Hot Topics Exam 3 Flashcards by Tyler Brown

Autoimmune
Females, 4th-5th decades
Dry mouth (xerostomia), dry eyes (xerophthalmia, kerato-conjunctivitis sicca)
Intense lymphocytic infiltrate in salivary glands
Increased risk for lymphoma (40x)
Parotid enlargement; uni/bilateral
Can be primary
Can be secondary occurs in setting of other autoimmune diseases

Sjogren’s Disease

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Most common neoplasm, 60% occur in parotid
Lobulated, firm on palpation
Variably encapsulated
Epithelial and myoepithelial components
10% recurrences
May undergo malignant transformation

Pleomorphic adenoma (benign)

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Primarily affects parotid gland
Cystic neoplasm with papillary infoldings and lymphoid tissue
10% bilateral

Warthin tumor (papillary cystadenoma lyphomatosum, benign)

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Squamous and mucous cells
Most common SG malignancy
Parotid and minor glands
May note bluish color due to mucin and cystic growth pattern

Mucoepidermoid carcinoma (malignant)

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inability of lower esophageal sphincter to relax

difficulty in swallowing

Achalasia

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Arise due to portal hypertension
Seen in 90% of cirrhotic patients
Often asymptomatic, but rupture can result in massive hemorrhage/death

Esophageal varices

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Extrinsic agents: Acids, Alkalis, Pill lodging, Chemical, Trauma, Heavy Smoking
Iatrogenic causes: Chemotherapy, Radiation, Graft versus host disease
Infectious agents: More common in immune-suppressed patients, include fungal and viral (CMV, HSV)

Intrinsic: reflux of gastric juices-central to GERD (gastroesophageal reflux disorder) associated mucosal injury
-Symptoms: dysphagia, heartburn, regurgitation gastric contents. Odynophagia
Oral manifestations of GI Reflux:
a. Gastric acid enamel erosion may be seen in patients with chronic gastric reflux (e.g. GERD, hiatal hernia, chronic alcoholism and bulimia)
b. Enamel loss often affects lingual/palatal surfaces
c. Extent of loss may reflect reflux duration or frequency

Esophagitis

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Intestinal metaplasia within the esophagus squamous mucosa
Complication of GERD with increased risk of adenocarcinoma.
NOTE: despite risk, most persons with ______do not develop esophageal tumors.
Diagnostic features for _____: 1) extension abnormal mucosa above gastro-esophageal junction, 2) demonstration of squamous metaplasia (intestinal metaplasia)

Barrett Esophagus

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Leiomyomas (tumors of smooth muscle), mucosal polyps, squamous papillomas, Lipomas (tumor of fat)

Esophagus benign lesions

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Worldwide rate < SCCa or esophagus
Usually affect the distal third of the esophagus
Associated with long-standing GERD or Barrett change
Increased in Caucasians
Increased in males over females (7:1)
Dysphagia, “Chest Pain”, weight loss
Often detected at late stage: 25% 5yr survival.

Esophageal adenocarcinoma

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Adults
> 45 yo
Males > females (4:1)
Esp. African-American males (6:1 vs white men)
Risk factors: EtOH, tobacco use, very hot beverages, caustic esophageal injury, vitamin/trace metal deficiencies, fungal contamination of food, nitrates and nitrosamines
Occurs primarily in the middle third of the esophagus
Most common esophageal malignancy worldwide, but regional variation recognized (Diet, environment, genetics, most common variant in China, Brazil, South Africa)
Plummer Vinson, Achalasia, Esophagitis
Very poor prognosis (9% 5 yr survival)

Squamous Cell Carcinoma of the Esophagus

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Abrupt, transient
Pathogenesis: Cigarettes, Alcohol, Stress, Ischemia, NSAID’s, aspirin, infection
May range from asymptomatic to pain, nausea and vomiting. May develop erosion and/or hemorrhage.
Pathology: Punctate hemorrhage, erosion, edema, acute inflammation

Acute gastritis (stomach-reactive lesion)

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Primarily caused by infection with Helicobacter pylori in patients with H. pylori (spiral or curved bacilli): 90% of cases.
Often acquire the infection in childhood.
Helicobacter pylori present in 65 % of gastric ulcers, 85-100 % of duodenal ulcers
Treatment with antibiotics and proton pump inhibitors.
Autoimmune-gastritis: 10 % of cases (E.g. Pernicious Anemia)
Pathology: Atrophic epithelium, chronic inflammation, intestinal metaplasia
Clinical course: Ulceration, cancer risk 2-4% (intestinal metaplasia)

