42 Chapter 1 Pigmented lesions in the CNS 1 Metastatic malignant melanoma ◆ Most common pigmented lesion in the CNS. 2 Melanocytoma ◆ The proliferating cells are melanocytes with the predilection for the leptome- ninges. ◆ Most of the lesions are benign, pigmented, meningeal-based tumors, so called meningeal melanocytoma. ◆ Half of lesions are located intracranially, especially in the posterior fossa. The rest occur in the spinal canal as intradural extramedullary masses in the cervi- cal and thoracic regions. ◆ While most meningeal melanocytomas occur without cutaneous stigmata, some patients have pigmented skin lesions, raising the possibility of metastatic malignant melanoma or a neurocutaneous syndrome. 3 Melanocytic schwannoma ◆ Distinctive psammomatous melanocytic schwannoma is easily recognized and can be associated with Carney complex (myxomas, spotty pigmentation, en- docrine overactivity, and multiple psammomatous melanotic schwannoma). 4 Meningeal melanocytosis ◆ Refers to a set of lesions characterized by a diffuse proliferation of melanocytic cells within leptomeninges without a dominant mass lesion. ◆ Presentation is usually in childhood and can manifest with increased intracra- nial pressure with hydrocephalus. Neuroimaging often reveals diffuse menin- geal enhancement. CSF cytology is usually positive. ◆ The main differential diagnosis in this rare disorder is superfi cial siderosis due to chronic leakage of blood into the CSF, which may accompany meningeal melanocytomas. ◆ Although the proliferating cells may appear cytologically benign, meningeal melanocytosis is a lethal disorder, with death often occurring within a year of diagnosis. • Among all the pigmented lesions in the CNS, metastatic malignant melanoma is the most common. • Other differential diagnoses in this group represent rare entities. However, distinguishing these lesions from malignant melanoma is critically important, since some of the lesions are benign and therefore the treatment is vastly different. Neuroanatomy and Neuropathology 43 Positive CSF cytology without a history of malignancy Type of malignancy Percentage of cases fi rst diagnosed by positive CSF cytology Unknown primary 70 Gastric adenocarcinoma 67 Bronchogenic carcinoma 18 Malignant melanoma 8 Primary CNS tumor (e.g. medulloblastoma, glioblastoma, etc.) 5 Malignant lymphoma 2 Ref: Bigner S.H., Johnston W.W. The diagnostic challenge of tumors manifested initially by the shedding of cells into cerebrospinal fl uid. Acta Cytol 1984; 28: 29–36. Rosenthal fi bers Rosenthal fi bers are observed in: 1 Reactive states ◆ Most often those associated with signifi cant chronicity, such as syringomye- lia and around the margins of nonglial, slow-growing tumors, such as cranio- pharyngioma and hemangioblastoma. • CSF samples that show malignant cells in the absence of any history of malignancy represent a special dilemma. • This accounts for approximately 11% of patients with positive CSF malignant cytology. Most occult carcinomas with leptomeningeal manifestations are in the lung or the stomach. However, the primary sites are unknown in the majority of cases. Breast carcinoma commonly involves the leptomeninges, but is usually clinically apparent prior to meningeal spread. • The diagnosis and classifi cation of malignancy that presents initially in the CSF should proceed in a stepwise fashion. The fi rst distinction is whether the cells are hematopoietic or nonhematopoietic. Then, the carcinomas can be further divided into adenocarcinoma, squamous cell carcinoma, small cell carcinoma, or undifferentiated carcinoma. In the next step, clinical and radiographic investigation will provide further clues to the diagnosis. As a general rule, most small cell carcinoma originates from the lung, whereas most squamous cell carcinoma comes from the head and neck. • Rosenthal fi bers are opaque, homogeneous, brightly eosinophilic intracytoplasmic structures, which exhibit elongated, anfractuous (corkscrew or lumpy-bumpy) profi les. 44 Chapter 1 2 Metabolic/genetic disorders ◆ Rosenthal fi bers are morphological hallmarks of Alexander disease (of which some forms are now known to arise from mutations of the gene encoding glial fi brillary acidic protein, GFAP). 