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.
… 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?
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?
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 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 ___.
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.
What is the PTEN gene? In what tumors is it often mutated?
Phosphatase and tensin homolog (PTEN) gene is on chromosome band 10q23.31. In addition to its role as a tumor suppressor, it has important roles in embryogenesis and maintenance of physiologic functions in many organ systems and is constitutively expressed in normal tissues. It is one of the most frequently inactivated genes in sporadic cancer. Sporadic mutations of PTEN occur frequently in many tumors such as glioblastoma, breast carcinoma, endometrial carcinoma, thyroid neoplasms, skin neoplasms, and advanced prostate cancer.
In what brain tumors can IDH1 and/or IDH2 gene mutations be seen?
Somatic mutations in the IDH1 gene (on 2q33.3, exon 4 (codon R132), mutations R132H, C, L, S, or G) encoding cytosolic NADP+ - dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas, and oligoastrocytomas of WHO grades II and III. IDH2 (on 15q26.1, exon 4 (codon R172), mutations R172G, M, or K) encoding mitochondrial NADP+ - dependent isocitrate dehydrogenase can also be mutated in gliomas, although in much lower frequencies. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and mutations inactivate enzyme activities.
By what mechanisms do gliomas with inactivation of the MGMT gene have increased sensitivity to alkylating chemotherapy?
The DNA-repair enzyme MGMT (O^6-methylguanine-DNA methyltransferase) rescues the cell from damage induced by TMZ (temozolomide) and leads to resistance to therapy. Gliomas with inactivation of the MGMT gene are less capable of repairing DNA, which leads to increased sensitivity to alkylating chemotherapy.
Giant cell glioblastoma is an uncommon subtype of glioblastoma multiforme (5% of cases). Does it have a better or worse prognosis than classic glioblastoma? Main DDx entity?
Better. Pleomorphic xanthoastrocytoma.
What entities are in the DDx of small round cell tumors of the kidney?
The differential diagnosis of small round cell tumors of the kidney includes blastema-predominant Wilms tumors, lymphoblastic lymphoma, clear cell sarcoma, small cell carcinoma, monophasic synovial sarcoma, neuroblastoma, rhabdomyosarcoma, desmoplastic round cell tumor, rhabdoid tumor and extraskeletal Ewing sarcoma/PNET.
What areas of the brain specifically are affected in kernicterus?
Bilirubin has a special affinity for the globus pallidus, the hippocampus, and the subthalamic nucleus. Many other structures, including the striatum, thalamus, cranial nerve nuclei, inferior olives and dentate nuclei of the cerebellum are less frequently affected.
CK-BB (CK1) is found primarily in the brain, with lesser amounts found in what other locations?
Stomach, bladder, and prostate.
In what locations are the natriuretic peptides ANP, BNP, and CNP produced?
ANP is synthesized mainly by atrial myocytes (but synthesis of ANP also takes place in the ventricles, brain, kidney, and adrenals). ANP is stored in granules and stimulation results in a rapid response. BNP is synthesized by ventricular myocytes (predominantly) and brain, as well as atrial myocytes under some conditions. BNP is secreted by a constitutive mechanism; only small amounts are stored and cells are dependent upon activation of the BNP gene when secretion is needed. CNP is synthesized by brain and endothelium.
What tumors are seen in patients with vHL disease?
Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.
vHL disease can be subtyped according to the clinical manifestations (although these groups often correlate with certain types of mutations present in the VHL gene). What are the subtypes?
Type 1 often has deletion or nonsense mutations. This group manifests mostly as hemangioblastomas whereas clear cell RCC and pheos are rare. Type 2 is subdivided into types 2A, 2B, and 2C, and are characterized mostly by missense mutations. Type 2A is at risk of hemangioblastomas and pheos, but not clear cell RCC. Type 2B is at risk of all 3 tumors, with a higher risk of clear cell RCC. Type 2C is at risk for only pheos. Type 3 has a risk of Chuvash polycythemia.
What tumors are seen commonly in tuberous sclerosis (the “major features” as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association)?
Facial angiofibromas (adenoma sebaceum) or forehead plaque. Nontraumatic ungual or periungual fibroma. >3 hypomelanotic macules. Shagreen patch (connective tissue nevus). Multiple retinal nodular hamartomas. Cortical tuber. Subependymal nodule. SEGA. Cardiac rhabdomyoma, single or multiple. LAM. Renal AML. Definite TSC is either 2 major features or one major plus 2 minor features.
MEN1 manifests with pituitary adenomas, parathyroid adenomas, and pancreatic islet cell tumors. What are nonendocrine lesions associated with MEN1?
Facial angiofibromas, collagenomas, lipomas, and meningiomas.
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
The Enteroviruses (coxsackie A and B, echoviruses, poliovirus) are the most common cause of aseptic meningitis in all age groups, causing up to 70% of cases. What are other viral causes of aseptic meningitis?
HSV, mumps virus, HIV, LCMV (lymphocytic choriomeningitis virus).
What is lymphocytic choriomeningitis?
LCM is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis, or meningoencephalitis. Its causative agent is the lymphocytic choriomeningitis virus, a member of the family Arenaviridae. Although LCMV is most commonly recognized as causing neurological disease, as its name implies, infection without symptoms or mild febrile illnesses are common clinical manifestations. Additionally, pregnancy-related infection has been associated with congenital hydrocephalus, chorioretinitis, and mental retardation.
What are the most common causes of meningitis in neonates?
GBS, GN aerobic bacilli (E. coli, Klebsiellae), L. monocytogenes.
What are the most common causes of meningitis in infants and young children?
N. meningitidis, S. pneumoniae, H. influenzae type B.
What are the most common causes of meningitis in adults and elderly adults?
In adults, S. pneumoniae, followed by N. meningitidis. In elderly adults, S. pneumoniae, followed by L. monocytogenes, followed by GN aerobic bacilli.
What are typical CSF findings in bacterial meningitis?
Low glucose (500 mg/dL), and high WBC (>1000/mL, predominantly neutrophils).
For the following clinical syndrome(s), give the causative agent(s) (list most common first): subacute sclerosing panencephalitis (SSPE
Measles virus (reactivation).
