Cns and other classificaiton

ALGORITHMIC APPROACH TO DIAGNOSIS EMPLOYING TABLES AND TEXTAn example of a case interpreted from start to finish employing an algorithmic approach and the tables and text is presented in Figure 10.1. As in any other organ system, an algorithmic approach to specimens, at the time of frozen section and subsequently, is valuable. It prevents overlooking key etiologic considerations including secondary pathologic processes.

Neoplasm or Not Neoplasm: This hypercellular lesion is composed of pleomorphic cells with atypical nuclei, which indicate neoplasm. If the lesion were not neoplastic, other etiologic categories, including infectious, inflammatory, toxic-metabolic, traumatic, vascular, developmental, and degenerative, would be considered.

Primary or Metastatic: These cells are fibrillar. They are plump and large, but not spindled or vacuolated. The neoplastic cell nuclei are moderately pleomorphic; the cells have small processes emanating from them. The lesion lacks rosettes. There is a vessel cuffed by many small, reactive-appearing mononuclear cells. There is no evidence of microvascular proliferation and neither necrosis nor mitotic activity is identified. No epithelial elements are recognized. The findings are those of a primary CNS neoplasm rather than a metastatic lesion (Tables 10.10 and 10.11).

Glial, Neuronal, and Other Primary Considerations: Possible primary CNS neoplasm diagnoses in Table 10.10 include giant-cell astrocytoma, gemistocytic astrocytoma, ganglion-cell tumor, or histiocytosis (Fig. 10.1). Although nuclei of the lesional cells have a slight resemblance to neuronal nuclei, their chromatin is more condensed. Their cytoplasm is pink without purple Nissl substance of neurons. Bielschowsky stain reveals passing axons of parenchyma infiltrated by this neoplasm, but no silver staining of neoplastic cells (Fig. 10.1); neoplastic cells were also negative for synaptophysin, a neuronal marker (not shown). Aggregate features do not support a ganglion-cell tumor. The neoplastic cells are positive for the intermediate filament glial fibrillary acidic protein (GFAP), a marker that accentuates their fibrillarity and confirms their astrocytic nature (Fig. 10.1). The related text in this chapter describes differences between gemistocytic astrocytoma and giant-cell astrocytoma. Gemistocytic astrocytomas resemble reactive astrocytes and have abundant, plump, hyaline cytoplasm and peripheralized nuclei. Macrophages (histiocytes) are GFAP-negative and lack the fibrillary structure highlighted by GFAP, arguing against the diagnosis histiocytosis. Neoplastic cells are negative for the T-lymphocyte marker CD45RO (Fig. 10.1D) and the B-lymphocyte marker CD20 (Fig. 10.1E), whereas polyclonal perivascular lymphocytes are positive. Therefore, the aggregate histologic, histochemical, and IHC findings support the diagnosis of gemistocytic astrocytoma. Most gemistocytic astrocytomas are grade II, although they tend to progress to a higher grade. Grading is further discussed in the “Gemistocytic Astrocytoma,” “Diffuse Astrocytoma,” and “Anaplastic Astrocytoma” sections. Other algorithmic approaches to the brain biopsy are available (9,10).

TABLE 10.1 Indications for Intraoperative Consultation at Biopsy

Lesion requires proper surgical sampling of tissue for diagnosis and gradingLesion may require special tissue processingCulture for microorganismsFixation for electron microscopyFixation for immunohistochemistryTouch preparationOther special processingDiagnosis affects immediate surgical procedure

TABLE 10.2 Surgery Directed Toward a Neurologic Symptom or Specific DiseaseCONFIRMATORY FEATURES OF SUSPECTED DISEASE

Symptom/Suspected Disease Structures Reactant Locationsaa

Herpes simplex encephalitis

Encephalitis (Table 10.3), Cowdry A amphophilic nuclear inclusions of 90-nm to 100-nm “target” capsids

HSV antigen Temporal or basilar frontal lobe, CNS; frequently bilateral

Toxoplasmosis Necrosis containing 3-nm to 5-nm tachyzoites; (cysts); (inflammation)b

Toxoplasma antigen

CNS, frequent multiple lesions

Progressive multifocal leukoencephalopathy

Demyelination, bizarre, glial, amphophilic nuclear inclusions of 15-nm to 25-nm or 30-nm to 40-nm diameter

JC/SV40 antigen, myelin, neurofilament

Cerebral white matter, CNS

Dementia/Creutzfeldt-Jakob disease

Cytoplasmic vacuoles indenting nuclei, gliosis (Table 10.3)