3 Neoplasia ◆ Most characteristic of pilocytic astrocytoma. ◆ It can also be found in a wide variety of gliomas. The importance of recognizing Rosenthal fi bers in an astrocytic neoplasm cannot be overemphasized. The nuclear polymorphism of most pilocytic astrocytomas is more than suffi cient to suggest anaplastic astrocytoma; the identifi cation of Rosenthal fi bers signifi cantly mitigates the risk of this potential overdiagnosis. 4 Others ◆ Axonal neuropathy Rosenthal fi bers Senile plaques 1 Elderly individuals ◆ Plaques occur in the cortex with increased frequency in aging. In normal aging, the plaques are mainly diffuse. ◆ There may be small numbers of neuritic plaques, most associated with ubi- quitin- and chromogranin-immunoreactive neuritis that do not contain tau protein. • Plaques are extracellular 20–150 μm structures consisting of a central pink amyloid core surrounded by blunt swollen neuritic processes. • The amyloid is composed of Aβ peptide, derived by proteolytic breakdown from a normal neuronal membrane protein called amyloid precursor protein (APP). Like tangles, they stain well with silver stains. • There are four main types of plaques; diffuse, primitive, classic, and burnt- out. It is believed that there is progression from diffuse through fi nally burnt-out plaques. However, there is no defi nitive evidence for this. Neuroanatomy and Neuropathology 45 2 Alzheimer disease (AD) ◆ Plaques are widely distributed in the brain of patients with AD. The neocortex and hippocampus are always involved. Most neuritic plaques include tau-im- munoreactive dystrophic neurites. 3 Amyloid angiopathy 4 Down syndrome Senile plaques Synucleinopathies 1 Lewy body disorders ◆ Lewy bodies are intracytoplasmic inclusions composed of several proteins, including ubiquitin and α-synuclein. α-synuclein immunohistochemistry is now widely used to recognize this pathological marker in both brainstem and cortical lesions. • The synucleinopathies are a subset of neurodegenerative disorders that have in common a pathological lesion composed of fi brillary aggregates of insoluble α-synuclein protein in selective populations of neurons and glia. • Synuclein belongs to a family of brain proteins. It consists of three members: α-, β-, and γ-synuclein. The α-synuclein gene is located on chromosome 4, and only α-synuclein is associated with the fi lamentous inclusions. In diseases where it aggregates, α-synuclein changes conformation and aggregates with fi brils of β-sheet structure similar to other amyloid proteins. • Abnormal fi lamentous aggregates of misfolded α-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neuritis, and the Papp-Lantos fi laments in oligodendroglial and neurons in multiple system atrophy linked to degeneration of affected brain regions. 46 Chapter 1 ◆ The presence and distribution of Lewy bodies has led to a clinicopathological classifi cation of Lewy body disorder spectrum. 1.1 Parkinson disease (PD): brainstem type of Lewy bodies ■ Sporadic form: most common ■ Familial form: 10% of cases ■ Autosomal dominant with α-synuclein mutations ■ Autosomal recessive with parkin gene or DJ-1 mutations 1.2 Dementia with Lewy bodies (DLB): both cortical and classic Lewy bodies ■ DLB is now recognized as the most frequent cause of degenerative de- mentia after AD. 1.3 Normal aging ■ Lewy bodies occur in the substantia nigra and brainstem in up to 10% of normal individuals. 1.4 Pure autonomic failure 2 Non-Lewy body disorders 2.1 Multiple system atrophy (MSA) ■ The histological hallmark is the presence of α-synuclein-positive cytoplas- mic inclusions in oligodendroglia, which is required for diagnosis. ■ Different clinical subtypes are recognized, including MSA-P, MSA-C and MSA-A. 2.2 Neurodegeneration with brain iron accumulation type 1 (NBIA I) ■ Previously referred to as Hallervorden-Spatz disease. ■ Represents a pantothenate-kinase associated neurodegeneration caused by the PANK2 gene, linked to chromosome 20p12.3–13. ■ Axonal spheroids, the hallmark of this condition, contain immunoreac- tive neurofi lament proteins, ubiquitin, superoxide dismustase, amyloid precursor protein, and α-synuclein. Tauopathies • A heterogeneous group of dementing illnesses and movement disorders, neuropathologically characterized by the presence of neuronal or neuronal and glial fi lamentous inclusions composed of tau, are collectively known as tauopathies. • The phosphorylated tau, encoded by a single gene localized on the long arm of chromosome 