Pathoma_Husain

Pathoma_Husain. F. Associated with MEN 2A and 2B (RET), von Hippel-Lindau disease, and neurofibromatosis type 1 I. BREAST A. Modified sweat gland embryologically derived from the skin 1. Breast tissue can develop anywhere along the milk line, which runs from the axilla to the vulva (e.g., supernumerary nipples). B. The terminal duct lobular unit is the functional unit of the breast (Fig. 16.1); lobules make milk that drains via ducts to the nipple. C. Lobules and ducts are lined by two layers of epithelium. 1. Luminal cell layer-inner cell layer lining the ducts and lobules; responsible for milk production in the lobules 2. Myoepithelial cell layer-outer cell layer lining ducts and lobules; contractile function propels milk towards the nipple. D. Breast tissue is hormone sensitive. 1. Before puberty, male and female breast tissue primarily consists oflarge ducts under the nipple. 2.


Pathoma_Husain

Pathoma_Husain. D. Breast tissue is hormone sensitive. 1. Before puberty, male and female breast tissue primarily consists oflarge ducts under the nipple. 2. Development after menarche is primarily driven by estrogen and progesterone; lobules and small ducts form and are present in highest density in the upper outer quadrant. 3. Breast tenderness during the menstrual cycle is a common complaint, especially prior to menstruation. 4. During pregnancy, breast lobules undergo hyperplasia. i. Hyperplasia is driven by estrogen and progesterone produced by the corpus luteum (early first trimester), fetus, and placenta (later in pregnancy) 5. After menopause, breast tissue undergoes atrophy. E. Galactorrhea refers to milk production outside oflactation. 1. It is not a symptom of breast cancer. 2. Causes include nipple stimulation (common physiologic cause), prolactinoma of the anterior pituitary (common pathologic cause), and drugs. I. ACUTE MASTITIS


Pathoma_Husain

Pathoma_Husain. 2. Causes include nipple stimulation (common physiologic cause), prolactinoma of the anterior pituitary (common pathologic cause), and drugs. I. ACUTE MASTITIS A. Bacterial infection of the breast, usually due to Staphylococcus aureus B. Associated with breast-feeding; fissures develop in the nipple providing a route of entry for microbes. C. Presents as an erythematous breast with purulent nipple discharge; may progress to abscess formation D. Treatment involves continued drainage (e.g., feeding) and antibiotics (e.g., dicloxacillin). II. PERIDUCTAL MASTITIS A. Inflammation of the subareolar ducts B. Usually seen in smokers pathoma.com 1. Relative vitamin A deficiency results in squamous metaplasia oflactiferous ducts, producing duct blockage and inflammation. C. Clinically presents as a subareolar mass with nipple retraction III. MAMMARY DUCT ECTASIA


Pathoma_Husain

Pathoma_Husain. C. Clinically presents as a subareolar mass with nipple retraction III. MAMMARY DUCT ECTASIA A. Inflammation with dilation (ectasia) of the subareolar ducts 1. Rare; classically arises in multiparous postmenopausal women B. Presents as a periareolar mass with green-brown nipple discharge (inflammatory debris) 1. Chronic inflammation with plasma cells is seen on biopsy. IV. FAT NECROSIS A. Necrosis of breast fat B. Usually related to trauma; however, a history of trauma may not always be evident. C. Presents as a mass on physical exam or abnormal calcification on mammography (due to saponification) D. Biopsy shows necrotic fat with associated calcifications and giant cells. I. FIBROCYSTIC CHANGE A. Development of fibrosis and cysts in the breast 1. Most common change in the premenopausal breast; thought to be hormone mediated B. Presents as vague irregularity of the breast tissue ('lumpy breast'), usually in the upper outer quadrant


Pathoma_Husain

Pathoma_Husain. B. Presents as vague irregularity of the breast tissue ('lumpy breast'), usually in the upper outer quadrant C. Cysts have a blue-dome appearance on gross exam. D. Benign, but some fibrocystic-related changes are associated with an increased risk for invasive carcinoma (increased risk applies to both breasts) 1. Fibrosis, cysts, and apocrine metaplasia (Fig. 16.2)-no increased risk 2. 3. II. INTRADUCTAL PAPILLOMA A. Papillary growth, usually into a large duct B. Characterized by fibrovascular projections lined by epithelial (luminal) and myoepithelial cells C. Classically presents as bloody nipple discharge in a premenopausal woman D. Must be distinguished from papillary carcinoma, which also presents as bloody nipple discharge o•o. 0~ O)~",.. ; ... ·~"-0 0 o·.::>i; • ·••~:?.t,00 Fig. 16.1 Terminal duct lobular unit. Fig. 16.2 Fibrocystic change with apocrine Fig. 16.3 Fibroadenoma. metaplasia. 1.


Pathoma_Husain

Pathoma_Husain. O)~",.. ; ... ·~"-0 0 o·.::>i; • ·••~:?.t,00 Fig. 16.1 Terminal duct lobular unit. Fig. 16.2 Fibrocystic change with apocrine Fig. 16.3 Fibroadenoma. metaplasia. 1. Papillary carcinoma is characterized by fibrovascular projections lined by epithelial cells without underlying myoepithelial cells. 2. Risk of papillary carcinoma increases with age; thus, it is more commonly seen in postmenopausal women. III. FIBROADENOMA A. Tumor of fibrous tissue and glands (Fig. 16.3) B. Most common benign neoplasm of the breast; usually seen in premenopausal women C. Presents as a well-circumscribed, mobile marble-like mass D. Estrogen sensitive-grows during pregnancy and may be painful during the menstrual cycle E. Benign, with no increased risk of carcinoma IV. PHYLLODES TUMOR A. Fibroadenoma-like tumor with overgrowth of the fibrous component; characteristic 'leaf-like' projections are seen on biopsy (Fig. 16.4). B. Most commonly seen in postmenopausal women


Pathoma_Husain

Pathoma_Husain. A. Fibroadenoma-like tumor with overgrowth of the fibrous component; characteristic 'leaf-like' projections are seen on biopsy (Fig. 16.4). B. Most commonly seen in postmenopausal women C. Can be malignant in some cases I. BASIC PRINCIPLES A. Most common carcinoma in women by incidence (excluding skin cancer) B. 2nd most common cause of cancer mortality in women C. Risk factors are mostly related to estrogen exposure. 1. 2. Age-Cancer usually arises in postmenopausal women, with the notable exception of hereditary breast cancer. 3. 4. 5. 6. First-degree relative (mother, sister, or daughter) with breast cancer II. DUCTAL CARCINOMA IN SITU (DCIS) A. Malignant proliferation of cells in ducts with no invasion of the basement membrane B. Often detected as calcification on mammography; DCIS does not usually produce a mass.


Pathoma_Husain

Pathoma_Husain. A. Malignant proliferation of cells in ducts with no invasion of the basement membrane B. Often detected as calcification on mammography; DCIS does not usually produce a mass. 1. Mammographic calcifications can also be associated with benign conditions such as fibrocystic changes (especially sclerosing adenosis) and fat necrosis. Fig. 16.4 Phyllodes tumor. Fig. 16.5 Ductal carcinoma in situ, comedo type. 2. Biopsy of calcifications is often necessary to distinguish between benign and malignant conditions. C. Histologic subtypes are based on architecture; comedo type is characterized by high-grade cells with necrosis and dystrophic calcification in the center of ducts (Fig. 16.5). D. Paget disease of the breast is DCIS that extends up the ducts to involve the skin of the nipple (Fig. 16.6). 1. Presents as nipple ulceration and erythema 2. Paget disease of the breast is almost always associated with an underlying carcinoma. III. INVASIVE DUCTAL CARCINOMA


Pathoma_Husain

Pathoma_Husain. 1. Presents as nipple ulceration and erythema 2. Paget disease of the breast is almost always associated with an underlying carcinoma. III. INVASIVE DUCTAL CARCINOMA A. Invasive carcinoma that classically forms duct-like structures B. Most common type of invasive carcinoma in the breast, accounting for > 80% of cases C. Presents as a mass detected by physical exam or by mammography 1. Clinically detected masses are usually 2 cm or greater. 2. Mammographically detected masses are usually 1 cm or greater. 3. Advanced tumors may result in dimpling of the skin or retraction of the nipple. D. Biopsy usually shows duct-like structures in a desmoplastic stroma; special subtypes of invasive ductal carcinoma include 1. Tubular carcinoma-characterized by well-differentiated tubules that lack myoepithelial cells (Fig. 16.7A); relatively good prognosis 2.


Pathoma_Husain

Pathoma_Husain. Tubular carcinoma-characterized by well-differentiated tubules that lack myoepithelial cells (Fig. 16.7A); relatively good prognosis 2. Mucinous carcinoma-characterized by carcinoma with abundant extracellular mucin ('tumor cells floating in a mucus pool', Fig. 16.7B) Fig. 16.6 Paget disease of the nipple. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy of Jerome Taxy, MD) ,';,: . ~ i, ,, :1/ -~: . rt·.· r:. .~!t_ ·~ p.•'l Fig. 16.7 Invasive ductal carcinoma. A, Tubular carcinoma. B, Mucinous ca rcinoma.


Pathoma_Husain

Pathoma_Husain. rt·.· r:. .~!t_ ·~ p.•'l Fig. 16.7 Invasive ductal carcinoma. A, Tubular carcinoma. B, Mucinous ca rcinoma. i. Tends to occur in older women (average age is 70 years) 11. Relatively good prognosis 3. Medullary carcinoma-characterized by large, high-grade cells growing in sheets with associated lymphocytes and plasma cells i. Grows as a well-circumscribed mass that can mimic fibroadenoma on mammography ii. Relatively good prognosis 111. Increased incidence in BRCAl carriers 4. Inflammatory carcinoma-characterized by carcinoma in dermal lymphatics (Fig. 16.8) i. Presents classically as an inflamed, swollen breast (tumor cells block drainage of lymphatics) with no discrete mass; can be mistaken for acute mastitis ii. Poor prognosis IV. A. Malignant proliferation of cells in lobules with no invasion of the basement membrane B. LCIS does not produce a mass or calcifications and is usually discovered incidentally on biopsy.


Pathoma_Husain

Pathoma_Husain. IV. A. Malignant proliferation of cells in lobules with no invasion of the basement membrane B. LCIS does not produce a mass or calcifications and is usually discovered incidentally on biopsy. C. Characterized by dyscohesive cells lacking E-cadherin adhesion protein D. Often multifocal and bilateral E. Treatment is tamoxifen (to reduce the risk of subsequent carcinoma) and close follow-up; low risk of progression to invasive carcinoma V. A. Invasive carcinoma that characteristically grows in a single-file pattern (Fig. 16.9); cells may exhibit signet-ring morphology. 1. No duct formation due to lack ofE-cadherin. VI. PROGNOSTIC AND PREDICTIVE FACTORS A. Prognosis in breast cancer is based on TNM staging. 1. Metastasis is the most important factor, but most patients present before metastasis occurs. 2.