GFAP, prion (DANGER)

Bilateral cerebral cortex, gray matter

Small-vessel disease Vasculitis or arterial sclerosis or congophilic angiopathy

Amyloid, iron Cerebrum, CNS; frequent multiple lesions

Dementia/Alzheimer disease

Argyrophilic plaques; neurofibrillary tangles of bihelical filaments

Neurofilament, tau Bilateral cerebral cortex

Demyelination Loss of myelin, gitter cells, with or without axonal preservation

Myelin, neurofilament

Cerebral white matter, CNS

Epilepsy Low-grade glioma or ganglioglioma (Table 10.10), or gliosis (Tables 10.3 and 10.18), or vascular malformation

GFAP, neurofilament, synaptophysin, iron

Temporal lobe, cerebral cortex

a Most common or most specific location is listed first.

b Parentheses around a differential feature indicate an uncommon feature very useful in differential diagnosis when found.CNS, central nervous system; GFAP, glial fibrillary acidic protein; HSV, herpes simplex virus; JC, JC virus; SV, simian virus.

TABLE 10.3 Differential Features of Cells Infiltrating Central Nervous ParenchymaDIFFERENTIAL FEATURES

Diagnosis Structures Reactant Locationsaa

Gliosisb Cells are fibrillar, uncrowded; round or oval nuclei

GFAP in glial filament CNS

Macrophages Cells and nuclei are round to elongated; cell content reflects injury

KP-1; α-ACT CNS, meninges

Encephalitis and/or cerebritis

Perivascular mixture of inflammatory cells

CD3, CD20, LCA, κ and λ Ig, α-ACT; KP-1, microorganism

CNS gray matter, CNS

Hemorrhage Red blood cells or macrophages with hemosiderin

Fibrin, iron Deep cerebrum, cerebellum, CNS

Margin of gliomasc

Cells are fibrillar; angular nuclei indent each other; (mitoses)c,d

GFAP CNS

Lymphoma Perivascular, noncohesive small, round cells

CD3, CD20, LCA, κ and λ Ig Deep cerebrum, CNS; meninges


b Nonspecific reaction to injury.

c Suspicion of margin of glioma on frozen section should be followed by a request for another, more central biopsy. Mitoses suggest margin of a high-grade glioma.

d Parentheses around a differential feature indicate an uncommon feature that is very useful in differential diagnosis when it is found.α-ACT, α-antichymotrypsin macrophage marker; CNS, central nervous system; GFAP, glial fibrillary acidic protein; Ig, immunoglobulin; LCA, leukocyte common antigen (CD45/45R).

P.353

TABLE 10.4 Viral Inclusions in the Central Nervous SystemNucleus Cytoplasm

NeuronsHerpes simplex and zoster + -Rabies - +SSPE (measles) + -OligodendrocytesPML (JC virus) + -SSPE (measles) + -Various cells (endothelial, ependymal, glial)Cytomegalovirus + +PML, progressive multifocal leukoencephalopathy; SSPE, subacute sclerosing panencephalitis.

TABLE 10.5 Causes to Consider in Intracranial HematomaTraumaticCerebral contusionEpidural or subdural hematomaInfectious and inflammatoryVasculitisFungus (mycotic aneurysm)Developmental vascularVascular malformation (arteriovenous, malformation, cavernous angioma)AneurysmHematologicThrombocytopeniaSickle cell anemiaNeoplasticPrimary (high-grade glioma)Metastatic (e.g., melanoma, renal cell carcinoma)Leukemia (chloroma in acute myelogenous leukemia)VascularAmyloid angiopathyHypertensionConversion of ischemic infarctToxic-metabolic: Anticoagulation-relatedCLINICAL AND RADIOGRAPHIC PERSPECTIVE OF LESIONSBiopsies should be examined with knowledge of the clinical history. If a specific diagnosis or differential is not suspected preoperatively, at the least a major neurologic symptom (e.g., weakness or visual loss) or category of neurologic disease (e.g., refractory epilepsy) is usually available to focus the search for a diagnosis (Table 10.2). The pathologist should always know,

at a minimum, the age and sex of the patient, the precise location of the targeted lesion, and imaging characteristics. Knowledge about past medical history (e.g., previous CNS or primary neoplasms, connective tissue disease, immunosuppressive disease) is critical to interpretation. Likewise, knowledge about preoperative therapy (e.g., corticosteroids, chemotherapy, radiation therapy, radiosurgery) is also critical to interpretation of findings (e.g., necrosis, vascular fibrosis).Certain pathologic entities predominate in pediatric, adult, or geriatric age categories as described in the text. A communication system between the operating rooms and the pathology diagnostic rooms is especially important to share relevant clinical and pathologic observations on individual cases examined by frozen section (Table 10.1).Radiology provides extremely valuable gross pathologic information—most importantly, computed axial tomography (CT scan) and magnetic resonance imaging (MRI); use of contrast and special imaging techniques (e.g., diffusion- and perfusion-weighted imaging) add additional data in characterizing normal and abnormal structures. Emerging imaging techniques including MR spectroscopy (evaluation of chemical components in a lesion) offer additional information about specific lesions (6,11).