For the following clinical syndrome(s), give the causative agent(s) (list most common first): progressive multifocal leukoencephalopathy (PML).
Why is prealbumin a relatively prominent component of CSF protein and a sharp prealbumin band a hallmark of CSF protein electrophoresis?
Prealbumin crosses the blood-brain barrier and is actively secreted into the CSF by the choroid plexus.
The blood-brain barrier transports transferrin into the CSF, but not before modifying a percentage of it to make ___.
The blood-brain barrier transports transferrin into the CSF, but not before modifying a percentage of it to make asialated transferrin (so-called Tau protein), while the rest of it is unmodified. Thus, the double transferrin peak that is one of the hallmarks of CSF protein electrophoresis.
How is CSF electrophoresis used to diagnose multiple sclerosis?
A diagnosis of multiple sclerosis is supported by finding oligoclonal bands (several distinct bands in the gamma region reflective of several clonal immunoglobulins). These bands should be absent from the patient’s serum, run concurrently, to be specific.
What diseases/conditions can cause oligoclonal bands in CSF?
Elevations in oligoclonally expanded immunoglobulin concentrations in the CSF, termed oligoclonal bands, may occur in any disorder that disrupts the blood-brain barrier. Oligoclonal bands may also be caused by intrathecal production of IgG, and the presence of such bands is a diagnostic criterion for multiple sclerosis. Other diseases that can cause oligoclonal bands in the CSF include infections (eg, nervous system Lyme disease), autoimmune diseases, brain tumors, and lymphoproliferative diseases.
What is the name of the naturally occuring anti-diuretic hormone in humans? Where is it synthesized?
Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure to oxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary. Here, it is stored in secretory granules in association with a carrier protein, neurophysin, in the terminal dilatations of secretory neurons that rest against blood vessels.
Anti-diuretic hormone (ADH)/arginine vasopressin (AVP). What are the 2 major stimuli for its secretion?
The major stimuli for AVP secretion are hyperosmolality and effective circulating volume depletion, which are sensed by osmoreceptors and baroreceptors, respectively. Osmoreceptors are specialized cells in the hypothalamus that perceive changes in the extracellular fluid (ECF) osmolality. Baroreceptors are located in the carotid sinus, aortic arch, and left atrium; these receptors participate in the nonosmolar control of AVP release by responding to a change in effective circulating volume.
Where do herpes viruses (simplex and varicella) remain latent?
Dorsal root ganglia.
When a moving head impacts against a firm surface, the brain contusions are located (beneath/opposite) the point of impact. When a resting head is struck with an object, the contusions are located (beneath/opposite) the point of impact.
When a moving head impacts against a firm surface, the brain contusions are located opposite the point of impact. When a resting head is struck with an object, the contusions are located beneath the point of impact.
The dura is especially adherent to the inner calvaria in what ages?
The elderly and infants. This is why epidural hemorrhages are uncommon in these groups.
Why can blood from an epidural hemorrhage provide valuable toxicology information?
The epidural blood may contain valuable toxicology information particularly if the person survives for some time after the injury. Since it is relatively sequestered, the toxicology findings may best represent the state of intoxication at the time of injury as opposed to blood collected at autopsy which would have undergone normal metabolism during the interval of survival.
What specific areas of the brain are affected in central pontine myelinolysis?
Central pontine myelinolysis is a concentrated, frequently symmetric, noninflammatory demyelination within the central basis pontis. In at least 10% of patients with central pontine myelinolysis, demyelination also occurs in extrapontine regions, including the mid brain, thalamus, basal nuclei, and cerebellum.
What conditions predispose a patient to central pontine myelinolysis?
Alcoholism, malnutrition, liver disease, liver transplantation, burn patients.
In Marchiafava-Bignami disease, what specific areas of the brain are affected?
Degeneration of the corpus callosum is a cardinal feature of MBD. The anterior and posterior commissures, the centrum semiovale, the brachium pontis, and the other white-matter tracts (eg, the long association fibers and the middle cerebral peduncles) may also be affected.
What is Marchiafava-Bignami disease?
Marchiafava–Bignami disease is a progressive neurological disease characterized by corpus callosum demyelination and necrosis and subsequent atrophy. It is seen classically in chronic alcoholics.
Central pontine myelinolysis and Marchiafava-Bignami disease both involve demyelination and are often seen in chronic alcoholics. How are they different?
CPM has demyelination in the central basis pontis, while MBD has demyelination in the corpus callosum.
How can IHC for beta-amyloid precursor protein be used in the evaluation of axonal injury?
Beta-amyloid precursor protein is a neuronal transmembrane glycoprotein that is transported by fast anterograde axoplasmic flow. In an uninjured brain, the protein is diffusely distributed in the axons and is not detected by the stain. In traumatic axonal injury, tearing or stress causes damage to the neuronal cytoskeleton and interrupts axonal transport. With axonal injury, the protein accumulates focally and can be detected by the IHC stain. Ischemic injury or traumatic axonal injury may result in accumulation of the protein, so anatomic location of the staining is important for interpretation.
Beta-amyloid precursor protein needs a survival interval of at least ___ to detect neuronal injury. Histochemical stains such as silver stain need survival intervals of at least ___ to detect injured neurons.
Beta-amyloid precursor protein needs a survival interval of at least 2 hours to detect neuronal injury. Histochemical stains such as silver stain need survival intervals of at least 12 hours to detect injured neurons.
Traumatic diffuse axonal injury is typically seen in what anatomic parts of the brain?
Corpus callosum, septum pellucidum, paraventricular areas, rostral pons.
What are the only 3 ameba that can cause primary CNS infection?
Naegleria fowleri causes a rapidly fatal infection of the CNS known as primary amebic meningoencephalitis. Acanthamoeba spp and Balamuthia mandrillaris can cause granulomatous amebic encephalitis, which is a subacute or chronic infection of the CNS seen mainly in immunocompromised individuals.
What are the 3 most common intramedullary spinal cord lesions in the pediatric population?
Astrocytomas (40-60%, with low grade fibrillary astrocytomas (WHO grade II) being more common than pilocytic astrocytomas (WHO grade I)). Ependymomas (20-30%). Gangliogliomas (15-27%).
What are Rosenthal fibers?