17, is a microtubule-associated protein involved in microtubule assembly and stabilization. Tau is primarily expressed by neurons. • Through alternative mRNA splicing, six tau isoforms are expressed in adult human brain, which differ from one another by the presence of three or four 31 or 32-amino-acid-long tandem repeats in the C-terminal microtubule binding region together with 0, 29, or 58 amino acid inserts in the N- terminal region. Neuroanatomy and Neuropathology 47 1 Primary tauopathies ◆ In this group of diseases, the characteristic neuropathological feature is the presence of abundant fi lamentous tau pathological fi ndings in the absence of extracellular protein deposits. ◆ The majority of such conditions are sporadic, with the exception of fronto- temporal dementia with parkinsonism, linked to chromosome 17, which is the major familial form of primary tauopathy. ■ Progressive supranuclear palsy (PSP) ■ Corticobasal ganglionic degeneration (CBGD) ■ Pick disease ■ Frontotemporal dementia (FTD) with Parkinsonism, linked to chromo- some 17 2 Secondary tauopathies ◆ In this group of diseases, the pathological changes include not only fi lamen- tous tau inclusions, but also extracellular, aggregated deposits of a secondary protein. ■ Alzheimer disease: most common ■ Gerstmann-Sträussler-Scheinker syndrome (GSS) ■ BRI2 gene related dementias ■ Familial British dementia (FBD) ■ Familial Danish dementia (FDD) Tumors: demyelination vs. glioma • A signifi cant number of neuroimaging studies in patients with demyelination may show lesions with a tumor-like appearance. This probably represents the acuteness and severity of the demyelinating lesion(s). • When this problem arises, clinical and radiological differentiation from glioma is often diffi cult, necessitating biopsy of the lesion(s). • Even with biopsy, there is considerable diffi culty in differentiating between the two. This is because tumor-like demyelinating lesions can also demonstrate hypercellularity, pleomorphism, necrosis, astrocytic mitosis as well as microcystic changes. • The following histopathologic features suggest that a clinically diagnosed ‘tumor’ is not a true neoplasm. ◆ Abundant lipid-laden macrophages ◆ Evenly spaced astrocytes with well-developed processes ◆ Sharp demarcation ◆ Perivascular chronic infl ammation 48 Chapter 1 Features Tumor-like demyelinating lesions Glioma Pleomorphism Present Present Microcystic changes Present Present Mitotic fi gures May be present Present Lipidized astrocytes May be present May be present Lipidized macrophages Present Rare Perivascular lymphocytes Present Less common Reactive astrocytes Present Less common Sharp demarcation Present Rare Response to steroids Marked response Response with varying degree Modifi ed from: Prayson R.A., Cohen M.L. Practical Differential Diagnosis in Surgical Neuropathology. 2000, Totowa, Humana Press. Tumors: glioblastoma vs. metastatic carcinoma Features Glioblastoma Metastatic carcinoma Age Peak at 3rd to 5th decade Older Multifocal Less common More common Tumor border Infi ltrative More discrete Leptomeningeal involvement Less common More common, especially in hematologic malignancies Fibrillary background Present Absent Desmoplastic stroma Absent Present Discrete cell borders May be present Absent Vascular proliferation More evident Less evident Perinecrotic pseudopalisading May be present Absent GFAP Positive Negative Cytokeratins Can be positive Positive, especially low- molecular weight keratin markers, e.g. CAM5.2 • Metastatic tumors are often the major differential diagnostic consideration in the evaluation of a poorly differentiated high-grade neoplasm in the central nervous system. • Metastases are the most common tumors in the CNS. However, spinal cord metastases are rare and are generally seen at the terminal stage of the disease process. • The most common tumors to metastasize to the brain include lung, breast, melanoma, renal cell carcinomas, and choriocarcinoma. • If one resorts to immunohistochemistry to distinguish a metastatic lesion from glioma, extra care needs to be taken not to confuse cross reactivity patterns of staining with certain markers. Neuroanatomy and Neuropathology 49 Tumors: gliosis vs. glioma Features Gliosis Glioma Age Any age Peak 3rd to 5th decade Location Gray or white matter White > gray matter Gross Firm Firm, obliterate gray-white