Neuro Flashcards
Approximately 10% of (what tumor?) produce an erythropoietin-like protein that results in secondary polycythemia vera.
Approximately 10% of hemangioblastomas produce an erythropoietin-like protein that results in secondary polycythemia vera.
Brain invasive meningiomas are considered WHO grade ___?
Brain invasive meningiomas are considered WHO grade II. Atypical meningiomas are also WHO grade II. Anaplastic (malignant) meningiomas are WHO grade III.
Chordoma. Definition, Incidence and Location, Gender and Age Distribution, Clinical Features, Radiologic Features, and Prognosis and Treatment.
Definition: Tumor derived from notochord remnants. Incidence and Location: Relatively uncommon tumor. Most common sites are sacrococcygeal region (about half), clivus or spheno-occipital region (a third), and associated with articulating vertebrae. Gender and Age Distribution: Any age, more common in adults. Clinical Features: Sacral tumors are marked by pain, sphincter disturbance, and neural deficits secondary to involvement of nerve roots. Base of skull tumors are characterized by headaches, diplopia, and cranial nerve palsies. Radiologic Features: Osseo-destructive mass with infiltration into adjacent soft tissue. Prognosis and Treatment: Wide surgical resection recommended; local recurrence with subtotal resection. Radiotherapy for subtotally resected tumors. Minority of tumors metastasize to the lung, nodes, and skin. Minority of tumors degenerate or dedifferentiate into sarcoma. Younger patients have a better prognosis.
Chordoma. Gross Findings, Microscopic Features, Ultrastructural Features, IHC Features, Genetics, DDx.
Gross Findings: Infiltrative, bone-based, lobulated mass. Mucoid appearance. Cartilaginous tissue in the chondroid variant. Microscopic Features: Lobulated architecture with fibrovascular septa. Epithelioid cells arranged in cords or rows against mucoid stroma. Physaliphorous cells with “bubble-like” vacuolated cytoplasm. Occasional mitotic figures and mild nuclear pleomorphism. Focal cartilaginous differentiation (chondroid chordoma). Ultrastructural Features: Abundant cytoplasmic mucus vacuoles and desmosomal junctions. IHC Features: Positive with antibodies to vimentin, cytokeratins, EMA, and S-100 protein. Genetics: No salient genetic alterations. DDx: Chondrosarcoma. Chordoid meningioma. Metastatic mucinous adenocarcinoma.
Examples of pseudoneoplastic lesions in the nervous system and their related neoplastic mimes.
Gliosis (low-grade gliomas). Active-phase plaques of multiple sclerosis (gliomas). Progressive multifocal leukoencephalopathy (gliomas). Paraventricular glial nodules of tuberous sclerosis (gliomas; gangliogliomas). Viral encephalitides (lymphoma). Other pseudotumors include inflammatory pseudotumor, tumefactive demyelination, radionecrosis, cortical dysplasia, calcified pseudoneoplasm of the neuraxis, meningioangiomatosis, lymphocytic hypophysitis, pineal cyst, and localized hypertrophic neuropathy.
GFAP and vimentin in astroglial cells.
GFAP and vimentin form intermediate filaments in astroglial cells and modulate their motility and shape. In particular, vimentin filaments are present at early developmental stages, while GFAP filaments are characteristic of differentiated and mature brain astrocytes.
Glioneuronal tumors.
… are tumors with an admixture of glial and neuronal components. Both cell types are thought to be part of the same neoplastic process. 3 well-established examples of this class of tumor are: DNETs (dysembryoplastic neuroepithelial tumors), gangliogliomas, and desmoplastic infantile ganglioglioma. More recently recognized entities are: rosette-forming tumor of the fourth ventricle, papillary glioneuronal tumor, rosetted glioneuronal tumor/glioneuronal tumor with neuropil-like islands.
Hemangioblastoma. Definition, Incidence and Location, Gender and Age Distribution, Clinical Features, Radiologic Features, and Prognosis and Treatment.
Definition: Tumor of uncertain histogenesis composed of stromal cells and abundant capillaries. Incidence and Location: Relatively uncommon tumor, 1-3% of intracranial tumors. Most commonly arise in the cerebellum; rarely arise in the brain stem, spinal cord, and supratentorium. Gender and Age Distribution: Slight male preponderance. Peak incidence at 25 to 40 years of age. Von Hippel-Lindau tumors typically develop at a younger age. Clinical Features: Symptoms related to CSF obstruction-increased intracranial pressure. 10% with secondary polycythemia. Radiologic Features: Contrast-enhancing nodule associated with a cyst or syrinx. Prognosis and Treatment: WHO grade I tumor. Good prognosis, curable with gross total resection. Radiotherapy may be of limited use in recurrent or nonresectable tumors. Increased risk of multiple/multifocal tumors in von Hippel-Lindau disease.
Hemangioblastoma. Gross Findings, Microscopic Features, Ultrastructural Features, IHC Features, Genetics, DDx.
Gross Findings: Well-circumscribed tumor with a cystic component and red (vascular) nodule(s). May be yellow if lipid-rich. Microscopic Features: Two components: prominent capillary vasculature and stromal cells with vacuolated or lightly eosinophilic cytoplasm. Stromal cells may demonstrate focal nuclear pleomorphism. Mitoses and necrosis unusual. Adjacent parenchyma gliotic with Rosenthal fibers. Ultrastructural Features: Abundant cytoplasmic lipid droplets in stromal cells. Stromal cell histogenesis not known. IHC Features: Focal vimentin positive; weak GFAP positivity of uncertain significance may be present. Stromal cells generally negative with factor VIII-related antigen, EMA, neurofilament, and keratin antibodies. Stromal cells positive for inhibin A and VEGF. Genetics: Von Hippel-Lindau cases (~25% of tumors) associated with tumor suppressor gene on chromosome 3p25-26. DDx: Metastatic clear cell carcinoma (especially renal cell carcinoma in the setting of von Hippel-Lindau disease). Pilocytic astrocytoma.