TABLE 10.6 Vascular Malformations

Malformationa Vessels Neuropile

Gliosis and Hemosiderin-Laden Macrophages

Arteriovenous malformation

Arteries, veins, arterialized veins

Absent, except around feeding vessels

Presentb

Cavernous angioma

Compact cluster thin-walled to thick-walled vessels, mineralization

Absent usually Presentb

Capillary telangiectasia

Capillaries, thin-walled Admixed Absent

Venous malformation

Veins, often dilated Admixed Absent

Varix Vein, dilated (vein of Galen) Absent Absent unless ruptureda Location: Each can be found anywhere in the central nervous system; capillary telangiectasias often in brainstem and venous malformations in the spinal leptomeninges.b Gliosis and hemosiderin-laden macrophages are consistent with leakage; they serve as a seizure focus, and they signal a tendency for spontaneous hemorrhage.

TABLE 10.7 Relative Frequency of Most Common Pediatric and Adult Brain NeoplasmsCHILDREN ADULTS

Location Diagnosis and Frequency Location Diagnosis and FrequencyAnterior fossa

Miscellaneous 33%Anterior fossa

Gliomas (cerebrum)a 33%Meningiomas (dura) 13%Metastases (cerebrum) 12%

Pituitary adenomas (sella) 5%Miscellaneous 4%

Total 67%Posterior fossa

Astrocytomas (cerebellum)a 26%Medulloblastomas (cerebellum)

24%

Ependymomas (fourth ventricle)

14%Posterior fossa

Schwannomas (8th cranial nerve)

8%

Miscellaneous 3% Miscellaneous 25%Total 67%Total 33%a Most common site in parentheses. See entry in text for other locations.

TABLE 10.8 World Health Organization Criteria for Grading of AstrocytomasGrade

Nomenclature

Histologic Features

1 Pilocytic Circumscribed; biphasic: bipolar piloid cells and multipolar cells; microcysts, Rosenthal fibers, and granular bodies; may or may not have rare mitotic figures, vascular proliferation, or focal necrosis

2 Diffuse Moderate hypercellularity of monotonous cells; mild nuclear atypia; no or minimal mitotic activity

3 Anaplastic Increased cellularity and diffuse infiltration; increased nuclear atypia; increased mitotic activity

4 Glioblastoma Vascular proliferation or necrosis; crowded anaplastic cells; marked nuclear atypia; brisk mitotic activity

From Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumours: Pathology and Genetics of Tumors of the Nervous System. Geneva: IARC Press, 2007, with permission.

TABLE 10.9 World Health Organization Criteria for Grading of OligodendrogliomasGrade Nomenclature Histologic Features2 Oligodendroglioma Moderate cellularity; homogeneously round nuclei, “fried egg”

halo (paraffin); fine capillary network; mineralization (microcalcifications)

3 Anaplastic oligodendroglioma

Increased cellularity; high mitotic rate; marked cytologic atypia; microvascular proliferation; necrosis

From Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumours: Pathology and Genetics of Tumors of the Nervous System. Geneva: IARC Press, 2007, with permission.

TABLE 10.10 Differential Diagnosis of a Mass of Fibrillar Cells

DiagnosisaDIFFERENTIAL FEATURES

Structures Reactant Locationsb

Fibrosis Spindle cells of Collagen; reticulin Meninges, CNS

meningeal or perivascular origin

Granuloma Like fibrosis with “whorls” and inflammation

Microorganisms Basal meninges, CNS

Pilocytic astrocytoma Hypercellularity; hairlike fibrillarity; Rosenthal fibers; microcysts

GFAP Cerebellum, thalamus/hypothalamus, optic nerve, CNS

Astrocytoma Hypercellularity; angular nuclei cluster and indent each other; infiltrates CNS

GFAP Cerebrum, brainstem, spinal cord, CNS

Anaplastic astrocytoma Increase in above features; mitoses

GFAP Cerebrum, brainstem, CNS

Gemistocytic astrocytoma

Hypercellularity; cells swollen with hyaline pink cytoplasm and eccentric pleomorphic nuclei; infiltrates CNS

