17Pathology/Histology
B The basal membrane thickens, and the internal elastic lamina fragments.
In cerebral amyloid angiopathy, amyloid deposits form in the walls of vessels, making them friable and prone to hemorrhage. Congo red staining reveals the amyloid deposits.
B Multiple sclerosis
Multiple sclerosis is a demyelinating disease (thus causing white matter pathology). Histologically, demyelination is seen along with a paucity of oligodendrocytes. Newly demyelinated axons are irregularly dilated and nonuniform. There is an infiltration of lymphocytes in active lesions. (A) In Creutzfeldt-Jakob disease, there are spongiform changes of the gray matter, with a loss of neurons and gliosis. Amyloid-like plaques also can be seen. (C) In subacute cerebral infarctions, macrophages predominate (after the neutrophils of acute infarctions), and neural cytoplasm is eosinophilic with pyknotic nuclei. Numerous reactive astrocytes are seen around zones of rarefaction (reduced cellular density). (D) In neurosarcoidosis, there are noncaseating granulomas with numerous surrounding lymphocytes. The absence of granulomas in this specimen argues against sarcoidosis.
A Alterations in chromosome 17, S-100, and nestin
S-100 is a sensitive marker for malignant peripheral nerve sheath tumors (MPNSTs), but it is not seen in all cases, as it is positive in only 50 to 90% of MPNSTs. Higher grade tumors tend to have an even lower incidence of S-100 positivity. CD56 also is sensitive but not specific for MPNSTs. Recent studies highlight that nestin expression is one of the most sensitive and specific markers for these tumors. The tumors also are associated with chromosome 17 mutations, as about 50% of them occur in individuals with neurofibromatosis type 1. (B) Chromosome 22 abnormalities are seen in neurofibromatosis type 2. GFAP (glial fibrillary acidic protein) is a marker found in the intermediate filaments of some glial cells (primarily astrocytes). CD10 often is used as a marker for various types of lymphomas. (C) Chromosome 6 abnormalities can be associated with Parkinson disease or Dandy-Walker malformation. Vimentin is a marker for sarcoma. MIB-1 is a proliferation marker. (D) Chromosome 4 abnormalities are associated with Huntington and Parkinson disease among other condition. AFP (α-fetoprotein) can be a useful marker for diagnosing germ cell tumors, especially yolk sac tumors. CD20 is a B-cell marker. (E) Trisomy of chromosome 18 results in Edwards syndrome. HCG is a marker for choriocarcinomas and germ cell tumors. Desmin is a marker for muscle intermediate filaments.
C Meningioma
Meningiomas are marked by vimentin, epithelial membrane antigen (EMA), and sometimes progesterone receptor immunoreactivity. They typically are dural based and may contain psammoma bodies. (A) Dural arteriovenous fistulas (dural arteriovenous malformations) are as described below for answer B, except that they have dural vessels as the feeding and draining vessels. They have no distinct nidus. (B) Arteriovenous malformations appear histologically as vascular channels of various wall thicknesses, in which arteries connect to veins without an intermediate capillary. Early draining veins are demonstrated on angiograms. There is a gross nidus on imaging. (D) Like all glial tumors, high-grade gliomas stain for glial fibrillary acidic protein. High-grade gliomas also can display gross elements of cysts, degeneration, mitotic figures, and necrosis. (E) Hemangioblastomas stain richly for reticulin, are positive for vimentin, and negative for EMA. They do not have calcifications, mitotic figures, or necrosis. Microscopically, they are seen as capillaries with hyperplastic endothelial elements with stromal cells and vacuoles. They do not stain with EMA.
B Adamantinomatous; wet
Adamantinomatous craniopharyngiomas typically occur in children, in contrast to papillary craniopharyngiomas, which occur more frequently in adults. The former contains “wet” keratin (keratinocytes in a loose stellate reticular zone), whereas the latter contains “dry” keratin. Both cause surrounding gliosis and have Rosenthal fibers present.