Rosenthal fibers are eosinophilic intracellular rod, beaded, or corkscrew-shaped inclusions. Measurements range from 0.5-25 μm in width and 30 μm in length, to 10–40 μm in width and 100 μm in length. By EM, the fibers correspond to intracellular non-membrane bound protein deposits associated with groups of intermediate filaments including GFAP, associated with chaperone proteins. They have been described in reactive tissue (such as the highly gliotic tissue surrounding cysts and vascular malformations), in neoplasms (such as juvenile pilocytic astrocytomas), and in Alexander disease.
What is Alexander disease?
AKA fibrinoid leukodystrophy, is a rare leukodystrophy with 3 clinical phenotypes: infantile (63%), juvenile (24%), and adult (13%). The majority of infantile and juvenile types are caused by a heterozygous (dominant) gain of function mutation in the gene encoding GFAP, located on chromosome 17q21.
What is the histologic appearance of Alexander disease AKA fibrinoid leukodystrophy?
The disease is characterized by dysmyelination and widespread accumulation of Rosenthal fibers in a subpial, subependymal, and perivascular distribution. Early in the disease process, Rosenthal fibers are noted in astrocyte cell bodies, but later accumulate in the astrocyte processes and end-feet in the subpial and perivascular locations. These findings are accompanied by gliosis and myelin disintegration, but no macrophages, as in multiple sclerosis or subacute infarcts. The areas of Rosenthal fiber accumulation do not correlate necessarily with areas of dysmyelination.
By EM, Rosenthal fibers correspond to intracellular non-membrane bound protein deposits associated with groups of intermediate filaments including GFAP, associated with chaperone proteins. What specific chaperone proteins?
The chaperone protein component is predominantly alpha/beta-crystallin (a heat shock protein normally expressed at low levels in astrocytes and oligodendrocytes), hsp27 (another small heat shock protein), and ubiquitin (a protein that regulates nonlysosomal degradation of other proteins). All of these proteins are considered “stress proteins” which accumulate in settings of metabolic stress, such as heat shock or hypoxia.
What is the mutation seen in Alexander disease AKA fibrinoid leukodystrophy?
Alexander disease has 3 clinical phenotypes: infantile (63%), juvenile (24%), and adult (13%). The majority of infantile and juvenile types are caused by a heterozygous (dominant) gain of function mutation in the gene encoding GFAP, located on chromosome 17q21. These mutations are typically sporadic and de novo. In Alexander disease, a heterozygous missense mutation in the GFAP gene appears to interfere with polymerization of the protein, and results in abnormal protein folding with overexpression and accumulation of the abnormal GFAP protein within Rosenthal fibers.
There are >20 known human diseases of intermediate filaments involving the keratins, desmin, lamin A/C, neurofilament, phakinin, and GFAP. Which disease differs from all other known intermediate filament disorders in that there is a gain of function mutation, rather than a loss of function mutation?
Alexander disease AKA fibrinoid leukodystrophy.
What brain tumors are associated with the following syndromes? Turcot syndrome (recently renamed Crail syndrome)/APC gene mutations. Tuberous sclerosis. Von Hippel Lindau disease. Li-Fraumeni syndrome. NF type 1. NF type 2. Gorlin syndrome.
Turcot syndrome (recently renamed Crail syndrome)/APC gene mutations: medulloblastoma, rarely ependymoma. Tuberous sclerosis: subependymal giant cell astrocytoma. Von Hippel Lindau disease: hemangioblastoma. Li-Fraumeni syndrome (with germline TP53 mutations): medulloblastoma, astrocytic tumors, meningioma, schwannoma, choroid plexus tumors, and central PNET. NF type 1: optic glioma, astrocytoma, glioblastoma multiforme. NF type 2: multiple meningiomas, bilateral vestibular schwannomas, spinal ependymomas. Gorlin syndrome: desmoplastic/nodular variant of medulloblastoma.
What is fibrolipomatous hamartoma AKA fibrolipomatous hamartoma of nerve AKA lipofibromatous hamartoma of nerve AKA neural lipofibroma AKA neurolipomatosis AKA lipomatosis of nerve?
Increased fibrofatty tissue infiltrating and surrounding nerves. Seen predominantly in children. Affects palmar surface of hand, wrist, or forearm, with median nerve and branches most commonly affected. Histologic appearance: Adipose tissue and fibrous tissue infiltrating around and between nerve branches and along perineurium. Epineurial and perineurial fibrous thickening. Perineurium can become hyperplastic (concentric layers, “onion bulb” intraneural hyperplasia). Nerve bundles become separated, atrophic in longstanding cases. DDx: Lipoma of nerve (circumscribed and confined within nerve). Neurofibroma (proliferation of neural elements with no fatty component). Neuroma (increased number of nerve bundles with no fatty component). Lipomatosis (usually affects skin and subcutis and spares nerves).
Loss of what protein/mutation of what gene is seen in atypical teratoid rhabdoid tumor?
ATRTs are highly malignant (WHO grade IV) CNS neoplasms seen in very young children. INI1 is a ubiquitously expressed protein encoded by the hSNF5/INI1 gene on chromosome 22q11.2. Mutations in this gene are seen in ATRT. Cytogenetic studies often show monosomy or deletion of chromosome 22; however, this is not as specific or sensitive as IHC, since other tumors with complex karyotypes may show loss of 22 in addition to other events, and the INI1 gene may be mutated by a mechanism other than deletion (i.e. point mutations) not detectable by FISH or LOH studies. The presence of an hSNF5/INI1 gene mutation or loss of the INI1 protein expression by IHC is sufficient to confer a diagnosis of ATRT.
In addition to colorectal polyps, ~__% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (__%), congenital hypertrophy of the retinal pigment epithelium (__%), desmoid-type fibromatosis (__%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (__x), duodenal carcinoma (__x), ampullary carcinoma (__x), nasopharyngeal adenofibroma (__x), thyroid carcinoma (__x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (__x), and pancreatic carcinoma (__x).
In addition to colorectal polyps, ~90% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (80%), congenital hypertrophy of the retinal pigment epithelium (70-80%), desmoid-type fibromatosis (15%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (847x), duodenal carcinoma (330x), ampullary carcinoma (123x), nasopharyngeal adenofibroma (25x), thyroid carcinoma (7.6x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (7x), and pancreatic carcinoma (4x).