Chronic Gastritis (stomach-reactive lesion)

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H. pylori, NSAID use
Gastric hyperacidity, recurrent ulcers with intermittent healing
98 % duodenum or stomach
Lifetime risk about 10 % for males, 4 % females
Peptic ulcer complications: Intractable pain, hemorrhage, perforation (5 %), obstruction-edema, fibrosis (2 %)

Peptic ulcer disease

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Hyperplastic, fundic gland polyps, adenomas & inflammatory polyps
Approximately 75% of gastric polyps are inflammatory or hyperplastic.
Leiomyomas

Benign stomach neoplasias

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90-95 % of gastric cancers these
Other malignant tumors of the stomach include: Lymphoma (4 %), Carcinoid (3 %), Spindle cell tumors (2 %)
3 % of all cancer deaths
Overall marked decrease in U.S. due to reduced use of smoked and salt-cured meat. There is an association with GERD-due to increased rates for cancer of gastric cardia. Linitis plastica, aggressive form of stomach cancer.
Risk factors for development of gastric adenocarcinomas: Hereditary factors, consumption of smoked and salt cured meat (Nitrites), GERD, Pernicious anemia (B12deficiency), atrophic gastritis (intestinal metaplasia), Chronic gastritis (H. pylori), A pre-existing adenomatous polyp
5 year survival < 10 % (advanced)
Prognosis: Dependent on depth of invasion, metastasis
Metastasis: Liver, lung, ovaries, supraclavicular lymph node (Virchow’s node)

Gastric Adenocarcinoma (stomach neoplasia)

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“leather bottle appearance” markedly thickened stomach wall, reactive to diffusely-infiltrative

Linitis plastica

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Celiac disease (Gluten allergen), Tropical sprue (Aerobic bacteria), Lactase (disaccharidase) deficiency, Abetalipoproteinemia (Transepithelial transport defect, mono- and triglycerides)

Small intestine malabsorptive diarrhea

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Gluten-sensitive enteropathy
Caucasians; 1:100-200
Hypersensitivity to gliadin
Morphology: Blunted villi, Inflammatory infiltrate
Dramatically improves with withdrawal of wheat gliadin and related grain proteins from the diet

Celiac disease

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Vibrio cholerae, Campylobacter jejuni-acute, self-limited colitis “traveler’s diarrhea”

Infectious enterocolitis

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Malabsorption of Iron, Pyridoxine, Folate, or B12 deficiency, bleeding from Vitamin K deficiency

Anemia

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Defective Ca, Mg, Vitamin D and protein absorption leads to

Osteopenia, tetany

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Generalized malnutrition can lead to these 3 things

Amenorrhea, impotence and infertility

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Peripheral neuropathy and nyctalopia can be due to deficiencies in these two vitamins

A and B12

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initial oral sign can be atrophic glossitis (bald, reddish tongue). Patchy or involvement of entire dorsum surface of tongue. Overt tongue lesions are usually tender. Burning sensation (glossopyrosis) is a common complaint.

oral manifestations of malabsorption (B12 and anemia)

Accounts for less than 6% of all GI tumors Benign: Adenoma, leiomyoma Malignant: Adenocarcinomas, carcinoid tumors (often associated with hormone production), lymphoma, sarcoma.

Tumors of Small Intestine

Most common malignancy of the GI tract. Dietary factors are implicated-especially low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat. Genetic component: increased incidence in FAP patients. Other risk factors: Age > 50 years, family history of colorectal carcinoma, inflammatory bowel disease, personal history of adenoma/colorectal carcinoma Most important prognostic indicators: Depth of invasion and lymph node metastases

Adenocarcinoma of the Colon

In the US this cancer is responsible for causing 15% of all CA deaths

Adenocarcinoma of the colon

Entails mutations of APC gene. Most common polyposis syndrome of the gastrointestinal tract Estimated penetrance for adenomas > 90 %: Adenomas throughout colorectum (average onset 16 yo) Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) Risk of affected patients developing colon cancer approaches 100% Require > or equal to 100 polyps to diagnose FAP