In oligodendrogliomas (or tumors with an oligodendroglial component), LOH in what gene is associated with a better response to therapy and a more favorable outcome?
LOH (Loss of Heterozygosity) in 1p19q is associated with a better response to therapy and a more favorable outcome.
List the histologic variants of meningioma, along with WHO grade and pathologic characteristics.
Syncytial (meningotheliomatous); WHO grade I; cells arranged in lobules separated by collagenous septa. Fibrous (fibroblastic); WHO grade I; cells spindled and arranged in interlacing bundles, psammoma bodies and whorling of cells around vessels common. Transitional (mixed); WHO grade I; demonstrates features of both syncytial and fibrous types. Psammomatous; WHO grade I; abundant psammoma bodies, particularly common in the spinal cord. Angiomatous; WHO grade I; numerous blood vessels in the background of an ordinary meningioma. Microcystic; WHO grade I; cells with elongated processes arranged against a loose, mucoid background. Secretory; WHO grade I; intracellular lumina with eosinophilic, PAS-positive material (pseudopsammoma bodies). Lymphoplasmacyte-rich; WHO grade I; extensive chronic inflammatory infiltrates. Metaplastic; WHO grade I; focal mesenchymal differentiation (bone, cartilage, adipose, xanthomatous). Chordoid; WHO grade II; areas resembling chordoma with trabeculae of eosinophilic and vacuolated cells arranged against a myxoid background. Clear cell; WHO grade II; polygonal cells with glycogen-rich, clear cytoplasm. Atypical; WHO grade II; tumor marked by either increased mitotic activity (4 or more mitotic figures per 10 high-power fields - 0.16 mm^2) or 3 or more of the following: increased cellularity, small cell change, prominent nucleoli, sheet-like growth pattern, or necrosis. Papillary; WHO grade III; perivascular pseudopapillary pattern. Rhabdoid; WHO grade III; presence of “rhabdoid cells” with eccentric nuclei and prominent eosinophilic cytoplasmic inclusions of intermediate filaments. Anaplastic (malignant); WHO grade III; tumor marked by either 20 or more mitotic figures per 10 high-power fields (0.16 mm^2) or excessive malignant cytology with an appearance similar to sarcoma, carcinoma, or melanoma.
Meningioma. Definition, Incidence and Location, Gender and Age Distribution, Clinical Features, Radiologic Features, and Prognosis and Treatment.
Definition: Generally slow-growing, dural-based tumors derived from meningothelial (arachnoid cap) cells. Incidence and Location: Account for ~20-30% of primary intracranial neoplasms. Annual incidence rate of ~6-13% per 100,000 persons. Most arise proximal to the dura within the intracranial, orbital, and intravertebral cavities. Most common sites of origin are parasagittal region, cavernous sinus, tuberculum sellae, lamina cribrosa, foramen magnum, and torcular zone. Gender and Age Distribution: Female preponderance, with M:F = 1:1.7. Can occur at any age. Most common in middle-aged and elderly patients, peak during the 6th and 7th decades. Atypical and malignant meningiomas more common in males. Clinical Features: Manifestations dependent on location of tumor. Since they are generally slow growing, they usually produce symptoms by compression of adjacent structures - focal neural deficits, increased intracranial pressure, and seizures are the most common symptoms. May cause hyperostosis of the overlying skull. Radiologic Features: Circumscribed isodense dural masses that enhance with contrast. May show evidence of calcification, bone, or cartilage. Dural tail - wedge-shaped extension of tumor at the edge, contrast enhancing. Malignant and brain invasive tumors associated with cerebral edema. Prognosis and Treatment: Most variants have an excellent prognosis and are curable by gross total resection. Major predictor of recurrence is the extent of surgical resection. Rare, more aggressive variants are more likely to recur and in some cases metastasize. Recurrence rates are 7-20% for WHO grade I, 29-40% for WHO grade II, and 50-78% for WHO grade III. Higher cell proliferative labeling indices correlate with increased risk of recurrence. Radiotherapy used to treat higher grade and aggressive tumors.
Meningioma. Gross Findings, Microscopic Features, Ultrastructural Features, IHC Features, Genetics, DDx.
Gross Findings: Dural-based, sharply demarcated, rubbery or firm mass that compresses adjacent brain parenchyma. Appearance may be altered by lipid content, cystic change, metaplastic components, vascularity, and calcification. Meningioma en plaque - flat growth pattern, most common along the sphenoid wing. Microscopic Features: Monomorphic cells arranged in a syncytium. Nuclei oval to round with inconspicuous nucleoli. Intranuclear pseudoinclusions (cytoplasmic invaginations). Psammoma bodies common. Ultrastructural Features: Prominent intermediate filaments, interdigitating cell processes, and desmosomal intercellular functions. IHC Features: Vimentin-almost all are positive. EMA-~80% focally positive. CEA, cytokeratins-focally positive in a minority of tumors; S-100 protein-20-40% focal positivity. GFAP-negative. Genetics: Most common abnormality-deletion on chromosome 22q. Mutations in the neurofibromatosis 2 gene in 60% of sporadic tumors. DDx: schwannoma, metastatic carcinoma, astrocytoma, sarcoma, solitary fibrous tumor.
Primary GBMs more typically show activation of the ___ pathway, while secondary GBMs more typically show ___ mutations together with other acquired molecular alterations.
Primary GBMs more typically show activation of the EGFR pathway, while secondary GBMs more typically show p53 mutations together with other acquired molecular alterations.
Schwannoma. Definition, Incidence and Location, Gender and Age Distribution, Clinical Features, Radiologic Features, and Prognosis and Treatment.