Which of these glycosphingolipid lysosomal storage diseases cause neurodegeneration? Fabry disease. Gaucher disease type II. GM1 gangliosidosis. GM2 gangliosidosis (Sandhoff disease, Tay-Sachs disease).
All except for Fabry disease.
Which of the following storage diseases have a positive Luxol Fast Blue stain? Gaucher disease type II. Neuronal ceroid lipofuscinosis. GM1 gangliosidosis. GM2 gangliosidosis (Sandhoff disease, Tay-Sachs disease). Niemann-Pick disease.
All except for Gaucher disease type II.
What is GM1 gangliosidosis?
An AR lysosomal storage disorder caused by deficiency of the beta-galactosidase enzyme due to mutations in the GLB1 gene on chromosome 3p. The function of the enzyme is to hydrolyze the terminal beta-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans. Without the enzyme function, GM1 gangliosides accumulate in lysosomes of various tissues, particularly the CNS. The 3 clinical phenotypes are: type 1 (infantile), type 2 (late infantile or juvenile), and type 3 (adult or chronic).
~__% of MPNSTs arise from neurofibromas. ~__% of MPNSTs arise in the setting of neurofibromatosis type 1.
~66% of MPNSTs arise from neurofibromas, often of the plexiform type. ~25-75% of MPNSTs arise in the setting of neurofibromatosis type 1.
What are the 3 histologic variants of MPNST, and which are associated with NF1?
Epithelioid variant, glandular variant, and malignant triton tumor (MTT)/MPNST with rhabdomyosarcomatous differentiation. The epithelioid variant is rare and not associated with NF1. The glandular variant contains foci of gland-forming epithelium that resembles intestine and may be keratin- and/or CEA-positive, often with intra- or extracellular mucin. Scattered NE cells immunoreactive for chromogranin, somatostatin, and serotonin are also a common finding. ~75% are associated with NF1. The MTT is 3-4x more common than the glandular variant and is often characterized by divergent mesenchymal differentiation with areas of chondrosarcoma, osteosarcoma, or epithelial glands. ~60% are associated with NF1.
What genetic abnormalities are seen in sporadic MPNST and in NF1-associated MPNST?
Both typically have complex karyotypic abnormalities that are both numerical and structural, but no consistent karyotypic pattern has been identified. On a molecular level, homozygous deletions of the CDKN2A gene, which encodes the p16 cell cycle inhibitory molecule, occurs in the progression of neurofibromas to MPNST, being identified in ~50% of MPNST but not in neurofibromas.
The IDH1 gene is mutated in __% of primary GBMs and in __% of secondary GBMs.
The IDH1 gene is mutated in 80% of secondary GBMs.
What is a composite pheochromocytoma/paraganglioma?
The term composite is used when a tumor combines features of pheochromocytoma or paraganglioma with those of MPNST, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Corticomedullary tumors, cauda equina paragangliomas showing ependymal differentiation, as well as gangliocytic paragangliomas that include Schwann-like cells and ganglion cells do not qualify as composite tumors. Moreover, scattered mature ganglion cells seen in pheochromocytomas/paragangliomas should not be misinterpreted as a component of a composite tumor.
What is the most frequent autoimmune disorder associated with ovarian teratomas?
Autoimmune encephalitis due to antibodies against the N-methyl-D-aspartate receptor (anti-NMDAR), a condition that frequently involves temporal lobes and hippocampus.
Its recognition is important, as removal of the ovarian tumor and early immunosuppressive therapy will often improve the outcome, with full recovery or only a residual mild neurologic deficit.
Lymphomatoid granulomatosis most commonly presents as multiple pulmonary nodules. What are other common sites of involvement?
Brain, kidney, liver, and skin.
What % of primary GBMs and secondary GBMs show: IDH mutations, MGMT methylation, EGFR mutation/amplification, 10q LOH, and PTEN mutations?
Primary GBMs: <5%.
Ethylene glycol is metabolized to what 3 metabolites by the action of alcohol dehydrogenase and aldehyde dehydrogenase? What do these metabolites cause?
Ethylene glycol is metabolized to glycolate, glyoxylate, and oxalate. The parent alcohol (ethylene glycol itself) is relatively nontoxic. The glycolate is responsible for the CNS manifestations and for the anion gap acidosis. Oxalate binds calcium to produce calcium oxalate, which is deposited in tissues, with the process often resulting in hypocalcemia. ARF is primarily due to glycolate-induced damage to tubules, although tubule obstruction from precipitated oxalate crystals may contribute.
Methanol is metabolized to what 2 metabolites by alcohol dehydrogenase and aldehyde dehydrogenase? What do these metabolites cause?
Methanol is metabolized to formaldehyde and formate. The parent alcohol (methanol itself) is relatively nontoxic. Formate causes retinal injury with optic disc hyperemia, edema, and eventually permanent blindness, as well as ischemic or hemorrhagic injury to the basal ganglia. These changes are postulated to result from disruption of mitochondrial function. The metabolites result in the anion gap acidosis and osmolal gap.
What neurologic complications are seen in sickle cell disease?
Neurologic complications are frequent in sickle cell disease, manifesting as TIA, cerebral infarcts, cerebral hemorrhage, cord infarction, sensorineural hearing loss, and meningitis. About 1 in 3 patients will have an angiographic appearance of moyamoya disease (segmental arterial stenoses with “puff of smoke” collaterals).
How does aspirin exert conflicting effects upon acid-base balance?
Aspirin directly stimulates the respiratory center in the medulla oblongata, promoting respiratory alkalosis. Also, aspirin uncouples oxidative phosphorylation and inhibits the Krebs cycle, shunting energy production towards anaerobic pathways with accumulation of organic acids including lactic acid and ketoacids, promoting metabolic acidosis.
What is the mechanism of arsenic toxicity, and what are clinical manifestations?
Arsenic inhibits the oxidative production of ATP. Thus, initial toxicity is manifested in dividing tissue such as GI mucosa, with nausea, vomiting, bloody diarrhea, and abdominal pain. The marrow is affected, causing cytopenias (with erythrocyte basophilic stippling similar to that seen in lead toxicity). Chronic toxicity results in peripheral neuropathy, nephropathy, skin hyperpigmentation and hyperkeratosis (particularly palms and soles) and transverse Mees lines in the nails.
