; usually no calcifications ● Markedly vascular tumor that bleeds profusely at surgery ● Cut surface is solid, focally hemorrhagic, and often with large vascular spaces Histopathology ● Variably cellular tumor with numerous small slitlike and large staghorn vascular channels ● Some tumors show predominantly spindle cells with collagenous background ● Tumor cells typically have plump oval or elongated nuclei with inconspicuous nucleoli and scant cytoplasm ● Typically lacks areas of necrosis ● Lacks tight whorls, psammoma bodies, or nuclear pseudoinclusions as seen in meningiomas ● Anaplastic hemangiopericytoma — Presence of necrosis or more than 5 mitoses/ 10 hpf; and at least two of the following microscopic features ◆ Hemorrhage ◆ Moderate to high nuclear atypia ◆ Moderate to high cellularity Special Stains and Immunohistochemistry ● Reticulin: surrounds individual cells ● CD34: patchy positivity ● CD99, factor XIIIa, bcl-2, and vimentin: strong diffuse positivity ● EMA: weak, focal positivity ● Factor VIII: endothelial cells are positive; tumor cells are negative ● Mib-1 labeling index: 5% to 10% Other Techniques for Diagnosis ● Electron microscopy: cells with basal lamina, primitive intercellular junctions, and whorled masses of intermediate filaments ● Molecular analysis: abnormalities of chromosomes 12 and 3

Figure 19-14.  Hemangiopericytoma. Classic staghorn vascular pattern is evident in this neoplasm composed of polygonal to spindleshaped cells.

Differential Diagnosis ❚ Meningioma ● Presence of psammoma bodies, whorls, calcification, and pseudoinclusions

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Typically lack large staghorn blood vessels and abundant reticulin ● EMA positive; CD34 negative; CD99 negative; bcl-2 negative ❚ Solitary fibrous tumor ● Areas of hyalinization and collagen deposition are frequent ● Typically lacks highly cellular areas seen in hemangiopericytoma ● Sparse reticulin deposition, around clusters of cells ● Strong and diffuse positivity for CD34, vimentin, and bcl-2 ●

Pearls ● High rate of local recurrence with frequent late distant metastases typically involving the bone, liver, or lung ● Surgical resection followed by radiotherapy is the usual treatment ● Postoperative radiation, chemotherapy, or both decreases tumor recurrence and may increase survival ● Anaplastic hemangiopericytomas are associated with increased rates of recurrence and decreased survivals ● Mib-1 labeling index unrelated to grade Selected References Rajaram V, Brat DJ, Perry A: Anaplastic meningioma versus meningeal hemangiopericyoma: Immunohistochemical and genetic markers. Hum Pathol 35:1413-1418, 2004. Ecker RD, Marsh WR, Pollock BE, et al: Hemangiopericytoma in the central nervous system: Treatment, pathological features, and long-term follow up in 38 patients. J Neurosurg 98:11821187, 2003. Tihan T, Viglione M, Rosenblum MK, et al: Solitary fibrous tumors in the central nervous system: A clinicopathologic review of 18 cases and comparison to meningeal hemangiopericytomas. Arch Pathol Lab Med 127:432-439, 2003. Perry A, Scheithauer BW, Nascemento AG: The immuno­ phenotypic spectrum of meningeal hemangiopericytoma: A comparison with fibrous meningioma and solitary fibrous tumor of meninges. Am J Surg Pathol 21:1354-1360, 1997.

Hemangioblastoma (WHO Grade I) Clinical Features ● Low-grade neoplasm, associated with VHL: autosomal dominant disorder characterized by hemangioblastomas of the CNS and retina, renal cell carcinoma, pheochromocytoma, pancreatic islet cell tumor, endolymphatic sac tumor, and visceral cysts ● About 25% of cerebellar hemangioblastomas occur in patients with VHL ● Of patients with VHL, 70% develop hemangioblastomas

Figure 19-15.  Hemangioblastoma. Abundant vascular channels and numerous lipid-laden stromal cells.

Sporadic cases are typically found in adults (fourth and fifth decades) and are usually single; multiple tumors are commonly seen in patients with VHL and occur at younger ages (third and fourth decades) ● Typically occurs in the cerebellum (80%); less commonly found in the spinal cord, brain stem, or cerebrum ● Symptoms are usually related to increased intracranial pressure when the tumor is in the posterior fossa; back pain and weakness or pain in extremities are seen in spinal cord tumors ● Tumor production of erythropoietin may cause secondary polycythemia ●

Gross Pathology ● Well-circumscribed, highly vascular mass, usually largely cystic with a solid mural nodule ● Cyst fluid is clear, often yellow, and may be hemorrhagic ● Neoplasm may be yellow owing to high lipid content and commonly has areas of hemorrhage Histopathology ● Characteristically shows a prominent dense network of capillaries lined by hyperplastic endothelial cells and pericytes; interspersed large thin-walled vessels are also present ● Interstitial stromal cells are large and have abundant vacuolated lipid-rich pale cytoplasm; nuclei are large, usually without nucleoli, and occasionally show slight to moderate pleomorphism ● Cyst wall is composed of reactive astrocytes and Rosenthal fibers that may resemble a pilocytic astrocytoma ● Mitotic activity is rare to absent

1024  Differential Diagnosis in Surgical Pathology

Special Stains and Immunohistochemistry GFAP: entrapped astrocytes positive; stromal cells negative ● Vimentin: stromal cells positive ● Inhibin A and oil red O (on fresh tissue): stromal cells positive ● S-100 and NSE: stromal cells variably positive ● EMA, cytokeratin, CD34, and factor VIII: stromal cells negative ● Reticulin highlights vessels and is present around tumor cells ● Mib-1 index: sparse positive nuclei (<2%) ●

Other Techniques for Diagnosis ● Ultrastructure: three cell types are identified: endothelial cells, pericytes, and stromal cells; the stromal cells contain lipid droplets, microfilaments, and electron-dense granules (associated with erythropoietin-like substance) ● Cytogenetics: VHL is caused by deletions or mutations in a tumor suppressor gene (chromosome 3p25-26) ● Germline mutations in this gene are found in some individuals presenting with hemangioblastoma ● Loss or inactivation of VHL gene is found in up to 50% of patients with sporadic neoplasms Differential Diagnosis ❚ Pilocytic astrocytoma ● Classically cells have elongated nuclei and fibrillary cytoplasm ● GFAP diffusely positive ❚ Metastatic clear cell renal cell carcinoma ● May occur in association with hemangioblastoma in VHL ● Usually not cystic ● Mitotic figures usually abundant ● Typically positive for EMA, cytokeratin (CAM5.2), and CD10; negative for inhibin A and NSE ❚ Paraganglioma ● Typically synaptophysin and chromogranin positive ❚ Meningioma (angiomatous) ● EMA positive and inhibin A negative

Takei H, Bhattacharjee MB, Rivera A, et al: New immuno­ histochemical markers in the evaluation of central nervous system tumors: A review of seven selected adult and pediatric brain tumors. Arch Pathol Lab Med 131:234-241, 2007. Hoang MP, Amirkhan MH: Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol 27:1152-1156, 2003.

Malignant Lymphoma (Non-Hodgkin and Hodgkin) Clinical Features Primary CNS lymphomas (PCNSLs) make up 6.6% of all primary brain tumors and occur in both immunocompetent and immunocompromised hosts ● PCNSL is non-Hodgkin type, and about 5% of primary cases are associated with acquired immunodeficiency syndrome (AIDS) ● Incidence of PCNSL has increased over the past 25 years, only partially attributable to occurrence in those with human immunodefiency virus (HIV) infection ● The peak ages of occurrence in the immuno­ competent individual are in the sixth and seventh decades, with a slightly higher occurrence in men than women ● Immunocompromised host mean age is 37 years in transplant recipients and 39 years in AIDS patients ● Most common location is in the parenchyma of the cerebral hemispheres, forming discrete or diffuse lesions — Occurs, with decreasing frequency, in the thalamus and basal ganglia, corpus callosum, ventricles, and cerebellum — Less common sites of occurrence are the leptomeninges, eye, and spinal cord ●

Pearls ● The stromal cell is considered the neoplastic component of the tumor, but its histogenesis has not been clarified ● Complete surgical resection offers excellent results; rare reports of tumor recurrence after incomplete resection ● Recent study suggests symptom progression is secondary to the increasing size of the cyst rather than growth of the neoplasm Selected References Aldape KD, Plate KH, Vortmeyer AO, et al: Hemangioblastoma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, France, IARC, 2007, pp 184-186.

Figure 19-16.  Malignant lymphoma. Classic angiocentric pattern for a malignant lymphoma involving the brain.

Central Nervous System  1025

Overall, up to 50% are multiple, but multifocality is more common in the immunocompromised patient (85%) ● Meningeal involvement is more common in secondary lesions ● The typical clinical presentation of PCNSL is with focal neurologic signs or symptoms (70%), followed by neuropsychiatric symptoms (43%) and increased intracranial pressure (33%) ● Primary Hodgkin disease in the CNS is extremely rare; more common is to have CNS involvement with known systemic disease ●

Gross Pathology ● An ill-defined mass involving the deep periventricular tissue or occurring superficially in the brain, causing thickening of the cortex, is most common ● Tumor may be yellow or gray-white, show areas of hemorrhage or necrosis, and be solid or cystic ● Hodgkin disease typically involves the dura, meninges, and skull-base structures Histopathology ❚ Non-Hodgkin lymphoma ● In both the immunocompetent and immunocom­ promised hosts, most are diffuse large B-cell type (>95%) ● Less commonly, low-grade B-cell type, marginal zone B-cell lymphoma, Burkitt lymphoma, or T-cell types ● Patchy clusters of cells with a predilection for perivascular spaces (evokes a deposition of reticulin fibers); diffuse sheets may also be seen ● Individual cells are usually large and round with scant circumscribed cytoplasm and pleomorphic nuclei with nucleoli ● Mitoses, apoptosis, and geographic necrosis are common ❚ Hodgkin disease ● Most common subtypes involving the brain are nodular sclerosing and mixed cellularity ● Characterized by neoplastic Reed-Sternberg cells (large, binucleated cells with each nucleus containing a single prominent nucleolus; abundant eosinophilic cytoplasm) in a background of mixed inflammatory cells, including lymphocytes, plasma cells, neutrophils, eosinophils, and macrophages Special Stains and Immunohistochemistry ● LCA (CD45) positive ● B- and T-cell markers: CD20/CD3 positive depending on lineage ● Epstein-Barr virus (EBV) in situ hybridization positive in lymphomas in AIDS patients and other immunocompromised hosts Other Techniques for Diagnosis ● Cytogenetics: gains of MALT1 and bcl-2 in 18q21 are the most common abnormality

Differential Diagnosis ❚ Metastatic neuroendocrine carcinoma ● Well-defined tumors typically lacking an infiltrative margin ● Cell cohesion and nuclear molding typically present ● Cytokeratin, synaptophysin, and chromogranin positive ● LCA and CD20 negative ❚ Oligodendroglioma ● Monomorphic oligodendroglial cells with perinuclear halos and less well-defined cytoplasm compared with lymphoma cells ● Cells typically do not infiltrate through the vessel walls as in lymphoma ● Microcalcifications are characteristic ● LCA and CD20 negative ● Deletions of chromosomes 1p and 19q frequent ❚ Reactive lymphocytosis (as in viral encephalitis and demyelinating diseases) ● Lymphocytes do not show significant cytologic atypia ● Lacks monoclonality (usually predominantly T lymphocytes, less B lymphocytes) ● Cluster in perivascular regions, but do not form solid sheets of cells in the parenchyma ● Consider progressive multifocal leukoencephalopathy (PML) and toxoplasmosis in the immunocompromised host ❚ Medulloblastoma and PNET ● Rosette formation may be seen ● Positive for synaptophysin, NSE, and neurofilament ● Negative for LCA Pearls ● Treatment with steroids before biopsy is to be avoided if possible because the treatment may disrupt cellular morphology so completely that pathologic diagnosis is not possible ● Surgical resection and radiation treatment have not been of long-term therapeutic benefit; radiation therapy is associated with marked neurotoxic effects, especially in older patients ● Methotrexate chemotherapy alone or in combination with other agents has resulted in durable responses, but most patients eventually relapse ● Prognostic markers: the following have been associated with a poor prognosis — Age greater than 60 years — Poor performance status — Increased lactate dehydrogenase level — Increased CSF protein — Deep location of tumor mass in the brain Selected References Commins DL: Pathology of primary central nervous system lymphoma. Neurosurg Focus 21:E2, 2006.