Pathoma_Husain

Pathoma_Husain. VI. PROGNOSTIC AND PREDICTIVE FACTORS A. Prognosis in breast cancer is based on TNM staging. 1. Metastasis is the most important factor, but most patients present before metastasis occurs. 2. Spread to axillary lymph nodes is the most useful prognostic factor (given that metastasis is not common at presentation); sentinel lymph node biopsy is used to assess axillary lymph nodes. B. Predictive factors predict response to treatment. 1. Most important factors are estrogen receptor (ER), progesterone receptor (PR), and HER2/neu gene amplification (overexpression) status. Fig. 16.8 Inflammatory carcinoma. A, Microscopic appearance. B, Clinical appearance. (8, Courtesy of Fig. 16.9 Invasive lobular carcinoma. Jerome Taxy, MD) 2. Presence of ER and PR is associated with response to antiestrogenic agents (e.g., tamoxifen); both receptors are located in the nucleus (Fig. 16.10). 3.


Pathoma_Husain

Pathoma_Husain. Presence of ER and PR is associated with response to antiestrogenic agents (e.g., tamoxifen); both receptors are located in the nucleus (Fig. 16.10). 3. HER2/neu amplification is associated with response to trastuzumab (Herceptin), a designer antibody directed against the HER2 receptor; HER2/neu is a growth factor receptor present on the cell surface (Fig. 16.11). 4. 'Triple-negative' tumors are negative for ER, PR, and HER2/neu and have a poor prognosis; African American women have an increased propensity to develop triple-negative carcinoma. VII. HEREDITARY BREAST CANCER A. Represents 10% of breast cancer cases B. Clinical features that suggest hereditary breast cancer include multiple first-degree relatives with breast cancer, tumor at an early age (premenopausal), and multiple tumors in a single patient. C. BRCAl and BRCA2 mutations are the most important single gene mutations associated with hereditary breast cancer. 1.


Pathoma_Husain

Pathoma_Husain. C. BRCAl and BRCA2 mutations are the most important single gene mutations associated with hereditary breast cancer. 1. BRCAl mutation is associated with breast and ovarian carcinoma. 2. BRCA2 mutation is associated with breast carcinoma in males. D. Women with a genetic propensity to develop breast cancer may choose to undergo removal of both breasts (bilateral mastectomy) to decrease the risk of developing carcinoma. 1. A small risk for cancer remains because breast tissue sometimes extends into the axilla or subcutaneous tissue of the chest wall. VIII. MALE BREAST CANCER A. Breast cancer is rare in males (represents 1 % of all breast cancers). B. Usually presents as a subareolar mass in older males 1. Highest density of breast tissue in males is underneath the nipple. 2. C. Most common histological subtype is invasive ductal carcinoma. 1. Lobular carcinoma is rare (the male breast develops very few lobules). D. Associated with BRCA2 mutations and Klinefelter syndrome


Pathoma_Husain

Pathoma_Husain. 1. Lobular carcinoma is rare (the male breast develops very few lobules). D. Associated with BRCA2 mutations and Klinefelter syndrome Fig. 16.10 Estrogen receptor, Fig. 16.11 HER2/neu amplification, immunohistochemical stain. immunohistochemical stain. I. NEURAL TUBE DEFECTS A. Arise from incomplete closure of the neural tube 1. Neural plate invaginates early in gestation to form the neural tube, which runs along the cranial-caudal axis of the embryo. 2. The wall of the neural tube forms central nervous system tissue, the hollow lumen forms the ventricles and spinal cord canal, and the neural crest forms the peripheral nervous system. B. Associated with low folate levels prior to conception C. Detected during prenatal care by elevated alpha-fetoprotein (AFP) levels in the amniotic fluid and maternal blood D. Anencephaly is absence of the skull and brain (disruption of the cranial end of the neural tube). 1. Leads to a 'frog-like' appearance of the fetus (Fig. 17.1) 2.


Pathoma_Husain

Pathoma_Husain. D. Anencephaly is absence of the skull and brain (disruption of the cranial end of the neural tube). 1. Leads to a 'frog-like' appearance of the fetus (Fig. 17.1) 2. Results in maternal polyhydramnios since fetal swallowing of amniotic fluid is impaired E. Spina bifida is failure of the posterior vertebral arch to close, resulting in a vertebral defect (disruption of the caudal end of the neural tube). 1. Spina bifida occulta presents as a dimple or patch of hair overlying the vertebral defect. 2. Spina bifida presents with cystic protrusion of the underlying tissue through the vertebral defect. i. Meningocele-protrusion of meninges ii. Meningomyelocele-protrusion of meninges and spinal cord II. CEREBRAL AQUEDUCT STENOSIS A. Congenital stenosis of the channel that drains cerebrospinal fluid (CSF) from the 3rd ventricle into the 4th ventricle B. Leads to accumulation of CSF in the ventricular space; most common cause of hydrocephalus in newborns 1.


Pathoma_Husain

Pathoma_Husain. B. Leads to accumulation of CSF in the ventricular space; most common cause of hydrocephalus in newborns 1. CSF is produced by the choroid plexus lining the ventricles. 2. Flows from the lateral ventricles into the 3rd ventricle via the interventricular foramen of Monro 3. Flows from the 3rd ventricle into the 4th ventricle via the cerebral aqueduct 4. Flows from the 4th ventricle into the subarachnoid space via the foramina of Magendie and Luschka C. Presents with enlarging head circumference due to dilation of the ventricles (cranial suture lines are not fused) Ill. DANDY-WALKER MALFORMATION A. Congenital failure of the cerebellar vermis to develop B. Presents as a massively dilated 4th ventricle (posterior fossa) with an absent cerebellum (Fig. 17.2); often accompanied by hydrocephalus pathoma.com IV. ARNOLD-CHIARI MALFORMATION (TYPE II) A. Congenital downward displacement of cerebellar vermis and tonsils through the foramen magnum


Pathoma_Husain

Pathoma_Husain. IV. ARNOLD-CHIARI MALFORMATION (TYPE II) A. Congenital downward displacement of cerebellar vermis and tonsils through the foramen magnum B. Obstruction of CSF flow commonly results in hydrocephalus. C. Often associated with meningomyelocele I. SYRINGOMYELIA A. Cystic degeneration of the spinal cord B. Arises with trauma or in association with a type 1 Arnold-Chiari malformation C. Usually occurs at CS-Tl 1. Presents as sensory loss of pain and temperature with sparing of fine touch and position sense in the upper extremities ("cape like" distribution)-due to involvement of the anterior white commissure of the spinothalamic tract with sparing of the dorsal column {Table 17.1) D. Syrinx expansion results in involvement of other spinal tracts leading to 1. Muscle atrophy and weakness with decreased muscle tone and impaired reflexes-due to damage to lower motor neurons of the anterior horn 2.


Pathoma_Husain

Pathoma_Husain. Muscle atrophy and weakness with decreased muscle tone and impaired reflexes-due to damage to lower motor neurons of the anterior horn 2. Horner syndrome with ptosis {droopy eyelid), miosis (constricted pupil), and anhidrosis (decreased sweating)-due to disruption of the lateral horn of the hypothalamospinal tract {Table 17.1) II. POLIOMYELITIS A. Damage to the anterior motor horn due to poliovirus infection B. Presents with lower motor neuron signs-flaccid paralysis with muscle atrophy, fasciculations, weakness with decreased muscle tone, impaired reflexes, and negative Babinski sign (downgoing toes) III. WERDNIG-HOFFMAN DISEASE A. Inherited degeneration of the anterior motor horn; autosomal recessive B. Presents as a "floppy baby;" death occurs within a few years after birth. IV. AMYOTROPHIC LATERAL SCLEROSIS (ALS)


Pathoma_Husain

Pathoma_Husain. A. Inherited degeneration of the anterior motor horn; autosomal recessive B. Presents as a "floppy baby;" death occurs within a few years after birth. IV. AMYOTROPHIC LATERAL SCLEROSIS (ALS) A. Degenerative disorder of upper and lower motor neurons of the corticospinal tract (Table 17.1) 1. Anterior motor horn degeneration leads to lower motor neuron signs-flaccid paralysis with muscle atrophy, fasciculations, weakness with decreased muscle tone, impaired reflexes, and negative Babinski sign. Fig. 17.1 Anencephaly. (Courtesy of humpath. Fig. 17.2 Dandy-Walker malformation, MRI. Fig. 17.3 Bacterial meningitis, gross appearance. com) (Courtesy of Robert Heng, MD) 2. Lateral corticospinal tract degeneration leads to upper motor neuron signsspastic paralysis with hyperreflexia, increased muscle tone, and positive Babinski sign. B. Atrophy and weakness of hands is an early sign. 1. Lack of sensory impairment distinguishes ALS from syringomyelia.


Pathoma_Husain

Pathoma_Husain. B. Atrophy and weakness of hands is an early sign. 1. Lack of sensory impairment distinguishes ALS from syringomyelia. C. Most cases are sporadic, arising in middle age adults. 1. Zinc-copper superoxide dismutase mutation (SODJ) is present in some familial cases; leads to free radical injury in neurons V. FRIEDREICH ATAXIA A. Degenerative disorder of the cerebellum and spinal cord 1. Degeneration of the cerebellum leads to ataxia. 2. Degeneration of multiple spinal cord tracts leads to loss of vibratory sense and proprioception, muscle weakness in the lower extremities, and loss of deep tendon reflexes. B. Autosomal recessive; due to expansion of an unstable trinucleotide repeat (GAA) in the frataxin gene 1. Frataxin is essential for mitochondrial iron regulation; loss results in iron buildup with free radical damage. C. Presents in early childhood; patients are wheelchair bound within a few years. D. Associated with hypertrophic cardiomyopathy I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. C. Presents in early childhood; patients are wheelchair bound within a few years. D. Associated with hypertrophic cardiomyopathy I. BASIC PRINCIPLES A. Inflammation of the leptomeninges (Fig. 17.3) 1. Meninges consist of three layers (dura, arachnoid, and pia) that lie between the brain and the skull. 2. Pia and arachnoid together are termed leptomeninges. Table 17.1: Spinal Cord Tracts Arises from posterior horn, immediately crosses Peripheral nerves to posterior horn; cell body is in dorsal root Thalamus to cortex temperature sensation) commissure, and ascends via ganglion. the spinothalamic tract to thalamus Arises from medulla, crosses lemniscus (pressure, to medulla via dorsal column; over, and ascends via the Thalamus to cortex touch, vibration, and cell body is in dorsal root medial lemniscus to thalamus proprioception) ganglion. Pyramidal neurons in cortex descend, cross over Arises from the anterior motor


Pathoma_Husain

Pathoma_Husain. Pyramidal neurons in cortex descend, cross over Arises from the anterior motor Lateral corticospinal in medullary pyramids, and horn and synapses on muscle (None)(voluntary movement) synapse on the anterior motor (lower motor neuron) horn of the cord (upper motor neuron). Hypothalamospinal Arises from the hypothalamus Arises from lateral horn at Tl (sympathetic input of the and synapses on the lateral and synapses on the superior eyelids, pupil, and skin of face B. Most commonly due to an infectious agent 1. Group B streptococci, E coli, and Listeria monocytogenes (neonates) 2. N meningitidis (children and teenagers), Streptococcus pneumoniae (adults and elderly), and H influenza (nonvaccinated infants) 3. 4. C. Presents with classic triad of headache, nuchal rigidity, and fever; photophobia, vomiting, and altered mental status may also be present. D. Diagnosis is made by lumbar puncture (sampling of CSF). 1.