junction and may have cystic component Hypervascularity Evenly distributed Unevenly distributed Cellularity Increased throughout Increased cellularity is unevenly distributed Distribution Usually focal Diffuse infi ltration Atypia Binucleated cells, more eosinophilic cytoplasm with long tapered processes High nuclear/cytoplasmic ratio, hyperchromatic, nuclear irregularity, and pleomorphism Mitosis Usually absent Usually present Calcifi cation None May be present Microcystic change None May be present Satellitosis None May be present Granulation None Can sometimes be seen in tumor Tumors: pattern of immunohistochemical positivity in CNS tumors • One of the most challenging differential diagnostic problems in surgical neuropathology is to distinguish between gliosis or reactive astrocytosis and a low-grade glial tumor. • In simple terms, gliosis is the brain’s way of reacting to injury, insult, or to something that should not be there (e.g. tumor). Therefore, it is common to observe some degree of reactive gliosis adjacent to a tumor. • In order to perform accurate interpretation, clinical and radiographic information should be available to pathologists. For example, a history of radiation may favor the presence of some gliosis. • In addition to light microscopic examination, immunohistochemical staining has a useful role in differentiating different types of CNS tumors. • The following information and examinations should be available to pathologists in order to perform accurate interpretation: ◆ Light microscopic examination 50 Chapter 1 Primary antibody Tumors showing positivity Glial fi brillary acidic protein (GFAP) Astrocytoma, glioblastoma Ependymoma Subependymoma Anaplastic ependymoma Gliosarcoma Ganglioglioma Mixed glioma Synaptophysin & neurofi lament Central neurocytoma Pineocytoma Medulloblastoma Neuroblastoma Ganglion cell tumor Epithelial membrane antigen (EMA) Meningioma Metastatic carcinoma S-100 protein Oligodendroglioma Anaplastic oligodendroglioma Neurofi broma Astrocytoma Melanoma Chordoma Neurilemoma HMB-45 Melanoma Vimentin Meningioma Sarcoma Cytokeratin Metastatic carcinoma Choroid plexus papilloma Choroid plexus carcinoma Craniopharyngioma Chordoma Most germ cell tumors Chromogranin Pituitary adenoma Metastatic neuroendocrine tumors ◆ Neuroanatomic distribution ◆ Relevant immunohistochemistry examination ◆ Ultrastructure ◆ Aging changes ◆ Reaction to injury ◆ Neoplastic counterparts Neuroanatomy and Neuropathology 51 Primary antibody Tumors showing positivity Alpha fetoprotein (AFP) Embryonal carcinoma Endodermal sinus (Yolk sac) tumor Placental alkaline phosphatase (PLAP) Germinoma Leukocyte common antigen (LCA) L-26 (B-cell marker) UCHL-1 (T-cell marker) Kappa and lambda light chains Monoclonal staining pattern in lymphomas Polyclonal staining pattern in reactive infl ammation and infections Modifi ed from: Vinters H.V., Farrell M.A., Mischel P.S., Anders K.H. Diagnostic Neuropathology. New York, Marcel Dekker, Inc. Tumors: oligodendroglioma and its mimics Features Oligodendroglioma DNET Central neurocytoma Clear cell ependymoma Infi ltration Yes Focal No No Perineuronal satellosis Ye s N o N o N o Minigemistocytes Yes No No No Floating neurons Yes No No No Cellular heterogeneity May be present Yes No May be present Neuropil No No Yes No Perivascular pseudorosettes No No No May be present Continued • Despite recent advances in immunohistochemical and molecular techniques, the oligodendroglioma still remains a tumor whose diagnosis is based on ‘good old H&E’. • The following are typical histological features of oligodendroglioma: ◆ The cells appear to be easily spread into the cerebral cortex, resulting in prominent perineuronal satellitosis. ◆ Calcifi cations, especially in a band-like pattern. ◆ Germinal-like nodules of hypercellularity. ◆ Admixed minigemistocytes. ◆ Perinuclear halos. • In addition to the above features, oligodendroglial-like components can be seen in the following tumors in which helpful differentiating features are provided below. [...]... increasingly recognized Diagnosis Percentage Progressive multifocal leukoencephalopathy (PML) Toxoplasmosis Malignant lymphoma Necrosis of unclear significance HIV encephalitis or leukoencephalopathy Tuberculoma Aspergilloma 32 28 19 15 2 2 2 Ref: Alesch F., Armbruster C., Budka H Diagnostic value of stereotactic biopsy of cerebral lesions in patients with AIDS Acta Neurochir (Wien) 1995; 134: 21 4 21 9 Neuroanatomy... 