Familial Adenomatous Polyposis

FAP + Extraintestinal lesions Oral manifestions of ______: Unerupted teeth, supernumerary teeth, dentigerous and mandibular cysts, increased risk for odontomas, delayed tooth eruption. Also develop benign skin lesions. Congenital hypertrophy of retinal pigment epithelium (CHRPE). Oral manifestations can contribute to early recognition of the condition and allow for appropriate screening for bowel disease and other neoplasms

Garner's Syndrome

Second most common polyposis syndrome Gastrointestinal hamartomatous polyps (Intussusception) and pigmented macules of mucous membranes and skin. Melanin deposits around nose, lips, buccal mucosa, hands and feet, genitalia and perianal region. Develop in early childhood Non-sun dependant freckling of the skin around the lips and the vermilion zone of the lips – Common feature. Average age at diagnosis: 23 -26 yo Gastrointestinal and non gastrointestinal cancer more common after 45 yo.

Peutz Jegher Syndrome

Clinical manifestations- Chronic intermittent diarrhea +/- blood, colicky abdominal pain; Presents in young adulthood Pathology- Segmental transmural inflammation of bowel, particularly ileum (distal small bowel) and colon. Any portion of the GI tract → Oral involvement frequently seen; Frequently spares the rectum; Ulcerations, granulomas, thickened bowel wall, stenotic, with fat wrapping, fissure and fistula formation, Noncaseating granulomas; Distribution: Often note “skip lesions”

Crohn disease

Oral manifestations of this disease: a. Multifocal, linear, nodular, polypoid or diffuse mucosal thickening with predilection for labial and buccal mucosa and mucosal folds –Can be confused with aphthous ulcers. b. Mucosal ulcer “cobblestone” Diseased tissue lower than normal tissue c. Subepithelial, noncaseating granulomatous inflammation identical to those seen in the bowel. Infections (fungal, TB) should be ruled out. d. Typically persistent and remit and relapse over the years

Crohn disease

Clinical: Diarrhea, tenesmus, colicky lower abdominal pain; Risk for development of carcinoma Pathology: Begins in rectosigmoid area and extends proximally. Not transmural Continuous (diffuse) involvement (pseudo-polyps), not patchy Small to large ulcerations, crypt abscesses Greater risk of dysplasia and adenocarcinoma Association with primary sclerosing cholangitis (PSC)

Ulcerative colitis

Oral manifestations of this disease: Rare, less common a. Scattered, clumped or linearly oriented arc-shaped pustules on an erythematous mucosa at multiple oral sites with variable severity, “snail-track” (Pyostomatitis Vegetans), but may also be seen in Crohn patients b. Long-standing lesions may become granular, polypoid or fissured and mimic Crohn disease c. 10% of patients develop arthritis of temporo-mandibular joints. d. Lesions mimic the crypt abscesses of colonic lesions with no evidence of granulomas. Rule out candidiasis, benign migratory glossitis, and pemphigus vegetans.

Ulcerative colitis

Among top 10 most common causes of death in the U.S and the primary route for liver-related deaths. Etiologies include: Alcohol (EtOH) abuse (toxicity, nutritional deprivation), viral hepatitis, non-EtOH steatohepatitis, biliary disease, obesity, DM, medications, iron overload. Iron overload can lead to hepatocyte death and inflammation. Complications include reduced liver function, portal hypertension and increased risk for hepatocellular Ca Morphologic changes are: 1) bridging fibrous septa, 2) parenchymal nodules, 3) changes in architecture, with parenchymal injury and scarring as the end result. A fibrotic liver has a markedly compromised blood supply and decreased function. Clinical manifestations: oNonspecific symptoms e.g. weight loss, weakness. Reserve may mask symptoms. oLiver failure oPortal hypertension-- Ascites; Collateral venous channels; Splenomegaly

Cirrhosis

Increased pressure of portal blood flow can occur: prehepatic (obstructive thrombi), intrahepatic (cirrhosis), and post hepatic (right sided heart failure). Consequences of ______: 1) ascites (excess fluid in peritoneal cavity-fluid is generally serous in nature), 2) esophageal varices, 3) splenomegaly, 4) hepatic encephalopathy, 5) hypogonadism.