1026  Differential Diagnosis in Surgical Pathology

Batchelor T, Loeffler JS: Primary CNS lymphoma. J Clin Oncol 24:1281-1288, 2006. Plotkin SR: Update on primary central nervous system lymphoma. Curr Opin Neurol 18:645-653, 2005. Ferreri AJM, Reni M: Prognostic factors in primary central nervous lymphomas. Hematol Oncol Clin N Am 19:629-649, 2005.

Germ Cell Tumors Clinical Features Intracranial counterpart of germ cell tumors found in gonads and other extracranial sites ● About 90% of patients present before age 20; more common in males ● Symptoms include signs of increased intracranial pressure, hydrocephalus, visual abnormalities, or various endocrinopathies, including diabetes insipidus or precocious puberty ● Typically located in the midline; most often involving the pineal or pituitary region (two thirds in pineal region, one third in pituitary region) ●

Gross Pathology ● See Chapters 11 and 12 Histopathology ● See Chapters 11 and 12 Special Stains and Immunohistochemistry ● See Chapters 11 and 12 Other Techniques for Diagnosis ● Cytogenetic analysis: most frequent chromosomal abnormalities in germinomas of the pineal region are loss of 13q and 18q

Figure 19-17.  Germinoma. Large polygonal and well-defined cells with abundant clear cytoplasm and nuclei with prominent nucleoli, intermixed with lymphocytes.

Differential Diagnosis ❚ Pineocytoma and pineoblastoma ● Presence of pineocytomatous rosettes or small blue cells ● Human chorionic gonadotropin, human placental lactogen, placental alkaline phosphatase, and cytokeratin negative ❚ See Chapters 11 and 12 for other differential diagnoses Pearls ● Overall, intracranial germ cell tumors are rare; represent 3% to 11% of all brain tumors in children and 1% in adults ● Sacrococcygeal teratomas are often identified in the neonatal period; more common in females and usually benign Selected References Hirato J, Nakazato Y: Pathology of pineal region tumors. J Neurooncol 54:239-249, 2001. Rickert CH, Simon R, Bergmann M, et al: Comparative genomic hybridization in pineal region germ cell tumors. J Neuropathol Exp Neurol 59:815-821, 2000. Balmaceda C, Modak S, Finlay J: Central nervous system germ cell tumors. Semin Oncol 25:243-250, 1998.

Neuraxial Cysts: Rathke Cleft Cyst, Colloid Cyst, and Enterogenous Cyst Clinical Features ❚ Rathke cleft cyst (RCC) ● Usually located in the sella or suprasellar region ● Often asymptomatic and found at autopsy, but may produce compressive symptoms (headache, hypopituitarism, hyperprolactinemia, and visual disturbance) owing to accumulated colloid secretions ❚ Colloid cyst (CC) ● Usually within third ventricle near the foramen of Monro ● May cause obstructive hydrocephalus ● Rarely associated with sudden death ● Mean age of occurrence is 40 years ❚ Enterogenous cyst (EntC) ● Located within the spinal canal, usually in the cervical and upper thoracic levels ● Rarely located intracranially ● Usually intradural, extramedullary, and anterior to the cord ● May be associated with vertebral abnormalities ● Usually occurs in children and young adults Gross Pathology ● Each cyst is thin walled with a smooth lining and filled with gray-white mucoid material ● CC often contains particularly dense cyst contents

Central Nervous System  1027

A

B

Figure 19-18.  Rathke cleft cyst. A, The cyst wall is lined by ciliated columnar epithelium overlying anterior pituitary tissue. B, Mucin stain showing positive goblet cells.

A

B

Figure 19-19.  A, Colloid cyst. The cyst wall is lined by cuboidal to columnar epithelium, overlying a fibrous stroma. B, Enterogenous cyst. The cyst wall is lined by ciliated or mucin-secreting columnar epithelium reminiscent of respiratory or intestinal linings, respectively.

Histopathology Cysts are lined by epithelium ranging from simple columnar or cuboidal cells to a pseudostratified layer of cells; cilia and mucin production are typically seen ● In RCC, cyst often overlies anterior pituitary gland cells ● Squamous metaplasia may be seen in RCC ●

Special Stains and Immunohistochemistry ● Cytokeratin and EMA: RCC, CC, and EntC lining cells positive ● Vimentin: RCC is positive; CC and EntC variably positive ● GFAP: RCC, CC, and EntC negative Other Techniques for Diagnosis ● Ultrastructure: ciliated and nonciliated epithelial cells with junctional complexes and microvilli, resting on a continuous basal lamina

Differential Diagnosis ❚ Craniopharyngioma versus RCC ● Presence of squamous metaplasia in RCC may make distinction difficult, but RCC usually lacks keratin formation ● Craniopharyngiomas contain solid epithelial islands, distinctive stellate reticulum, and basally palisaded epithelium ❚ Distinction between RCC, CC, and EntC ● Difficult to distinguish histologically ● Location is likely to be helpful ❚ Ependymal cyst ● Most are in the deep white matter ● Epithelial lining of low cuboidal to columnar cells that are frequently ciliated ● Cyst lining is positive for GFAP and S-100 protein ❚ Arachnoid cyst ● No epithelial lining; lined by meningothelial cells ● Lining cells positive for EMA; negative for GFAP and S-100 protein

1028  Differential Diagnosis in Surgical Pathology

❚ Cysticercosis of ventricular system or subarachnoid space ● Presence of fragments of parasite on biopsy indicates correct diagnosis Pearls ● Each cyst is benign and usually cured by complete excision Selected References Osborn AG, Preece MT: Intracranial cysts: Radiologic-pathologic correlation and imaging approach. Radiology 239:650-664, 2006. Takei H, Fuller GN, Powell SZ: Intracranial cysts of endodermal or respiratory epithelial origin. In McLendon RE, Rosenblum MK, Bigner DD (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System, 7th ed. New York, Hodder Arnold, 2006, pp 591-598. Kleinschmidt-DeMasters BK, Lillehei KO, Stears JC: The pathologic, surgical, and MR spectrum of Rathke cleft cysts. Surg Neurol 44:19-27, 1995.

Pituitary Adenoma (Including Typical and Atypical Adenomas), Pituitary Carcinoma, and Pituitary Hyperplasia Clinical Features ❚ Pituitary adenomas ● Most frequently found in women in their third through sixth decades; rarely seen in children ● Represent about 15% of all intracranial neoplasms ● May occasionally be found incidentally at autopsy ● Patients present with endocrinopathy in two thirds of the cases (hormone secretion by tumor or pressure on stalk or hypothalamus) or with visual complaints (a nonsecretory tumor is more likely to grow large enough to compress optic tracts)

Figure 19-20.  Pituitary adenoma. Sinusoidal pattern of uniform cells with distinct cytoplasm and round nuclei containing salt-and-pepper chromatin.

Functional tumors have variable presentation depending on what hormone they secrete — Growth hormone (GH)–secreting adenomas produce acromegaly — Prolactin (PRL)–secreting adenomas produce galactorrhea — Adrenocorticotropic hormone (ACTH)–secreting adenomas produce Cushing disease or Nelson syndrome — Gonadotrophic adenomas (follicle-stimulating hormone [FSH] or luteinizing hormone [LH] producing) are not usually biochemically active and present as nonfunctioning tumors — Thyroid-stimulating hormone (TSH)–producing adenomas produce hyperthyroidism ● May be associated with MEN I ● Atypical pituitary adenoma — Accounts for about 5% of adenomas — Defined histopathologically (see under “Histopathology”) ❚ Pituitary carcinoma: defined only by the presence of metastasis ❚ Pituitary hyperplasia ● Clinical presentation is the same as for adenomas ● Radiologic studies may show diffuse enlargement of pituitary gland without a discernible rim of normal tissue ●

Gross Pathology ● Range in size from microadenomas to several centimeters, with enlargement of the sella and occasionally extrasellar extension ● Soft masses with occasional cystic degeneration or necrosis in larger lesions ● Invasive pituitary adenoma — Shows extensive dural, vascular, osseous, neural, or sinus invasion; this designation is best made radiographically or intraoperatively — Invasion is present in about 50% of all adenomas Histopathology ● Tumor has a nested architecture with large groups of cells surrounded by incomplete reticulin network; may show focal papillary architecture ● Compression of adjacent normal pituitary gland may be seen ● Tumor is generally composed of monomorphic cells with round nuclei and inconspicuous nucleoli; a moderate degree of nuclear pleomorphism may occasionally be seen (see characteristics specific to hormone production) ● Oncocytic differentiation may occasionally be present ● Mitotic figures are rare ● Microcalcifications may be present ● Large adenomas may show focal necrosis, infarction, or hemorrhage (pituitary apoplexy) ● Complete tumor infarction may rarely occur

Central Nervous System  1029

Characteristics specific to hormone production — PRL-containing adenomas ◆ Sparsely granulated adenomas Usually are responsive to dopamine agonists and show changes secondary to treatment Small cells in fibrous stroma and focal staining for PRL Untreated tumors are chromophobic with abundant cytoplasm and strong PRL positivity ◆ Densely granulated adenomas: acidophilic to chromophobic cells with strong diffuse positivity to PRL ◆ Acidophil stem cell adenoma: oncocytic change and variably positive to PRL and GH with CAM5.2 fibrous bodies — GH-containing adenomas ◆ Sparsely granulated adenomas: weak positivity for GH, and CAM5.2 identifies fibrous bodies ◆ Densely granulated adenomas: eosinophilic cytoplasm and perinuclear dotlike reactivity with CAM5.2 ◆ Mammosomatotroph adenoma: may also produce and secrete prolactin in addition to GH or PRL and TSH (plurihormonal adenoma) — ACTH-containing adenomas ◆ May be sparsely or densely granulated ◆ Most microadenomas are densely granulated ◆ Composed of basophilic cells with strong PAS positivity and CAM5.2 positivity ◆ Adjacent nonadenomatous gland shows Crooke hyaline change (concentric whorls of hyaline material in cytoplasm) — TSH-secreting adenomas ◆ Usually large infiltrative masses with fibrosis and atypia ◆ Composed of chromophobic cells ● Nonfunctioning adenomas — Most are gonadotrophic adenomas without clinical evidence of hormonal secretion — Solid sheets, nests, or sinusoidal pattern of acidophilic cells; pseudopapillae and rosettes may also be seen — Oncocytic change may be present — Positive for FSH and LH ● Plurihormonal adenomas — Most frequent combinations include GH, PRL, and one or more of the following: TSH, FSH, or LH ● Silent subtype 3 adenoma — Often positive for PRL, GH, and TSH — Intense stromal fibrosis and high vascularity — Characteristic ultrastructure — Aggressive behavior and poor prognosis ● Atypical adenomas — Usually show invasive growth — Increased mitoses, and Mib-1 labeling index greater than 3% — Extensive nuclear positivity for TP53 ●