C AIDS dementia complex
AIDS dementia complex is seen in 50% of AIDS patients and is characterized by the triad of cognitive dysfunction, behavioral changes, and motor deficits. (A) Toxoplasmosis is seen in 10% of AIDS cases at autopsy and is the most common cause of focal neurologic symptoms in AIDS patients. Treatment is with pyrimethamine and sulfadiazine. (B) Primary central nervous system lymphoma (B-cell origin) is seen in 5% of AIDS cases at autopsy. The Epstein-Barr virus frequently is detected in the affected cells. (D) Encephalitis is characterized by microglial nodules in white matter and subcortical gray matter, with focal demyelination and neuronal loss. Multinucleated giant cells may be seen and are unique to HIV infection. (E) Vacuolar myelopathy (diagnosed during pathological tissue examination) may be symptomatic or asymptomatic, and is detected in 50% of AIDS cases at autopsy. Myelopathy may involve the posterior and lateral columns of the lower thoracic cord and is detected clinically in less than 50% of AIDS patients.
A Amiodarone
Amiodarone is associated with myelinopathy, which also may be seen with other agents such as hexachlorophene, perhexiline, and toluene. The other agents listed as options more typically cause a neuropathy.
A Subgaleal hematoma
Subgaleal hematomas are associated with linear, nondisplaced skull fractures in children. They can cross sutures as they separate the galea from the periosteum. They may present as fluctuant masses. (B) Subperiosteal hematomas (also known as cephalohematomas) are seen in newborns and are associated with parturition. Bleeding elevates the periosteum, but the extent is limited by the sutures. Subperiosteal hematomas usually are firm and can calcify. (C) Subdural hematomas are not in the scalp. (D) Temporalis contusions are intramuscular and are not in the loose connective tissue of the scalp.
B Secondary glioblastoma
A high-grade glial neoplasm with neovascularization and necrosis is diagnostic for glioblastoma. The younger age of this patient and the presence of a TP53 mutation argue for a secondary glioblastoma through malignant degeneration. In contrast, primary glioblastomas are associated with EGFR amplification in older patients. (C) Rhabdoid meningiomas are grade III meningiomas that often behave aggressively and are not glial tumors. (D) Medulloblastomas have small, densely packed, undifferentiated cells and often are referred to as blue cell tumors given their hypercellularity and scant cytoplasm. They are WHO grade IV tumors. (E) Chordomas are low-grade tumors distinguished by the pathological finding of physaliphorous cells.
B Neurofibromatosis type 1
Neurofibromatosis type 1 is associated with optic gliomas (usually pilocytic in nature) in which histology can demonstrate Rosenthal fibers. These fibers also are seen in Alexander disease and in areas of gliosis. (A) Von Hippel-Lindau disease is associated with hemangioblastomas, which are the most common primary tumors of the posterior fossa. Hemangioblastomas do occur in the retinae. (C) Neurofibromatosis type 2 is associated with bilateral vestibular schwannomas and the MISME syndrome (multiple inherited schwannomas, meningiomas, and ependymomas). Patients can have retinal hamartomas. (D) Tuberous sclerosis is associated with subependymal giant cell astrocytomas and cortical tubers. Retinal tumors (hamartomas) can occur. (E) Sturge-Weber syndrome is associated with cortical atrophy and calcifications, an ipsilateral port-wine facial nevus, meningeal venous proliferation, and contralateral seizures. Patients can have retinal angiomas.
D Prolactin
The pituitary adenoma is characterized by a monomorphic proliferation of cells. The most common secreting adenoma is prolactinoma, followed by growth hormone adenoma.
C Hirano body
Hirano bodies are eosinophilic cytoplasmic inclusions within neurons. They are composed of actin, and have a paracrystalline appearance with electron microscopy. (A) Amyloid usually does not accumulate in the cytoplasm of neurons. (B) Evidence of granulovacuolar degeneration (small dark dots inside a vacuole in the cytoplasm of neurons) also is seen in this field. (D) Lewy bodies typically are seen in Parkinson disease. (E) Neurofibrillary tangles are elongated, filamentous, cytoplasmic inclusions in neurons in Alzheimer disease.
A Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is marked by a loss of neurons in the anterior horn cell region as seen in the image accompanying the question. Patients often have symptoms of both upper and lower motor neuron disease. (C, D) The spinal muscular atrophies (types I and 2) may show a pathology similar to that of amyotrophic lateral sclerosis but present earlier in life (childhood or infancy). (E) Degeneration of the posterior columns is the hallmark of tabes dorsalis associated with syphilis.
C Grade 3
Germinal matrix hemorrhages are a complication of prematurity. Grade 3 germinal matrix hemorrhages show rupture of the blood from the germinal matrix into the ventricles with ventricular expansion. (A) Grade 1 germinal matrix hemorrhages are limited to the germinal matrix. (B) Grade 2 germinal matrix hemorrhages show rupture of the blood from the germinal matrix into the ventricles without ventricular expansion. (D) Grade 4 germinal matrix hemorrhages show intraventricular hemorrhage and hemorrhage into hemispheric parenchyma (periventricular venous infarct). Parenchymal involvement is worse than ventricular involvement because the latter can be treated with cerebrospinal fluid diversion. (E) Grade 5 germinal matrix hemorrhages do not exist in this schema.
B Amyotrophic lateral sclerosis
Bunina bodies are a feature of amyotrophic lateral sclerosis and are seen in areas of neuronal loss in the anterior horn cell region of the spinal cord. (A) Hirano bodies are eosinophilic cytoplasmic inclusions within neurons seen in patients with Alzheimer disease. (C–E) Prominent neuronal inclusions typically are not seen in Huntington chorea, Machado-Joseph disease, or olivopontocerebellar atrophy of Menzel.
C Contusion
A contusion is defined as a bruise when referring to skin and soft issue. In the brain, a contusion translates into an infarct secondary to trauma. (A) An abrasion represents a scrape of the skin (i.e., a surface injury). (B) An avulsion is a large tear of the tissue creating a tissue flap. (D) A laceration is the result of blunt force injury causing a tear in the skin and underlying soft tissues.
C Melan-A and HMB-45 positivity
Melanomas stain with antibodies to S-100 protein, melan-A (MART 1), and HMB-45 and do not stain with the other antibodies listed as options.
E Notochord remnants
The tumor shown in the image accompanying the question represents a chordoma. It contains epithelioid cells with a vacuolated cytoplasm arranged against a chondromyxoid-like stroma. These tumors arise from notochordal remnants, especially in the clival or the sacrococcygeal regions.
C Normal pineal gland
The tissue sample shown in the image accompanying the question demonstrates a vaguely lobular arrangement of cells against a fibrillary-type background, consistent with normal pineal gland tissue. Calcifications commonly are seen in the gland. Occasionally, gliotic cysts, sometimes with Rosenthal fibers, also are present.
A CD1a
CD1a is the best and most specific stain to highlight Langerhans histiocytes. By electron microscopy, these cells contain Birbeck granules (likened to tennis rackets). (D, E) CD68 and HAM56 are macrophage markers that are not specific for Langerhans cells.
B Lysosomes
The cytoplasmic granularity of the tumor shown in the image accompanying the question is due to an increased number of large lysosomes.
A NF2
The tumor shown in the image accompanying the question represents a schwannoma. Tumor cells typically are elongated with pointed nuclear ends. The pleomorphism displayed represents what is sometimes referred to as “ancient change,” which does not impact prognosis. Schwannomas are associated with neurofibromatosis type 2 and may show alterations in the NF2 gene. (B) TP53 gene mutations are seen in Li-Fraumeni syndrome. (C) PTEN gene mutations are observed in a variety of cancers including secondary glioblastomas. (D) SOD1 gene mutations occur in apoptosis and amyotrophic lateral sclerosis. (E) TSC2 gene mutations are seen in tuberous sclerosis.
D Breast
(A–E) Each of these tumors generally is described as being highly resistant to radiation therapy, with the exception of breast cancer, which is moderately sensitive. Highly sensitive tumors include small and germ cell tumors, lymphoma, leukemia, and multiple myeloma.