Pathoma_Husain

Pathoma_Husain. D. Diagnosis is made by lumbar puncture (sampling of CSF). 1. Performed by placing a needle between L4 and LS (level of the iliac crest). Spinal cord ends at L2, but subarachnoid space and cauda equina continue to S2. 2. Layers crossed include skin, ligaments, epidural space, dura, and arachnoid. E. CSF findings 1. Bacterial meningitis-neutrophils with 1-CSF glucose; gram stain and culture often identify the causative organism. 2. Viral meningitis-lymphocytes with normal CSF glucose 3. Fungal meningitis-lymphocytes with 1-CSF glucose F. Complications are usually seen with bacterial meningitis. 1. Death-herniation secondary to cerebral edema 2. Hydrocephalus, hearing loss, and seizures-sequelae related to fibrosis I. BASIC PRINCIPLES A. Neurologic deficit due to cerebrovascular compromise; major cause of morbidity and mortality


Pathoma_Husain

Pathoma_Husain. Hydrocephalus, hearing loss, and seizures-sequelae related to fibrosis I. BASIC PRINCIPLES A. Neurologic deficit due to cerebrovascular compromise; major cause of morbidity and mortality B. Due to ischemia (85% of cases) or hemorrhage (15% of cases) 1. Neurons are dependent on serum glucose as an essential energy source and are particularly susceptible to ischemia (undergo necrosis within 3-5 minutes). II. GLOBAL CEREBRAL ISCHEMIA A. Global ischemia to the brain B. Major etiologies 1. Low perfusion (e.g., atherosclerosis) 2. Acute decrease in blood flow (e.g., cardiogenic shock) 3. Chronic hypoxia (e.g., anemia) 4. Repeated episodes of hypoglycemia (e.g., insulinoma) C. Clinical features are based on duration and magnitude of the insult. 1. Mild global ischemia results in transient confusion with prompt recovery. Fig . 17.4 Pale infarct, cortex. (Courtesy of Robert Fig. 17.5 Lacunar infarcts. (Courtesy of Robert Wollmann, MD) Wollmann, MD) 2.


Pathoma_Husain

Pathoma_Husain. Fig . 17.4 Pale infarct, cortex. (Courtesy of Robert Fig. 17.5 Lacunar infarcts. (Courtesy of Robert Wollmann, MD) Wollmann, MD) 2. Severe global ischemia results in diffuse necrosis; survival leads to a 'vegetative state.' 3. Moderate global ischemia leads to infarcts in watershed areas (e.g., area lying between regions fed by the anterior and middle cerebral artery) and damage to highly vulnerable regions such as i. Pyramidal neurons of the cerebral cortex (layers 3, 5, and 6)-leads to laminar necrosis ii. Pyramidal neurons of the hippocampus (temporal lobe)-important in longterm memory iii. Purkinje layer of the cerebellum-integrates sensory perception with motor control III. ISCHEMIC STROKE A. Regional ischemia to the brain that results in focal neurologic deficits lasting > 24 hours 1. If symptoms last < 24 hours, the event is termed a transient ischemic attack (TIA). B. Subtypes include thrombotic, embolic, and lacunar strokes.


Pathoma_Husain

Pathoma_Husain. B. Subtypes include thrombotic, embolic, and lacunar strokes. 1. Thrombotic stroke is due to rupture of an atherosclerotic plaque. i. Atherosclerosis usually develops at branch points (e.g., bifurcation of internal carotid and middle cerebral artery in the circle of Willis). ii. Results in a pale infarct at the periphery of the cortex (Fig. 17.4) 2. Embolic stroke is due to thromboemboli. 1. Most common source of emboli is the left side of the heart (e.g., atrial fibrillation). ii. Usually involves the middle cerebral artery u1. Results in a hemorrhagic infarct at the periphery of the cortex 3. Lacunar stroke occurs secondary to hyaline arteriolosclerosis, a complication of hypertension. i. Most commonly involves lenticulostriate vessels, resulting in small cystic areas of infarction (Fig. 17.5) 11. Involvement of the internal capsule leads to a pure motor stroke. u1. Involvement of the thalamus leads to a pure sensory stroke.


Pathoma_Husain

Pathoma_Husain. C. Ischemic stroke results in liquefactive necrosis. 1. Eosinophilic change in the cytoplasm of neurons (red neurons, Fig. 17.6A) is an early microscopic finding (12 hours after infarction). 2. Necrosis (24 hours), infiltration by neutrophils (days 1-3) and microglial cells (days 4-7), and gliosis (weeks 2-3) then ensue. 3. Results in formation of a fluid-filled cystic space surrounded by gliosis (Fig. 17.6B) ' ' i w , . •> f Fig. 17.6 Brain infarct. A, Red neurons. B, Cyst formation. (Courtesy of Robert Wollmann, MD) IV. A. Bleeding into brain parenchyma B. Classically due to rupture of Charcot-Bouchard microaneurysms of the lenticulostriate vessels 1. Complication of hypertension; treatment of hypertension reduces incidence by half. 2. Basal ganglia is the most common site (Fig. 17.7). C. Presents as severe headache, nausea, vomiting, and eventual coma V. A. Bleeding into the subarachnoid space (Fig. 17.8)


Pathoma_Husain

Pathoma_Husain. 2. Basal ganglia is the most common site (Fig. 17.7). C. Presents as severe headache, nausea, vomiting, and eventual coma V. A. Bleeding into the subarachnoid space (Fig. 17.8) B. Presents as a sudden headache ("worst headache of my life") with nuchal rigidity C. Lumbar puncture shows xanthochromia (yellow hue due to bilirubin). D. Most frequently (85%) due to rupture of a berry aneurysm; other causes include AV malformations and an anticoagulated state. 1. Berry aneurysms are thin-walled saccular outpouchings that lack a media layer (Fig. 17.9), increasing the risk for rupture. 2. Most frequently located in the anterior circle of Willis at branch points of the anterior communicating artery 3. Associated with Marfan syndrome and autosomal dominant polycystic kidney disease I. EPIDURAL HEMATOMA A. Collection of blood between the dura and the skull


Pathoma_Husain

Pathoma_Husain. Associated with Marfan syndrome and autosomal dominant polycystic kidney disease I. EPIDURAL HEMATOMA A. Collection of blood between the dura and the skull B. Classically due to fracture of the temporal bone with rupture of the middle meningeal artery; bleeding separates the dura from the skull. 1. 2. Lucid interval may precede neurologic signs. C. Herniation is a lethal complication. II. SUBDURAL HEMATOMA A. Collection of blood underneath the dura; blood covers the surface of the brain (Fig. 17.10). B. Due to tearing of bridging veins that lie between the dura and arachnoid; usually arises with trauma 1. 2. Presents with progressive neurologic signs Fig. 17.7 lntracerebral hemorrhage, basal Fig. 17.8 Subarachnoid hemorrhage. (Courtesy of ganglia. (Courtesy of Robert Wollmann, MD) Jerome Taxy, MD) 3. Increased rate of occurrence in the elderly due to age-related cerebral atrophy, which stretches the veins C. Herniation is a lethal complication. III. HERNIATION


Pathoma_Husain

Pathoma_Husain. C. Herniation is a lethal complication. III. HERNIATION A. Displacement of brain tissue due to mass effect or increased intracranial pressure B. Tonsillar herniation involves displacement of the cerebellar tonsils into the foramen magnum. 1. Compression of the brain stem leads to cardiopulmonary arrest. C. Subfalcine herniation involves displacement of the cingulate gyrus under the falx cerebri. 1. Compression of the anterior cerebral artery leads to infarction. D. Uncal herniation involves displacement of the temporal lobe uncus under the tentorium cerebelli. 1. Compression of cranial nerve III (oculomotor) leads to the eye moving "down and out" and a dilated pupil. 2. Compression of posterior cerebral artery leads to infarction of occipital lobe (contralateral homonymous hemianopsia). 3. Rupture of the paramedian artery leads to Duret (brainstem) hemorrhage. I. BASIC PRINCIPLES A. Myelin insulates axons, improving the speed and efficiency of conduction. 1.


Pathoma_Husain

Pathoma_Husain. 3. Rupture of the paramedian artery leads to Duret (brainstem) hemorrhage. I. BASIC PRINCIPLES A. Myelin insulates axons, improving the speed and efficiency of conduction. 1. Oligodendrocytes myelinate the central nervous system. 2. Schwann cells myelinate the peripheral nervous system. B. Demyelinating disorders are characterized by destruction of myelin or oligodendrocytes; axons are generally preserved. II. LEUKODYSTROPHIES A. Inherited mutations in enzymes necessary for production or maintenance of myelin B. Metachromatic leukodystrophy is due to a deficiency of arylsulfatase (autosomal recessive); most common leukodystrophy 1. Sulfatides cannot be degraded and accumulate in the lysosomes of oligodendrocytes (lysosomal storage disease). C. Krabbe disease is due to a deficiency of galactocerebrosidase (autosomal recessive). 1. Galactocerebroside accumulates in macrophages.


Pathoma_Husain

Pathoma_Husain. C. Krabbe disease is due to a deficiency of galactocerebrosidase (autosomal recessive). 1. Galactocerebroside accumulates in macrophages. D. Adrenoleukodystrophy is due to impaired addition of coenzyme A to long-chain fatty acids (X-linked defect). Fig. 17.9 Berry aneurysm. (Courtesy of Jerome Fig. 17.10 Subdural hematoma. (Courtesy of Fig. 17.11 Gray plaque, multiple sclerosis. Taxy, MD) Robert Wollmann, MD) (Courtesy of Peter Pytel, MD) 1. Accumulation of fatty acids damages adrenal glands and white matter of the brain. III. MULTIPLE SCLEROSIS A. Autoimmune destruction of CNS myelin and oligodendrocytes 1. Most common chronic CNS disease of young adults (20-30 years of age); more commonly seen in women 2. Associated with HLA-DR2 3. More commonly seen in regions away from the equator B. Presents with relapsing neurologic deficits with periods of remission (multiple lesions in time and space). Clinical features include 1. 2. 3. 4.