Invasive pituitary adenoma — Defined by invasion into bone, sphenoid or cavernous sinus, and diaphragm sellae; same histologic features as typical pituitary adenomas; no reliable light or electron microscopic findings help distinguish this subtype — May show elevation of Mib-1 and TP53 positivity ● Pituitary hyperplasia — Pituitary acini expanded by cells of one hormonal type with intermixed cells staining for all hormones — Reticulum network remains intact but expanded — Often difficult to distinguish from normal gland ● Pituitary carcinoma — Rare pituitary tumor — Morphologically cannot be separated from typical pituitary adenoma — Two thirds are functional and produce PRL or ACTH — Definitive diagnosis is based on the presence of distant metastases ●

Special Stains and Immunohistochemistry ● Variably positive or negative staining for pituitary gland hormones (see detailed description under “Histopathology”) ● Mib-1: correlation between invasiveness and high Mib-1 index has been reported; labeling index of greater than 3% for atypical adenomas ● Extensive positivity for TP53 in atypical adenomas Other Techniques for Diagnosis ● Electron microscopy: distribution and morphology of secretory granules help to classify adenomas ● Several genomic alterations have been associated with invasiveness (overexpression of EGFR in recurrent GH adenomas) Differential Diagnosis ❚ Normal pituitary gland ● Small clusters of monomorphic cells with uniform nuclei completely surrounded by reticulin network ❚ Craniopharyngioma ● Distinctive morphology: cords and solid areas of squamous epithelium with palisaded basal cells, keratin formation, and calcification ❚ Hypophysitis ● May occur as a primary process confined to the gland or secondary to systemic disease ❚ Lymphocytic hypophysitis (primary) ● More common in women, especially peripartum ● Partial or total pituitary hypofunction ● Lymphoplasmacytic infiltrate of gland; lymphoid follicles may be seen

1030  Differential Diagnosis in Surgical Pathology

❚ Granulomatous hypophysitis (primary) ● Well-formed granulomas composed of epithelioid histiocytes, giant cells, and lymphocytes ● Infectious etiology should be considered ● May be the primary manifestation of sarcoidosis ● Idiopathic form exists; hypothesized to be of autoimmune origin ❚ RCC ● Single layer of ciliated cuboidal to columnar cells forming a cyst wall, often overlying pituitary gland ● Squamous metaplasia may occur ❚ Spindle cell oncocytoma of the adenohypophysis (WHO grade I) ● Suspected to derive from folliculostellate cells of anterior pituitary gland ● Interlacing spindle and epithelioid cells with eosinophilic oncocytic cytoplasm ● May see nuclear atypia ● EMA and S-100 positive ● GFAP, cytokeratin, and synaptophysin negative ❚ Granular cell tumor of the neurohypophysis ● Polygonal cells with granular cytoplasm ● GFAP and cytokeratin negative Pearls ● Hemorrhagic necrosis of a pituitary adenoma (pituitary apoplexy) constitutes a surgical emergency (occurs in less than 1% of cases) Selected References Fuller GN, Scheithauer BW, Roncaroli F, Wesseling P: Spindle cell oncocytoma of the adenohypophysis. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 245-246. Al-Brahim NYY, Asa SL: My approach to pathology of the pituitary gland. J Clin Pathol 59:1245-1253, 2006. Al-Shraim M, Asa SL: The 2004 World Health Organization classification of pituitary tumors: What is new? Acta Neuropathol 111:1-7, 2006. Kontogeorgos G: Classification and pathology of pituitary tumors. Endocrine 28:27-35, 2005.

Pituicytoma (WHO Grade I) Clinical Features ● Low-grade glial neoplasm arising in the neurohypophysis or infundibulum ● Extremely rare; occurs in adults; men are affected more than women ● Signs and symptoms are secondary to mass effect: visual disturbance, headache, and hypopituitarism; may also see compression of infundibulum and secondary hyperprolactinemia Gross Pathology ● Circumscribed solid mass

Histopathology Spindle cells forming fascicles or storiform pattern Cells range from elongated to rounded and contain nuclei with little atypia ● No mitoses ● No intermixed axons or axonal swellings ● ●

Special Stains and Immunohistochemistry ● GFAP positive, but may vary in intensity and extent ● Vimentin and S-100 positive ● Neurofilament, synaptophysin, and chromogranin negative ● Cytokeratin and pituitary hormones negative ● Mib-1 labeling: 0.5% to 2.0% Other Techniques for Diagnosis ● Noncontributory Differential Diagnosis ❚ Pituitary adenoma ● Morphologically composed of epithelial cells forming sheets, trabeculae, or ribbons ● Cytokeratin positive ● GFAP negative ❚ Granular cell tumor of the neurohypophysis (WHO grade I) ● Polygonal cells with abundant granular cytoplasm forming nodules or sheets ● S-100, CD68, α1-antitrypsin, and α1-antichymotrypsin positive ● GFAP, synaptophysin, and cytokeratin negative ❚ Spindle cell oncocytoma of the adenohypophysis ● Spindle and epithelioid cells ● GFAP negative ● EMA positive ❚ Pilocytic astrocytoma ● Characteristically has dense and loose architecture ● Presence of Rosenthal fibers and eosinophilic granular bodies Pearls ● Pituicytes are specialized cells of posterior pituitary with glial characteristics ● Indolent growth and no reports of malignant transformation Selected References Fuller GN, Wesseling P: Granular cell tumor of the neurohypophysis. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 241-242. Figarella-Branger D, Dufour H, Fernandez C, et al: Pituicytomas, a mis-diagnosed benign tumor of the neurohypophysis: Report of three cases. Acta Neuropathol (Berlin) 104:313-319, 2002. Brat DJ, Scheithauer BW, Staugaitis SM, et al: Pituicytoma: A distinctive low-grade glioma of the neurohypophysis. Am J Surg Pathol 24:362-368, 2000.

Central Nervous System  1031

Craniopharyngioma (WHO Grade I) Clinical Features Represents about 3% of all intracranial tumors Usually suprasellar; may be found within the sella, both suprasellar and infrasellar (dumbbell shape) or in the third ventricle, or rarely in the pineal region ● Has two peaks of incidence: children and older adults (fifth and sixth decades) ● Two histologic subtypes — Adamantinomatous variant usually presents in the first or second decade — Papillary variant typically occurs in adults (mean age, 45 years) ● Presenting symptoms are of three types — Visual abnormalities — Symptoms secondary to pituitary or hypothalamic dysfunction (typically short stature, diabetes insipidus, delayed sexual development, obesity, psychomotor retardation) — Symptoms secondary to increased intracranial pressure ● On MRI, adamantinomatous subtypes show cystic lesions frequently with calcifications; the solid areas are isointense and enhancing; papillary subtypes do not calcify ● ●

Gross Pathology ● Classically forms a variably sized, lobulated suprasellar mass that may distort the roof of the third ventricle and infiltrate adjacent brain; usually interdigitates with surrounding brain tissue

Adamantinomatous type shows cysts filled with thick, dark-brown fluid (resembling motor oil) and small glistening cholesterol crystals, and calcification; poorly circumscribed and frequently infiltrates surrounding brain tissue ● Papillary type is entirely solid or has a small cystic component; more circumscribed than the adamantinomatous variant ●

Histopathology ● Two subtypes; mixture of both subtypes may be seen — Adamantinomatous variant ◆ Lobules of basally palisading squamous epithelium underlying a stellate reticulum of loose cells topped by keratin formation ◆ Keratin pearls or wet keratin (nodules of plump eosinophilic, keratinized cells with ghost nuclei) are characteristic histologic features; often associated with calcification ◆ Degeneration results in cystic cavities filled with fluid or acellular debris ◆ Typically these tumors show local invasion of the surrounding brain tissue ◆ Adjacent brain tissue usually shows marked chronic inflammation, cholesterol clefts, foreign-body giant cells, and Rosenthal fiber–rich astrocytosis — Papillary variant ◆ Papillary architecture composed of welldifferentiated epithelial cells with distinct fibrovascular cores ◆ No microcyst formation, nuclear palisading, keratin pearls, wet keratin, calcification, or significant inflammatory component Special Stains and Immunohistochemistry ● Cytokeratin highlights epithelial component ● Mib-1 labeling index: no association between index and recurrence Other Techniques for Diagnosis ● Electron microscopy: epithelial component shows well-formed desmosomes and bundles of tonofilaments ● Cytogenetics: mutations of the β-catenin gene in more than 70% (adamantinomatous type)

Figure 19-21.  Craniopharyngioma. Section shows adamantinomatous squamous epithelium exhibiting keratinization and typical peripherally palisading nuclei.

Differential Diagnosis ❚ RCC ● Well-defined, thin-walled, fluid-filled cyst lined by a single layer of columnar and mucus-secreting cells ● Lacks papillary or solid architecture, keratin formation, and calcification ❚ Pilocytic astrocytoma ● Confusion with pilocytic astrocytoma may arise because of reactive astrocytosis and Rosenthal fibers surrounding the neoplasm

1032  Differential Diagnosis in Surgical Pathology

Consists of pilocytic areas (elongated astrocytic cells with Rosenthal fibers) and a microcystic background ● Lacks cholesterol crystals and chronic inflammatory infiltrate ● Negative for cytokeratin, positive for GFAP ❚ Epidermoid cyst ● Squamous epithelium lacks basal palisading, keratohyaline granules, and wet keratin ❚ Xanthogranuloma ● Composed of chronic inflammation, macrophages, and cholesterol clefts ● No significant component of epithelium ●

Pearls ● Histogenesis is debated; one hypothesis is that craniopharyngiomas occur from a developmental remnant of the Rathke cleft pouch; the other is that they arise from metaplastic squamous cells of the anterior pituitary gland ● Incomplete resection leads to recurrence even though most lesions are slow growing; postoperative radiotherapy may be given to tumors that are incompletely resected or recurrent, with improved patient survival ● Malignant change is extremely rare, with only a few cases reported in the literature, two occurring in the setting of prior radiation therapy Selected References Rodriguez FJ, Scheithauer BW, Tsunoda S, et al: The spectrum of malignancy in craniopharyngioma. Am J Surg Pathol 31:1020-1028, 2007. Rushing EJ, Giangaspero F, Paulus W, Burger PC: Craniopharyngioma. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 238-240. Crotty TB, Scheithauer BW, Young WF Jr, et al: Papillary craniopharyngioma: A clinicopathological study of 48 cases. J Neurosurg 83:206-214, 1995.