The major adverse consequences of tricyclic overdose take place within the CNS and cardiac systems. Describe.
CNS: sedation, coma, seizures. Cardiac: tachycardia, hypotension, conduction abnormalities (V tach and V fib, particularly when QRS prolongation is present). A QRS interval longer than 0.16 sec is strongly associated with arrhythmia, while a QRS interval longer than 0.1 sec is associated with a high risk of seizures.
What are acrodynia and erethism?
Conditions that result from chronic exposure to mercury. Other names for acrodynia are hydrargyria, mercurialism, erythredema, erythredema polyneuropathy, Pink’s disease, Bilderbeck’s disease, Selter’s disease, Swift’s disease, Swift-Feer disease, and Feer syndrome. Another name for erethism is erethism mercurialis.
What symptoms are seen in acrodynia (AKA hydrargyria, mercurialism, erythredema, erythredema polyneuropathy, Pink’s disease, Bilderbeck’s disease, Selter’s disease, Swift’s disease, Swift-Feer disease, and Feer syndrome)?
Acrodynia results from chronic exposure to mercury and occurs most often in infants and young children. Symptoms include irritability, photophobia, polyneuritis, autonomic manifestations (sweating, hemodynamic instability), and a desquamative erythematous rash on the palms and soles. It is associated with increased urinary catecholamines and can in many ways mimic pheochromocytoma. The presentation may also be similar to Kawasaki disease.
What symptoms are seen in erethism AKA erethism mercurialis?
Erethism (from French erethisme - abnormal irritability or responsiveness to stimulation) is a neurological disorder resulting from chronic exposure to mercury. Symptoms include irritability, depression, personality changes, memory loss, delirium, and fine motor disturbances.
What are the biochemokinetics of mercury toxicity in its metallic/elemental, inorganic, and organic forms?
Pulmonary absorption of mercury vapor (elemental form) is high; however, this form of mercury is only poorly absorbed from the GI tract and across the skin. The kidney is the major site of deposition for mercury derived from inhalation exposure of mercury vapor. A significant fraction of the mercury vapor taken into the lung is eliminated via exhalation; most of the absorbed mercury is eliminated in the feces. GI absorption of inorganic mercury is on the order of 15 percent. The kidney is the major site of deposition for inorganic mercury compounds. Organic mercury compounds such as methylmercury are highly absorbed from the GI tract and later de-alkylated. The kidney, hair, and CNS are major sites of deposition. Organic mercury readily crosses the placenta, causing severe neurologic impairments in the fetus.
What are symptoms of exposure to organic mercury?
Clinical manifestations include paresthesias around the mouth, peripheral neuropathy, tremor, malaise, constriction of the visual field, deafness, and ataxia. The fetus is particularly vulnerable (organic mercury crosses the placenta readily), even if the pregnant mother shows no signs of toxicity.
Systemic forms of amyloidosis, most frequently caused by the deposition of AA, AL, or sometimes ATTR amyloid variants, typically (do/do not) affect cerebral arteries.
Systemic forms of amyloidosis, most frequently caused by the deposition of AA, AL, or sometimes ATTR amyloid variants, typically do not affect cerebral arteries. Cerebral amyloid deposits are characteristically of the “beta” type and limited to the brain.
The polyoma viruses JC virus and BK virus are typically acquired in childhood and enter latency. If immunosuppression occurs, viral reactivation may lead to progressive multifocal leukoencephalopathy due to JC virus or hemorrhagic cystitis due to BK virus. What cells show viral inclusions in each entitiy?
Urothelial cells with BK virus. Oligodendroglial cells with JC virus.
Astroblastoma and anaplastic astroblastoma WHO grades?
No WHO grades are assigned for astroblastoma or anaplastic astroblastoma.
What are the clinical syndromes caused by measles virus infection?
Classic measles infection in immunocompetent patients. Modified measles (an attenuated infection in patients with preexisting, but incompletely protective, anti-measles antibody). Atypical measles (in patients immunized with the killed virus vaccine and subsequently exposed to wild-type measles virus; is rare since the killed virus vaccine was used in the US from 1963-67). Neurologic syndromes following measles infection, including acute disseminated encephalomyelitis (ADEM) and subacute sclerosing panencephalitis (SSPE). Severe measles. Complications of measles including secondary infection, giant cell pneumonia, and measles inclusion body encephalitis.
What is the risk of subacute sclerosing panencephalitis with natural measles infection vs. after receiving measles vaccination.
With natural infection, the risk of SSPE is 0.001% (with higher risk if measles is acquired at an early age), with an incubation period of 7-10 yrs. With vaccination, the risk of SSPE is 0.0001% with an incubation period of 3 yrs.
Enteroviruses are the most common cause of viral meningitis (aseptic meningitis). What technique is the gold standard for making the Dx of enterovirus in CSF?
RT-PCR. It demonstrates excellent sensitivity and same-day turnaround time. Cell culture should be performed as well, in case the PCR test is negative.
What can cause spongiform changes in the brain?
Many vacuoles in the neuropil are characteristic of transmissible spongiform encephalopathies. Spongiform changes can be seen in the neocortex in ALS dementia and occasionally in Alzheimer’s and Lewy body diseases, but the sponginess is restricted to the upper cortical layers and is far more irregular than in TSEs. Infarcts would also be spongy, particularly at an early edematous stage, but the sponginess would be more irregular, and one would also see acute eosinophilic changes in neurons or tissue necrosis.
What conditions are caused by mutations in the PTCH1/patched 1 gene?
More than 225 mutations in PTCH1 have been found to cause Gorlin syndrome/nevoid basal cell carcinoma syndrome. Somatic mutations are associated with sporadic basal cell carcinoma, medulloblastoma, breast cancer, colon cancer, and keratocystic odontogenic tumors. At least seven mutations in PTCH1 have been found to cause nonsyndromic holoprosencephaly.
What are Alzheimer type II astrocytes?