Pathoma_Husain

Pathoma_Husain. B. Presents with relapsing neurologic deficits with periods of remission (multiple lesions in time and space). Clinical features include 1. 2. 3. 4. Hemiparesis or unilateral loss of sensation (cerebral white matter, usually periventricular) 5. Lower extremity loss of sensation or weakness (spinal cord) 6. Bowel, bladder, and sexual dysfunction (autonomic nervous system) C. Diagnosis is made by MRI and lumbar puncture. 1. MRI reveals plaques (areas of white matter demyelination). 2. Lumbar puncture shows increased lymphocytes, increased immunoglobulins with oligoclonal IgG bands on high resolution electrophoresis, and myelin basic protein. D. Gross examination shows gray-appearing plaques in the white matter (Fig. 17.11). E. Treatment of acute attacks includes high-dose steroids. 1. Long-term treatment with interferon beta slows progression of disease. IV. A. Progressive, debilitating encephalitis leading to death


Pathoma_Husain

Pathoma_Husain. E. Treatment of acute attacks includes high-dose steroids. 1. Long-term treatment with interferon beta slows progression of disease. IV. A. Progressive, debilitating encephalitis leading to death B. Due to slowly progressing, persistent infection of the brain by measles virus. 1. Infection occurs in infancy; neurologic signs arise years later (during childhood). C. Characterized by viral inclusions within neurons (gray matter) and oligodendrocytes (white matter) V. A. JC virus infection of oligodendrocytes (white matter) 1. Immunosuppression (e.g., AIDS or leukemia) leads to reactivation of the latent virus. B. Presents with rapidly progressive neurologic signs (visual loss, weakness, dementia) leading to death VI. CENTRAL PONTINE MYELINOLYSIS A. Focal demyelination of the pons (anterior brain stem) B. Due to rapid intravenous correction of hyponatremia 1. Occurs in severely malnourished patients (e.g., alcoholics and patients with liver disease)


Pathoma_Husain

Pathoma_Husain. B. Due to rapid intravenous correction of hyponatremia 1. Occurs in severely malnourished patients (e.g., alcoholics and patients with liver disease) C. Classically presents as acute bilateral paralysis ("locked in" syndrome) I. BASIC PRINCIPLES A. Characterized by loss of neurons within the gray matter; often due to accumulation of protein which damages neurons B. Degeneration of the cortex leads to dementia. C. Degeneration of the brainstem and basal ganglia leads to movement disorders. II. ALZHEIMER DISEASE (AD) A. Degenerative disease of cortex; most common cause of dementia B. Clinical features 1. Slow-onset memory loss (begins with short-term memory loss and progresses to long-term memory loss) and progressive disorientation 2. 3. 4. Patients become mute and bedridden; infection is a common cause of death. 5. Focal neurologic deficits are not seen in early disease. C. Most cases (95%) are sporadic and seen in the elderly. 1.


Pathoma_Husain

Pathoma_Husain. Patients become mute and bedridden; infection is a common cause of death. 5. Focal neurologic deficits are not seen in early disease. C. Most cases (95%) are sporadic and seen in the elderly. 1. Risk increases with age (doubles every 5 years after the age of60). 2. E4 allele ofapolipoprotein E (APOE) is associated with increased risk, E2 allele with decreased risk. D. Early-onset AD is seen in 1. Familial cases-associated with presenilin 1 and presenilin 2 mutations 2. Down syndrome-commonly occurs by 40 years of age E. Morphologic features include 1. Cerebral atrophy with narrowing of the gyri, widening of the sulci, and dilation of the ventricles (Fig. 17.12A) 2. Neuritic plaques-extracellular core comprised of A~ amyloid with entangled neuritic processes (Fig. 17.12B) i. A~ amyloid is derived from amyloid precursor protein (APP), which is coded on chromosome 21. APP normally undergoes alpha cleavage; beta cleavage results in A~ amyloid.


Pathoma_Husain

Pathoma_Husain. ii. Amyloid may also deposit around vessels, increasing the risk of hemorrhage. 3. Neurofibrillary tangles-intracellular aggregates of fibers composed of hyperphosphorylated tau protein (Fig. 17.12C) i. Tau is a microtubule-associated protein. 4. Loss of cholinergic neurons in the nucleus basalis of Meynert F. Diagnosis is made by clinical and pathological correlation. 1. Presumptive diagnosis is made clinically after excluding other causes. 2. III. VASCULAR DEMENTIA A. Multifocal infarction and injury due to hypertension, atherosclerosis, or vasculitis B. 2nd most common cause of dementia Fig. 17.12 Alzheimer disease. A, Cerebral atrophy. B, Neuritic plaque. C, Neurofibrillary tangle. (A, Courtesy of Jerome Taxy, MD. Band C, Courtesy of Peter Pytel, MD) IV. A. Degenerative disease of the frontal and temporal cortex; spares the parietal and occipital lobes B. Characterized by round aggregates of tau protein (Pick bodies) in neurons of the cortex


Pathoma_Husain

Pathoma_Husain. IV. A. Degenerative disease of the frontal and temporal cortex; spares the parietal and occipital lobes B. Characterized by round aggregates of tau protein (Pick bodies) in neurons of the cortex C. Behavioral and language symptoms arise early; eventually progresses to dementia V. A. Degenerative loss of dopaminergic neurons in the substantia nigra of the basal ganglia (Fig. 17.13A,B) 1. Nigrostriatal pathway of basal ganglia uses dopamine to initiate movement. B. Common disorder related to aging; seen in 2% of older adults C. Unknown etiology; historically, rare cases were related to MPTP exposure (a contaminant in illicit drugs). D. Clinical features ('TRAP') 1. Tremor-pill rolling tremor at rest; disappears with movement 2. Rigidity-cogwheel rigidity in the extremities 3. Akinesia/bradykinesia-slowing of voluntary movement; expressionless face 4.


Pathoma_Husain

Pathoma_Husain. Tremor-pill rolling tremor at rest; disappears with movement 2. Rigidity-cogwheel rigidity in the extremities 3. Akinesia/bradykinesia-slowing of voluntary movement; expressionless face 4. E. Histology reveals loss of pigmented neurons in the substantia nigra and round, eosinophilic inclusions of a-synuclein (Lewy bodies, Fig. 17.13C) in affected neurons. F. Dementia is a common feature oflate disease. 1. Early-onset dementia is suggestive of Lewy body dementia, which is characterized by dementia, hallucinations and parkinsonian features; histology reveals cortical Lewy bodies. VI. HUNTINGTON DISEASE A. Degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia (Fig. 17.14) 1. Autosomal dominant disorder (chromosome 4) characterized by expanded trinucleotide repeats (CAG) in the huntingtin gene 2. Further expansion of repeats during spermatogenesis leads to anticipation.


Pathoma_Husain

Pathoma_Husain. Autosomal dominant disorder (chromosome 4) characterized by expanded trinucleotide repeats (CAG) in the huntingtin gene 2. Further expansion of repeats during spermatogenesis leads to anticipation. B. Presents with chorea that can progress to dementia and depression; average age at presentation is 40 years. C. Suicide is a common cause of death. VII. NORMAL PRESSURE HYDROCEPHALUS A. Increased CSF resulting in dilated ventricles B. Can cause dementia in adults; usually idiopathic Fig. 17.13 Parkinson disease. A, Loss of pigmented neurons in substantia nigra. B, Normal substantia nigra for comparison. C, Lewy body. (A and B, Courtesy of Robert Wollmann, MD) C. Presents as triad of urinary incontinence, gait instability, and dementia ("wet, wobbly, and wacky") D. Lumbar puncture improves symptoms; treatment is ventriculoperitoneal shunting. VIII. SPONGIFORM ENCEPHALOPATHY


Pathoma_Husain

Pathoma_Husain. D. Lumbar puncture improves symptoms; treatment is ventriculoperitoneal shunting. VIII. SPONGIFORM ENCEPHALOPATHY A. Degenerative disease due to prion protein 1. Prion protein is normally expressed in CNS neurons in an a-helical configuration (PrPc). B. Disease arises with conversion to a ~-pleated conformation (PrP'c). 1. Conversion can be sporadic, inherited (familial forms of disease), or transmitted. C. Pathologic protein is not degradable and converts normal protein into the pathologic form, resulting in a vicious cycle. 1. Damage to neurons and glial cells is characterized by intracellular vacuoles (spongy degeneration, Fig. 17.15). D. Creutzfeldt-Jakob disease (CJD) is the most common spongiform encephalopathy. 1. Usually sporadic; rarely can arise due to exposure to prion-infected human tissue (e.g., human growth hormone or corneal transplant) 2.


Pathoma_Husain

Pathoma_Husain. 1. Usually sporadic; rarely can arise due to exposure to prion-infected human tissue (e.g., human growth hormone or corneal transplant) 2. Presents as rapidly progressive dementia associated with ataxia (cerebellar involvement) and startle myoclonus i. Periodic sharp waves are seen on EEG. ii. Results in death, usually in < 1 year 3. Variant CJD is a special form of disease that is related to exposure to bovine spongiform encephalopathy ('mad cow'). E. Familial fatal insomnia is an inherited form of prion disease characterized by severe insomnia and an exaggerated startle response. I. BASIC PRINCIPLES A. Can be metastatic (50%) or primary (50%) B. Metastatic tumors characteristically present as multiple, well-circumscribed lesions at the gray-white junction. 1. Lung, breast, and kidney are common sources. C. Primary tumors are classified according to cell type of origin (e.g., astrocytes, meningothelial cells, ependymal cells, oligodendrocytes, or neuroectoderm).