Chordoma Clinical Features ● Rare tumors (1% of all intracranial tumors; 4% of primary bone tumors) ● Arise from notochord remnants, usually in or near the midline, anywhere from the sella turcica to the sacrum ● About one third occur in the sacrum, one third in the spheno-occipital region or clivus, and one third in the vertebrae ● Typically found in adults (peak in fourth decade); rare in children ● Patients with sacral chordomas present with pain, anal sphincter dysfunction, or neurologic symptoms secondary to pressure on the adjacent nerve roots

Figure 19-22.  Chordoma. Classic trabecular pattern of the physaliferous cells in a mucoid background.

Intracranial tumors generally produce headache and cranial nerve palsies ● Radiographically, tumors are expansile, are destructive of bone, and extend into soft tissue; MRI scans show hypointense signal on T1-weighted images and high signal intensity on T2-weighted images and enhancement after contrast administration ●

Gross Pathology ● Locally invasive and destructive lesions that commonly destroy adjacent bone and entrap regional nerves ● Typically lobulated gelatinous or mucoid gray masses Histopathology ● May be divided into conventional, chondroid, or dedifferentiated subtypes — Conventional chordoma ◆ Well-defined, lobular architecture separated by bands of fibrous tissue that may exhibit chronic inflammation ◆ Lobules are composed of cords of epithelialappearing cells and a mucoid background ◆ Cells have variably sized central nuclei and abundant, pale-pink to clear, vacuolated cytoplasm (physaliphorous cells) ◆ Necrosis and recent or old hemorrhage may be present ◆ Mitoses are infrequent — Chondroid chordoma ◆ Variant of chordoma that contains cartilaginous areas resembling chondrosarcoma ◆ Distinction is important because it usually has a better prognosis than either typical chordoma or high-grade chondrosarcoma

Central Nervous System  1033

— Dedifferentiated chordoma ◆ Rarely, chordomas show transformation into a malignant tumor with features of malignant fibrous histiocytoma, chondrosarcoma, or malignant undifferentiated spindle cell tumor or dedifferentiated chordoma Special Stains and Immunohistochemistry ● PAS and PAS with diastase stains identify glycogen in cytoplasm (PAS positive; PAS with diastase sensitive) ● Mucin stain: stroma stains lightly ● Alcian blue: stroma strongly positive ● Mixed mesenchymal and epithelial immunophenotype of neoplastic cells — Vimentin positive — Cytokeratin (CK8, CK15, CK18, and CK19) positive — S-100 protein: most are positive — Brachyury (newly described protein found in notochord and notochord-derived tumors) positive Other Techniques for Diagnosis ● Electron microscopy: distinct features of epithelial cells, including well-formed desmosomes and intracytoplasmic lumens; extracellular mucin is typically abundant ● Cytogenetic analyses have shown losses in chromosomes 1 and 3 and gains in chromosome 7 Differential Diagnosis ❚ Chondrosarcoma ● Vacuolated (physaliphorous) cells are not characteristic ● Negative for cytokeratin and EMA, positive for S-100 ❚ Myxopapillary ependymoma ● Almost exclusively found in the filum terminale ● Pseudopapillary architecture with elongated monomorphic cells ● Positive for GFAP ❚ Metastatic mucinous adenocarcinoma ● Cytologically more anaplastic appearing with pleomorphism, hyperchromatism ● Necrosis and mitoses ● Likely S-100 negative ❚ Chordoid meningioma ● Foci of whorls, intranuclear pseudoinclusions, and psammoma bodies ● Cytokeratin negative ❚ Chordoid glioma ● Typically arise in third ventricular and suprasellar regions ● GFAP positive; most cells are negative for EMA and cytokeratin Pearls ● Treatment typically involves an attempt at complete resection and postoperative radiotherapy

Chordomas often recur and occasionally show distant metastases to lymph nodes, lung, or skin ● Chondroid chordomas occur more frequently in skull base than sacrum ● Dedifferentiated chordomas occur more frequently in sacrum ● Factors associated with a worse prognosis include — Female sex — Age more than 40 years at time of diagnosis — Presence of mitotic activity or necrosis — Large tumor volume — Incomplete resection ●

Selected References Rosenberg AE: Chordoma and related lesions, chondrosarcoma and osteosarcoma of the cranium. In McClendon RE, Rosenblum MK, Bigner DD (eds): Russell and Rubenstein’s Pathology of Tumors of the Nervous System. New York, Oxford, 2006, pp. 765-786. Vujovic S, Handerson S, Presneau N, et al: Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 209:157-165, 2006. Radner H, Katenkamp D, Reifenberger G, et al: New developments in the pathology of skull base tumors. Virchows Arch 438:321-335, 2001.

Secondary Tumors Clinical Features ● Metastases typically occur through hematogenous route or by direct extension from skull or spinal column lesions ● Direct extension — Carcinomas metastatic to bone (commonly breast, prostate, or lung) may expand and compress brain or spinal cord — May also metastasize directly to dura — Head and neck neoplasms may extend along nerves in a patchy way, appearing metastatic

Figure 19-23.  Metastatic ductal carcinoma from the breast. Solid proliferation of malignant epithelial cells with focal necrosis.

1034  Differential Diagnosis in Surgical Pathology

Hematogenous route — Up to 10% of carcinomas metastatic to CNS are not recognized before presentation of CNS metastasis — Metastatic tumors are the most common neoplasms of the CNS — About 30% of intracranial brain tumors in adults are due to metastatic carcinoma — Common primary sites of malignancy that may metastasize to the brain in adults include, in decreasing order of frequency, lung carcinoma (especially small cell and adenocarcinoma), breast carcinoma, melanoma, renal cell carcinoma, and colon carcinoma — Metastases are usually multiple and radio­ graphically show distinct, contrast-enhancing masses with a surrounding zone of cerebral edema — Patients often present with headaches, focal neurologic deficits, or altered mental status ● Carcinomatous meningitis — Metastases involving the meninges, predominantly the subarachnoid space, without an intraparenchymal mass lesion — More commonly occurs with adenocarcinoma of lung, breast, or stomach — Headache, stroke, encephalopathy, and cranial nerve deficit are typical presenting symptoms — Cytologic examination of the CSF is positive in about 60% of cases ●

Gross Pathology ● Typically gray-white to tan and well-circumscribed masses with a pushing rather than an infiltrative margin ● Hemorrhage and necrosis are common, especially in melanoma, choriocarcinoma, and renal cell carcinoma ● Brown-black pigmentation is common in metastatic melanoma Histopathology ● Histologic features similar to those of the primary tumors ● Discrete lesions usually displacing rather than infiltrating the adjacent brain tissue; small cell carcinoma often shows limited infiltrative borders ● Neoplastic cells often have prominent perivascular distribution with more viable tumor located around blood vessels ● Necrosis is typically extensive ● Vascular proliferation is not a characteristic feature ● Meningeal carcinomatosis shows tumor cells freely floating within the subarachnoid space with extension along Virchow-Robin spaces and into superficial brain parenchyma

Special Stains and Immunohistochemistry Cytokeratin, EMA: carcinomas S-100 protein, HMB-45: malignant melanoma ● LCA: lymphoma ● GFAP negative in most metastatic neoplasms ● ●

Other Techniques for Diagnosis ● Electron microscopy: features similar to those of the primary neoplasm ● Cytogenetics: same genetic abnormalities as found in primary neoplasm Differential Diagnosis ❚ Glial neoplasms with epithelioid, sarcomatous, or smallcell differentiation ● Infiltrative tumors with areas morphologically typical for glioma ● Positive for GFAP ● May be positive for cytokeratin AE1/3, but usually not other cytokeratins ● EMA positivity reported in some gliomas ❚ Primitive neuroectodermal neoplasms including medulloblastomas ● Cytokeratin negative ● CD99 and EWS/FLI-1 negative ● Uncommon in adults ❚ Anaplastic meningioma ● Cytokeratin usually negative ● EMA positive ● Usually focal areas morphologically suggestive of meningioma ❚ Choroid plexus carcinoma (versus metastatic papillary adenocarcinoma) ● Choroid plexus carcinomas are rare in adults ● S-100 variably positive ● GFAP positive in 20% Pearls ● Most patients with brain metastasis have multiple lesions ● Features reliably used to distinguish metastatic carcinomas from primary CNS tumors on frozen section include cell cohesion, tumor circumscription, and prominent fibrous septa around groups of tumor cells; smear preparations are usually better for evaluation of cytologic characteristics Selected References Wesseling P, von Deimling A, Aldape KD: Metastatic tumors of the CNS. In Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds): World Health Organization: Classification of Tumours of the Central Nervous System. Lyon, IARC, 2007, pp 248-249. Srodon M, Westra WH: Immunohistochemical staining for thyroid transcription factor-1: A helpful aid in discerning primary site of tumor origin in patients with brain metastases. Hum Pathol 33:642-645, 2002.

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Giordana MT, Cordera S, Boghi A: Cerebral metastases as first symptom of cancer: A clinico-pathologic study. J Neurooncol 50: 265-273, 2000.

Non-neoplastic Conditions Vascular Malformations Clinical Features ❚ Arteriovenous malformation (AVM) ● Commonly found in adults; occasionally seen in children ● Presentation is usually before 40 years of age ● Two thirds are discovered when the patient presents with signs or symptoms of intracerebral hemorrhage; most of the remaining are discovered during evaluation for headache, seizures, or focal neurologic deficits; few are discovered incidentally ● Multiple AVMs are associated with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) ❚ Cavernous hemangioma ● Patients may present with seizures or focal neurologic deficits ● Average age of onset is 30 years ● Hemorrhages are common but are usually small and do not cause significant mass effect ● About 20% are incidental findings at autopsy ● Most are found in the cerebrum; other common locations include brain stem, cerebellum, spinal cord, and leptomeninges ● Familial forms (autosomal dominant) exist — About 50% of familial cases occur in HispanicAmerican individuals — Multiple angiomas are found ❚ Capillary telangiectasia ● Usually found in the brain stem (basis pontis) or spinal cord ● Typically an incidental postmortem finding and of little clinical significance ❚ Venous hemangioma ● Typically found in the subarachnoid space of the spinal cord (usually lower thoracic); may be seen within the brain ● Rarely symptomatic; typically an incidental postmortem finding ● Angiography shows veins with a caput medusa appearance Gross Pathology ❚ AVM ● Variable size with large lesions causing displacement of the adjacent brain tissue ● Typically arises in the vicinity of the middle cerebral artery

A

B

C Figure 19-24.  A, Arteriovenous malformation. Numerous intraparenchymal arteries and veins. B, Cavernous hemangioma. Numerous dilated thin-walled blood vessels without intervening brain parenchyma. C, Capillary telangiectasia. Numerous capillaries are scattered in the basis pontis.