portal hypertension

1.Excess bilirubin. 2.0 mg/dl •Unconjugated: Insoluble, toxic •Conjugated: Soluble, nontoxic 2.Causes of jaundice: hemolytic anemias (#1), bilirubin overproduction, hepatitis, obstruction of bile flow. 3.Function of hepatic bile: 1) emulsification of fats with bile salts, 2) elimination of bilirubin, excess cholesterol, xenobiotics, etc. Yellow color of skin and sclera

Jaundice and cholestasis

yellow color of sclera

icterus

a benign, self-limiting disease. ___viremia is transient-rarely screen donor blood for ____ - Fecal-oral route of transmission, seen with overcrowding/unsanitary conditions. Ingestion of contaminated water and food - Incubation 2-6 weeks - NO carrier state. No chronic disease

Hep A

a.acute hepatitis with recovery and clearance (Self-limited in 90% cases) b.nonprogressive chronic hepatitis c.progressive disease ending in cirrhosis d.asymptomatic carrier state. ___induced liver disease is an important precursor for hepatocellular carcinoma. •DNA virus •Parenteral contact/sexual spread •Incubation 4-26 weeks •Host immune response determines the ultimate outcome. Hepatocyte damage-likely reflects CD8+ cytotoxic T cell damage to ______infected hepatocytes. Optimal outcome is to obtain viral clearance without a lot of collateral damage to liver tissues. Serology: Remains in blood Vaccine: 95 % protective Ab response Increased risk of hepatocellular response

Hep B

5. a major cause of liver disease worldwide. With ____ infection the progression to chronic disease occurs in the majority of patients and cirrhosis develops in 20-30% of infected individuals. With ___note persistent infection, chronic hepatitis. •RNA virus •Parenteral contact/sexual spread •Incubation 7-8 weeks, acute phase is asymptomatic •No vaccine because of genomic instability •Cirrhosis occurs in approximately 80-85%, and may develop 5 to 20 years later. •Risk factor for hepatocellular carcinoma. •Most frequent viral infection associated with the need for liver transplantation. Previously treated with interferon and ribavirin. Treatment with protease and nucleoside inhibitors now considered curative. oCombination drugs: Harvoni (2014, sofosbuvir & ledipasvir). 12 week course, several others since 2014; often given with ribavirin oCurative in most patients. Side effects fatigue and headache. Very expensive (Harvoni $95K, Mavyret [2017] 12 weeks $40K)

Hep C

(requires presence of Hepatitis B for infection) occurs as a co-infection. Co-infection presents like Hepatitis B-usually transient and self-limited

Hep D

(similar to A) is an enterically transmitted, water-borne infection-high mortality rate in pregnant women. Not associated with chronic liver disease

Hep E

(some similarity to C but is not hepatotropic) infection does not increase liver enzymes such as serum aminotransferases. Replicates in bone marrow and spleen

Hep G

is a chronic, progressive, hepatitis variant with an unknown etiology. Pathology is associated with T-cell mediated autoimmunity

Autoimmune Hepatitis

o3 overlapping forms: 1) hepatic steatosis, 2) EtOH hepatitis, 3) cirrhosis (only develops in a minority of patients). o60 % of chronic liver disease associated with overuse of alcohol 40-50 % of deaths due to cirrhosis

Alcoholic Liver Disease

little fibrosis at onset, increased deposition with EtOH consumption. ____change is reversible if discontinue EtOH consumption. Mallory or Mallory-Denk bodies: clumps of cytokeratins, eosinophilic cytoplasmic inclusions.

Fatty liver from EtOH

the liver resembles from both macro and micro cirrhosis developing from hepatitis.

Final stage of cirrhosis

chronic disorder, steatosis, hepatitis, progressive fibrosis, cirrhosis, marked perturbations of vascular perfusion. Only develop cirrhosis in a small fraction of alcoholics

EtOH liver disease

Patients develop hepatocyte injury, and 10-20% progress to cirrhosis (seen primarily in obese patients). •Approximately 70% obese persons have some form of fatty liver disease •Liver biopsy necessary to establish the diagnosis, note increased liver enzymes in 90% of affected patients.