1 Seen in: 1 Recurrent acquired demyelinating disorders 2 Hereditary hypertrophic neuropathies ◆ Dejerine-Sottas sensory neuropathy (HMSN III) ◆ Hypertrophic form of Charcot-Marie-Tooth disease ◆ Refsum disease Onion bulb formation Skin biopsy in neurological disorders • • Skin biopsy is not a common investigation used to evaluate patients with neurological disorders However, it may be useful in diagnosing... Clinical Syndromes 63 Kyphoscoliosis in neurological disorders 87 Lhermitte sign 88 Monoplegia 88 Muscular wasting of the small hand muscles 89 Neck stiffness 89 Palatal myoclonus 90 Paraplegia 91 Pes cavus 92 Pyramidal versus extrapyramidal syndromes: spasticity vs rigidity 92 Recurrent falls: neurological causes 93 Romberg sign 94 Scapular winging 95 Temperature-sensitive neurological conditions 95 Upper... Cerebellopontine angle syndrome 100 Geschwind syndrome 101 Horner syndrome 101 Kluver-Bucy syndrome 1 02 Orbitofrontal syndrome 103 Thoracic outlet syndrome 103 Tolosa-Hunt syndrome 104 Wernicke encephalopathy and Korsakoff syndrome 105 64 Chapter 2 Motor and sensory signs and their localizations • • • The following are useful neurological signs, commonly seen in clinical settings Their common localizations... movement (locked-in syndrome) Bilateral ventral pontine lesions Quadriparesis but preserved facial movements, Bilateral medullary lesions but no tongue or palatal movement or speech Bilateral arm weakness with relatively spared lower extremity function (man-in-the-barrel syndrome) Lesions in the cerebral border zones Quadriparesis with ventilatory support, diaphragmatic respiration Bilateral C1-C4 lesions... Clinical Syndromes 73 2 Locked-in syndrome (Pseudocoma or de-efferented state) ◆ In patients with locked-in syndrome, there is no alteration of consciousness The patient is completely paralyzed except for vertical eye movements and is able to communicate complex ideas by blinking Morse code ◆ Lesions are located in the ventral pons 3 Akinetic mutism (sometimes called extrapyramidal locked-in syndrome) ◆... capillary endothelium, smooth muscle cells, and even sweat glands (skin biopsy only) ◆ ■ ■ ■ ■ ■ ■ Neurological Differential Diagnosis: A Prioritized Approach Roongroj Bhidayasiri, Michael F Waters, Christopher C Giza, Copyright © 20 05 Roongroj Bhidayasiri, Michael F Waters and Christopher C Giza Chapter 2 Clinical Syndromes Motor and sensory signs and their localizations 64 Clinical signs and symptoms 66 Alexia... altered responsiveness Neurological conditions associated with lack of awareness 71 72 73 Confabulation 74 Disconnection language syndromes 75 Dysarthria 76 Dysphagia 76 Dysphonia/aphonia 78 Excessive daytime sleepiness (EDS) 78 Frontal release signs 80 Hemifacial sensory loss 81 Gait abnormalities 82 Hearing loss: Rinne and Weber tests 84 Hemiplegia 85 Intracranial hypotension 62 66 86 Clinical Syndromes... not be attributed to strength, coordination, sensory loss, or impaired comprehension Apraxia is less predictable in left-handed individuals than in right-handed ones Left-handers have right dominance for praxis regardless of which hemisphere is dominant for language Apraxia in right-handed individuals is almost always associated with a left hemispheric lesion, although only about 50% of aphasic patients... 52 Chapter 1 Features Oligodendroglioma DNET Central neurocytoma Clear cell ependymoma GFAP Minigemistocytes Astrocytic areas Weak/focal coexpression Punctate cytoplasmic Synaptophysin No May be present Yes No DNET – dysembryoplastic neuroepithelial tumor Ref: Prayson R.A., Cohen M.L Practical Differential Diagnosis in Surgical Neuropathology 20 00, Totowa, Humana Press Tumors: . of α-synuclein-positive cytoplas- mic inclusions in oligodendroglia, which is required for diagnosis. ■ Different clinical subtypes are recognized, including MSA-P, MSA-C and MSA-A. 2. 2 Neurodegeneration. presence of three or four 31 or 3 2- amino-acid-long tandem repeats in the C-terminal microtubule binding region together with 0, 29 , or 58 amino acid inserts in the N- terminal region. Neuroanatomy. Previously referred to as Hallervorden-Spatz disease. ■ Represents a pantothenate-kinase associated neurodegeneration caused by the PANK2 gene, linked to chromosome 20 p 12. 3–13. ■ Axonal spheroids,