Consists of a mass of tangled and tortuous vessels with intervening and surrounding brain parenchyma ● Often has thrombosed or dilated vessels ● Necrosis of the brain parenchyma and old and recent hemorrhage is common ❚ Cavernous hemangioma ● Most commonly found in the subcortical white matter or brain stem ●

1036  Differential Diagnosis in Surgical Pathology

Well-defined mass composed of compact tangles of vessels ● Typically measure less than 3 cm in diameter ● Thrombosis is commonly found ● Evidence of prior bleeding in the form of a peripheral rim of hemosiderin is present in virtually all lesions ❚ Capillary telangiectasia ● Usually small with a diameter of less than 2 cm ● Poorly defined lesions typically causing an ill-defined stippling or discoloration of the brain parenchyma ❚ Venous hemangioma ● Composed of network of thin-walled, dilated, bloodfilled veins ●

Histopathology ❚ AVM ● Composed of variably sized arteries and veins without intervening capillaries ● Vessel walls show varying degrees of fibrosis, thinning, and dilation ● Necrosis and hemosiderin-laden macrophages are often seen in brain tissue if thrombosed vessels are present ❚ Cavernous hemangioma ● Compact network of vessels without smooth muscle or elastic lamella ● Vessels are tightly packed with no brain parenchyma between the vascular network ● Hemosiderin and reactive gliosis seen in the surrounding brain parenchyma ● Calcification is common ❚ Capillary telangiectasia ● Composed of thin-walled, delicate, dilated vessels without smooth muscle ● Hemorrhage is rare ● Intervening and adjacent brain parenchyma is unremarkable without gliosis or hemosiderin ❚ Venous hemangioma ● Consists of a small collection of delicate veins formed of endothelium and collagen without smooth muscle ● Veins lie within brain parenchyma that only rarely shows gliosis or hemorrhage Special Stains and Immunohistochemistry ● Elastic highlights elastic lamella of the arteries seen in AVMs ● Trichrome highlights collagen and smooth muscle of vessel walls Other Techniques for Diagnosis ● Cytogenetic analysis: in familial cavernous angiomas, mutations in three genes have been identified in association with disease, on chromosomes 7p, 7q, and 3q

Differential Diagnosis Discussed earlier under “Histopathology” Difficult to distinguish venous angioma from capillary telangiectasia

● ●

Pearls ● AVMs are the most dangerous because of their size and likelihood to rupture ● First hemorrhage from AVMs carries 10% to 15% mortality rate ● Surgical removal, stereotactic radiotherapy, and embolization are common methods of treatment for AVMs ● Increased occurrence of aneurysms in patients with AVMs Selected References Labauge P, Denier C, Bergametti F, Tournier-Lasserve E: Genetics of cavernous angiomas. Lancet Neurol 6:237-244, 2007. Zabramski JM, Henn JS, Coons S: Pathology of cerebral vascular malformations. Neurosurg Clin N Am 10:395-410, 1999. The Arteriovenous Malformation Study Group: Arteriovenous malformations of the brain in adults. N Engl J Med 340:18121818, 1999. Challa VR, Moody DM, Brown WR: Vascular malformations of the central nervous system. J Neuropathol Exper Neurol 54:609-621, 1995.

Cerebral Infarction and Intracerebral Hematomas Clinical Features ❚ Ischemic cerebral infarctions ● Patients typically present with sudden onset of neurologic impairment ● Neurologic deficits vary depending on location and size of infarction ● Atherosclerosis and cardiac emboli (mural thrombi or valvular heart disease) are the most common causes; multiple infarcts are often related to emboli ● May radiographically mimic malignant glioma ● Multiple ischemic infarcts may cause dementia (multi-infarct dementia; see “Dementia” for further discussion) ❚ Venous cerebral infarcts ● Result from thrombosis of the dural sinuses and cerebral veins; are classified as primary or secondary; are most often hemorrhagic ● Primary (aseptic) infarcts are associated with hypercoagulable states, including dehydration, pregnancy, oral contraceptive use, and hemolytic anemias ● Secondary (septic) infarcts are associated with bacterial infections of the face or sinuses, subdural abscesses, and meningitis

Central Nervous System  1037

A

B

Figure 19-25.  Acute cerebral infarct. A, Several acutely hypoxic neurons are present. Note the brightly eosinophilic cytoplasm and the pyknotic nucleus. B, Acutely infarcted brain tissue showing red neurons, necrosis, and acute inflammation.

A

B

Figure 19-26.  Amyloid angiopathy. A, Intraparenchymal arteriole containing amorphous eosinophilic material in the media. B, Thioflavin S–stained arterioles viewed under ultraviolet light are positive for amyloid deposition.

❚ Intracerebral hematomas ● Associated with hypertension, aneurysms (hematomas occur secondary to blood under high pressure from ruptured or leaking aneurysm), vascular malformations, amyloid angiopathy, and neoplasms (most commonly metastatic, occasionally primary) ● Bleeding typically causes significant mass effect with compression of adjacent structures ● Hypertension-associated hemorrhages most commonly develop in deep gray matter, cerebellum, or pons ● Amyloid-associated hemorrhages are typically lobar (frontal, temporal, parietal, or occipital), occur in elderly individuals, and occur secondary to weakening of the arterial walls owing to deposition of Aβ amyloid

Gross Pathology ❚ Ischemic infarcts ● Grossly recognizable 2 to 4 days after stroke ● Acute lesions are discolored, soft, and swollen; confined to the distribution of a single blood vessel ● Subacute infarcts contain soft, friable necrotic brain tissue ● Old infarcts show cavitation ❚ Venous infarcts ● More commonly involve white matter and are often hemorrhagic ● Bilateral parasagittal hemorrhagic infarcts are associated with superior sagittal sinus occlusion ❚ Intracerebral hematomas ● Well-defined lesion consisting of fresh or organizing hemorrhage

1038  Differential Diagnosis in Surgical Pathology

With organization, a fibrous capsule is formed around the hematoma ● In older lesions, adjacent brain tissue is yellow-brown (accumulation of hemosiderin-laden macrophages) ●

Histopathology ❚ Ischemic infarcts due to arterial compromise ● Show varying features, depending on the age of the infarct — Six to 24 hours: eosinophilic neurons become visible — Twelve to 24 hours: polymorphonuclear leukocyte infiltrate (peaks at about 24 hours and gone by 7 days) and cerebral edema (peaks at 3 to 4 days) — Days 2 to 3: infiltration of lipid-laden macrophages and vascular proliferation — Day 7: beginning of cavitation is evident; proliferation of surrounding astrocytes — Days 14 to 30: sheets of lipid-laden macrophages; clustering of macrophages around blood vessels is common — More than 3 months: cystic space surrounded by numerous fibrillary astrocytes ● General rule is that a 1-cm infarct takes 3 months to become cystic ● Exact timing of microscopic changes varies from brain to brain and is dependent on infarct size ❚ Venous infarcts ● Similar histologic features as described previously ● Typically more hemorrhagic ❚ Intracerebral hematomas ● Consist of organizing hemorrhage with numerous hemosiderin-laden macrophages ● Proliferation of fibroblasts at periphery forms capsule ● Reactive astrocytosis is evident in surrounding brain ● Underlying cause of hematoma should be looked for: vascular malformation, neoplasm, hyaline arteriolosclerosis in hypertension, and acellular thickening of the small and medium-sized arteries in amyloid angiopathy Special Stains and Immunohistochemistry ● CD68, HAM-56 highlight macrophages ● PAS: myelin debris within macrophages is positive ● GFAP: reactive astrocytes are positive ● Congo red identifies vascular amyloid deposition; shows apple-green birefringence in polarized light ● Thioflavin-S identifies vascular amyloid, is fluorescent under ultraviolet light ● Aβ amyloid immunohistochemistry: positive in vessels in amyloid angiopathy Other Techniques for Diagnosis ● Electron microscopy: vessels containing Aβ amyloid show bundles of 10-nm filaments in the adventitia at the media-adventitia interface

Differential Diagnosis ❚ Glioma (oligodendroglioma or astrocytoma) ● Distinction from reactive process is difficult in small biopsies ● Typically lacks macrophages (macrophage markers are negative) ❚ GBM ● Foamy macrophages and necrosis may be seen ● Shows marked cytologic atypia, which is absent in areas of infarction ● Mitoses present; elevated Mib-1 staining ❚ Demyelinating diseases ● Usually occur in younger individuals ● Multiple sclerosis (MS) is typically a multifocal disease with numerous small plaques without respect for vascular territory ● Axons are relatively preserved (neurofilament positive) in areas of demyelination and are destroyed in areas of infarction ● Presence of T lymphocytes in perivascular distribution ❚ Encephalitis ● Areas of necrosis typically seen ● Abundant acute and chronic inflammatory cells ● Organisms (bacteria, viral inclusions, parasites) may be seen Pearls ● Uncommonly, cerebral infarctions may radiographic­ ally mimic a neoplasm, prompting biopsy to rule out a neoplasm ● Lymphocytes are typically scant or absent in infarcts; if present within lesion or around blood vessels, consider vasculitis (primary or secondary) Selected References Vinters HV: Cerebrovascular disease—practical issues in surgical and autopsy pathology. Curr Top Pathol 95:51-99, 2001. Garcia JH, Menan H: Vascular diseases. In Neuropathology: The Diagnostic Approach. St. Louis, Mosby, 1997, pp 263-320.

Vasculitis Clinical Features ● Involvement of the CNS by vasculitis may be divided into primary or secondary; secondary vasculitis may occur in systemic vasculitis, often in association with collagen vascular diseases, or in infectious processes ❚ Infectious vasculitis ● Occasionally seen with chronic infections, such as tertiary syphilis and tuberculosis ● Associated with cerebritis due to aspergillosis and mucormycosis infections ● Viral infections of the brain causing vasculitis include varicella-zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus, and HIV

Central Nervous System  1039

Histopathology

Figure 19-27.  Vasculitis. Section of a medium-sized blood vessel showing fibrinoid necrosis of the wall, multinucleated giant cells, and chronic inflammation.

❚ Vasculitis in association with collagen vascular diseases and other noninfectious causes ● Brain involvement is uncommon in patients with systemic vasculitides ● Occurs in polyarteritis nodosa and Wegener granulomatosis and less commonly in Takayasu arteritis, Behçet disease, Kawasaki disease, and Sjögren syndrome ● Systemic lupus erythematosus (SLE) is more likely to cause vasculopathy and is rarely associated with cerebral vasculitis; similar morphologic findings to malignant hypertension ● CNS vasculitis may be associated with radiation damage and illicit drugs (e.g., amphetamines, cocaine) ● Vasculitis also uncommonly occurs in association with deposition of Aβ protein (amyloid angiopathy) in the cerebral cortical and leptomeningeal vessels ❚ Primary (or isolated) vasculitis of the CNS, also known as granulomatous vasculitis, occurs without systemic involvement ● Occurs in fourth to sixth decades ● Affects leptomeningeal, cortical, and subcortical small and medium-sized arteries and less frequently veins and venules ● Radiologic evaluation includes cerebral angiogram; may be negative with small-vessel involvement ● MRI shows lesions indicative of ischemia and inflammation involving the meninges, cortex, and white matter, usually bilaterally ● Severe headaches, focal or multifocal neurologic deficits, altered cognition or consciousness, and uncommonly stroke Gross Pathology ● Uncomplicated vasculitis may not be recognized grossly ● Complications include brain infarction and hemorrhage