B Chromosome 9q and 16p
Tuberous sclerosis is an autosomal dominant disease characterized by seizures, mental retardation, and sebaceous adenomas; 10 to 15% of patients present with subependymal giant cell astrocytomas, which occur at the foramen of Monro and can cause hydrocephalus. Pathology of the subependymal giant cell astrocytomas shows large cells with abundant cytoplasm and prominent nucleoli. Vascular proliferation and necrosis can be seen without being suggestive of a more malignant tumor. (A) Chromosome 17p is associated with TP53 gene mutations. Li-Fraumeni syndrome is characterized by TP53 mutations and is associated with a 25 times increased risk for developing malignant tumors by age 50. (C) Chromosome 1p and 19q deletions can be seen in oligodendrogliomas, and these mutations often predict a better response to chemotherapy with a longer tumor-free survival. (D) Chromosomes 3 and 7 are associated with the development of cavernomas. (E) Chromosome 15 is associated with Angelman and Prader-Willi syndromes, characterized by seizures and mental retardation but not tumors.
C Dermoid cyst
The cyst lining is characterized by squamous epithelium and shows evidence of skin adnexal structures in the cyst wall that may include structures such as sebaceous glands, apocrine glands, hair, or eccrine glands. These findings are consistent with a dermoid cyst.
B Chondrosarcoma
The tumor shown in the image accompanying the question is marked by a malignant spindled cell component next to an atypical cartilaginous component, consistent with a chondrosarcoma.
C Most pontine tumors have high-grade histology.
The axial T2 and contrast-enhanced T1 -weighted images demonstrate a nonenhancing, infiltrative, expansile lesion involving the pons, most compatible with a diffuse infiltrative pontine glioma. These lesions are more common in children than in adults. Histologically, they may originate from astrocytes, oligodendrocytes, or ependymal cells, but the great majority (95%) are astrocytic. Most brain-stem gliomas arise in the pons, and most pontine tumors have a high-grade histology, being either anaplastic astrocytomas or glioblastomas. In contrast, tumors arising in the tectum and cervicomedullary junction as well as those that are cystic or exophytic usually are low grade. Enhancement is variable. Prognosis usually is poor, even for presumed low-grade histologies. (A) Diffuse intrinsic pontine gliomas are aggressive lesions, but they rarely metastasize to distant sites. Instead, they tend to infiltrate along anatomic fiber tracts and can extend cranially to involve the midbrain and thalami. (B) Hydrocephalus is a late complication of diffuse intrinsic pontine gliomas, and is more commonly seen in tectal lesions. (D) Calcifications are unusual in diffuse intrinsic pontine gliomas.
E Osteosarcoma
The malignant tumor shown in the image accompanying the question is marked by bone formation (the dark purple material). Osteosarcoma is the best diagnosis for this tumor. These lesions rarely may represent a primary tumor arising in the meninges or skull or distant metastatic disease. (A) Chondrosarcomas contain atypical cartilage within the tumor. (B) Glial fibrillary acidic protein (GFAP) negativity rules out a gliosarcoma. (C) Hemangiopericytomas often are malignant meningeal tumors that lack bone formation. (D) Metaplastic meningiomas are benign tumors marked by meningothelial cells intermixed with benign mesenchymal tissue such as bone or cartilage.
C 12 hours
The earliest changes indicating ischemic damage are apparent in neuronal cells at 12 to 24 hours after the precipitating event. The cells shrink in size, acquire cytoplasmic hypereosinophilia, and show nuclei shrinkage (the “red and dead” look).
B Filum terminale
The tumor shown in the image accompanying the question represents a paraganglioma, which generally is marked by cells arranged in loose nests (zellballen). The nests of cells are delimited by spindled, S-100-positive staining sustentacular cells. The tumor cells in the nests stain with neural markers such as chromogranin and neuron-specific enolase. In the central nervous system, paragangliomas most commonly arise in the spinal cord region.
E CD138
The lesion shown in the image accompanying the question is composed of plasma cells and represents a plasma cell dyscrasia. CD138 is an antibody that targets plasma cells. These lesions typically demonstrate evidence of monoclonality with either kappa or lambda immunostaining.
A Cerebellopontine angle
This simple squamous epithelial-lined cyst represents an epidermoid cyst. It lacks the adnexal structures that mark a dermoid cyst. Epidermoid cysts most commonly arise in the cerebellopontine angle region.