Pathoma_Husain

Pathoma_Husain. C. Primary tumors are classified according to cell type of origin (e.g., astrocytes, meningothelial cells, ependymal cells, oligodendrocytes, or neuroectoderm). D. In adults, primary tumors are usually supratentorial. 1. Most common tumors in adults are glioblastoma multiforme, meningioma, and schwannoma. E. In children, primary tumors are usually infratentorial. Fig. 17.14 Huntington disease. A, Degeneration of caudate nucleus. B, Normal caudate nucleus for Fig. 17.15 Spongiform encephalopath y. (Courtesy comparison. (Courtesy of Peter Pytel, MD) of Peter Pytel, MD) 1. Most common tumors in children are pilocytic astrocytoma, ependymoma, and medulloblastoma. F. Primary malignant CNS tumors are locally destructive, but rarely metastasize. II. GLIOBLASTOMA MULTIFORME (GBM) A. Malignant, high-grade tumor of astrocytes B. Most common primary malignant CNS tumor in adults


Pathoma_Husain

Pathoma_Husain. II. GLIOBLASTOMA MULTIFORME (GBM) A. Malignant, high-grade tumor of astrocytes B. Most common primary malignant CNS tumor in adults C. Usually arises in the cerebral hemisphere; characteristically crosses the corpus callosum ('butterfly' lesion, Fig. 17.16A) D. Characterized by regions of necrosis surrounded by tumor cells (pseudopalisading, Fig. 17.16B) and endothelial cell proliferation; tumor cells are GFAP positive. E. Poor prognosis III. MENINGIOMA A. Benign tumor of arachnoid cells B. Most common benign CNS tumor in adults 1. More commonly seen in women; rare in children C. May present as seizures; tumor compresses, but does not invade, the cortex. D. Imaging reveals a round mass attached to the dura. E. Histology shows a whorled pattern (Fig. 17.17); psammoma bodies may be present. IV. A. Benign tumor of Schwann cells


Pathoma_Husain

Pathoma_Husain. D. Imaging reveals a round mass attached to the dura. E. Histology shows a whorled pattern (Fig. 17.17); psammoma bodies may be present. IV. A. Benign tumor of Schwann cells B. Involves cranial or spinal nerves; within the cranium, most frequently involves cranial nerve VIII at the cerebellopontine angle (presents as loss of hearing and tinnitus) C. Tumor cells are S-100+. D. Bilateral tumors are seen in neurofibromatosis type 2. V. A. Malignant tumor of oligodendrocytes B. Imaging reveals a calcified tumor in the white matter, usually involving the frontal lobe; may present with seizures C. 'Fried-egg' appearance of cells on biopsy (Fig. 17.18) VI. PILOCYTIC ASTROCYTOMA A. Benign tumor of astrocytes B. Most common CNS tumor in children; usually arises in the cerebellum C. Imaging reveals a cystic lesion with a mural nodule (Fig. 17.19A). Fig. 17.16 Glioblastoma multiforme. A, 'Butterfly' lesion. B, Pseudopalisading. (Courtesy of Peter Pytel, MD)


Pathoma_Husain

Pathoma_Husain. C. Imaging reveals a cystic lesion with a mural nodule (Fig. 17.19A). Fig. 17.16 Glioblastoma multiforme. A, 'Butterfly' lesion. B, Pseudopalisading. (Courtesy of Peter Pytel, MD) D. Biopsy shows Rosenthal fibers (thick eosinophilic processes of astrocytes, Fig. 17.19B) and eosinophilic granular bodies; tumor cells are GFAP positive. VII. MEDULLOBLASTOMA A. Malignant tumor derived from the granular cells of the cerebellum (neuroectoderm) B. Usually arises in children C. Histology reveals small, round blue cells; Homer-Wright rosettes may be present. D. Poor prognosis; tumor grows rapidly and spreads via CSF. 1. Metastasis to the cauda equina is termed 'drop metastasis.' VIII. EPENDYMOMA A. Malignant tumor of ependymal cells; usually seen in children B. Most commonly arises in the 4th ventricle; may present with hydrocephalus C. Perivascular pseudorosettes are a characteristic finding on biopsy (Fig. 17.20). IX. CRANIOPHARYNGIOMA


Pathoma_Husain

Pathoma_Husain. B. Most commonly arises in the 4th ventricle; may present with hydrocephalus C. Perivascular pseudorosettes are a characteristic finding on biopsy (Fig. 17.20). IX. CRANIOPHARYNGIOMA A. Tumor that arises from epithelial remnants ofRathke's pouch B. Presents as a supratentorial mass in a child or young adult; may compress the optic chiasm leading to bitemporal hemianopsia C. Calcifications are commonly seen on imaging (derived from "tooth-like" tissue). D. Benign, but tends to recur after resection Fig. 17.17 Meningioma. Fig. 17.18 Oligodendroglioma. (Courtesy of Peter Pytel, MD) .: ~i'~'. , f, . ,. l Fig. 17.19 Pi locytic astrocytoma. A, Cystic lesion with mural nodule. B, Rosentha l fibers. (A, Courtesy Fig. 17.20 Ependymoma. of Peter Pytel, MD) I. ACHONDROPLASIA A. Impaired cartilage proliferation in the growth plate; common cause of dwarfism B. Due to an activating mutation in fibroblast growth factor receptor 3 (FGFR3); autosomal dominant 1.


Pathoma_Husain

Pathoma_Husain. A. Impaired cartilage proliferation in the growth plate; common cause of dwarfism B. Due to an activating mutation in fibroblast growth factor receptor 3 (FGFR3); autosomal dominant 1. Overexpression of FGFR3 inhibits growth. 2. Most mutations are sporadic and related to increased paternal age. C. Clinical features 1. Short extremities with normal-sized head and chest-due to poor endochondral bone formation; intramembranous bone formation is not affected. i. Endochondral bone formation is characterized by formation of a cartilage matrix, which is then replaced by bone; it is the mechanism by which long bones grow. ii. Intramembranous bone formation is characterized by formation of bone without a preexisting cartilage matrix; it is the mechanism by which flat bones (e.g., skull and rib cage) develop. D. Mental function, life span, and fertility are not affected. II. OSTEOGENESIS IMPERFECTA A. Congenital defect of bone formation resulting in structurally weak bone


Pathoma_Husain

Pathoma_Husain. D. Mental function, life span, and fertility are not affected. II. OSTEOGENESIS IMPERFECTA A. Congenital defect of bone formation resulting in structurally weak bone B. Most commonly due to an autosomal dominant defect in collagen type I synthesis C. Clinical features 1. Multiple fractures of bone (can mimic child abuse, but bruising is absent) 2. Blue sclera-Thinning ofscleral collagen reveals underlying choroidal veins. 3. Hearing loss-Bones of the middle ear easily fracture. III. OSTEOPETROSIS A. Inherited defect of bone resorption resulting in abnormally thick, heavy bone that fractures easily B. Due to poor osteoclast function C. Multiple genetic variants exist; carbonic anhydrase II mutation leads to loss of the acidic microenvironment required for bone resorption. D. Clinical features include 1. 2. Anemia, thrombocytopenia, and leukopenia with extramedullary hematopoiesis-due to bony replacement of the marrow (myelophthisic process, Fig. 18.1) 3.


Pathoma_Husain

Pathoma_Husain. D. Clinical features include 1. 2. Anemia, thrombocytopenia, and leukopenia with extramedullary hematopoiesis-due to bony replacement of the marrow (myelophthisic process, Fig. 18.1) 3. Vision and hearing impairment-due to impingement on cranial nerves 4. Hydrocephalus-due to narrowing of the fora men magnum 5. Renal tubular acidosis-seen with carbonic anhydrase II mutation i. Lack ofcarbonic anhydrase results in decreased tubular reabsorption of HCO -, leading to metabolic acidosis. E. Treatment is bone marrow transplant; osteoclasts are derived from monocytes. pathoma.com IV. A. Defective mineralization of osteoid 1. Osteoblasts normally produce osteoid, which is then mineralized with calcium and phosphate to form bone. B. Due to low levels ofvitamin D, which results in low serum calcium and phosphate 1. Vitamin Dis normally derived from the skin upon exposure to sunlight (85%) and from the diet (15%). 2.


Pathoma_Husain

Pathoma_Husain. B. Due to low levels ofvitamin D, which results in low serum calcium and phosphate 1. Vitamin Dis normally derived from the skin upon exposure to sunlight (85%) and from the diet (15%). 2. Activation requires 25 -hydroxylation by the liver followed by 1-alphahydroxylation by the proximal tubule cells of the kidney. 3. i. Intestine-increases absorption of calcium and phosphate ii. Kidney-increases reabsorption of calcium and phosphate iii. Bone-increases resorption of calcium and phosphate 4. Vitamin D deficiency is seen with decreased sun exposure (e.g., northern latitudes), poor diet, malabsorption, liver failure, and renal failure. C. Rickets is due to low vitamin D in children, resulting in abnormal bone mineralization.


Pathoma_Husain

Pathoma_Husain. C. Rickets is due to low vitamin D in children, resulting in abnormal bone mineralization. 1. Most commonly arises in children < 1 year of age; presents with i. Pigeon-breast deformity-inward bending of the ribs with anterior protrusion of the sternum ii. Frontal bossing (enlarged forehead) -due to osteoid deposition on the skull iii. Rachi tic rosary-due to osteoid deposition at the costochondral junction iv. Bowing of the legs may be seen in ambulating children. D. Osteomalacia is due to low vitamin D in adults. 1. Inadequate mineralization results in weak bone with an increased risk for fracture. 2. Laboratory findings include --1.-serum calcium, --1.-serum phosphate, t PTH, and t alkaline phosphatase. V. A. Reduction in trabecular bone mass B. Results in porous bone with an increased risk for fracture C. Risk of osteoporosis is based on peak bone mass (attained in early adulthood) and rate of bone loss that follows thereafter. 1.


Pathoma_Husain

Pathoma_Husain. B. Results in porous bone with an increased risk for fracture C. Risk of osteoporosis is based on peak bone mass (attained in early adulthood) and rate of bone loss that follows thereafter. 1. Peak bone mass is achieved by 30 years of age and is based on (1) genetics (e.g., vitamin D receptor variants), (2) diet, and (3) exercise. 2. Thereafter, slightly less than 1% of bone mass is lost each year; bone mass is lost more quickly with lack of weight-bearing exercise (e.g., space travel), poor diet, or decreased estrogen (e.g., menopause). D. Most common forms of osteoporosis are senile and postmenopausal. Fig. 18.1 Osteopetrosis. (Published with Fig. 18.2 Paget disease of bone. permission from LearningRadiology.com) E. Clinical features 1. Bone pain and fractures in weight-bearing areas such as the vertebrae (leads to loss of height and kyphosis), hip, and distal radius 2. Bone density is measured using a DEXA scan. 3.


Pathoma_Husain

Pathoma_Husain. Bone pain and fractures in weight-bearing areas such as the vertebrae (leads to loss of height and kyphosis), hip, and distal radius 2. Bone density is measured using a DEXA scan. 3. Serum calcium, phosphate, PTH, and alkaline phosphatase are normal; labs help to exclude osteomalacia (which has a similar clinical presentation). F. Treatment includes 1. Exercise, vitamin D, and calcium-limit bone loss 2. Bisphosphonates-induce apoptosis of osteoclasts 3. Estrogen replacement therapy is debated (currently not recommended). 4. Glucocorticoids are contraindicated (worsen osteoporosis). VI. PAGET DISEASE OF BONE A. Imbalance between osteoclast and osteoblast function 1. Usually seen in late adulthood (average age > 60 years) B. Etiology is unknown; possibly viral C. Localized process involving one or more bones; does not involve the entire skeleton D. Three distinct stages are (1) osteoclastic, (2) mixed osteoblastic-osteoclastic, and (3) osteoblastic. 1.


Pathoma_Husain

Pathoma_Husain. C. Localized process involving one or more bones; does not involve the entire skeleton D. Three distinct stages are (1) osteoclastic, (2) mixed osteoblastic-osteoclastic, and (3) osteoblastic. 1. End result is thick, sclerotic bone that fractures easily. 2. Biopsy reveals a mosaic pattern of lamellar bone (Fig. 18.2). E. Clinical features 1. Bone pain-due to microfractures 2. Increasing hat size-Skull is commonly affected. 3. 4. Lion-like facies-involvement of craniofacial bones 5. Isolated elevated alkaline phosphatase-most common cause of isolated elevated alkaline phosphatase in patients > 40 years old F. Treatment includes 1. 2. Bisphosphonates-induces apoptosis of osteoclasts G. Complications include 1. High-output cardiac failure-due to formation of AV shunts in bone 2. VII. OSTEOMYELITIS A. Infection of marrow and bone 1. Usually occurs in children B. Most commonly bacterial; arises via hematogenous spread 1.