Definition: Benign tumor derived from Schwann cells; also known as neurilemoma, acoustic neuroma. Incidence and Location: Most frequently arise in association with peripheral nerves, most commonly in the head and neck region and on the extremities. 8% of intracranial and 29% of spinal tumors (extramedullary). Association with neurofibromatosis type 2. Gender and Age Distribution: No gender predilection except for intracranial tumors (F:M = 2:1). Any age, peaks between the fourth and sixth decades. Clinical Features: Most commonly occur as asymptomatic masses. Occasionally with pain, cord compression. CN VIII tumors - hearing loss, facial paresthesias, tinnitus. Radiologic Features: Well-circumscribed, heterogeneously enhancing, sometimes cystic mass. Prognosis and Treatment: Excellent prognosis (WHO grade I), only rarely undergoes malignant degeneration. Curable with surgical resection.
Schwannoma. Gross Findings, Microscopic Features, Ultrastructural Features, IHC Features, Genetics, DDx.
Gross Findings: Circumscribed masses, frequently encapsulated, sometimes cystic. Light tan color; may be yellow (macrophages) or red (hemorrhagic). Microscopic Features: Cells with spindled nuclei, tapered ends. Biphasic cellularity: compact cellular Antoni A pattern and loose microcystic Antoni B pattern. Nuclear palisading - Verocay bodies. Occasional mitotic figures and nuclear pleomorphism acceptable. Sclerotic vessel change common. Cellular variant - hypercellular, predominantly Antoni A pattern. Melanotic schwannoma - may have psammoma bodies (associated with Carney’s complex). Plexiform variant - multinodular, associated with neurofibromatosis type 2. Ultrastructural Features: Cells with convoluted cytoplasmic processes lined by continuous basal lamina. IHC Features: S-100 positive, can be focally GFAP positive. Genetics: NF2 gene (merlin protein) associated with sporadic schwannomas (60%). Subset with chromosome 22q losses. DDx: Fibrous meningioma. Neurofibroma. Sarcoma (especially malignant peripheral nerve sheath tumor). Glioma.
What are primary and secondary GBMs?
Primary GBMs develop de novo. Secondary GBMs develop out of progression of lower-grade infiltrating astrocytomas.
What immunostain reacts with the endothelium of cerebral capillaries, placental vasculature, and juveline capillary angiomas?
GLUT-1.
What primary CNS neoplasms can contain melanin pigment?
Gliomas, medulloblastomas, and schwannomas can contain focal melanin pigment. Melanocytoma and melanoma contain more.
CLIPPERS is a recently described CNS inflammatory condition that should be considered in the DDx when a prominent lymphocytic inflammatory infiltrate is encountered in brainstem, spinal cord, midbrain, or cerebellar biopsies. What does CLIPPERS stand for?
Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids. The inflammatory focus involves the pons with extension into adjacent CNS areas. This entity is a diagnosis of exclusion; histopathologic features must be correlated with the clinical and radiologic findings to arrive at an accurate diagnosis.
What bacterium is the most commonly identified cause of Guillain-Barre syndrome?
C. jejuni, most commonly type O:19, is the most commonly identified cause, implicated in ~30% of cases.
What is Austrian syndrome?
Austrian syndrome was first described by Robert Austrian in 1957. The classical triad consists of meningitis, pneumonia, and endocarditis all caused by Streptococcus pneumoniae. It is associated with alcoholism, due to the presence of hyposplenia, and can been seen in males between 40–60 years old.
HSV 1 is a common cause of (encephalitis and/or meningitis), and HSV 2 is a common cause of (encephalitis and/or meningitis). The best way to diagnose both of these is ___.
HSV 1 is a common cause of encephalitis, and HSV 2 is a common cause of meningitis. The best way to diagnose both of these is CSF PCR.
What tumors are seen in the subtypes of MEN syndrome?
MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.
What are some clear cell tumors seen in the central nervous system which have similar morphologic features?
Oligodendroglioma, hemangioblastoma, clear cell ependymoma, clear cell meningioma, central neurocytoma, and renal cell carcinoma.
What are secondary structures of Scherer?
The morphologic patterns of glioma cell infiltration have been referred to as secondary structures of Scherer. They are perineuronal satellitosis, perivascular satellitosis, subpial spread/aggregation, and invasion along white matter tracts.
IDH and gliomas.
IDH1 is a mitochondrial protein that is mutated in most infiltrating gliomas: astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. In contrast, mutant IDH is rarely detected in other primary CNS tumors: neuronal, circumscribed gliomas, ependymomas, meningiomas, or systemic malignancies, with the exception of a subset of acute myeloid leukemias. Mutations can occur in IDH1 and IDH2; however, IDH1 mutations are more frequently observed. Approximately 70% to 80% of all oligodendrogliomas harbor IDH mutations. The most common IDH1 mutation involves codon 132, where arginine is replaced by histidine (R132H). A monoclonal antibody for the most-common mutant form of IDH1 (R132H) has been developed. This mutant-specific antibody has proven to be very helpful in the differential diagnosis of infiltrating gliomas from other primary CNS tumors and from reactive conditions that can mimic low-grade gliomas. Glial tumors harboring IDH mutations have a more favorable outcome, which may help stratify patient status and to tailor therapy.
Location of central neurocytomas.
Central neurocytomas are benign tumors that commonly arise in the midline of the cerebral ventricular system. The lateral ventricles and foramen of Monroe are the most common locations for central neurocytomas. Attachment to the septum pellucidum is frequently seen. Their peak incidence is in the third decade of life. Symptoms are due to cerebrospinal fluid obstruction and associated increased intracranial pressure.
Histologic appearance and staining pattern of central neurocytomas.