A Epidural space
Over 90% of epidural hemorrhages are associated with a skull fracture and are associated with a torn middle meningeal artery. Less commonly, epidural hemorrhages result from a dural sinus tear or a tear in the middle meningeal vein.
A 2 hours
Usually within 2 hours of diffuse axonal injury, axonal swelling can be visualized with β-amyloid precursor protein immunostaining.
A Dermatomyositis
The biopsy shown in the image accompanying the question demonstrates predominantly perivascular-based chronic inflammation and atrophy around the perimeter of the muscle fascicles (perifascicular atrophy). Perifascicular atrophy in the setting of an inflammatory myopathy is highly suggestive of dermatomyositis.
B Dystrophin
The clinical history is suggestive of Duchenne muscular dystrophy. The biopsy is marked by a prominent variation in muscle fiber size with increased endomysial fibrosis. One would anticipate an absence of membrane staining with dystrophin antibody in this case.
A Arachnoid cyst
The cyst shown is lined by a thin layer of meningothelial cells or arachnoid cap cells, consistent with an arachnoid cyst.
E No available therapies
The pathological findings shown in the image accompanying the question are consistent with inclusion body myositis. The biopsy shows inflammation, a variation in muscle fiber size, and rimmed vacuoles (vacuoles with basophilic granularity). Currently, there is no known effective treatment for inclusion body myositis.
E Ryanodine receptor gene mutation
The findings in the biopsy illustrate a core myopathy, one of the congenital myopathies marked by a focal decrease in oxidative activity as manifested by the staining pattern. The condition generally is inherited as an autosomal dominant condition and is associated with mutations in the ryanodine receptor gene. There is an association of this condition with malignant hyperthermia.
A Acid maltase deficiency
Glycogen-filled vacuoles suggest a glycogen storage disease. Acid maltase deficiency is the only one of the glycogenoses that is lysosomal associated and stains with acid phosphatase (a lysosomal associated enzyme).
C Kappa light chain protein
Most of the amyloid encountered in the brain is β-amyloid. Less commonly, other proteins may arrange themselves in a β-pleated sheet configuration to form amyloid. Kappa light chain protein is unlikely to deposit in the brain. (A) Cystatin C is a serum indicator of kidney function and may be involved in Alzheimer amyloid. (B) Gelsolin is a regulator of actin filament assembly/disassembly and is associated with β-amyloid formation in the brain. (D) Prion protein causes spongiform encephalopathy.
D HTT gene
The trinucleotide repeat in the HTT gene that encodes the huntingtin protein is associated with Huntington disease. The normal CAG repeat length is up to 35 repeats, whereas in Huntington disease, there are 36 or more repeats. (A, B) Ataxin-2 and CACNA1A gene repeats are associated with forms of hereditary spinocerebellar ataxia. (C) Chorein gene alterations are associated with a rare condition known as neuroacanthocytosis. (E) The myotonin gene is implicated in myotonic dystrophy.
A Alzheimer disease
The globular, extracellular structures highlighted with the silver stain represent senile plaques and are associated most classically with Alzheimer disease. Current pathological diagnostic criteria rely on plaque and neurofibrillary tangle counts as well as an assessment of the distribution of amyloid deposition. Plaques are composed variably of neuritic processes (highlighted with the silver stain), amyloid, and associated microglial cells.
D Tau
The dark-staining, elongated structures located within the cytoplasm of neurons represent neurofibrillary tangles. They can be highlighted with tau immunostaining. (A) α-synuclein is a good stain to highlight Lewy bodies. (B, E) Congo red and thioflavin S stains highlight amyloid.
D Lymphoma
Lymphomas often are B cell in origin and are identified by white blood cells with angiocentric growth patterns forming perivascular cuffs by tumor cells. (A) Germinomas show large, epithelioid cells with abundant PAS-positive cytoplasm. The cells have irregular nuclei that may have prominent nests of lymphocytes with occasional granulomatous inflammation. (B) Ependymomas classically have dark, small nuclei with perivascular and true rosettes. (C) Chordomas characteristically are described by physaliphorous cells and represent a remnant of the nucleus pulposus. (E) Hemangioblastomas have numerous capillary channels lined by a single layer of endothelium surrounded by reticulin.