Acute hepatic encephalopathy, whether acquired or in Wilson disease, shows Alzheimer type II astrocytes. These astrocytes have enlarged nuclei with clear marginated chromatin, eccentric nucleolus, and scant cytoplasm. They may be found in the deep cerebral cortex, basal ganglia, thalamus, dentate nucleus of the cerebellum and brain stem. They are not associated with Alzheimer’s disease.
Alzheimer type II astrocytes are astrocytes that have enlarged nuclei with clear marginated chromatin, eccentric nucleolus, and scant cytoplasm. They may be found in the deep cerebral cortex, basal ganglia, thalamus, dentate nucleus of the cerebellum and brain stem. They are not associated with Alzheimer’s disease. In what disorders/conditions are they seen?
Acute hepatic encephalopathy, whether acquired or in Wilson disease.
What is the characteristic histologic lesion seen with myelin stains in acute disseminated encephalomyelitis?
Acute disseminated encephalomyelitis is an acute postviral or postvaccinal demyelinating disease. The typical lesion seen is a perivenular demyelination.
Cryptococcal meningitis causes (marked/little) inflammatory reaction in the meninges.
Cryptococcal meningitis causes little inflammatory reaction in the meninges.
True or false. Medulloblastomas are composed of primitive cells that may show features of neuronal or glial differentiation. Rare tumors contain mutations in the patched gene, an important regulator of sonic hedgehog signaling. Tumor cells tend to be dyscohesive, and seeding through the CSF pathways is common.
What is periventricular leukomalacia?
PVL refers to injury of cerebral white matter that occurs in a characteristic distribution and consists of periventricular focal necrosis, with subsequent cystic formation, and more diffuse cerebral white matter injury. It can be caused by ischemia or infection. It is the major form of brain white matter injury that affects premature infants, and is associated with the subsequent development of cerebral palsy, intellectual impairment, and visual disturbances.
Intraventricular hemorrhage (AKA subependymal or germinal matrix hemorrhage) is an important cause of brain injury in premature infants. What is the pathogenesis?
Pathogenesis is twofold: Germinal matrix fragility from the lack of structural support of rete of immature blood vessels due to immaturity. Disturbances of cerebral blood flow, particularly ischemia-reperfusion, increased arterial flow, or increased venous pressure.
Intraventricular hemorrhage (AKA subependymal or germinal matrix hemorrhage) is an important cause of brain injury in premature infants. What is the specific location of hemorrhage?
In preterm infants, the site of origin of bleeding is generally the subependymal germinal matrix, which is located between the caudate nucleus and the thalamus at the level of the foramen of Monro (“subventricular zones at the angles of the lateral ventricles at the coronal level of the head of the caudate nucleus”). In term infants, the locations may be more variable.
What CNS cell types do the following organisms infect: rabies virus, CMV, HIV, JC virus, HSV1?
Rabies - hippocampal pyramidal cells, neurons of the cerebral cortex, Purkinje cells. CMV - ependymal cells. HIV - cerebral microglial/monocyte/macrophage cells. JC virus - oligodendrocytes, astrocytes. HSV1 - cortical neurons.
True or false. Amyloid deposition in cerebral vessels is related to the degree of hypertension.
False. Amyloid deposition is not known to be associated with hypertension.
What are conditions associated with a positive ANA?
SLE, other autoimmune diseases (Sjogren syndrome, scleroderma, RA), multiple sclerosis, infections, malignancies, and fibromyalgia.
What diseases are associated with the following HLA types: HLA-DR2, HLA-DR3, HLA-DR4, HLA-B27?
HLA-DR2: multiple sclerosis, narcolepsy, protective for IDDM. HLA-DR3: SLE, Sjogren syndrome, myasthenia gravis, Graves disease (The DR3-DQ2 linkage is associated with IDDM, dermatitis herpetiformis, and celiac disease). HLA-DR4: IDDM, RA, pemphigus vulgaris. HLA-B27: ankylosing spondylitis and other “reactive” arthritidies.
Cutaneous meningioma. What are the 3 types?
Cutaneous meningioma is a rare tumor that most commonly occurs on the scalp and occurs in both congenital and acquired forms. The classification system divides cutaneous meningiomas into 3 types. Type I is the congenital type that is present at birth and generally occurs on the scalp and paravertebral regions. Type I tumors develop from ectopic arachnoid cells (meningothelial cells) that become trapped in the dermis and subcutis during development. This results from the failure of neural tube closure to completely trap all neural elements. Type II tumors consist of ectopic soft tissue meningiomas that extend to the skin by contiguity. These tend to occur around the eyes, ears, nose, and mouth. An important finding in this type of cutaneous meningioma is the lack of corresponding meningioma of the neuroaxis. Type III tumors are those that have extended into the dermis or subcutis from a primary meningioma that involves the neuroaxis (ie, a primary intracranial meningioma). Type III lesions are primary meningeal tumors that secondarily involve the skin by direct extension of underlying tumors through bone, traumatic defects, or surgical defects.
Cutaneous meningioma. How do they present clinically? What are gross and microscopic appearances? What entities are in the DDx? IHC?
Clinically, cutaneous meningiomas present as firm painless subcutaneous nodules ranging in color from pallid to slightly dark. Lesions demonstrating both alopecia and hypertrichosis have been described. Grossly, lesions are solitary, firm, gray/white nodules. Microscopically, most primary lesions (type I) show meningothelial cells in nests and with psammoma bodies, as well as structures resembling psammoma bodies but lacking calcification (collagen bodies). Acquired lesions (types II and III) tend to have similar cytologic detail as congenital lesions but usually have less collagen, are more lobulated and cellular, and extend higher into the dermis. DDx for cutaneous meningioma is broad and includes nevus sebaceous, cyst, fibroma, glioma, hemangioma, lipoma, scar, verrucous hamartoma, and alopecia areata. IHC is positive for EMA and vimentin, and negative for keratins.
Huntington’s disease produces neuronal loss and gliosis in what part of the brain?
Adrenoleukodystrophy produces elevated levels of ___ in the tissues and serum. Low ___ levels are characteristic of metachromatic leukodystrophy. ___ activity is low in Krabbe’s leukodystrophy.
Adrenoleukodystrophy (and other diseases of the peroxisome such as Refsum’s disease and Zellweger’s hepatorenal encephalopathy) produces elevated levels of very long chain fatty acids in the tissues and serum. Low sulfatase levels are characteristic of metachromatic leukodystrophy. Beta-galactosidase activity is low in Krabbe’s leukodystrophy.