Histologically, central neurocytomas are composed of sheets of uniform cells with small, round nuclei; salt-and-pepper chromatin; and fine, granular eosinophilic cytoplasm that stains positive for synaptophysin. Homer-Wright rosettes may be present. Occasionally, ganglionic cells with Nissl substance can be detected. The tumor cells express neuronal markers, such as class III-b tubulin, microtubuleassociated protein 2 (MAP2), NeuN, and neurofilament protein. Of note, GFAP may be focally positive, which has been interpreted as reactive astroglia. Because of their capillary network, central neurocytomas may present with bleeding. Microcalcifications can also be observed. Mitoses, nuclear atypia, or hyperchromasia are usually not detected. Tumors that show microvascular proliferation, necrosis, and mitotic activity have been designated as atypical neurocytomas. Recurrence is associated with incomplete surgical resection and a proliferation index (Ki-67) more than 2%.
What is the most common cause of pituitary hyperplasia?
Pregnancy.
What are histologic features seen in cortical tubers associated with tuberous sclerosis?
Histological sections of cortical tubers can show variable features. Common to all tubers is a disorganized cortical architectural pattern or cortical dysplasia (malformation of cortical development). This usually consists of an altered cortical architecture, including abnormal cortical layering, an abnormal orientation or positioning of neurons within the cortex, occasional dysmorphic neurons, and large ballooned cells. The ballooned cells are characterized by abundant eosinophilic cytoplasm with eccentrically placed round to oval nuclei. The cortex usually demonstrates marked reactive gliosis, most pronounced under the cortical surface (subpial gliosis) and around blood vessels in the superficial cortex. Dystrophic calcification is variably present.
Spinal muscular atrophy is a recessive disorder caused by loss of what genes?
Spinal muscular atrophy is a recessive disorder caused by loss of the survival motor neuron (SMN1 and SMN2) genes. Spinal muscular atrophy, types I, II, III, and IV, reflect increasing age of onset and decreasing disease severity.
Amyotrophic lateral sclerosis is a disease of motor neurons, linked to the accumulation of pathogenic proteins in the central nervous system, including __ and __. About __% of individuals with ALS have at least one other affected family member (familial ALS). Superoxide dismutase gene mutations occur in __% of patients with familial ALS and __% of sporadic cases.
Amyotrophic lateral sclerosis is a disease of motor neurons, linked to the accumulation of pathogenic proteins in the central nervous system, including TDP-43 and ubiquitin. About 10% of individuals with ALS have at least one other affected family member (familial ALS). Superoxide dismutase gene mutations occur in 20% of patients with familial ALS and 3% of sporadic cases.
What are the two most common causes of angulated, atrophic fibers (AAFs) in muscle?
Denervation and type-2 fiber atrophy. Group atrophy of AAF is an important feature that distinguishes denervation atrophy from type-2 fiber atrophy.
What are adenosine triphosphate stains used on muscle for?
Adenosine triphosphate stains are used for distinguishing type-1 (slow, oxidative) and type-2 (fast, glycolytic) fibers. These are stains for enzyme activity, which require frozen sections, and can be technically difficult to perform. With the stain for myosin ATPase at pH ~10.5, type 2 myofibers are stained brown, and type 1 fibers are stained pink with an eosin counterstain to make them visible. The same stain, performed at a pH of ~4.3, would demonstrate staining of the type 1 myofibers, such that the section would show exactly the reverse pattern. Staining of normal muscle shows a random, almost checkerboard distribution of the 2 types of myofibers. However, IHC stains for slow myosin found in type-1 fibers and fast myosin found in type-2 fibers is available. Also, the IHC stains are permanent, but the myosin ATPase stain fades after a few months.
Cerebellar liponeurocytoma.
Cerebellar liponeurocytoma is a rare neoplasm which has also been called lipomatous medulloblastoma, lipidized medulloblastoma, medullocytoma, neurolipocytoma, and lipidized mature neuroectodermal tumor of the cerebellum. It typically involves the cerebellar hemispheres of middle-aged to older adults. The tumor is composed of a uniform population of neurocytic cells possessing round to oval nuclei and pale to clear cytoplasm. A variable degree of lipidization of the tumor cells is present, lending a resemblance to mature adipose tissue. Immunohistochemistry serves to confirm the neurocytic differentiation of the tumor cells. The tumor cells typically express synaptophysin, neuron specific enolase, and microtubule-associated protein 2 (MAP-2). Expression of GFAP has been reported in most cases, although staining is typically focal and of limited intensity. The MIB-1 (Ki-67) labeling index is typically between 1% and 3% but may be higher. Also, intracytoplasmic lipid can be confirmed with oil red O on frozen sections. In the 2007 WHO, it is classified with the neuronal and mixed neuronal-glial neoplasms, and was reclassified as a grade II neoplasm to reflect a higher recurrence rate than was previously appreciated (liponeurocytoma was considered a grade I tumor in theWHO 2000 classification).
Clear cell meningiomas are classified as WHO grade __.
Clear cell meningioma is a variant of meningiomas classified as WHO grade II for its propensity to recur. Similar to atypical meningiomas, recurrence can be local or distant and may have a mortality rate of up to 23%.
Clear cell meningiomas. Histologic appearance, common locations, and differential diagnosis.
Clear cell meningioma is a variant of meningiomas classified as WHO grade II for its propensity to recur. Similar to atypical meningiomas, recurrence can be local or distant and may have a mortality rate of up to 23%. It commonly affects children and young adults. Clear cell meningiomas are often rich in glycogen, which gives them their clear cell appearance. Collagen bands are common, and sometimes, the tumor has a sclerotic appearance with only sparse clear cells in between the collagen bands. Clear cell meningioma diagnoses are challenging because the defining meningothelial features are usually focal or ill defined. It is important to differentiate this tumor from other clear cell tumors, such as ependymomas, oligodendrogliomas, and central neurocytomas. Clear cell meningiomas are often found in the cerebellopontine angle and the cauda equina. Although rare, meningiomas can occur in the ventricles, and if the morphology has clear cells, a diagnostic challenge arises in differentiating these tumors from central neurocytomas or clear cell ependymomas.