Pathoma_Husain

Pathoma_Husain. VII. OSTEOMYELITIS A. Infection of marrow and bone 1. Usually occurs in children B. Most commonly bacterial; arises via hematogenous spread 1. Transient bacteremia (children) seeds metaphysis. 2. Open-wound bacteremia (adults) seeds epiphysis. C. Causes include 1. Staphylococcus aureus-most common cause (90% of cases) 2. 3. 4. 5. Pasteurella-associated with cat or dog bite/scratches 6. D. Clinical features 1. Bone pain with systemic signs of infection (e.g., fever and leukocytosis) 2. Lytic focus (abscess) surrounded by sclerosis of bone on x-ray; lytic focus is called sequestrum, and sclerosis is called involucrum. E. Diagnosis is made by blood culture. _ _____________F_U_N_D_AMENTALS OF PATHOLOGY________. VIII. AVASCULAR (ASEPTIC) NECROSIS A. Ischemic necrosis of bone and bone marrow B. Causes include trauma or fracture (most common), steroids, sickle cell anemia, and caisson disease. C. Osteoarthritis and fracture are major complications. I. OSTEOMA


Pathoma_Husain

Pathoma_Husain. B. Causes include trauma or fracture (most common), steroids, sickle cell anemia, and caisson disease. C. Osteoarthritis and fracture are major complications. I. OSTEOMA A. Benign tumor of bone B. Most commonly arises on the surface of facial bones C. Associated with Gardner syndrome II. OSTEOID OSTEOMA A. Benign tumor of osteoblasts (that produce osteoid) surrounded by a rim of reactive bone B. Occurs in young adults < 25 years ofage (more common in males) C. Arises in cortex of long bones (e.g., femur) D. Presents as bone pain that resolves with aspirin E. Imaging reveals a bony mass(< 2 cm) with a radiolucent core (osteoid). F. Osteoblastoma is similar to osteoid osteoma but is larger(> 2 cm), arises in vertebrae, and presents as bone pain that does not respond to aspirin. III. OSTEOCHONDROMA A. Tumor of bone with an overlying cartilage cap (Fig. 18.3); most common benign tumor ofbone


Pathoma_Husain

Pathoma_Husain. III. OSTEOCHONDROMA A. Tumor of bone with an overlying cartilage cap (Fig. 18.3); most common benign tumor ofbone B. Arises from a lateral projection of the growth plate (metaphysis); bone is continuous with the marrow space. C. Overlying cartilage can transform (rarely) to chondrosarcoma. IV. OSTEOSARCOMA A. Malignant proliferation of osteoblasts B. Peak incidence is seen in teenagers; less commonly seen in the elderly 1. Risk factors include familial retinoblastoma, Paget disease, and radiation exposure. 2. Arises in the metaphysis of long bones, usually the distal femur or proximal tibia (region of the knee) C. Presents as a pathologic fracture or bone pain with swelling D. Imaging reveals a destructive mass with a 'sunburst' appearance and lifting of the periosteum (Codman triangle, Fig. 18.4A). Fig. 18.3 Osteochondroma. (Courtesy of Fig. 18.4 Osteosarcoma. A, X-ray. B, Microscopic appearance. (A, Courtesy of Bu lent Celasun, MD) humpath.com)


Pathoma_Husain

Pathoma_Husain. Fig. 18.3 Osteochondroma. (Courtesy of Fig. 18.4 Osteosarcoma. A, X-ray. B, Microscopic appearance. (A, Courtesy of Bu lent Celasun, MD) humpath.com) E. Biopsy reveals pleomorphic cells that produce osteoid (Fig. 18.4B). V. GIANT CELL TUMOR A. Tumor comprised of multinucleated giant cells and stromal cells B. Occurs in young adults C. Arises in the epiphysis of long bones, usually the distal femur or proximal tibia (region of the knee) D. 'Soap-bubble' appearance on x-ray E. Locally aggressive tumor; may recur VI. EWING SARCOMA A. Malignant proliferation of poorly-differentiated cells derived from neuroectoderm B. Arises in the diaphysis oflong bones; usually in male children(< 15 years ofage) C. 'Onion-skin' appearance on x-ray D. Biopsy reveals small, round blue cells that resemble lymphocytes (Fig. 18.5). 1. Can be confused with lymphoma or chronic osteomyelitis 2. (11;22) translocation is characteristic.


Pathoma_Husain

Pathoma_Husain. D. Biopsy reveals small, round blue cells that resemble lymphocytes (Fig. 18.5). 1. Can be confused with lymphoma or chronic osteomyelitis 2. (11;22) translocation is characteristic. E. Often presents with metastasis; responsive to chemotherapy Vil. CHONDROMA A. Benign tumor of cartilage B. Usually arises in the medulla of small bones of the hands and feet (Fig. 18.6) VIII. CHONDROSARCOMA A. Malignant cartilage-forming tumor B. Arises in medulla of the pelvis or central skeleton IX. METASTATIC TUMORS A. More common than primary tumors B. Usually result in osteolytic (punched-out) lesions 1. Prostatic carcinoma classically produces osteoblastic lesions. I. BASIC PRINCIPLES A. Connection between two bones B. Solid joints are tightly connected to provide structural strength (e.g., cranial sutures). C. Synovial joints have a joint space to allow for motion.


Pathoma_Husain

Pathoma_Husain. A. Connection between two bones B. Solid joints are tightly connected to provide structural strength (e.g., cranial sutures). C. Synovial joints have a joint space to allow for motion. 1. Articular surface of adjoining bones is made ofhyaline cartilage (type II collagen) that is surrounded by a joint capsule. Fig. 18.S Ewing sarcoma. Fig. 18.6 Chondroma. (Published with permi ssion from LearningRadiology.com) 2. Synovium lining the joint capsule secretes fluid rich in hyaluronic acid to lubricate the joint and facilitate smooth motion. II. DEGENERATIVE JOINT DISEASE (OSTEOARTHRITIS) A. Progressive degeneration of articular cartilage; most common type of arthritis B. Most often due to 'wear and tear' C. Major risk factor is age (common after 60 years); additional risk factors include obesity and trauma.


Pathoma_Husain

Pathoma_Husain. B. Most often due to 'wear and tear' C. Major risk factor is age (common after 60 years); additional risk factors include obesity and trauma. D. Affects a limited number of joints (oligoarticular); hips, lower lumbar spine, knees, and the distal interphalangeal joints (DIP) and proximal interphalangeal joints (PIP) of fingers are common sites. E. Classic presentation is joint stiffness in the morning that worsens during the day. F. Pathologic features include 1. Disruption of the cartilage that lines the articular surface (Fig. 18.7); fragments of cartilage floating in the joint space are called 'joint mice.' 2. Eburnation of the subchondral bone 3. Osteophyte formation (reactive bony outgrowths); classically arises in the DIP (Heberden nodes) and PIP (Bouchard nodes) joints of the fingers III. RHEUMATOID ARTHRITIS A. Chronic, systemic autoimmune disease 1. Classically arises in women of late childbearing age 2. Associated with HLA-DR4


Pathoma_Husain

Pathoma_Husain. III. RHEUMATOID ARTHRITIS A. Chronic, systemic autoimmune disease 1. Classically arises in women of late childbearing age 2. Associated with HLA-DR4 B. Characterized by involvement ofjoints 1. Hallmark is synovitis leading to formation of a pannus (inflamed granulation tissue). 2. Leads to destruction of cartilage and ankylosis (fusion) of the joint C. Clinical features 1. Arthritis with morning stiffness that improves with activity. i. Symmetric involvement of PIP joints of the fingers (swan-neck deformity), wrists (radial deviation), elbows, ankles, and knees is characteristic (Fig. 18.8); DIP is usually spared (unlike osteoarthritis). ii. Joint-space narrowing, loss of cartilage, and osteopenia are seen on x-ray. 2. Fever, malaise, weight loss, and myalgias 3. Rheumatoid nodules-central zone of necrosis surrounded by epithelioid histiocytes; arise in skin and visceral organs 4. Vasculitis-Multiple organs may be involved. 5.


Pathoma_Husain

Pathoma_Husain. Rheumatoid nodules-central zone of necrosis surrounded by epithelioid histiocytes; arise in skin and visceral organs 4. Vasculitis-Multiple organs may be involved. 5. Baker cyst-swelling of bursa behind the knee 6. Pleural effusions, lymphadenopathy, and interstitial lung fibrosis Fig. 18.7 Degenerative joint disease. Fig. 18.8 Rheumatoid arthritis. (Courtesy of James Heilman, MD, Wikipedia) D. Laboratory findings 1. IgM autoantibody against Fe portion ofigG (rheumatoid factor); marker of tissue damage and disease activity 2. E. Complications include anemia of chronic disease and secondary amyloidosis. IV. A. Group ofjoint disorders characterized by 1. Lack of rheumatoid factor 2. Axial skeleton involvement 3. HLA-B27 association B. Ankylosing spondyloarthritis involves the sacroiliac joints and spine. 1. Arises in young adults, most often male 2.


Pathoma_Husain

Pathoma_Husain. Axial skeleton involvement 3. HLA-B27 association B. Ankylosing spondyloarthritis involves the sacroiliac joints and spine. 1. Arises in young adults, most often male 2. Presents with low back pain; involvement ofvertebral bodies eventually arises, leading to fusion of the vertebrae ('bamboo spine'). 3. Extra-articular manifestations include uveitis and aortitis (leading to aortic regurgitation). C. Reactive arthritis is characterized by the triad of arthritis, urethritis, and conjunctivitis. 1. Arises in young adults (usually males) weeks after a GI or Chlamydia trachomatis infection D. Psoriatic arthritis is seen in 10% of cases of psoriasis. 1. Involves axial and peripheral joints; DIP joints of the hands and feet are most commonly affected, leading to "sausage" fingers or toes. V. A. Arthritis due to an infectious agent, usually bacterial B. Causes include 1. N gonorrhoeae-young adults; most common cause 2. S aureus-older children and adults; 2nd most common cause


Pathoma_Husain

Pathoma_Husain. V. A. Arthritis due to an infectious agent, usually bacterial B. Causes include 1. N gonorrhoeae-young adults; most common cause 2. S aureus-older children and adults; 2nd most common cause C. Classically involves a single joint, usually the knee D. Presents as a warm joint with limited range of motion; fever, increased white count, and elevated ESR are often present. VI. GOUT A. Deposition of monosodium urate (MSU) crystals in tissues, especially the joints B. Due to hyperuricemia; related to overproduction or decreased excretion of uric acid 1. Uric acid is derived from purine metabolism and is excreted by the kidney. C. Primary gout is the most common form; etiology ofhyperuricemia is unknown. D. Secondary gout is seen with 1. Leukemia and myeloproliferative disorders-Increased cell turnover leads to hyperuricemia. 2. Lesch-Nyhan syndrome-X-linked deficiency ofhypoxanthine-guanine phosphoribosyltransferase (HGPRT); presents with mental retardation and selfmutilation 3.