❚ Primary vasculitis ● Segmental acute and/or chronic inflammation of small arteries and arterioles with intimal proliferation and fibrosis in association with fibrinoid necrosis of the vessel wall ● Granulomatosis response (multinucleated giant cells) may be present (<50%) ● Thrombosis of the affected vessels may be evident ● Brain adjacent to affected vessels may show ischemia, infarction, or hemorrhage ❚ Secondary vasculitis ● In infection-associated processes, viral inclusions or fungal organisms occasionally seen in the parenchyma or vessel walls, respectively ● Special stains (see later) may help identify microorganisms ● Occasionally, affected vessels show aneurysmal dilation due to septic emboli (mycotic aneurysms); usually due to fungal and bacterial infections Special Stains and Immunohistochemistry ● Special stains for organisms: PAS, Gomori methenamine silver (GMS), and acid-fact bacilli (AFB) ● Elastic highlights elastic lamina Other Techniques for Diagnosis ● In situ hybridization: DNA or RNA radioactive probes may be useful in identifying viral agents Differential Diagnosis ❚ Primary CNS lymphoma ● Perivascular lymphoid cells have atypical morphology and are mostly of B-cell origin ❚ MS and acute demyelinating encephalomyelitis (ADEM) ● Inflammatory infiltrate is typically perivascular and is not associated with wall destruction ● Both MS and ADEM are characterized by areas of demyelinated (not usually necrotic) brain parenchyma ❚ Viral encephalitis ● Perivascular and parenchymal lymphocytic inflammation without vessel wall destruction ● Microglial nodules are characteristic ❚ Sarcoidosis ● Characterized by perivascular and parenchymal granulomas without necrosis; no destruction of the vessel walls ● Predilection for hypothalamic and suprasellar regions ❚ Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) ● Newly codified entity associated with autoimmune thyroiditis (Hashimoto encephalopathy) and other autoimmune disorders (Sjögren syndrome, SLE) ● Clinical manifestations are variable but usually include cognitive impairment and behavioral changes

1040  Differential Diagnosis in Surgical Pathology

Typically steroid responsive Pathologic studies are few; perivascular lymphocytic infiltrate without vasculitis and variable parenchymal involvement has been described

● ●

Pearls ● Primary CNS vasculitis is typically focal and segmental; a negative biopsy does not exclude the diagnosis Selected References Volcy M, Toro ME, Uribe CS, Toro G: Primary angiitis of the central nervous system: Report of five biopsy-confirmed cases from Colombia. J Neurol Sci 227:85-89, 2004. Josephs KA, Rubino FA, Diskson DW: Nonvasculitic autoimmune inflammatory meningoencephalitis. Neuropathology 24:149-152, 2004. Chu CT, Gray L, Goldstein LB, Hulette CM: Diagnosis of intracranial vasculitis: A multidisciplinary approach. J Neuropathol Exp Neurol 57:30-38, 1998. Parisi JE, Moore PM: The role of biopsy in vasculitis of the central nervous system. Semin Neurol 14:341-349, 1994.

Brain Abscess Clinical Features ● Most occur during the third and fourth decades; males are affected more than females ● May be due to local extension from an extracerebral infection, including ear, sinus, or dental infections; hematogenous spread from a systemic infection is less common; penetrating head trauma may also cause brain abscess ● Immunosuppressed individuals (AIDS patients, transplant recipients, cancer patients) at greater risk ● Occasionally brain abscess may be a complication of neurosurgery

Figure 19-28.  Brain abscess. Section shows a central area of purulent material, surrounded by vascular and fibroblast proliferation and numerous chronic inflammatory cells (periodic acid–Schiff stain).

Features of local or systemic infections are often absent ● Presenting signs and symptoms are often nonspecific but may include headache, fever, and altered level of consciousness ● Various organisms, including bacteria, fungi, mycobacteria, and parasites (cysticercosis and toxoplasmosis), are the causative agents; bacteria are the most frequently isolated organisms (Streptococci, Staphylococci, Fusobacterium, and Bacteroides species are most common) in patients with intact immune systems ● Gram-negative rods, Aspergillus, Candida, and Mucor species occur in the neutropenic patient; T-cell dysfunction is associated with Toxoplasma, Listeria, Nocardia, Cryptococcus, and Mycobacteria species ● Typically found in the white matter or at the graywhite junction; usually seen in the frontal, temporal, or parietal lobe ● CT shows a cystic mass with ring enhancement and surrounding edema; MRI gives better resolution ●

Gross Pathology ● Well-defined area of central necrosis surrounded by hyperemic and edematous brain tissue ● Older lesions show a distinct organized fibrous capsule surrounding the necrotic tissue ● Aspergillus infection especially associated with hemorrhagic necrosis Histopathology ● Characteristically shows three distinct zones — Central area of necrosis with abundant acute inflammatory cells — Zone of acute or chronically inflamed granulation tissue, consisting of fibroblastic and vascular proliferation — Peripheral area of edematous brain tissue with a reactive gliosis and a fibrous capsule in later stages ● Organisms may be identified within or adjacent to the necrotic tissue ● Caseating granulomas are characteristic of tuberculosis ● Multinucleated giant cells are usually seen in fungal or tuberculous infection ● May identify parasite (most commonly cysticercosis and toxoplasmosis) ● Gummas in syphilis are rare tumor-like, nonsuppurative lesions Special Stains and Immunohistochemistry ● Special stains: Gram, PAS, GMS, AFB, Fite, and Warthin-Starry may identify microorganisms

Central Nervous System  1041

Other Techniques for Diagnosis Culture of the necrotic tissue may yield positive results ● Polymerase chain reaction (PCR) may identify mycobacteria (tuberculosis) and selected other bacteria ● Immunohistochemistry: available for identification of toxoplasmosis

Aspergillus species brain infection has been reported in patients with asthma and chronic steroid use as their only risk factor





Differential Diagnosis ❚ GBM ● On imaging studies, high-grade astrocytoma, brain metastasis, and brain abscess may have similar characteristics ● Histologic examination shows high cellularity, neoplastic astrocytes and associated mitoses, necrosis, and endothelial proliferation Pearls ● Mortality rates are variable depending on the etiologic agent; overall mortality rates have dropped dramatically owing to better diagnostic and treatment modalities ● Tissue for culture should be taken in operating room rather than in pathology laboratory

Selected References Kleinschmidt-DeMasters BK: Central nervous system aspergillosis: A 20-year retrospective series. Hum Pathol 33:116-124, 2002. Calfee DP, Wispelwey B: Brain abscess. Semin Neurol 20:353360, 2000. Pendlebury WW, Perl DP, Munoz DG: Multiple microabscesses in the central nervous system: A clinicopathologic study. J Neuropathol Exper Neurol 48:290-300, 1989.

Encephalitis and Meningoencephalitis Clinical Features ● Infection of the cerebral parenchyma characterized by altered level of consciousness, seizures, and focal neurologic deficits ● Infection of both the meninges and parenchyma often occurs (meningoencephalitis) ❚ Common causative agents: viral ● Viral encephalitis: togaviruses (Eastern equine encephalitis), flaviviruses (St. Louis encephalitis),

A

B

C

D

Figure 19-29.  A, Acute meningitis. Low-power view shows dense acute inflammatory infiltrate of the leptomeninges. B, HIV encephalitis. A microglial nodule containing a multinucleated giant cell. C, Viral encephalitis. Low-power view shows classic perivascular lymphocytic infiltrate of the brain parenchyma. D, Rabies encephalitis. Classic intracytoplasmic inclusions in cytoplasm of the Purkinje cell of the cerebellum. Continued

1042  Differential Diagnosis in Surgical Pathology

E

F

G

H

Figure 19-29, cont’d.  E, Toxoplasmosis. An area of encephalitis showing acute inflammation and two cysts containing Toxoplasma bradyzoites. F, Cysticercosis. Shown is the wall of a cyst of cysticercus. G, Cysticercosis, gross photograph. A cluster of cysts (racemose form) of cysticercosis occurs in the ventricles and cisterns of the brain. H, Cryptococcus meningitis. Mucin stain shows numerous round microorganisms. Notice the lack of staining of the capsule and the absent inflammatory response (periodic acid–Schiff stain).

enteroviruses, and herpesvirus are the most common causative agents ● Herpesvirus infections of the nervous system include herpes simplex virus types 1 and 2 (HSV-1, HSV-2), EBV, CMV, VZV, and human herpesvirus type 6 (HHV-6) — HSV-1 ◆ Causes frontotemporal lobe encephalitis (usually asymmetrical) occurring in immunocompetent older children and adults ◆ Most common sporadic encephalitis without seasonal occurrence — HSV-2 ◆ Usually causes aseptic meningitis in adults (women are affected more than men) and neonates; less commonly a cause of encephalomyelitis in adult immunocompetent or immunocompromised hosts

— CMV ◆ Encephalitis occurs most often in AIDS patients; congenital CMV infection also occurs (meningitis and encephalitis) — EBV ◆ Variable CNS involvement: meningitis, encephalitis, cranial nerve involvement, cerebellitis, and neuromuscular involvement; usually severe neurologic impairment does not occur — HHV-6 ◆ Meningoencephalitis occurs in immunosuppressed patients ● West Nile virus encephalitis — Currently the most common cause of epidemic viral encephalitis in the United States ● HIV infection — Brain impairment secondary to HIV virus usually occurs in late-stage AIDS patients

Central Nervous System  1043

❚ Common causative agents: bacterial ● Tuberculous meningitis ● Spirochete infections include both syphilis (Treponema pallidum) and Lyme disease (Borrelia burgdorferi) ● Whipple disease caused by Tropheryma whippelii — Systemic disease; often intestinal dysfunction with weight loss, lymphadenopathy, and arthralgias ❚ Common causative agents: parasitic ● Parasite infections are numerous and include trichinosis, strongyloidiasis, cysticercosis, echinococcosis, toxoplasmosis, schistosomiasis, and amebiasis (Entamoeba histolytica and Naegleria, Acanthamoeba species) — Cysticercosis is most common parasite worldwide ◆ Patients present with seizures ◆ Parasite may localize in the subarachnoid space, parenchyma, or ventricles — Toxoplasmosis and most fungal infections are seen in immunocompromised hosts (e.g., patients with AIDS) ❚ Common causative agents: fungal ● Common fungal infections include candidiasis, histoplasmosis, blastomycosis, cryptococcosis, aspergillosis, mucormycosis, and coccidioidomycosis Gross Pathology ❚ Encephalitis ● Brain may appear normal or be edematous ● Herpes simplex type 1 infection most commonly affects the temporal lobes, orbital and insular cortexes, and cingulate gyri causing hemorrhagic necrosis ● AIDS dementia complex: generalized cortical atrophy; gray discoloration of white matter ❚ Meningoencephalitis ● If meninges are involved, exudate may be present in subarachnoid space Histopathology ❚ Viral encephalitis ● Predominantly lymphocytic infiltrate involving the leptomeninges with extension into the underlying brain parenchyma ● Infiltrate is primarily located in a perivascular distribution ● Microglial nodules are characteristic histologic findings ❚ Herpesvirus encephalitis ● Extensive hemorrhage and tissue destruction ● Cowdry type A inclusions (nuclear inclusions consisting of an eosinophilic body surrounded by a clear halo) ● Inclusions may be found in neurons, astrocytes, or oligodendrocytes ❚ Cytomegalovirus ● Cowdry type A inclusions (may be nuclear or cytoplasmic) most commonly involving ependymal cells, neurons, or glial cells