Locations of hemangioblastoma.
Hemangioblastomas are relatively uncommon neoplasms that can occur sporadically or in the setting of von Hippel- Lindau disease. Sporadic cases are usually seen in the cerebellum as a single lesion in patients with a mean age of 45 years. Tumors associated with von Hippel-Lindau disease present at a younger age (mean, 36 years), they can be multiple, and they can occur in unusual locations, such as retina, brain, and spinal cord.
Hemangioblastomas. Histologic appearance and IHC.
Histologically, the tumor is well circumscribed and may have a thin capsule. The cells can range from clear cytoplasm with minimal nuclear pleomorphism to very bubbly cytoplasm with moderate or even marked nuclear atypia. Despite areas of nuclear pleomorphism, mitoses are seldom found. The tumor is embedded in a rich anastomosing network of capillaries. Extramedullary hematopoiesis and mast cells can be part of the tumor, and, in some instances, patients may have increased erythropoietin that normalizes after the tumor is resected. Immunohistochemically, the tumor cells, also called stromal cells, have variable reactivity for NSE, S100, and CD56. Vimentin and VEGF are usually diffusely positive. Staining with GFAP is generally negative, but can be seen in some cells.
What is a Triton tumor?
A benign Triton tumor is a neuromuscular hamartoma/choristoma. It is a rare developmental lesion of mature skeletal muscle and nerve. Microscopically, is made up of multiple nodules, each 3-5 mm, separated by narrow bands of connective tissue. Nodules are composed of fasicles of striated muscle of varying size with nerve fibers (myelinated or not) within same perimysial fibrous sheath. Stroma may be more cellular with bland spindle cells and resemble fibromatosis. A malignant Triton tumor is made up of both malignant schwannoma cells and malignant rhabdomyoblasts, and is classified as a MPNST with rhabdomyosarcomatous differentiation. The name “triton” was first used in reference to observation of supernumerary limbs containing bone and muscle growing the backs of tritons (a name given to some species of sea snails) after the implantation of the sciatic nerve into the soft tissues of the back.
Nerve sheath myxoma. Clinical presentation, histologic appearance, and differential diagnosis.
Nerve sheath myxomas are rare, distinct tumors of the peripheral nerve sheath, with a peak incidence in the 30’s. Patients present with solitary, superficial, multinodular, painless masses up to 2.5 cm, usually in the extremities. Tumors are typically slow growing, and often were present for years before being resected. They typically involve the dermis or subcutis, forming multinodular, avascular masses with abundant myxoid matrix and a peripheral fibrous border. Epithelioid Schwann cells are present in corded, nested, or syncytial-like aggregates. Stellate Schwann cells with cytoplasmic-nuclear invaginations are also present. The Schwann cells are strongly immunoreactive for S100 protein, GFAP, NSE and CD57. Occasional EMA+ perineurial cells are usually present, primarily in fibrous tissue. There are few/no mitotic figures. The differential diagnosis includes low grade fibromyxoid sarcoma of soft tissue, which typically has MFH-like areas, curvilinear vessels (thick walled with a broad arc) with condensation of cells around the vessels, and often non-specific cytogenetic aberrations. Neurothekeomas may have a myxoid stroma, but are distinct lesions by differential gene expression profiles and immunohistochemistry, and thought to be a variant of fibrous histiocytoma.
Overview of PML.
Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal demyelinating disease characterized by progressive multifocal white matter damage and inflammation, due to the JC virus. It is almost always associated with immunosuppression, including immunosuppressive/biologic therapy for autoimmune diseases, such as natalizumab for multiple sclerosis, and other agents for rheumatoid arthritis or lymphoma. Lytic infection of CNS oligodendrocytes leads to their destruction and progressive demyelination, resulting in multifocal lesions. Although PML previously was relatively rare, it now occurs in 3-5% of HIV+ individuals, and is classified as an AIDS-defining illness. Biopsies show multiple foci of demyelination with enlarged and bizzare astrocytes, which are often multinucleated and have multiple large processes. Oligodendrocytes may have eosinophilic or basophilic nuclear inclusions, due to virions. Lymphocytic infiltration is variable. Necrosis with inflammation resembling an infarct may also be seen. Treatment consists of reversal of the immunosuppression, if possible.
Malignant peripheral nerve sheath tumor overview.
MPNSTs arise from peripheral nerves or show differentiation along the lines of nerve sheath elements (Schwann cells, perineural cells, fibroblasts). MPNSTs account for 5-10% of all soft tissue sarcomas, and one-fourth to one-half of them occur in patients with NF-1. Most lesions present as enlarging masses with or without associated pain and arise in association with major nerve trunks including the brachial plexus, sacral plexus and the sciatic nerve.
IHC for MPNST.
IHC stains for S100, CD57, myelin basic protein, and p53 are usually positive. Staining for S100 should be focally positive, but if strong, diffuse staining is present, a diagnosis of cellular schwannoma should be considered. MPNSTs are commonly negative for EMA, CK7, and CK19, which can differentiate this tumor from synovial sarcoma.
How are cellular schwannomas defined?
Cellular schwannomas can be mistakenly diagnosed as malignant due to their high cellularity, mitotic activity and occasional bone destruction. This entity is defined as a schwannoma that is composed predominantly of Antoni A areas (usually less than 10% Antoni B areas) with absence of Verocay bodies. These lesions occur in the deep soft tissues of the extremities in ~1/4 of cases. Histologically, cellular schwannomas show short, intersecting fascicles and whorls of Schwann cells that can be arranged in a herringbone pattern. Mitotic activity can be seen, but is usually low. Cellular schwannomas lack the hyperchromatic and anaplastic cells seen in MPNSTs and display strong positivity for S100 protein.
What is ecchordosis physaliphora?