Pyruvate decarboxylase deficiency (some forms of Leigh’s disease) shows what characteristic histologic changes in the brain?
Neuronal loss and hypervascularity in periaqueductal nuclei of the midbrain.
Progressive supranuclear palsy, a degenerative movement disorder, shows what characteristic histologic changes in the brain?
Neuronal cell loss and neurofibrillary tangle formation in a number of deep hemispheric and brainstem nuclei, including the subthalamic nucleus and periaqueductal gray matter.
Multiple system atrophy refers to a group of degenerative disorders that present clinically with a variety of autonomic, parkinsonian and abnormal cerebellar signs and symptoms. What characteristic histologic changes in the brain are seen?
Inclusions in oligodendrocyte cytoplasm (glial cytoplasmic inclusions), silver staining alpha-synuclein- and ubiquitin-positive filamentous structures.
Usually, __ mL to __ mL of a rapidly expanding mass, such as an epidural hemorrhage or large infarct, is needed to cause uncal herniation.
Usually, 60 mL to 75 mL of a rapidly expanding mass, such as an epidural hemorrhage or large infarct, is needed to cause uncal herniation.
What is the NeuN immunostain? What entities does it stain?
The Ab recognizes the DNA binding neuron-specific protein NeuN (NEUronal Nuclei). Positive normal staining is seen in mature postmitotic neurons. Positive staining in disease is seen in epithelioid GBMs (100%), central neurocytomas (87%), supratentorial pediatric ependymoma, neuroendocrine carcinoma (50-90%), and amyloid bodies. No/reduced NeuN expression is associated with immature/diseased neurons. Negative staining in cerebellar Purkinje cells and Golgi cells, olfactory Mitral cells, retinal photoreceptors, pilocytic astrocytoma and oligodendroglioma. Negative/weak staining seen in neurons of substantia nigra.
Cells from primary CNS tumors are infrequently present in CSF specimens. Exceptions to this include what 3 malignancies?
Medulloblastomas, intracranial neuroblastomas, and retinoblastomas, which commonly shed cells into the CSF. Malignant cells appear relatively monotonous, with hyperchromatic nuclei, scanty cytoplasm and often prominent nucleoli.
What is Mollaret’s meningitis?
Mollaret’s meningitis is a form of recurrent benign aseptic/lymphocytic meningitis, an uncommon illness characterized by greater than three episodes of fever and meningismus lasting two to five days, followed by spontaneous resolution. The most common etiologic agent in Mollaret’s meningitis is HSV, especially HSV-2, although some patients do not have evidence of genital lesions at the time of presentation. Also, noninfectious etiologies for Mollaret’s meningitis have also been proposed (intracranial epidermoid cyst or other cystic abnormalities in the brain with intermittent leakage causing meningeal irritation).
Mollaret’s meningitis is a form of recurrent benign aseptic/lymphocytic meningitis, an uncommon illness characterized by greater than three episodes of fever and meningismus lasting two to five days, followed by spontaneous resolution. What is the etiology?
The most common etiologic agent in Mollaret’s meningitis is HSV, especially HSV-2, although some patients do not have evidence of genital lesions at the time of presentation. Also, noninfectious etiologies for Mollaret’s meningitis have also been proposed (intracranial epidermoid cyst or other cystic abnormalities in the brain with intermittent leakage causing meningeal irritation).
What is seen on CSF cytology in Mollaret’s meningitis?
Cytologic findings are nonspecific, but there is often a markedly increased cellularity with pleocytosis, and marked predominance of monocytes. So-called “Mollaret cells,” monocytes with deep nuclear clefts that impart a footprint-like appearance to the nucleus, are seen within the first 24 hours of the onset of symptoms. They are characteristic of but not specific for MM; they can be seen in other diseases like sarcoidois and Behcet disease. The background shows mostly small mature lymphocytes, but plasma cells and neutrophils can be seen as well.
Intraocular medulloepithelioma. Epidemiology.
Intraocular medulloepithelioma is a congenital tumor of the nonpigmented ciliary epithelium, usually diagnosed in childhood. Rare in comparison to retinoblastoma, medulloepithelioma is still the second most common primary intraocular neoplasm during the first decade of life. Intraocular medulloepithelioma shares many histopathologic feature with medulloepithelioma of the CNS, but its overall prognosis is considerably better. There is no gender or race predilection, and it is not associated with any congenital malformation or cytogenetic abnormality.
Intraocular medulloepithelioma. Microscopic appearance.
Microscopically, the tumor is characterized by cords of primitive pseudostratified neuroepithelial cells that resemble the embryonic retina or neural tube, surrounded by a loose mesenchymal tissue rich in hyaluronic acid. The neuroepithelial surface facing the stroma is lined by a thin basement membrane, corresponding to the internal limiting membrane of the neurosensory retina. The opposite surface is lined by a series of terminal bars, which corresponds to the external limiting membrane of the neurosensory retina. When the medullary epithelium folds so that the vitreous surface faces inwards, it creates cysts rich in hyaluronic acid. Such proliferating cysts can detach from the main tumor and appear as free-floating cysts in the anterior or posterior segment of the eye. The spaces between anastomosing cords of neuroepithelial cells may be filled in with sheets of undifferentiated neuroblasts, indistinguishable microscopically from from cells seen in retinoblastoma. Both Homer Wright and Flexner-Wintersteiner rosettes can be observed among undifferentiated neuroblasts. Neuroepithelial tubules and absence of calcifications are also features of medulloepithelioma not found in retinoblastoma. The designation teratoid medulloepithelioma applies when heteroplastic tissue is present. More than a third of medulloepitheliomas contain heteroplastic elements. Mature hyaline cartilage is the most common heteroplastic element, but neuroglial tissue resembling disorganized brain and rhabdomyoblasts also can be seen. Nonteratoid and teratoid medulloepitheliomas can both be either benign or malignant. The diagnosis of malignant medulloepithelioma is based on the presence of undifferentiated neuroblastic cells, high mitotic rate, and tissue invasion. IHC has different patterns of reactivity depending on whether the tissue of interest is neuroepithelial or heteroplastic. The nonteratoid component is typically positive for vimentin and NSE.