Nonalcoholic steatohepatitis (NASH)

Excessive accumulation of body iron. Most is deposited in liver, pancreas and heart. 4 hereditary forms (autosomal recessive, chromosome 6) and acquired form with excess iron intake. •Liver features: Micronodular cirrhosis with hemosiderin, Hepatosplenomegaly, diabetes mellitus, skin pigmentation •Lifetime accumulation of Fe-symptoms generally slow onset and notice around 5th or 6th decade of life. •Males to females: 5 to 7:1 •Associated with abnormal regulation of intestinal absorption of Fe •Clinical and microscopic features of hereditary hemochromatosis: increased in males, hepatomegaly, abdominal pain, increased skin pigmentation (especially after UV light), deranged glucose metabolism, cardiac arrhythmias, atypical arthritis. Classic triad: cirrhosis with hepatomegaly, diabetes mellitus, and skin pigmentation. •Diagnosis obtained by assessing serum Fe. Treatment: Phlebotomy, Fe chelators

Hemochromatosis

Results from a failure to incorporate copper (Cu) into ceruloplasmin-consequently get accumulation of toxic Cu levels in liver, brain and eye. •Usually presents between 6 to 40 years of age. •Autosomal recessive •Morphology: Acute/chronic, steatosis, necrosis, cirrhosis •Presentation: acute or chronic liver disease. May present with tremor or behavioral changes. •Screening test-NOT serum (as levels may actually be low), instead use Cu levels in urine (good for screening) or Cu levels in liver (definitive diagnosis). •Chelation: D-Penicillamine

Wilson's Disease

Develop pulmonary emphysema from protein degrading enzymes. Also develop liver disease, formation of Mallory bodies and PAS positive granules within hepatocytes

Alpha-1-antitrypsin deficiency

results from obstruction extrahepatic duct a. Biliary tree obstruction-the primary cause is cholelithiasis (gall stones), then malignancies of biliary tree or head of pancreas. b. Develop secondary inflammation-then fibrosis, hepatic scarring

Secondary Biliary cirrhosis

a.Inflammatory autoimmune disease-affects intrahepatic bile ducts. b.Primary feature-nonsuppurative inflammatory destruction of medium sized intrahepatic ducts-also get portal inflammation, scarring and eventually cirrhosis. Thought to be an autoimmune etiology

Primary biliary cirrhosis

a. Fibrosing cholangitis of bile ducts-develop luminal obliteration b. Liver eventually develops biliary cirrhosis c. NOTE: same common endpoint i.e. biliary cirrhosis as primary and secondary biliary cirrhosis d. Note an increase in chronic pancreatitis and hepatocellular carcinoma (HCC) in PCS patients

Primary sclerosis cholagitis

single or multiple nodules may develop a. In a non-cirrhotic liver “focal nodular hyperplasia” or “nodular regenerative hyperplasia” b. Common factor-focal or diffuse alteration in hepatic blood supply, resulting in obliteration of the portal veins and a compensatory increase in arterial supply

Nodular hyperplasia

Cavernous hemangioma Hepatic adenoma-increase in young women using oral contraceptives Concerns with these: 1) mimic HCC, 2) subcapsular hemorrhage-from a rupture and bleed, 3) may transform to HCC. Are associated with hormonal stimulation

Benign liver neoplasms

* Cancer of biliary tree-most are adeno CAs * Very desmoplastic tumor-tumors are firm and gritty * Can get collision tumor with HCC * Asymptomatic until late stage * Generally fatal within 6 months

Cholangiocarcinoma

•Most common liver tumor in young pediatric patients •Epithelioid type •Mixed epithelial-mesenchymal •Treatment-chemotherapy then surgical resection Is rapidly fatal (within months) if not treated

Hepatoblastoma

* Benign * Association with oral contraceptives, if discontinued, may regress * Presentation * Acute abdomen * Intra-abdominal bleed * Histology: bland hepatocytes and no bile ducts

Hepatocellular adenoma

* Worldwide- 3rd most common cause of cancer deaths; 3:1 males * Etiologic factors-cirrhosis (90%), due to chronic viral infection (HBV, HCV) or chronic alcoholism, NASH (nonalcoholic steatohepatitis), food contaminants (primarily aflatoxins). * All HCC variants-strong propensity for vascular invasion