Pathoma_Husain

Pathoma_Husain. 2. Lesch-Nyhan syndrome-X-linked deficiency ofhypoxanthine-guanine phosphoribosyltransferase (HGPRT); presents with mental retardation and selfmutilation 3. Renal insufficiency-decreased renal excretion of uric acid E. Acute gout presents as exquisitely painful arthritis of the great toe (podagra) 1. MSU crystals deposit in the joint, triggering an acute inflammatory reaction. 2. Alcohol or consumption of meat may precipitate arthritis. F. Chronic gout leads to 1. Development of tophi-white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in the soft tissue and joints (Fig. 18.9A) 2. Renal failure-Urate crystals may deposit in kidney tubules (urate nephropathy). G. Laboratory findings include hyperuricemia; synovial fluid shows needle-shaped crystals with negative birefringence under polarized light (Fig. 18.9B).


Pathoma_Husain

Pathoma_Husain. G. Laboratory findings include hyperuricemia; synovial fluid shows needle-shaped crystals with negative birefringence under polarized light (Fig. 18.9B). H. Pseudogout resembles gout clinically, but is due to deposition of calcium pyrophosphate dihydrate (CPPD); synovial fluid shows rhomboid-shaped crystals with weakly positive birefringence under polarized light. I. DERMATOMYOSITIS A. Inflammatory disorder of the skin and skeletal muscle B. Unknown etiology; some cases are associated with carcinoma (e.g., gastric carcinoma). C. Clinical features 1. Bilateral proximal muscle weakness; distal involvement can develop late in disease. 2. Rash of the upper eyelids (heliotrope rash); malar rash may also be seen. 3. Red papules on the elbows, knuckles, and knees (Gottron papules) D. Laboratory findings 1. 2. 3. Perimysial inflammation (CD4+ T cells) with perifascicular atrophy on biopsy (Fig. 18.10) E. Treatment is corticosteroids. II. POLYMYOSITIS


Pathoma_Husain

Pathoma_Husain. D. Laboratory findings 1. 2. 3. Perimysial inflammation (CD4+ T cells) with perifascicular atrophy on biopsy (Fig. 18.10) E. Treatment is corticosteroids. II. POLYMYOSITIS A. Inflammatory disorder of skeletal muscle B. Resembles dermatomyositis clinically, but skin is not involved; endomysial inflammation (CDS+ T cells) with necrotic muscle fibers is seen on biopsy. III. X-LINKED MUSCULAR DYSTROPHY A. Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by adipose tissue B. Due to defects of dystrophin gene 1. Dystrophin is important for anchoring the muscle cytoskeleton to the extracellular matrix. 2. Mutations are often spontaneous; large gene size predisposes to high rate of mutation. C. Duchenne muscular dystrophy is due to deletion of dystrophin. 1. Presents as proximal muscle weakness at 1 year of age; progresses to involve distal muscles i. Calf pseudohypertrophy is a characteristic finding.


Pathoma_Husain

Pathoma_Husain. 1. Presents as proximal muscle weakness at 1 year of age; progresses to involve distal muscles i. Calf pseudohypertrophy is a characteristic finding. ii. Serum creatine kinase is elevated. 2. Death results from cardiac or respiratory failure; myocardium is commonly involved. D. Becker muscular dystrophy is due to mutated dystrophin; clinically results in milder disease I. MYASTHENIA GRAVIS A. Autoantibodies against the postsynaptic acetylcholine receptor at the neuromuscular junction B. More commonly seen in women C. Clinical features 1. Muscle weakness that worsens with use and improves with rest; classically involves the eyes, leading to ptosis and diplopia 2. Symptoms improve with anticholinesterase agents. 3. Associated with thymic hyperplasia or thymoma; thymectomy improves symptoms. II. LAMBERT-EATON SYNDROME A. Antibodies against presynaptic calcium channels of the neuromuscular junction


Pathoma_Husain

Pathoma_Husain. 3. Associated with thymic hyperplasia or thymoma; thymectomy improves symptoms. II. LAMBERT-EATON SYNDROME A. Antibodies against presynaptic calcium channels of the neuromuscular junction B. Arises as a paraneoplastic syndrome, most commonly due to small cell carcinoma of the lung C. Leads to impaired acetylcholine release 1. Firing of presynaptic calcium channels is required for acetylcholine release. D. Clinical features 1. Proximal muscle weakness that improves with use; eyes are usually spared. 2. Anticholinesterase agents do not improve symptoms. 3. Resolves with resection of the cancer I. LIPOMA A. Benign tumor of adipose tissue B. Most common benign soft tissue tumor in adults II. LIPOSARCOMA A. Malignant tumor of adipose tissue B. Most common malignant soft tissue tumor in adults C. Lipoblast is the characteristic cell. III. RHABDOMYOMA A. Benign tumor of skeletal muscle B. Cardiac rhabdomyoma is associated with tuberous sclerosis. IV. RHABDOMYOSARCOMA


Pathoma_Husain

Pathoma_Husain. C. Lipoblast is the characteristic cell. III. RHABDOMYOMA A. Benign tumor of skeletal muscle B. Cardiac rhabdomyoma is associated with tuberous sclerosis. IV. RHABDOMYOSARCOMA A. Malignant tumor of skeletal muscle B. Most common malignant soft tissue tumor in children C. Rhabdomyoblast is the characteristic cell; desmin positive D. Most common site is the head and neck; vagina is the classic site in young girls. Fig. 18.9 Gout. A, Tophi. B, Negative birefringence. (B, Courtesy of Ed Uthman, MD) Fig. 18.10 Dermatomyositis. (Courtesy of Peter Pytel, MD) I. SKIN A. Functions as a barrier against environmental insults and fluid loss B. Composed of an epidermis and dermis C. Epidermis is comprised of keratinocytes and has four layers (Fig. 19.1). 1. 2. 3. 4. D. Dermis consists of connective tissue, nerve endings, blood and lymphatic vessels, and adnexal structures (e.g., hair shafts, sweat glands, and sebaceous glands). I. ATOPIC (ECZEMATOUS) DERMATITIS


Pathoma_Husain

Pathoma_Husain. I. ATOPIC (ECZEMATOUS) DERMATITIS A. Pruritic, erythematous, oozing rash with vesicles and edema; often involves the face and flexor surfaces B. Type I hypersensitivity reaction; associated with asthma and allergic rhinitis II. CONTACT DERMATITIS A. Pruritic, erythematous, oozing rash with vesicles and edema B. Arises upon exposure to allergens such as 1. 2. Irritant chemicals (e.g., detergents) 3. Drugs (e.g., penicillin) C. Treatment involves removal of the offending agent and topical glucocorticoids, if needed. III. ACNE VULGARIS A. Comedones (whiteheads and blackheads), pustules (pimples), and nodules; extremely common, especially in adolescents B. Due to chronic inflammation of hair follicles and associated sebaceous glands 1. Hormone-associated increase in sebum production (sebaceous glands have androgen receptors) and excess keratin production block follicles, forming comedones. 2.


Pathoma_Husain

Pathoma_Husain. Hormone-associated increase in sebum production (sebaceous glands have androgen receptors) and excess keratin production block follicles, forming comedones. 2. Propionibacterium acnes infection produces lipases that break down sebum, releasing proinflammatory fatty acids; results in pustule or nodule formation C. Treatment includes benzoyl peroxide (antimicrobial) and vitamin A derivatives (e.g., isotretinoin), which reduce keratin production. IV. PSORIASIS A. Well-circumscribed, salmon-colored plaques with silvery scale, usually on extensor surfaces and the scalp (Fig. 19.2A); pitting of nails may also be present. B. Due to excessive keratinocyte proliferation pat homa.com C. Possible autoimmune etiology 1. Associated with HLA-C 2. Lesions often arise in areas of trauma (environmental trigger). D. Histology (Fig. 19.2B) shows 1. 2. Parakeratosis (hyperkeratosis with retention ofkeratinocyte nuclei in the stratum corneum) 3.


Pathoma_Husain

Pathoma_Husain. Lesions often arise in areas of trauma (environmental trigger). D. Histology (Fig. 19.2B) shows 1. 2. Parakeratosis (hyperkeratosis with retention ofkeratinocyte nuclei in the stratum corneum) 3. Collections of neutrophils in the stratum corneum (Munro microabscesses) 4. Thinning of the epidermis above elongated dermal papillae; results in bleeding when scale is picked off (Auspitz sign) E. Treatment involves corticosteroids, UV light with psoralen, or immune-modulating therapy. V. LICHEN PLANUS A. Pruritic, planar, polygonal, purple papules (Fig. 19.3A), often with reticular white lines on their surface (Wickham striae); commonly involves wrists, elbows, and oral mucosa 1. Oral involvement manifests as Wickham striae. B. Histology shows inflammation of the dermal-epidermal junction with a 'saw-tooth' appearance (Fig. 19.3B). C. Etiology is unknown; associated with chronic hepatitis C virus infection I. PEMPHIGUS VULGARIS


Pathoma_Husain

Pathoma_Husain. C. Etiology is unknown; associated with chronic hepatitis C virus infection I. PEMPHIGUS VULGARIS A. Autoimmune destruction of desmosomes between keratinocytes Fig. 19.1 Skin histology, normal. Fig. 19.2 Psoriasis. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy ofVesna PetronicRosic, MD) Fig. 19.3 Lichen planus. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy ofVesna Petronic-Rosic, MD) B. Due to IgG antibody against desmoglein (type II hypersensitivity) C. Presents as skin and oral mucosa bullae (Fig. 19.4A). 1. Acantholysis (separation) of stratum spinosum keratinocytes (normally connected by desmosomes) results in suprabasal blisters. 2. Basal layer cells remain attached to basement membrane via hemidesmosomes ('tombstone' appearance, Fig. 19.4B). 3. Thin-walled bullae rupture easily (Nikolsky sign), leading to shallow erosions with dried crust. 4. Immunofluorescence highlights IgG surrounding keratinocytes in a 'fish net' pattern.


