cns and other classificaiton
TRANSCRIPT
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
a Most common or most specific location is listed first.
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).
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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
DiagnosisaDIFFERENTIAL FEATURES
Structures Reactant Locationsb
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
Cytoplasmic lipid, reticulin, factor VIII
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
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; 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
DiagnosisaDIFFERENTIAL FEATURES
Structures Reactant Locationsb
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
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.
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
a Most common or most specific location is listed first.
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
DiagnosisDIFFERENTIAL FEATURES
Structures Reactant Locationsa
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
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 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
DiagnosisDIFFERENTIAL FEATURES
Structures Reactant Locationsa
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)
Cytoplasmic lipid, reticulin, factor VIII
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
DiagnosisDIFFERENTIAL FEATURES
Structures Reactant Locationsa
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.