A notochordal remnant usually found incidentally at autopsy. It is a small gelatinous hamartomatous lesion located in the intradural space and attached by a pedicle to the clivus. It has similar histological features of chordoma but does not destroy bone or invade tissues.
What is a gangliorhabdomyosarcoma?
Embryonal rhabdomyosarcoma is a primitive soft tissue sarcoma with small blue cells resembling embryonic skeletal muscle. It is the most common rhabdomyosarcoma (RMS) subtype (65% of RMS cases), and usually occurs in children ages 3-10 years in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Gangliorhabdomyosarcoma is a rare variant of embryonal rhabdomyosarcoma which also has cells exhibiting neuronal differentiation. A related entity is malignant ectomesenchymoma, composed of a malignant mesenchymal component (often but not exclusively rhabdomyosarcoma) and a neuroectodermal component (often ganglion cells or neuroblasts). The differential diagnosis includes Triton tumor (rhabdomyosarcoma plus MPNST), Wilms tumor, and teratoma. Optimal treatment is not well defined for this rare tumor, but most authors recommend a combination of surgery, radiotherapy, and a chemotherapeutic protocol based on the RMS component.
The National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for the pathologic diagnosis of AD recommends a minimum of 13 histologic sections to evaluate for Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury, microvascular lesions, and hippocampal sclerosis. These same 13 sections may be used for the evaluation frontotemporal lobar degeneration (FTLD). What are they?
- Middle frontal gyrus. 2. Superior and middle temporal gyri. 3. Inferior parietal lobule. 4. Occipital cortex. 5. Anterior cingulate gyrus. 6. Amygdala. 7. Hippocampus with dentate gyrus and entorhinal cortex. 8. Basal ganglia at the level of the anterior commissure with caudate, putamen, globus pallidus, and the nucleus basalis of Meynert. 9. Thalamus with subthalamic nucleus. 10. Cerebellar cortex and dentate nucleus. 11. Midbrain with substantia nigra. 12. Pons with locus coeruleus. 13. Medulla with dorsal motor nucleus of the vagus and hypoglossal nucleus.
What is the most frequent CNS manifestation of Langerhans cell histiocytosis?
Central diabetes insipidus (DI) is the most frequent CNS manifestation of LCH, occurring in approximately 25% of pts. Multisystem LCH and craniofacial bone lesions with associated soft tissue masses are the 2 most important risk factors for the development of DI in patients with LCH.
Differential diagnosis for elastofibroma.
Spindle cell lipoma also occurs in the shoulder/back region, but it is more common in men. It shows thick, rope-like collagen bundles and characteristic spindled cells, often admixed with mast cells. Low grade myxofibrosarcoma is rarely seen in the trunk region. It characteristically shows a distinct multinodular growth pattern, prominent myxoid matrix, curvilinear blood vessels and cytologic atypia. Nuchal-type fibroma is more common in men and shows thick, haphazardly arranged collagen fibers and elastic-poor fibrous tissue. Many cases are associated with diabetes mellitus. Desmoid-type fibromatosis shares the infiltrative pattern and poor margination with elastofibroma. However, it is usually hypercellular and associated with skeletal muscle. Elastofibroma in contrast is not muscle invasive. A myxoid variant of neurofibroma certainly enters the differential diagnosis but immunohistochemical staining for S-100 and the typical wavy nuclei help to distinguish it from elastofibroma.
___ deletions are detected in ~70% of atypical teratoid/rhabdoid tumors; however, loss of the corresponding ___ protein is even more common than the genetic alteration. Loss of ___ nuclear immunoreactivity in tumor cells is used as a surrogate for genetic testing to demonstrate biallelic inactivation of the gene.
INI1/BAF47 deletions are detected in ~70% of atypical teratoid/rhabdoid tumors; however, loss of the corresponding INI1 protein is even more common than the genetic alteration. Loss of INI1 nuclear immunoreactivity in tumor cells is used as a surrogate for genetic testing to demonstrate biallelic inactivation of the gene.
Isocitrate dehydrogenase (IDH1/IDH2) mutations have been detected in the majority of diffuse gliomas, with the notable exception of ___, and appear to play a fundamental and early role in oncogenesis. The most common mutation is in the IDH1 gene (R132H), and is recognized by monoclonal antibody IDH-1. Diagnostically, the IHC stain shows greatest promise for its potential to distinguish low-grade diffuse glioma from gliosis. Prognostically, the presence of this mutation is favorable, as such tumors appear to show greater response to therapy.
Isocitrate dehydrogenase (IDH1/IDH2) mutations have been detected in the majority of diffuse gliomas, with the notable exception of primary (de novo) GBM, and appear to play a fundamental and early role in oncogenesis. The most common mutation is in the IDH1 gene (R132H), and is recognized by monoclonal antibody IDH-1. Diagnostically, the IHC stain shows greatest promise for its potential to distinguish low-grade diffuse glioma from gliosis. Prognostically, the presence of this mutation is favorable, as such tumors appear to show greater response to therapy.
The classic histologic appearance of acute neuronal necrosis includes (1) variably intense cytoplasmic eosinophilia (accounting for the name “red neurons”) and (2) shrunken pyknotic nuclei. Red neurons require __ to __ hours to develop within a living brain; individuals who die within minutes or a few hours of an ischemic stroke do not show red neurons in affected region(s). Although red neurons are commonly caused by ischemia, many insults (hypoxia, hypoglycemia, epilepsy, HSV infection) can also cause neuronal necrosis. Also, a common artifact caused by overmanipulation of fresh brain tissue can cause normal healthy neurons to (superficially) resemble red neurons. Neurons affected by this “dark cell change” usually show more basophilia than red neurons, a nucleus that is less distinct within the cell body, and an apical dendrite that resembles a spiral or corkscrew.