GFAP Cerebrum

Giant-cell astrocytoma Giant astrocytes with thick fibrils; large round or oval nuclei

GFAP Lateral ventricle, subependymal

Astroblastoma Perivascular rosettes with expanded glial cell processes

Nonfibrillar GFAP Cerebrum, CNS

Pleomorphic xanthoastrocytoma

Pleomorphic cells are often vacuolated

GFAP, reticulin, lipid

Leptomeninges, cerebral cortex

Ependymoma Hypercellularity; ependymal and/or perivascular rosettes; round or oval nuclei, cilia, and basal bodies

GFAP, EMA Cerebrum, cerebellum, spinal cord, CNS

Tanycytic ependymoma or subependymoma

Combination of astrocytoma and ependymoma; round or oval nuclei cluster among fibrillar mats; ependymal cytology

GFAP Spinal cord, fourth ventricle, subependymal, CNS

Anaplastic ependymoma Above features with mitoses; necrosis

GFAP, S-100 Cerebrum, cerebellum

Giloblastoma multiforme Regions of coagulation GFAP, S-100 Cerebrum, CNS

necrosis; mitoses; pleomorphism; endothelial proliferation

Gilosarcoma Glioblastoma plus fibrosarcoma intermixed

GFAP, reticulin, collagen

Cerebrum

Ganglion-cell tumors Binucleated and pleomorphic neurons; diagnosis dependent on gliomatous and neuroblastic elements

GFAP, synaptophysin, PGP 9.5; neurofilament, Nissl

Cerebrum, CNS

Central neurocytoma Round cells and nuclei; thin fibrils near vessels

Synaptophysin, neurofilament

Septum pellucidum, lateral ventricles, CNS

Pineocytoma Normal pineal structures

Synaptophysin, neurofilament

Pineal

Fibroblastic meningioma Spindle cells; interdigitating cell processes and desmosomes; (thick collagen); (whorls)c

Vimentin, EMA, reticulin, progesterone receptor

Falx, tentorium, meninges; choroid plexus

Fibrosarcoma/malignant fibrous histiocytoma

Hypercellular; pleomorphic spindle cells and nuclei; mitoses; necrosis

Reticulin, collagenMeninges, CNS

Schwannoma Verocay bodies; Antoni A and B; thin pericellular basement membrane

Reticulin, S-100, collagen

8th cranial nerve, spinal roots, PNS

Neurofibroma Multiple cell types spread axons

Neurofilament, myelin, S-100, Leu-7

Spinal root, PNS; cranial nerve

Histiocytosis Sheetlike pattern of macrophages, fibroblasts, and leukocytes

α-ACT, S-100 Parasellar, CNS, systemic

Hemangioblastoma Multivacuolated stromal cells between many capillaries; hypervascularity; (fibrillarity is frozen section artifact)

Cytoplasmic lipid, reticulin, factor VIII

Cerebellum, spinal cord, CNS

Melanoma Anaplasia, mitoses, necrosis

Melanin, HMB45 antigen; S-100

CNS or meninges, frequent, multiple metastases; systemic

a The order of tabulated lesions follows their order in text.

b Most common or most specific location is listed first.

c Parentheses around a differential feature indicate an uncommon feature that is very useful in differential diagnosis when it is found.α-ACT, α-antichymotrypsin macrophage marker; CNS, central nervous system; EMA, epithelial membrane antigen; GFAP, glial fibrillary acitic protein; PNS, peripheral nervous system; PTAH, phosphotungstic acid hematoxylin.

TABLE 10.11 Differential Diagnosis of a Mass of Epithelioid Cells



Gitter cells or xanthogranuloma

Crowded macrophages engorged with lipid vacuoles; eccentric nucleus; noncohesive cells

α-ACT; KP-1; muramidase

CNS

Oligodendroglioma Round cells and nuclei with prominent perinuclear halos; nests of cells between delicate vessels

Leu-7, S-100; del 1p 19q

Cerebrum, CNS

Anaplastic oligodendroglioma

Above features with mitoses and pleomorphism

Above markers Cerebrum, CNS

Choroid plexus papilloma

Large mass with structure of choroid plexus

Laminin, cytokeratin, transthyretin, mucinc

Fourth ventricle, lateral ventricle, cerebellopontine angle, choroid plexus

Choroid plexus carcinoma

Above features with anaplasia and mitoses; (necrosis)