Pathoma_Husain

Pathoma_Husain. 3. Thin-walled bullae rupture easily (Nikolsky sign), leading to shallow erosions with dried crust. 4. Immunofluorescence highlights IgG surrounding keratinocytes in a 'fish net' pattern. II. BULLOUS PEMPHIGOID A. Autoimmune destruction ofhemidesmosomes between basal cells and the underlying basement membrane B. Due to IgG antibody against hemidesmosome components (BP180) of the basement membrane C. Presents as blisters of the skin (Fig. 19.SA), usually in the elderly; oral mucosa is spared. 1. Basal cell layer is detached from the basement membrane (Fig. 19.SB). 2. D. Immunofluorescence highlights IgG along basement membrane (linear pattern). III. DERMATITIS HERPETIFORMIS A. Autoimmune deposition of IgA at the tips of dermal papillae B. Presents as pruritic vesicles and bullae that are grouped (herpetiform, Fig. 19.6) C. Strong association with celiac disease; resolves with gluten-free diet


Pathoma_Husain

Pathoma_Husain. B. Presents as pruritic vesicles and bullae that are grouped (herpetiform, Fig. 19.6) C. Strong association with celiac disease; resolves with gluten-free diet Fig. 19.4 Pemphigus vulgaris. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy of Vesna Petronic-Rosic, MD) Fig. 19.5 Bullous pemphigoid. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy of Vesna Petronic-Rosic, MD) IV. ERYTHEMA MULTIFORME (EM) A. Hypersensitivity reaction characterized by targetoid rash and bullae (Fig. 19.7) 1. Targetoid appearance is due to central epidermal necrosis surrounded by erythema. B. Most commonly associated with HSV infection; other associations include Mycoplasma infection, drugs (penicillin and sulfonamides), autoimmune disease (e.g., SLE), and malignancy. C. EM with oral mucosa/lip involvement and fever is termed Stevens-Johnson syndrome (SJS).


Pathoma_Husain

Pathoma_Husain. C. EM with oral mucosa/lip involvement and fever is termed Stevens-Johnson syndrome (SJS). 1. Toxic epidermal necrolysis is a severe form of SJS characterized by diffuse sloughing of skin, resembling a large burn; most often due to an adverse drug reaction I. SEBORRHEIC KERATOSIS A. Benign squamous proliferation; common tumor in the elderly B. Presents as raised, discolored plaques on the extremities or face; often has a coinlike, waxy, 'stuck-on' appearance (Fig. 19.8A) 1. Characterized by keratin pseudocysts on histology (Fig. 19.8B) C. Leser-Trelat sign is the sudden onset of multiple seborrheic keratoses and suggests underlying carcinoma of the GI tract (Fig. 19.SC). II. ACANTHOSIS NIGRICANS A. Epidermal hyperplasia with darkening of the skin ('velvet-like' skin, Fig. 19.9); often involves the axilla or groin Fig. 19.6 Dermatitis herpetiformis. (Courtesy of Fig. 19.7 Erythema multiforme. (Courtesy of Vesna Petronic-Rosic, MD) James Heilman, MD, Wikipedia)


Pathoma_Husain

Pathoma_Husain. Fig. 19.6 Dermatitis herpetiformis. (Courtesy of Fig. 19.7 Erythema multiforme. (Courtesy of Vesna Petronic-Rosic, MD) James Heilman, MD, Wikipedia) Fig. 19.8 Seborrheic keratosis. A, Clinical appearance. B, Microscopic appearance. C, Sign of Leser-Trelat. (A and C, Courtesy of Vesna Petronic-Rosic, MD) B. Associated with insulin resistance (e.g., non-insulin-dependent diabetes) or malignancy (especially gastric carcinoma) III. BASAL CELL CARCINOMA A. Malignant proliferation of the basal cells of the epidermis 1. Most common cutaneous malignancy B. Risk factors stem from DVB-induced DNA damage and include prolonged exposure to sunlight, albinism, and xeroderma pigmentosum. C. Presents as an elevated nodule with a central, ulcerated crater surrounded by dilated (telangiectatic) vessels (Fig. 19.lOA); 'pink, pearl-like papule' 1. Classic location is the upper lip. D. Histology shows nodules of basal cells with peripheral palisading (Fig. 19.lOB).


Pathoma_Husain

Pathoma_Husain. D. Histology shows nodules of basal cells with peripheral palisading (Fig. 19.lOB). E. Treatment is surgical excision; metastasis is rare. IV. SQUAMOUS CELL CARCINOMA A. Malignant proliferation of squamous cells characterized by formation of keratin pearls. B. Risk factors stem from DVB-induced DNA damage and include prolonged exposure to sunlight, albinism, and xeroderma pigmentosum. 1. Additional risk factors include immunosuppressive therapy, arsenic exposure, and chronic inflammation (e.g., scar from burn or draining sinus tract). C. Presents as an ulcerated, nodular mass, usually on the face (classically involving the lower lip) D. Treatment is excision; metastasis is uncommon. E. Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a hyperkeratotic, scaly plaque, often on the face, back, or neck.


Pathoma_Husain

Pathoma_Husain. E. Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a hyperkeratotic, scaly plaque, often on the face, back, or neck. F. Keratoacanthoma is well-differentiated squamous cell carcinoma that develops rapidly and regresses spontaneously; presents as a cup-shaped tumor filled with keratin debris I. BASIC PRINCIPLES A. Melanocytes are responsible for skin pigmentation and are present in the basal layer of the epidermis. 1. Derived from the neural crest 2. Synthesize melanin in melanosomes using tyrosine as a precursor molecule 3. Pass melanosomes to keratinocytes Fig. 19.9 Acanthosis nigricans. (Courtesy ofVesna Fig. 19.10 Basal cell carcinoma. A, Clinical appearance. B, Microscopic appearance. (A, Courtesy of Petronic-Rosic, MD) Vesna Petronic-Rosic, MD) II. VITILIGO A. Localized loss of skin pigmentation (Fig. 19.11) B. Due to autoimmune destruction of melanocytes III. ALBINISM A. Congenital lack of pigmentation


Pathoma_Husain

Pathoma_Husain. II. VITILIGO A. Localized loss of skin pigmentation (Fig. 19.11) B. Due to autoimmune destruction of melanocytes III. ALBINISM A. Congenital lack of pigmentation B. Due to an enzyme defect (usually tyrosinase) that impairs melanin production C. May involve the eyes (ocular form) or both the eyes and skin (oculocutaneous form) D. Increased risk of squamous cell carcinoma, basal cell carcinoma, and melanoma due to reduced protection against UVB IV. A. Small, tan to brown macule; darkens when exposed to sunlight B. Due to increased number of melanosomes (melanocytes are not increased) V. A. Mask-like hyperpigmentation of the cheeks B. Associated with pregnancy and oral contraceptives VI. NEVUS (MOLE) A. Benign neoplasm of melanocytes B. Congenital nevus is present at birth; often associated with hair (Fig. 19.12) C. Acquired nevus arises later in life. 1.


Pathoma_Husain

Pathoma_Husain. VI. NEVUS (MOLE) A. Benign neoplasm of melanocytes B. Congenital nevus is present at birth; often associated with hair (Fig. 19.12) C. Acquired nevus arises later in life. 1. Begins as nests of melanocytes at the dermal-epidermal junction (junctional nevus); most common mole in children 2. Grows by extension into the dermis (compound nevus) 3. Junctional component is eventually lost resulting in an intradermal nevus, which is the most common mole in adults. D. Characterized by a flat macule or raised papule with symmetry, sharp borders, evenly distributed color, and small diameter(< 6 mm) E. Dysplasia may arise (dysplastic nevus), which is a precursor to melanoma. VII. MELANOMA A. Malignant neoplasm of melanocytes; most common cause of death from skin cancer


Pathoma_Husain

Pathoma_Husain. E. Dysplasia may arise (dysplastic nevus), which is a precursor to melanoma. VII. MELANOMA A. Malignant neoplasm of melanocytes; most common cause of death from skin cancer B. Risk factors are based on UVB-induced DNA damage and include prolonged exposure to sunlight, albinism, and xeroderma pigmentosum; an additional risk factor is dysplastic nevus syndrome (autosomal dominant disorder characterized by formation of dysplastic nevi that may progress to melanoma). C. Presents as a mole-like growth with "ABCD" (Fig. 19.13) Fig, 19,11 Vitiligo. (Courtesy of James Heilman, Fig. 19.12 Congenital nevus. (Courtesy ofVesna Flg. 19,13 Melanoma. (Courtesy ofVesna MD, Wikipedia) Petronic-Rosic, MD) Petronic-Rosic, MD) 1. 2. Borders are irregular. 3. Color is not uniform. 4. D. Characterized by two growth phases 1. Radial growth horizontally along the epidermis and superficial dermis; low risk of metastasis 2.


Pathoma_Husain

Pathoma_Husain. 2. Borders are irregular. 3. Color is not uniform. 4. D. Characterized by two growth phases 1. Radial growth horizontally along the epidermis and superficial dermis; low risk of metastasis 2. Vertical growth into the deep dermis 1. Increased risk of metastasis; depth of extension (Breslow thickness) is the most important prognostic factor in predicting metastasis. E. Variants include 1. Superficial spreading-most common subtype; dominant early radial growth results in good prognosis. 2. 3. 4. Acral lentiginous-arises on the palms or soles, often in dark-skinned individuals; not related to UV light exposure I. IMPETIGO A. Superficial bacterial skin infection, most often due to S aureus or S pyogenes B. Commonly affects children C. Presents as erythematous macules that progress to pustules, usually on the face; rupture of pustules results in erosions and dry, crusted, honey-colored serum. II. CELLULITIS


Pathoma_Husain

Pathoma_Husain. C. Presents as erythematous macules that progress to pustules, usually on the face; rupture of pustules results in erosions and dry, crusted, honey-colored serum. II. CELLULITIS A. Deeper (dermal and subcutaneous) infection, usually due to S aureus or Spyogenes B. Presents as a red, tender, swollen rash with fever C. Risk factors include recent surgery, trauma, or insect bite. D. Can progress to necrotizing fasciitis with necrosis ofsubcutaneous tissues due to infection with anaerobic 'flesh-eating' bacteria 1. Production of CO2 leads to crepitus. 2. III. STAPHYLOCOCCAL SCALDED SKIN SYNDROME A. Sloughing of skin with erythematous rash and fever; leads to significant skin loss B. Due to S aureus infection; exfoliative A and B toxins result in epidermolysis of the stratum granulosum. Fig. 19.14 Verruca. (Courtesy ofVesna Petronic-Fig. 19.15 Molluscum bodies. Rosie, MD)


Pathoma_Husain

Pathoma_Husain. B. Due to S aureus infection; exfoliative A and B toxins result in epidermolysis of the stratum granulosum. Fig. 19.14 Verruca. (Courtesy ofVesna Petronic-Fig. 19.15 Molluscum bodies. Rosie, MD) C. Distinguished histologically from toxic epidermal necrolysis by level of skin separation; separation in TEN occurs at the dermal-epidermal junction. IV. A. Flesh-colored papules with a rough surface {Fig. 19.14) B. Due to HPV infection of keratinocytes; characterized by koilocytic change C. Hands and feet are common locations. V. A. Firm, pink, umbilicated papules due to poxvirus; affected keratinocytes show cytoplasmic inclusions (molluscum bodies, Fig. 19.15) B. Most often arise in children; also occur in sexually active adults and immunocompromised individuals