Hepatocellular Carcinoma

``` Variant of HCC oYoung males and females (20-40 yo) oDistinct from HCC oNo known risk factors o“Scirrhous tumor” oPatients generally do NOT have underlying liver disease-better prognosis. oTreatment: Surgery Better prognosis (32 % 5 yr survival) ```

Fibrolamellar Variant

* ______- primary soft tissue sites for metastases to occur. Metastatic tumors are more common than primary tumors * Most common primary cancers are colon, breast, lung and pancreas * Liver weight may exceed several kilograms. Often multiple nodules * Often only sign is hepatomegaly-liver has tremendous functional reserve

Liver and lungs

10-20% of adults. Increased risk with increasing age and obesity, Caucasian women over men (2:1), cholesterol (80 %) and pigment/bilirubin stones (20 %). •Cholesterol cholelithiasis (mostly radiolucent) vs bilirubin cholelithiasis (mostly radiopaque) •Pigment stones → Hemolysis, GI disorders, Biliary infections Increased with estrogen (pregnancy and oral contraceptives) Increased with gall bladder stasis Hereditary contribution 80% of patients with stones remain asymptomatic If symptomatic, develop colicky biliary pain, inflammation, may eventually note perforation, obstruction of gall bladder or erode into ileum with GI obstruction.

Cholelithiasis (gall stones)

1.May be acute or chronic, 4th – 6th decades, F > M 2.Almost always occurs in association with gallstones 3.Note upper right quadrant pain, may note low level fever, anorexia, tachycardia, nausea, vomiting. Acute symptoms-can arise very abruptly. 4.Chronic-not as dramatic a presentation. Note recurrent bouts of colicky epigastric or right quadrant pain. •Vague symptoms, Stones (90 %), Fibrosis & Inflammation

Cholecystitis

1.Increased frequency in women in their seventh decade of life. 2.Whites > Blacks 3.5th among GI malignancies 4.Mean five year survival is 5% Risk factors include _____(95 % associated with ____) or infectious agents within the ______

Cancer of the gall bladder (adenocarcinoma) | ...include gallstones...with stones...the gallbladder

•Reversible parenchymal injury associated with inflammation, 80% of cases related to biliary tract disease or alcoholism; infections e.g. mumps, trauma, metabolic diseases (e.g. hypercalcemic states), medications (e.g. estrogens, chemotherapy), idiopathic •Release of lipases, inflammation, proteolysis. Necrosis of vessels with hemorrhage. Fat necrosis. •Symptoms are ABDOMINAL PAIN. This is the cardinal manifestation. “upper back intense pain”. Full blown acute pancreatitis is a medical emergency due to the potential to release toxic enzymes. Elevated enzymes (Amylase, Lipase), Organ failure, Abscess, Mortality (8 %)

Acute Pancreatitis

•Develop irreversible destruction exocrine pancreas, with ensuing fibrosis and eventual destruction of the endocrine parenchyma. •Etiology unclear: Alcoholism, biliary disease, hypercalcemia, hyperlipidemia, oxidative stress, idiopathic? genetic? •Morphology: Reduced acini, chronic inflammation, fibrosis, obstruction ducts, spare islets •Symptoms range from severe abdominal pain to silent (only detected once the patient develops diabetes mellitus). Diagnosis-requires a high degree of suspicion-may have already destroyed acinar cells, so may not see an increase in serum amylase

Chronic Pancreatitis

serous cystadenomas, females over males, 2:1, usually seventh decade •Close to 95% of mucinous cystic neoplasms arise in women. Can be associated with invasive cancer. Intraductal papillary mucinous neoplasms increased males over females

cystic pancreatic neoplasms

•Fourth leading cause of cancer death in the US (lung, colon, breast, pancreas) •Precursor lesion is PanINS (pancreatic intraepithelial neoplasias) •Primarily a disease of the elderly, 80% of the cases between 60-80 years •Environmental influence-primarily cigarette smoking (Doubles risk) •Also increased risk with diabetes mellitus & chronic pancreatitis •New onset diabetes mellitus in older patient-raises concern re: Pancreatic Cancer •Often remain silent until invade into adjacent structures. Pain is usually the first sign, but typically too late. Obstructive jaundice is associated with tumors at the pancreatic head. •Trousseau sign: Migratory thrombophlebitis-formation of platelet aggregation factors and procoagulants from tumor or its necrotic products. Clinical course is very brief and very aggressive. Rapidly fatal. Most patients die within 6 months

Pancreatic cancers (infiltrating ductal carcinomas of the pancreas)

refers to an abnormal opening of the urethra along the ventral aspect of the penis, and occurs in 1/300 live male births. The opening may be restricted and lead to an increased risk of urinary tract infections

hypospadias