D Froin syndrome
Froin syndrome is stagnation of the cerebrospinal fluid (CSF) from an inflammatory or neoplastic lesion, causing increased exudation from the tumor itself and activation of coagulation factors. (A) A positive Queckenstedt test is a failure of jugular vein compression to increase CSF pressure, which it will normally do in the absence of a block of the venous outflow. (B) Coup de poignard of Michon is sudden excruciating back pain with subarachnoid hemorrhage in patients with a spinal vascular malformation. (C) A positive Froment sign (during an evaluation of the ulnar nerve) occurs when a patient is unable to grasp a sheet of paper between his thumb and extended index finger and will instead pinch the paper, as the action of the weak adductor pollicis (ulnar innervated) is substituted for the action of the strong flexor pollicis longus (anterior interosseous innervated). (E) Foix-Alajouanine is an acute/subacute neurologic deterioration without hemorrhage in patients with a spinal vascular malformation.
D Seizure
The epithelial-lined cyst shown in the image accompanying the question represents a colloid cyst. Seizures are not an expected presenting symptom. (A, B, E) Headaches, incontinence, and even sudden death can occur with the development of hydrocephalus secondary to colloid cysts, especially if a “ball-valving” phenomenon occurs.
A β-amyloid
β-amyloid is the best and most specific stain for the type of amyloid that accumulates in patients with Alzheimer disease. (B) Luxol fast blue is a myelin stain. (C) Mucicarmine stains mucin such as in an adenocarcinoma. (D) Prussian blue is an iron stain. (E) Trichrome highlights connective tissue and collagen.
B Cavernous malformation
Cavernous malformations appear on MRI with hemosiderin and a “popcorn-like” appearance, with irregular thick- and thin-walled sinusoidal vascular channels without intervening neural parenchyma, large feeding arteries, or draining veins. (A) Microscopically, capillary telangiectasias have slightly enlarged capillaries with low flow and intervening neural tissue. (C) Venous malformations (venous angiomas, also known as developmental venous anomalies) are abnormal veins draining normal brain. They often present as a starburst pattern (caput medusa on angiogram) and are associated with cavernomas. (D) Arteriovenous malformations appear as tangles of abnormal vessels of various diameters separated by gliotic tissue without an intervening capillary bed. There may be evidence of prior hemorrhage. (E) Dural arteriovenous fistulas are true arteriovenous shunts within the leaflets of the dura matter and usually are found adjacent to dural sinuses.
D Sporadically with no obvious genetic transmission
Sturge-Weber disease has no known genetic transmission and is characterized by a facial nevus in the ophthalmic division of the trigeminal nerve, along with leptomeningeal venous angiomas and intracortical tram-track calcifications.
A SNCA
The neuron displayed with the eosinophilic cytoplasmic inclusion also has brown melanin pigment in its cytoplasm, with these components representing a Lewy body. α-synuclein (encoded by the SCNA gene) is the best stain for highlighting Lewy bodies. The most common gene to be affected in familial cases of Parkinson disease is the SCNA gene. Less commonly, alterations in the various PARK genes have been described in the disease.
A L-iduronidase
The described patient has Hurler syndrome. (B) Iduronate sulfatase deficiency (Hunter syndrome) causes symptoms similar to those seen in Hurler syndrome, except that Hunter syndrome is milder, without mental retardation, with minimal corneal involvement, slower progressing, and with a life span into adulthood. (C) Galactose 6-sulfatase and β-galactosidase deficiencies (Morquio syndrome) are inherited in an autosomal recessive manner and are characterized by severe skeletal abnormalities, ligamentous laxity, dwarfism, myelopathy, and a lack of mental retardation. (D) Sulfatase B deficiency (Maroteaux-Lamy) presents with carpal tunnel syndrome, valvular heart disease, and without mental retardation. (E) β-glucuronidase deficiency is inherited in an autosomal recessive manner and is characterized by moderate mental retardation, corneal clouding, hydrocephalus, hepatosplenomegaly, and various bony changes.
A Low posterior hairline, brevicollis, and decreased neck motion
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