Cytokeratin, (transthyretin, mucin)

Above lesions

Medulloepithelioma Columnar epithelium with “basement membrane” on both surfaces; fibrovascular base for papillae and tubules

Nestin Deep cerebrum, cauda equina, CNS

Meningioma Whorls, psammoma bodies, interdigitating cell processes and desmosomes; (thick collagen)

Vimentin, EMA, progesterone receptors

Falx, tentorium; meninges; choroid plexus; (extracranial)

Chordoma Masses or cords of physaliphorous cells

Cytokeratin, EMA; (mucin)

Sacrococcygeal tissues, cauda equina, clivus, spinal canal

Paraganglioma Nests of clear or granular cells surrounded by many capillaries

Chromogranin Petrous ridge, spinal cord, epidural

Pituitary adenoma Secondary granules Pituitary peptides; chromogranin

Sellar, suprasellar

Endodermal sinus tumor

Schiller-Duvall bodies AFP Pineal, parasellar

Embryonal carcinomaAnaplasia, mitoses AFP, (PLAP) Pineal, parasellarHemangioblastoma Multivacuolated stromal cells

between many capillaries; hypervascularity


Cerebellum, spinal cord, CNS

Craniopharyngioma Squamous, adamantinomatous

Cholesterol cytokeratin

Suprasellar, sellar

Carcinoma Distinct margin with CNS; anaplasia, mitoses, necrosis

Cytokeratin, EMA, (mucin)

Cerebrum, cerebellum, meninges, CNS; frequent multiples masses; systemic

Melanoma Anaplasia, mitoses, necrosis Melanin, HMB45, tyrosinase

Above locations



c Parentheses around a differential feature indicate an uncommon feature that is very useful in differential diagnosis when it is found.α-ACT, α-antichymotrypsin macrophage marker; AFP, α-fetoprotein; CNS, central nervous system; EMA, epithelial membrane antigen; PLAP, placental alkaline phosphatase.Major categories of lesions of the brain, spinal cord, and meninges, such as solitary or multiple masses, cysts, vascular malformations, or abscesses, are likely to be recognized by imaging or upon viewing a gross specimen. The neurosurgical lesions summarized in Tables 10.6, 10.7, 10.8, 10.9, 10.10, 10.11, 10.12, 10.13, 10.14, 10.15, 10.16, 10.17, 10.18 and 10.19 are usually focal, whereas the lesions in the biopsies directed toward a neurologic disease tend to be more diffuse (Table 10.2). One particularly problematic diagnosis is vasculitis that can be focal, multifocal, or diffuse. If you are lucky enough to be consulted on any multifocal case, advise the surgeon to target a new or subacute radiographic lesion.Multiple lesions can be produced by neoplasms or by inflammatory, vascular, and infectious diseases. If inflammation or infection is suspected prior to or seen at biopsy, cultures for appropriate microorganisms should be sent in sterile containers directly from the Operating

Room to Microbiology. The “M-rule” for common multiple CNS neoplasms includes metastases, malignant lymphoma, melanoma, and (late stages only) medulloblastoma.In some settings (e.g., in a patient with neurologic deficits), a biopsy is performed in a desperate attempt to find a diagnosis. In such a setting, to optimize the probability of a pathologic diagnosis, the biopsy should be directed at a region of recent radiologic abnormality such as contrast enhancement, and optimally should include (a) dura, (b) arachnoid, (c) gray matter, and (d) white matter. In the setting of radiologic lesions, biopsy of a normal radiologic region or a so-called unguided or undirected (“blind”) biopsy is, in our experience, a useless waste of everyone's time. It is a ritual that helps the clinician say that everything was tried on a moribund patient.The tomographic density of hemorrhage is sufficiently unique at certain stages of organization to preoperatively identify hemorrhage as a major component of a lesion. In general, calcifications and relationships with the skull are resolved well by CT. Gray and white matter, edema, and melanin are resolved well by MRI. Vascular abnormalities are frequently appreciated clinically and angiographically. CT or MRI angiography of flow voids is sometimes sufficient and is less invasive than classic angiography.