The classic histologic appearance of acute neuronal necrosis includes (1) variably intense cytoplasmic eosinophilia (accounting for the name “red neurons”) and (2) shrunken pyknotic nuclei. Red neurons require 12 to 24 hours to develop within a living brain; individuals who die within minutes or a few hours of an ischemic stroke do not show red neurons in affected region(s). Although red neurons are commonly caused by ischemia, many insults (hypoxia, hypoglycemia, epilepsy, HSV infection) can also cause neuronal necrosis. Also, a common artifact caused by overmanipulation of fresh brain tissue can cause normal healthy neurons to (superficially) resemble red neurons. Neurons affected by this “dark cell change” usually show more basophilia than red neurons, a nucleus that is less distinct within the cell body, and an apical dendrite that resembles a spiral or corkscrew.
What IHC stains are positive in microglia?
Microglial cells are of monocytic lineage and are consequently immunoreactive for LCA, CD68, and CD163. In response to various signals, these cells undergo activation, whereupon they change their morphology (appearing as irregular elongated “rod cells”), become motile, and intensify their communication with other cells via secreted factors such as cytokines and interleukins. They may also participate in limited phagocytosis.
In the WHO classification and grading of CNS tumors, what are the entities under “astrocytic tumors” and what are the grades?
Pilocytic astrocytoma (PA) - WHO grade I. Pilomyxoid astrocytoma (PMA) - WHO grade II. Subependymal giant cell astrocytoma (SEGA) - WHO grade I. Pleomorphic xanthoastrocytoma (PXA) - WHO grade II. Diffuse (infiltrating) astrocytomas (DA) - WHO grade II: Fibrillary astrocytoma; Gemistocytic astrocytoma; Protoplasmic astrocytoma. Anaplastic astrocytoma (AA) - WHO grade III. Glioblastoma multiforme (GBM) - WHO grade IV: Giant cell GBM; Gliosarcoma. Gliomatosis cerebri - WHO grade III.
In the WHO classification and grading of CNS tumors, what are the entities under “oligodendroglial tumors” and what are the grades?
Oligodendroglioma - WHO grade II. Anaplastic oligodendroglioma - WHO grade III.
In the WHO classification and grading of CNS tumors, what are the entities under “oligoastrocytic tumors” and what are the grades?
Oligoastrocytoma - WHO grade II. Anaplastic oligoastrocytoma - WHO grade III.
In the WHO classification and grading of CNS tumors, what are the entities under “ependymal tumors” and what are the grades?
Subependymoma - WHO grade I. Myxopapillary ependymoma - WHO grade I. Ependymoma - WHO grade II: Cellular; Papillary; Clear cell; Tanycytic. Anaplastic ependymoma - WHO grade III.
In the WHO classification and grading of CNS tumors, what are the entities under “choroid plexus tumors” and what are the grades?
Choroid plexus papilloma - WHO grade I. Atypical choroid plexus papilloma - WHO grade II. Choroid plexus carcinoma - WHO grade III.
In the WHO classification and grading of CNS tumors, what are the entities under “other neuroepithelial tumors” and what are the grades?
Astroblastoma (AB) - not yet graded. Angiocentric glioma (AG) - WHO grade I. Chordoid glioma of the third ventricle (CG) - WHO grade II.
In the WHO classification and grading of CNS tumors, what are the entities under “neuronal and mixed neuronal-glial tumors” and what are the grades?
Dysplastic cerebellar gangliocytoma (DCG) (Lhermitte-Duclos disease) - WHO grade I. Desmoplastic infantile astrocytoma/desmoplastic infantile ganglioglioma (DIA/DIG) - WHO grade I. Dysembryoplastic neuroepithelial tumor (DNT) - WHO grade I. Gangliocytoma - WHO grade I. Ganglioglioma (GG) - WHO grade I. Anaplastic GG - WHO grade III. Central neurocytoma - WHO grade II. Extraventricular neurocytoma - WHO grade II. Cerebellar liponeurocytoma - WHO grade II. Papillary glioneuronal tumor (PGNT) - WHO grade I. Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) - WHO grade I. Paraganglioma - WHO grade I.
In the WHO classification and grading of CNS tumors, what are the entities under “tumors of the pineal region” and what are the grades?
Pineocytoma - WHO grade I. Pineal parenchymal tumor of intermediate differentiation (PPTID) - WHO grade II and III. Papillary tumor of the pineal region (PTPR) - WHO grade II and III. Pineoblastoma - WHO grade IV.
In the WHO classification and grading of CNS tumors, what are the entities under “embryonal tumors” and what are the grades?
Medulloblastoma - WHO grade IV: Desmoplastic/nodular medulloblastoma; Medulloblastoma with extensive nodularity; Anaplastic medulloblastoma; Large cell medulloblastoma. CNS PNET - WHO grade IV: CNS neuroblastoma; CNS ganglioneuroblastoma; Medulloepithelioma; Ependymoblastoma. Atypical teratoid/rhabdoid tumor (AT/RT) - WHO grade IV.
In the WHO classification and grading of CNS tumors, what are the entities under “tumors of cranial and paraspinal nerves” and what are the grades?
Schwannoma (neurilemoma, neurinomas) - WHO grade I: Cellular; Plexiform; Melanotic. Neurofibroma - WHO grade I: Plexiform. Perineurioma, NOS - WHO grade I, II, or III: Perineurioma (intraneural) - WHO grade I; Malignant perineurioma - WHO grade III. MPNST - WHO grade II or III: Epithelioid MPNST; MPNST with mesenchymal differentiation; Melanotic MPNST; MPNST with glandular differentiation.
In the WHO classification and grading of CNS tumors, what are the subtypes of meningioma and what are the grades?
Benign meningiomas (WHO grade I): Meningothelial; Fibrous (fibroblastic); Transitional (mixed); Psammomatous; Angiomatous; Microcystic; Secretory; Lymphoplasmacyte-rich; Metaplastic. Atypical meningiomas (WHO grade II): Chordoid; Clear cell; Atypical. Anaplastic (malignant) meningiomas (WHO grade III): Papillary; Rhabdoid; Anaplastic (malignant).