❚ Rabies encephalitis ● Negri bodies (large intracytoplasmic eosinophilic inclusions typically involving neurons of the Purkinje cells, and pyramidal cells of the hippocampus) ❚ HIV encephalitis and leukoencephalopathy ● Diffuse microglial activation and microglial nodules containing multinucleated giant cells ● Diffuse astrocytosis and perivascular chronic inflammation ● Diffuse pallor of white matter ❚ Tuberculous meningitis and tuberculoma ● Caseating granulomas with a lymphoplasmacytic inflammation ● Parenchymal involvement consists of granulomatous inflammation with central necrosis ● Endarteritis obliterans may cause ischemic infarction ● Meningeal involvement is particularly severe on base of brain ❚ Neurosyphilis: meningovascular and parenchymal forms ● Meningovascular — Meninges show a lymphoplasmacytic infiltrate predominantly around blood vessels; may progress to a vasculitis with intimal proliferation and luminal narrowing, resulting in ischemic changes — Spirochetes may be present in the meninges ● Parenchymal form (general paresis) — Invasion of the brain leads to neuronal loss and a reactive gliosis — Many rod-shaped microglia in brain parenchyma; perivascular lymphocytes and plasma cells — Spirochetes may be present ❚ Other causes of meningitis and encephalitis ● In fungal and parasitic infections, a predominantly chronic inflammatory infiltrate is in subarachnoid space or parenchyma ● Parenchymal infection with fungi or parasites consists of cerebritis, which may progress to abscess (dependent on host immune response) ● Aspergillus species cause hemorrhagic necrosis owing to vessel infiltration by hyphae ● In Whipple disease, aggregates of PAS-positive macrophages Special Stains and Immunohistochemistry ● Special stains for microorganisms such as Gram, PAS, GMS, AFB, and Fite ● Immunohistochemistry for selected agents such as herpesvirus, Toxoplasma species Other Techniques for Diagnosis ● Culture of the CSF or the necrotic brain tissue ● In situ hybridization using DNA or RNA probes or PCR on CSF or tissue for viruses (e.g., mycobacteria, treponemes [Lyme disease], Tropheryma whippelii)

1044  Differential Diagnosis in Surgical Pathology

Differential Diagnosis ❚ Sarcoidosis ● Only rarely involves the CNS and is usually limited to the meninges ● Characterized by noncaseating granulomas ● Special stains for organisms are negative ❚ Noninfectious vasculitis ● No organisms identified ● Inflammation likely to be primarily in vessel wall ❚ Nonspecific autoimmune encephalomyelitis ● Associated with autoimmune disorders ● Characteristically steroid responsive ❚ Paraneoplastic encephalitis ● Clinical signs and symptoms may precede diagnosis of underlying neoplasm ● Characterized by perivascular lymphocytes and microglial modules ● Analysis of cerebrospinal fluid for related antibodies is indicated (e.g., anti-Hu, anti-Jo) Pearls ● Patients with viral or bacterial meningitis typically do not undergo brain biopsy; with clinical features of encephalitis, biopsy may be performed to isolate the causative organism and to rule out a vasculitis or demyelinating disease ● Cowdry type A inclusions are usually only found during the first few days of herpes infection; later, only nonspecific features of encephalitis are found Selected References Scaravilli F, Bazille C, Gray F: Neuropathologic contributions to understanding AIDS and the central nervous system. Brain Pathol 17:197-208, 2007. Davis LE, DeBiasi R, Goade DE, et al: West Nile virus neuroinvasive disease. Ann Neurol 60:286-300, 2006. Gyure KA: Infections. In Prayson RA, Goldblum JR (eds): Neuropathology. Philadelphia, Elsevier, 2005, pp 287-338. Kleinschmidt-DeMasters BK, Gilden DH: The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 11:440-451, 2001.

Progressive Multifocal Leukoencephalopathy Clinical Features Demyelinating disease typically seen in immunocompromised patients, typically those with AIDS, hematologic cancer, or organ transplantation ● Caused by infection of oligodendrocytes with a papovavirus that produces focal areas of demyelination ● Patients present with visual deficits, personality changes (dementia), and motor deficits ● Typically multifocal; when single, may mimic a neoplasm on CT or MRI ●

A

B Figure 19-30.  Progressive multifocal leukoencephalopathy. A, Lowpower view shows multiple irregular areas of demyelination (myelin stain). B, Classic intranuclear viral inclusion in oligodendroglial cell is evident in the center of the photomicrograph.

CT and MRI show white matter lesions without mass effect; most often involve occipital lobe; typically nonenhancing



Gross Pathology ● Variably sized, patchy areas of softening or discoloration of the white matter Histopathology ● Sparse perivascular lymphocytes and moderate to numerous macrophages are seen ● Within the areas of demyelination, reactive gliosis, with both oligodendrocytes and astrocytes showing considerable nuclear atypia (may mimic glial neoplasm) ● Infected glial cells (mostly oligodendrocytes and astrocytes) are diagnostic and consist of cells with enlarged, glassy, dark, round nuclei; best appreciated at the edge of the lesion Special Stains and Immunohistochemistry ● JC virus immunohistochemistry positive in infected cells ● Klüver stain shows areas of demyelination

Central Nervous System  1045

Neurofilament shows relative preservation of axons; there may be axonal loss in the center of a lesion



Other Techniques for Diagnosis ● Electron microscopy: characteristic intranuclear inclusions consisting of stick-and-ball–shaped virion particles ● In situ hybridization for JC virus DNA on CSF or tissue sample confirms the diagnosis Differential Diagnosis ❚ Malignant glioma (astrocytoma or oligodendroglioma) ● Lacks macrophage component, areas of demyelination, inflammation, and inclusions ❚ MS ● May create a difficult diagnostic problem ● Do not see oligodendrocytes with characteristic inclusions ● Immunohistochemistry and in situ hybridization for JC virus are negative Pearls ● PML is associated with reactivation of JC virus in an immunocompromised patient ● JC virus is a polyomavirus believed to be acquired in most individuals at a young age, persisting in a latent form in the kidney ● PML has an aggressive clinical course, with death usually resulting in a few months ● There have been several recent reports of PML developing after treatment with natalizumab (a monoclonal antibody to α4-integrins) in patients with MS and Crohn disease

A

B Figure 19-31.  A, Multiple sclerosis. Edge of an active plaque of multiple sclerosis showing abrupt loss of myelin, macrophages, reactive astrocytes, and perivascular lymphocytes (myelin stain). B, Acute hemorrhagic leukoencephalitis. An area of acute parenchymal hemorrhage is evident surrounding a necrotic vessel.

Selected References Kleinschmidt-DeMasters BK, Tyler KL: Progressive multifocal leukoencephalopathy complicating treatment with Natalizumab and Interferon Beta-1a for multiple sclerosis. N Engl J Med 353:369-374, 2005. Koralnik IJ, Schellingerhout D, Frosch MP: Case 14-2004: A 66year-old man with progressive neurologic deficits. N Engl J Med 350:1882-1893, 2004. Weber T, Major EO: Progressive multifocal leukoencephalopathy: Molecular biology, pathogenesis and clinical impact. Intervirology 40:98-111, 1997. Aksamit AJ Jr: Progressive multifocal leukoencephalopathy: A review of the pathology and pathogenesis. Microsc Res Tech 32:302-311, 1995.

Demyelinating Diseases Clinical Features ❚ MS ● Signs and symptoms are markedly variable: visual symptoms, paralysis, ataxia, motor and sensory disturbances, optic neuritis, bladder and bowel dysfunction

Classically disseminated in space and time Wide range of onset: 15 to 55 years ● Women are more commonly affected ● Plaques are commonly located adjacent to the lateral ventricles: optic pathway, cerebellum, and spinal cord are also often affected ● Large plaques causing significant mass effect may radiographically mimic brain tumors ❚ Marburg type of MS (acute MS) ● Rare variant set apart because of its aggressive course ● Death occurs usually 1 to 6 months after onset ● Usually involves cerebral hemispheres; large confluent lesions ❚ Concentric sclerosis of Baló ● Distinguished by separate concentric rings of demyelinated and myelinated white matter visible, in some instances, on MRI and seen microscopically ● Clinically similar to Marburg variant ❚ Devic disease (neuromyelitis optica): involvement of optic nerve and spinal cord predominates ● ●

1046  Differential Diagnosis in Surgical Pathology

Likely distinct from MS pathogenetically Associated with serum autoantibody NMO-IgG ❚ ADEM ● Found in both children and adults ● Acute demyelinating disease, usually monophasic, may be associated with or follow infection or vaccination; may also occur without identified predisposing factors ● Acute presentation with neurologic symptoms: ataxia, headache, and weakness ❚ Acute hemorrhagic leukoencephalitis (Hurst disease) ● Believed to be a hyperacute form of ADEM ● Clinical presentation: fever, nausea, vomiting, focal neurologic deficits, and seizures ● Progression to coma and death or recovery with severe disability ● ●

Gross Pathology ❚ MS ● Plaques appear as well-defined, pink to gray gelatinous lesions ● Plaques are often periventricular ❚ Acute demyelinating encephalomyelitis ● Lesions are usually in cerebral white matter bilaterally and brain stem ❚ Acute hemorrhagic leukoencephalitis ● Brain swelling ● White matter exhibits scattered petechial hemorrhages and necrotic foci Histopathology ❚ MS ● Active plaques are discrete, hypercellular lesions composed primarily of macrophages and reactive astrocytes ● Macrophages have round uniform nuclei, vacuolated or granular cytoplasm (containing myelin debris), and distinct cell borders ● Occasional mitotic figures may be seen (in astrocytes called Creutzfeldt cells) ● Perivascular cuffs of lymphocytes (predominantly T cells) are prominent in active lesions ● Inactive plaques are hypocellular and exhibit fibrillary astrocytosis and few macrophages ● Marburg variant shows abundant Luxol fast blue (LFB)-containing macrophages in the demyelinated plaques ● Baló concentric sclerosis variant shows alternating bands of myelinated and unmyelinated white matter with myelin stain ● Devic disease: lesions are particularly destructive and may cavitate, contain abundant macrophages and inflammatory cells, and axonal loss in addition to myelin loss ❚ ADEM ● Characterized by foci of demyelination, which are usually perivenous or perivenular

Numerous lipid-laden macrophages and a perivascular, mononuclear cell infiltrate ● All lesions show similar levels of activity or age ❚ Acute hemorrhagic leukoencephalitis ● Fibrinoid necrosis of white matter blood vessels with surrounding hemorrhage and demyelination or necrosis ● Neutrophils and lymphocytes surround vessels ●

Special Stains and Immunohistochemistry ● LFB with PAS shows discrete areas of demyelination and highlights macrophages containing myelin debris (LFB-positive debris implies acute process, PASpositive debris implies subacute process) ● Neurofilament: shows relative preservation of axons in demyelinated areas Other Techniques for Diagnosis ● Electron microscopy: breakdown of myelin and ingestion by macrophages, demyelinated axons, sparse oligodendrocytes, and inflammatory cells Differential Diagnosis ❚ Cerebral infarction ● Symptoms are typically acute ● Variable histologic features depending on the age of the infarct ● Neurofilament immunostain shows axonal loss equal to myelin loss ❚ Progressive multifocal leukoencephalopathy ● Typically found in an immunocompromised host ● Glial cells have characteristic nuclear inclusions ● Immunohistochemistry and in situ hybridization for JC virus confirms diagnosis ❚ Astrocytoma ● Do not see macrophage component that characterizes demyelinating diseases ● Lacks areas of demyelination ● No perivascular lymphocytes ❚ Leukodystrophies ● Adrenoleukodystrophy or adrenomyeloneuropathy — Presence of inflammatory cells may lead to confusion with MS — Clinical features are distinct from MS — Diffuse nature of lesion rather than focal plaques — Elevated levels of long-chain fatty acids in plasma ● Other leukodystrophies — Often inherited and with distinctive clinical presentations — Diffuse nature of lesion rather than focal plaques — Morphologic findings may also be distinctive (metachromatic deposits or globoid cells) Pearls ● In MS, solitary plaques may radiographically resemble a neoplasm (tumefactive MS), prompting biopsy of the lesion

Central Nervous System  1047

In ADEM, most patients eventually recover with resolution of symptoms and eventual remyelination ● In acute hemorrhagic leukoencephalitis, much higher fatality rate ●

Selected References Love S: Demyelinating diseases. J Clin Pathol 59:1151-1159, 2006. Kleinschmidt-DeMasters BK, Simon JH: Dysmyelinating and demyelinating disorders. In Prayson RA, Goldblum JR (eds): Neuropathology. Philadelphia, Elsevier, 2005, pp 181-222. Lucchinetti CF, Brueck W, Rodriguez M, Lassmann H: Multiple sclerosis: Lessons from neuropathology. Semin Neurol 18:337-349, 1998. Zagzag D, Miller DC, Kleinman GM, et al: Demyelinating disease versus tumor in surgical neuropathology: Clues to a correct pathologic diagnosis. Am J Surg Pathol 17:537-545, 1993.