TABLE 10.12 Differential Diagnosis of a Mass of Conspicuously Different Cells



Oligoastrocytoma Mixture of astrocytoma (Table 10.10) and oligodendroglioma (Table 10.11)

GFAP, Leu-7, S-100 Cerebrum, CNS

Anaplastic oligoastrocytoma

Above features with mitoses and pleomorphism, necrosis, MVP

GFAP, Leu-7, S-100 Cerebrum, CNS

Glioblastoma or gliosarcoma with epithelial metaplasia

Structures of glioblastoma or gliosarcoma (Table 10.10) plus epithelial regions

GFAP, S-100, cytokeratin, EMA

Cerebrum, CNS

Ependymoma/malignant ependymoma

Structures of ependymoma or malignant ependymoma (Table 10.10) plus epithelioid cells

GFAP Cerebellum, cerebrum, spinal cord, CNS

Myxopapillary ependymoma

Cuboidal and/or columnar epithelium on hyaline fibrovascular papillae; variable fibrillarity

Mucin, GFAP Regions of the filum terminale

Ganglion cell tumors Binucleated and pleomorphic neurons plus glioma (Table 10.10) plus

GFAP, synaptophysin, PGP 9.5, neurofilament,

Cerebrum, CNS

fibrosis plus inflammation Nissl, collagen, reticulin

Desmoplastic medulloblastoma

Regions of medulloblastoma (Table 10.13) and desmoplasia (Table 10.10)

Synaptophysin, S-100, reticulin, (neurofilament); (GFAP)c

Lateral cerebellum, CNS, meninges; (extra-axial)

Transitional meningioma Regions of fibrous (Table 10.10) and syncytial (Table 10.14) meningioma

Vimentin, EMA, reticulin, PR

Falx, tentorium; meninges; choroid plexus

Germinoma Regions of large epithelioid cells and small lymphocytes

PLAP, CD117 Pineal, parasellar, CNS

Teratoma Well-differentiated tissues from more than one germinal layer; may contain another germ cell tumor component (Table 10.11)

Mucin, collagen, GFAP; others

Pineal, suprasellar, sacrococcygeal

Choriocarcinoma Syncytial and cytotrophoblast

Human chorionic gonadotropin

Pineal, parasellar, CNSd

Desmoplastic carcinoma Regions of carcinoma (Table 10.11) and fibrosis (Table 10.10) plus inflammation

Cytokeratin, EMA; (mucin); (TTF-1)

Cerebrum, cerebellum, meninges, CNS, frequent multiple masses, systemic

Melanoma Regions of fibrillar and epithelioid melanoma (Tables 10.10 and 10.11) GFAP, Leu-7, S-100

Melanin, HMB45 antigen, S-100, tyrosinase

Cerebrum, cerebellum, meninges, CNS; frequently multiple masses, systemic



c Parentheses around a differential feature indicate an uncommon feature that is very useful in differential diagnosis when it is found.

d As a primary midline tumor or metastasis to the CNS from a pelvic or gonadal primary tumor.CNS, central nervous system; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; PLAP, placental alkaline phosphatase; MVP, microvascular proliferation; PR, progesterone receptors; TTF-1, thyroid transcription factor 1.

INTRAOPERATIVE CONSULTATIONCertain entities that may be either suspected clinically or suggested on cytologic preparation and frozen section can affect the immediate surgical procedure (see “Primary Open Biopsy” section and Table 10.1). Most significantly, attempts at total resection are often made for these neoplasms: meningiomas, schwannomas, solitary metastases, cysts, ependymomas, hemangioblastomas, cerebellar pilocytic astrocytomas, and craniopharyngiomas. Therefore, assessment of such specimens requires careful clinicopathologic correlation at the time of the primary operation, and intraoperative consultation guides the procedure.Any undefined lesion should be biopsied and inspected by both cytologic preparation and frozen sections. Cytologic preparations add fine nuclear detail and the presence or absence of (a) glial-type processes, (b) discohesiveness in pituitary adenomas, oligodendrogliomas, medulloblastomas, and lymphomas, and (c) “epithelioid” features, with cellular cohesion (suggesting junctions) in carcinomas. The value of such preparations has been demonstrated (12,13) and, in some centers, intraoperative diagnosis is based only on evaluation of cytologic preparations. Although smear and crush preparations may be done, touch preparations minimize effort and artifact. Touch a glass slide to the wet tissue and then immediately fix it in ethanol before it dries. Stain with H&E or with a cytologic stain.