In the WHO classification and grading of CNS tumors, what are the entities that are WHO grade IV?
GBM: Giant cell GBM; Gliosarcoma. Pineoblastoma. All of the “embryonal tumors” category: (Medulloblastoma: Desmoplastic/nodular medulloblastoma; Medulloblastoma with extensive nodularity; Anaplastic medulloblastoma; Large cell medulloblastoma. CNS PNET: CNS neuroblastoma; CNS ganglioneuroblastoma; Medulloepithelioma; Ependymoblastoma. Atypical teratoid/rhabdoid tumor (AT/RT)).
Mesenchymal tumors account for ~3.5% of salivary gland tumors. What are the top 3 mesenchymal salivary gland tumors?
Schwannoma > lipoma > hemangioma.
Oligoclonal bands seen in CSF protein electrophoresis but not in a concurrent serum protein electrophoresis support a diagnosis of ___.
Multiple sclerosis.
What are the most common adverse events seen when correcting hyponatremia too slowly and when correcting hyponatremia too rapidly?
When correcting hyponatremia too slowly: cerebral edema. When correcting hyponatremia too rapidly: central pontine myelinolysis.
What conditions is ACD associated with?
ACD appears to be due to defective iron utilization/metabolism and is associated with chronic nonhematologic disorders such as chronic infections, connective tissue disorders, malignancy, and renal, thyroid, and pituitary disorders.
Inhalation, cutaneous, and GI anthrax can be complicated by meningitis, which occurs in about _% of cases.
Inhalation, cutaneous, and GI anthrax can be complicated by meningitis, which occurs in about 5% of cases.
How can you distinguish between a GI schwannoma and a bland spindled GIST?
GI schwannoma: commonly has a peripheral lymphoid cuff, frequent cell size variation, no skeinoid fibers, S100 positive in 100%, GFAP positive in 65-100%, CD117 negative. Bland spindled GIST: lacks peripheral lymphoid cuff, generally uniform cell size, may have skeinoid fibers, S100 positive in 5% (20% in small intestine), GFAP negative, CD117 positive in 74-95%.
What entities are in the differential diagnosis of an epithelioid GIST?
Poorly differentiated carcinoma. Melanoma/clear cell sarcoma. Glomus tumor. Gangliocytic paraganglioma. GI endocrine carcinoma. Extramedullary myeloid tumor. GI mucosal benign epithelioid nerve sheath tumor.
Infectious meningitis is divided into acute, subacute, and chronic clinical syndromes, based on duration of symptoms. What are probable pathogens based on these categories?
Acute (onset/duration of <24 hours): Pyogenic bacteria. Subacute (onset/duration of 1-7 days): Enteroviruses, pyogenic bacteria. Chronic (persisting at least 4 weeks): M. tuberculosis, T. pallidum, Brucella sp., L. interrogans, B. burgdorferi, C. neoformans, C. immitis, H. capsulatum.
What are common bacterial causes of acute meningitis by age, for neonates-3 months, 4 months-6 years, 6-45 years, and >45 years?
Neonates-3 months: Group B streptococcus, E. coli, L. monocytogenes (Listeria can cause meningitis in immunocompromised individuals in all age groups). 4 months-6 years (Incidence of meningitis due to HIB in the US has declined dramatically due to vaccination): S. pneumoniae. 6-45 years: N. meningitidis. >45 years: S. pneumoniae, L. monocytogenes, Group B streptococcus.
For CSF, in addition to smears stained with the Gram stain and bacterial culture, the supernatant of a centrifuged specimen or the original fluid may be used to perform latex agglutination tests for detection of antigens of ___.
For CSF, in addition to smears stained with the Gram stain and bacterial culture, the supernatant of a centrifuged specimen or the original fluid may be used to perform latex agglutination tests for detection of antigens of Streptococcus agalactiae, S. pneumoniae, some serotypes of Neisseria meningitidis, Escherichia coli (the K1 capsular antigen cross-reacts with that of N. meningitidis type B), and H. influenzae type b.
Currently, nucleic acid amplification tests are used most often for diagnosis of viral infections of the central nervous system. Other diagnostic methods are ___ (primarily for detection of enteroviruses, although PCR is preferred) and ___ for viruses that cause encephalitis (western equine, eastern equine, Venezuelan equine, St Louis, Japanese, and La Crosse and West Nile).
Currently, nucleic acid amplification tests are used most often for diagnosis of viral infections of the central nervous system. Other diagnostic methods are conventional cell culture (primarily for detection of enteroviruses, although PCR is preferred) and serologic tests for viruses that cause encephalitis (western equine, eastern equine, Venezuelan equine, St Louis, Japanese, and La Crosse and West Nile).
Where can intracranial xanthogranulomas be seen?
Intracranial xanthogranulomas are somewhat rare, benign lesions and occur most commonly as choroid plexus xanthogranulomas. The exact etiology is uncertain. Most xanthogranulomas of the choroid plexus arise in the lateral ventricular choroid plexus. They are usually asymptomatic incidental findings, found in 2-7% of postmortem examinations. The xanthomatous reaction usually involves the stroma of the choroid plexus, and to a lesser extent, the epithelium. Like other xanthogranulomas, these choroid plexus xanthogranulomas are composed of xanthoma cells, cholesterol clefts, giant cells, hemosiderin, fibrosis, and occasional calcium deposits.
In what locations are myxopapillary ependymomas seen?
They are seen almost exclusively near conus medullaris, cauda equina, or filum terminale, occasionally seen in cervical-thoracic spine, intraventricular, or in brain parenchyma, or rarely may arise as a subcutaneous sacrococcygeal or presacral mass.