A

Dementia Clinical Features ❚ Alzheimer disease ● Most common cause of dementia ● Affects adults of all ages; older age is an important risk factor ● Patients present with memory loss and cognitive impairment; progresses over several years ❚ Lewy body dementia ● Presents with cognitive impairment with prominent behavioral abnormalities, hallucinations, and fluctuating clinical course followed by parkinsonian signs and symptoms ❚ Vascular dementia ● Pathologic substrate of vascular dementia is variable ● Presence of infarcts in brain regions is strategically critical for cognition; multiple lacunar infarcts in deep gray matter (less frequently cortex) or white matter, and multiple large infarcts have each been shown to cause dementia ● Presence of multiple white matter infarcts often in association with hypertension has been called subcortical arteriosclerotic leukoencephalopathy (Binswanger disease) ● Clinical course is more variable than in Alzheimer disease: usually relatively sudden onset of impairment and tendency for stepwise progression and fluctuation ● Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) — Most common form of hereditary (autosomal dominant) stroke leading to dementia — Characteristic white matter hyperintensities on MRI — Wide range of onset of first stroke: 28 to 60 years of age ❚ Creutzfeldt-Jakob disease ● Believed to be caused by a proteinaceous, infectious particle called a prion

B Figure 19-32.  A, Alzheimer disease. A neuritic plaque, diffuse plaque, and neurofibrillary tangle in the cerebral cortex (modified Bielschowsky stain). B, Parkinson disease. A pigmented substantia nigra neuron containing a classic Lewy body in the cytoplasm. Note the brightly eosinophilic body surrounded by a halo.

Classic nonfamilial patients develop a rapidly progressive dementia with myoclonus and ataxia ● Characteristic electroencephalogram findings of periodic sharp wave complexes ❚ Frontotemporal lobar degeneration (FTLD) ● FTLD is a general term that encompasses several neurodegenerative diseases in which the most severe pathology involves the frontal and temporal lobes ● Included in this category are the following entities: frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Pick disease (PiD), frontotemporal lobar degeneration with ubiquitinpositive deposits with or without motor neuron disease (FTLD-U, FTLD-MND), dementia lacking distinctive histology (DLDH), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD); a detailed discussion of these entities is beyond the scope of this chapter ● Clinical presentation is usually with language or behavioral changes; motor weakness, eye movement abnormalities, and extrapyramidal signs may also be present ●

1048  Differential Diagnosis in Surgical Pathology

Gross Pathology ❚ Alzheimer disease ● Brain weight is decreased ● Gyral atrophy affecting primarily frontal, temporal, and parietal lobes ● Increased size of lateral ventricles is typical, especially temporal horns ❚ Lewy body dementia ● Marked depigmentation of the substantia nigra and locus ceruleus ● Usually diffuse cortical atrophy and ventricular enlargement ❚ Vascular dementia ● Caused by multiple cerebral infarcts in various combinations of size and location (cortical, subcortical) ● Multiple white matter infarcts suggest subcortical arteriosclerotic leukoencephalopathy or CADASIL ❚ Creutzfeldt-Jakob disease ● Mild cerebral cortical or cerebellar atrophy ❚ Frontotemporal lobar degeneration ● In FTDP-17, PiD, FTLD-U, and FTLD-MND: atrophy of frontotemporal cortexes, often in association with anterior basal ganglia atrophy ● Perirolandic cortical atrophy and substantia nigra pallor is seen in CBD ● Substantia nigra pallor and atrophy of midbrain, subthalamic nucleus, and cerebellar peduncles are seen in PSP Histopathology ❚ Alzheimer disease ● Characteristically, two major histologic lesions are seen — Neurofibrillary tangles: intraneuronal cytoplasmic fibrillary accumulations especially prominent within the association cortexes and mesial temporal lobe (entorhinal cortex and hippocampus) ◆ Flame-shaped or globose, depending on whether location is cortical or subcortical — Senile plaques: found throughout the cerebral cortex; less dense in subcortical gray matter and cerebellum ◆ Multiple subtypes ◆ Diffuse plaque contains Aβ protein ◆ Neuritic plaque composed of Aβ protein and tau protein ❚ Lewy body dementia ● Cortical Lewy bodies — Eosinophilic, cytoplasmic round inclusions with no halo — Found in lower layers of cortex, especially prominent in the anterior cingulate gyrus and parahippocampal gyrus ● Lewy bodies are also in pigmented nuclei (most commonly in the substantia nigra) and consist of

intracytoplasmic eosinophilic inclusions surround by a clear halo that are found within the affected neurons ❚ Vascular dementia ● Ischemic necrosis of varying ages; acute (eosinophilic neurons and edema) to old (cystic cavity with glial scar) ● Arteriolosclerosis is typically severe when multiple lacunes are present ● CADASIL: thickening of the walls of arteries due to the deposition of granular eosinophilic material (PAS positive) associated with infarcts in the white matter ❚ Creutzfeldt-Jakob disease ● Spongiform degeneration with neuronal loss and astrocytosis seen in the affected gray matter; white matter is typically not involved; no inflammatory cells ● About 10% of cases have prion amyloid plaques in cerebellum ● Familial form of prion disease (Gerstmann-SträusslerScheinker disease) exhibits plaques and neurofibrillary tangles in the neocortex ❚ Frontotemporal lobar degeneration ● FTDP-17, FTLD-U, FTLD-MND: varying degrees of neuronal loss and astrocytosis in the frontal and temporal lobes; basal ganglia and substantia nigra may show neuronal loss ● PiD: severe neuronal loss and astrocytosis in frontotemporal lobes with Pick bodies and Pick cells ● PSP: neuronal loss in substantia nigra, subthalamic nucleus, dentate nucleus, and additional deep gray matter and brain stem nuclei ● CBD: neuronal loss in substantia nigra, basal ganglia, and motor and sensory cortexes Special Stains and Immunohistochemistry ❚ Alzheimer disease ● Bielschowsky silver stain identifies neurofibrillary tangles and neuritic plaques ● Aβ antibodies identify amyloid component of plaque; tau antibodies identify neuritic plaques and neurofibrillary tangles ❚ Lewy body dementia ● α-Synuclein antibodies identify cortical and subcortical Lewy bodies ❚ Vascular dementia ● Klüver and neurofilament immunostain in white matter to evaluate white matter ● CADASIL: granular eosinophilic deposits may be visualized immunohistochemically ❚ Creutzfeldt-Jakob disease ● Prion protein immunohistochemistry positive ❚ Frontotemporal lobar degeneration ● FTDP-17: tau-positive deposits ● PiD: Pick bodies (cytoplasmic neuronal inclusions): silver and tau positive; Pick cells (ballooned neurons) are neurofilament positive

Central Nervous System  1049

FTLD-U and FTLD-MND: TDP-53 and ubiquitin positive neuronal nuclear and cytoplasmic deposits, dystrophic neurites, and glial cytoplasmic inclusions ● DLDH: no positive inclusions ● PSP: a variety of tau-positive structures are present; most prominent are the neurofibrillary tangles and tufted astrocytes ● CBD: a variety of tau-positive structures are present; most prominent are the astrocytic plaques and threadlike processes ●

Other Techniques for Diagnosis ❚ Alzheimer disease ● Several gene mutations identified in early onset familial Alzheimer disease — Amyloid precursor protein (chromosome 21) — Presenilin 1 (chromosome 14) — Presenilin 2 (chromosome 1) ❚ Vascular dementia ● CADASIL — Ultrastructural examination of the brain or vessels from skin biopsy shows deposition of specific granular osmiophilic material (GOM) evident in basal lamina adjacent to degenerating smooth muscle cells of arteries — Cytogenetics: mutation in Notch3 gene on chromosome 19 ❚ Creutzfeldt-Jakob disease ● Western blot for protease-resistant prion protein ● Genetic analysis for mutation in prion protein gene ❚ Frontotemporal lobar degeneration ● FTDP-17: mutation in tau gene on chromosome 17 ● FTLD-U: progranulin gene mutation, valosincontaining protein mutation, linkage to chromosome 9q Differential Diagnosis ❚ Kufs disease (adult form of neuronal ceroid lipofuscinosis) ● Rare storage disease involving the central nervous system of adults ● Age of onset is about 30 years

Slowly progressive disease with dementia; some patients have myoclonic epilepsy and ataxia, whereas others have behavioral and motor disturbances ● Excessive deposition of lipofuscin-like substance in neurons and gastrointestinal tract ❚ Status spongiosus ● May be mistaken for spongiform degeneration of Creutzfeldt-Jakob disease ● Found in acute infarcts and end-stage neurodegenerative diseases ● Vacuoles are predominantly pericellular rather than in the neuropil or intraneuronal ●

Pearls ● Premortem diagnosis of Alzheimer disease is usually based primarily on clinical symptoms; definitive diagnosis can only be made on tissue examination ● Dementia with atypical clinical presentation is more likely to warrant biopsy ● In prion disease, infectious agent is resistant to formalin fixation; treatment of fixed tissue with formic acid before processing, embedding, and cutting is suggested to decrease infectivity of tissue ● Important to snap-freeze portion of brain biopsy for possible genetic or biochemical studies when clinical history is dementia Selected References Cairns NJ, Bigio EH, Mackenzie IRA, et al: Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 144:5-22, 2007. Cochran EJ: Neurodegenerative diseases. In Prayson RA, Goldblum JR (eds): Neuropathology. Philadelphia, Elsevier, 2005, pp 223-286. Kalimo H, Ruchous M-M, Viitanen M, Kalaria RN: CADASIL: A common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 12:371-384, 2002. McKeith IG, Galaski D, Kosaka K, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DBL): Report of the consortium on DBL international workshop. Neurology 47:1113-1124, 1996.