After a bite from an animal with rabies, the virus travels by retrograde axoplasmic flow from the bite site to the CNS. At autopsy, the virus may be detected in practically any tissue. Where, however, is the primary site of replication?
Histologic appearance of neurocysticercosis.
Histologically, cysticerci manifest 4 distinct stages in addition to the racemose form. The vesicular stage consists of vesicles with viable organisms. Each viable organism is composed of a larva containing an invaginated scolex (head) and is surrounded by translucent fluid that is lined by a thin membranous wall. The reactive inflammatory response and associated changes, which are most likely to correlate with clinical symptoms, are usually not elicited with viable cysticerci but instead are found with degenerating cysts. The inflammatory response induced by degnerating cysticerci consists predominantly of lymphocytes and plasma cells, with variable edema, gliosis, fibrosis, and necrosis. The degeneration process begins with the colloidal stage. The vesicle fluid becomes more turbid and the larvae become hyalinized. The inflammatory infiltrate becomes more intense, extending to surrounding structures, and includes lymphocytes, some neutrophils and eosinophils, and the formation of multinucleated histiocytic giant cells. The reactive inflammatory process can cause arteritis, arachnoiditis, and ependymitis. The granular-nodular stage involves progressive degenerative changes with increased larval decay, vesicle involution, and thickening of the vesicle wall. The larvae in this stage begin to mineralize with calcium. The degenerative process ends with the nodular-calcified stage. In this stage, cysticerci are replaced by collagen and calcify. Although this stage is associated with decreased inflammation, foreign body giant cells and gliosis may persist. The racemose form of neurocysticercosis most likely represents cysticercal decay with cyst enlargement and hydropic changes. Racemose cysticerci usually do not contain scolices and are considered nonviable encysted organisms. The degenerated vesicle wall is characteristically convoluted with extenal bulbous projections and evokes an inflammatory response. The associated reactive process elicited by the racemose form can also cause meningitis. The racemose form has a high mortality rate.
Gross appearance of neurocysticercosis.
Grossly, cysticerci are round to oval, contain semitranslucent to whitish fluid, and usually measure 1-2 cm. The number of cysts can range from one to several hundred. Cysticerci are most commonly located in the cerebrum (91%) but can form in the ventricles (6%) and the subarachnoid space (2%). Spinal cord involvement is rare (0.2%). Other nonspecific neurocysticercosis findings include cerebral edema and compression. The racemose form of neurocysticercosis consists of a single large visicle or mass of vesicles that often resembles a cluster of grapes and may measure up to 10 cm. This expansive type of neurocysticercosis accounts for 10% of cases and is most frequently found in the basal cisterns, Sylvian fissure, and ventricles. This form of neurocysticercosis can extend into the brain parenchyma and is associated with obstructive hydrocephalus.
In the WHO classification of tumors of peripheral nerves, what entities fall under the categories of intermediate (locally aggressive), intermediate (rarely metastasizing), and malignant?
Intermediate (locally aggressive): none. Intermediate (rarely metastasizing): none. Malignant: malignant peripheral nerve sheath tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, ectomesenchymoma.
What is Lafora body disease?
Lafora body disease is a rare and severe form of progressive myoclonic epilepsy. This autosomal recessive disorder, with onset occurring between the ages of 10 and 18, is characterized by a course of generalized seizures followed by progressively worsening myoclonus, cognitive decline leading to dementia, and eventual death within 10 years. While the clinical course is distinctive, the diagnosis must usually be confirmed by demonstrating pathognomonic Lafora bodies, which are aggregates of polyglucosan, poorly constructed glycogen molecules with long strands that make them insoluble. Skin biopsy is the preferred method for diagnosis, and shows PAS positive inclusions in peripheral cells of eccrine sweat ducts and within peripheral nerves.
Malignant peripheral nerve sheath tumors. What % arise from preexisting neurofibromas vs de novo? What % are associated with NF1?
33-50% are thought to arise from preexisting neurofibromas, and 50% arise de novo. 50% of MPNSTs are associated with NF1.
What is the trinucleotide repeat that expands in Huntington disease?
Alleles in the HTT gene for Huntington disease are classified as normal, intermediate, or HD-causing depending on the number of CAG repeats. What numbers of repeats are normal, intermediate, and disease-causing?
Normal: 26 or fewer CAG repeats. Intermediate (also called “mutable normal alleles”): 27-35 CAG repeats. HD-causing alleles are subclassified into reduced penetrance (36-39 CAG repeats) and full penetrance (40 or more CAG repeats).
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type _), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type _).
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]).
What is the gene that is affected in Niemann-Pick disease types A and B?
SMPD1 (sphingomyelin phosphodiesterase 1).
The gene affected in Niemann-Pick disease types A and B is SMPD1 (sphingomyelin phosphodiesterase 1). What are the normal and abnormal gene products?
Normal gene product: Acid sphingomyelinase (sphingomyelin phosphodiesterase) is a lysosomal enzyme responsible for hydrolyzing sphingomyelin to ceramide and phosphorylcholine. Abnormal gene product: SMPD1 pathogenic variants result in an enzyme with altered activity that leads to decreased hydrolysis of the substrate and its subsequent accumulation in cells, particularly in the monocyte macrophage system.
IDH1/2 is mutated in 80% of grade II‐III astrocytomas and oligodendrogliomas, and >90% of secondary GBMs. The wild type enzyme converts isocitrate to alpha-ketoglutarate while the mutant converts it to ___.
IDH1/2 is mutated in 80% of grade II‐III astrocytomas and oligodendrogliomas, and >90% of secondary GBMs. The wild type enzyme converts isocitrate to alpha-ketoglutarate while the mutant converts it to D‐2-hydroxyglutarate.
What is Crail syndrome?
The condition of young-onset colonic polyposis and brain tumors originally termed Turcot’s syndrome has been reclassified into 2 conditions depending on the underlying genetic condition. Brain tumors, typically medulloblastomas, in association with FAP-related colonic polyposis, is now termed Crail’s syndrome. Lynch syndrome (HNPCC) in association with glioblastomas are properly classified as Turcot’s syndrome.