TABLE 10.13 Differential Diagnosis of a Mass of Small, Crowded, Anaplastic Cells

DiagnosisDIFFERENTIAL FEATURES

Structures Reactant Locationsa

Ependymoblastoma Like PNET; ribbons or cords of cells; true ependymal rosettes

GFAP, S-100 Cerebrum, cerebellum

Medulloblastoma, pineoblastoma, neuroblastoma, or PNET

Slight fibrillarity; (Homer Wright rosettes); (palisades); “carrot” nuclei; (neural or glial foci)b

Synaptophysin; PGP 9.5; (S-100); (neurofilament); (GFAP)

Cerebellum, brainstem, pineal, CNS; (extra-axial)

Rhabdomyosarcoma or medullomyoblastoma

Muscle striations Desmin, muscle specific actin, SMA

Pineal, cerebellum, CNS

Hemangiopericytoma Hypercellularity; thick pericellular matrix, mitoses

Reticulin Falx, tentorium; meninges; (extracranial)

Lymphoma Noncohesive, round cells; vascular wall invasion

Reticulin, collagen, L26, UCHL1, LCA, monoclonal κ and λ Ig

Deep cerebrum, CNS, meninges; may be multiple

Small-cell carcinoma Cohesive cells; (epithelioid); (desmosomes)

Cytokeratin, EMA CNS, meninges; frequent multiple masses, systemic


b Parentheses around a differential feature indicate an uncommon feature that is very useful in differential diagnosis when it is found.CNS, central nervous system; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; Ig, immunoglobulin; LCA, leukocyte common antigen; PGP, protein gene product; PNET, primitive neuroectodermal tumor; UCHL1, T-lymphocyte marker CD45RO; SMA, smooth muscle actin.Difficult access to, and fragility of, central nervous tissue places a high premium on obtaining tissue suitable for diagnosis during the first surgical procedure and avoiding secondary biopsy after a primary nondiagnostic biopsy (4). The goal of the pathologist in the intraoperative setting is not to definitively diagnose and grade every case but, rather, to (a) ensure that a lesional tissue has been obtained for subsequent diagnosis and grading; (b) to ensure the lesional tissue has been appropriately sampled (e.g., that high grade features are noted on a suspected glioblastoma based on imaging features); (c) to provide sufficient preliminary diagnostic information to optimize surgery; and (d) to perform appropriate special tissue processing (Table 10.1). Optimizing surgery depends upon the individual case and upon whether open biopsy or stereotactic needle biopsy is being done (see sections below).

TABLE 10.14 Differential Diagnosis of a Mass That Includes Syncytial Cells



Meningiomas Whorls, psammoma bodies; interdigitating cell processes and desmosomes; (thick collagen)b

Vimentin, epithelial membrane antigen, PR

Falx, tentorium meninges; choroid plexus; (extracranial)

Anaplastic meningioma

Decrease in above features; mitoses, necrosis; central nervous system invasion

Above chemicals Above locations

Choriocarcinoma Syncytium usually mixed with cytotrophoblast (Table 10.12)

Human chorionic gonadotropin

Pineal, suprasellar


b Parentheses around a differential feature indicate an uncommon feature very useful in differential diagnosis when it is found.PR, progesterone receptors.Given the constraints of intraoperative evaluation of tissue, including sampling limitations and freezing artifact, precise diagnosis is often neither possible nor necessary for a successful intraoperative consultation. The surgical pathologist need only go as far as necessary with her/his diagnosis (e.g., high-grade glioma, metastatic neoplasm, atypical lymphoid infiltrate suspicious for lymphoma, abundant neutrophils suggestive of abscess, granulomatous inflammation) to guide the surgery without attempting to make complex diagnoses that optimally employ paraffin sections. The pathologist's microscopic impression, even if rendered as a differential, guides the surgical procedure.

In the setting of a glial neoplasm, it is not wise to offer a grade during intraoperative frozen section or touch preparation interpretation. Because gliomas are quite heterogeneous, diagnostic features that affect the classification and grade may be revealed only in the “permanent” specimens, and not on frozen section. For instance, oligodendroglial elements in a mixed glioma may not be well represented or recognized on the frozen material; the characteristic halo is a paraffin-embedding artifact. A diagnosis of “primary glial neoplasm with abundant mitotic activity, at least WHO grade III,” or “high-grade glioma,” effectively characterizes a biopsy when malignant glial cells are unequivocally identified on cytologic and frozen section preparations, and allows for the later identification of oligodendroglial and other elements not evident on the fresh sample.

TABLE 10.15 World Health Organization Criteria for Grading of Meningiomasa

Meningioma (grade I)Fails to meet diagnostic criteria below<4 mitotic figures per 10 hpf (0.16 mm2)Atypical meningioma (grade II)Increased mitotic activity: 4-19 per 10 hpf (0.16 mm2)OR three or more of the following:Increased cellularitySmall cells with high nuclear:cytoplasmic ratioProminent nucleoliSheetlike and/or patternless growth patternFoci of “spontaneous” or “geographic” necrosisAnaplastic meningioma (grade III)Increased mitotic activity >19 per 10 hpf (0.16 mm2)OR“Malignant” and/or anaplastic cytologic appearance (e.g., resembling sarcoma, carcinoma, melanoma)aBrain invasion not a criterion for increased grade; WHO grade II also assigned to intracranial clear-cell and chordoid meningiomas; WHO grade III assigned to rhabdoid and papillary meningiomas.Modified from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumours of the Central Nervous System. Geneva: IARC Press, 2007.

TABLE 10.16 Histiocytoses Affecting the Central Nervous System Compared with Macrophages

Disease Characteristic HistologyCD68 (KP-1)

S-100

CD1a

Birbeck Granules (EM)

Macrophage Foamy, epithelioid, multinucleated giant cells

+ - - -

Erdheim-Chester Touton giant cells + +/-a - -Rosai-Dorfman Emperipolesis + + - -

Langerhans histiocytosis

Reniform nuclei, eosinophilic cytoplasm

+ + + +

a S-100 has been positive in some, but not all, cases of Erdheim-Chester disease.EM, electron microscopy.

TABLE 10.17 Carcinomas and Melanoma Metastatic to BrainPrimary Tumor Frequency with Which the Primary

Tumor Metastasizes to the BrainFrequency of a Brain Metastasis

Originating from the Primary TumorLung 26%-42% 35%Breast 15%-25% 20%Skin (melanoma) 39%-92% 10%Kidney 10%-25% 10%Gastrointestinal tract

5%-7% 5%

Choriocarcinoma High LowAll others Variable <20%P.360

TABLE 10.18 Differential Diagnosis of Cyst with Wall of Fibrillar Cells



Cavitary gliosis Wall of gliosis (Table 10.3) GFAP in glial filaments Cerebrum, CNSAbscess Wall of granulation tissue;

fibrosis (Table 10.10); inflammation and gliosis; purulent contents

Collagen, reticulin, L26, UCHL1, LCA, κ and λ Ig, α-ACT, microorganisms

Basal frontal and temporal lobes, CNS

Cystic astrocytoma Wall of pilocytic astrocytoma (Table 10.10)

GFAP Cerebellum, CNS

Hemangioblastoma Wall of gliosis; mural nodule of hemagioblastoma (Table 10.3)


Cerebellum, CNS

Glial cyst, simple cyst, or wall of syrinx

Wall of gliosis (Table 10.10); Rosenthal fibers

GFAP in glial filaments Pineal, cerebellum, and spinal cord; brainstem

Pineal cyst Wall of fibrillary cells, rarely ependymal

Pineal

Meningeal cyst Wall of dura, arachnoid; syncytial cells

Collagen, PR Spinal epidural surface

a Most common or most specific location is listed first.α-ACT, α-antichymotrypsin macrophage marker; CNS, central nervous system; GFAP, glial fibrillary acidic protein; Ig, immunoglobulin; LCA, leukocyte common antigen; UHCL1, T-

lymphocyte marker CD45RO; PR, progesterone receptors.The intraoperative consultation provides the opportunity to obtain tissue for microbiologic culture, special fixation (e.g., lymphoma), and special processing (e.g., flow cytometry, cytogenetics, molecular evaluation, and electron microscopy) when preliminary assessment deems it necessary or pragmatic (see “Tissue Processing” below).

TABLE 10.19 Differential Diagnosis of a Cyst with Wall Lined by Epithelium



Cystic craniopharyngioma

Wall of adamantinomatous or incompletely keratinized squamous epithelium; cyst contains “motor oil”

Cytokeratin, cholesterol

Suprasellar, sella

Ependymal cyst Columnar epithelium usually ciliated

GFAP Spinal cord, brain

Colloid cyst Fibrous wall lined by inner ciliated and/or nonciliated simple columnar epithelium; cyst contains colloid and cell ghosts

Mucin Third ventricle

Dermoid cyst Epidermoid cyst features plus adnexa of skin; cyst contains sebum, squames, and hair

Keratin, cholesterol

Midline cerebellum, fourth ventricle, skull, spinal dura, cauda equina

Epidermoid cyst Fibrous wall lined by inner keratinizing stratified squamous epithelium; cyst contains waxy squames

Keratin, cholesterol

Cerebellar pontine angle, temporal lobe, spinal dura, pineal, sella, brainstem, central nervous system

Enterogenous cyst Columnar epithelium cyst contains mucin; rests on collagen

Mucin Spinal cord

a Most common or most specific location is listed first.GFAP, glial fibrillary acidic protein.

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