refers to the urethral opening on the dorsal aspect of the penis. This abnormality is less common, but also exhibits an increased prevalence of urinary tract infections in addition to predisposition to urinary incontinence

epispadias

is a synonym for carcinoma in situ of the penis. ____disease is not specific to the penis but may occur on other cutaneous or mucosal surfaces. Its major clinical importance lies in the potential progression to invasive squamous cell carcinoma

Bowen disease

- accounts for about 0.4% of cancer in males. - most common penile neoplasms. - extremely rare among men who are circumcised early in life. - Human papillomavirus (HPV 16/18) may be involved with development of ____ cancer, and circumcision may improve hygiene and lessen exposure to oncogenic viruses. - over 40 and may be preceded by Bowen’s disease. - begins as a crusted plaque or nodule with irregular margins that usually develops a central ulceration. - Less frequently, it forms a papillary mass. Treatment - surgical excision. - 5-year survival is 66%. - Widespread metastasis is rare; - local metastasis to inguinal lymph nodes reduces 5-yr survival to 27%

Squamous cell carcinoma of the penis

* Inflammatory processes, fungal infections, dermatoses * Rare neoplasms; most squamous cell carcinoma * 1st human cancer associated with occupational (environmental) factors (chimney sweeps)

Disorders of the scrotum

- failure of testicular descent from the abdomen to the scrotum. - diagnosis cannot be confirmed until 1 year of age because the timing of completion of the descent is variable. - present in 1% of the male population and may be unilateral or bilateral (10%). - Untreated bilateral ____ results in sterility. - In unilateral cases, the contralateral descended testis may undergo atrophy, also leading to sterility. - Failure of descent also is associated with a 3-5 times increased risk of testicular malignancy manifesting as intratubular germ cell neoplasia developing within the atrophic tubules. - Surgical placement of the testes into the scrotum (orchiopexy) before puberty reduces but does not eliminate the risk of cancer and infertility

Cryptorchidism

- inflammation of the testes. - the inflammation begins as a primary urinary tract infection - secondary ascending infection of the testes. - Epididymitis is more common than ___. - Swelling and tenderness are common signs in affected patients. - Frequently the origin is a STD - other common causes including nonspecific ___, mumps, and tuberculosis. - complicates mumps in 20% of infected adult males but rarely in children. In severe cases, mumps-associated ___ can result in sterility

Orchitis

Cancers of the testes typically are divided into

seminomas or nonseminomatous germ cell tumors

2 markers for staging, diagnosis and follow-up for cancers of testis

- a-fetoprotein | - HCG

arise from the epithelium of the seminiferous tubules and remain localized for long periods. However, spread occurs via lymphatics. They respond well to chemotherapy and are extremely radiosensitive. Therefore, they are one of the most curable cancers

seminomas

spread earlier, are less radiosensitive and utilize the hematogenous and lymphatic routes, with the lungs and liver often involved at the time of diagnosis. As Lance Armstrong can attest, treatment of testicular neoplasms is a modern medical success story. Of the 8K cases each year in the US, only about 400 die of their disease

nonseminomatous tumors

small gland associated with pathoses that vary from benign and significantly symptomatic to silent but deadly

prostate

- clinically apparent inflammation of the __ which may be acute or chronic. The __ will be enlarged and tender. - Bacterial __ may be acute or chronic and is caused by the same organisms which commonly produce urinary tract infections (E. coli). - Chronic nonbacterial ___ (90-95 % of cases), also known as chronic pelvic pain syndrome, is of unknown etiology and doesn’t respond to antibiotics. - Both acute and chronic __ present with dysuria, urinary frequency, lower back pain and poorly localized suprapubic or pelvic pain. - Antibiotics penetrate the __ poorly, and the most common cause of recurrent urinary tract infections is the surviving bacteria

prostatitis

- refers to hyperplastic enlargement of the prostate, often associated with urinary symptoms. - Benign prostatic hypertrophy is a time-honored synonym, which is a misnomer and has been replaced with benign prostatic hyperplasia. - The alteration is a common pathosis that begins during the forties (20 % of men) and increases with age; 90% are affected by the eighth decade. - Stromal and glandular proliferation result in enlargement. The central portions of the gland adjacent to the urethra (Inner periurethral zone) are involved most frequently; impingement on the prostatic urethra leads to dysuria - No more than 10% of men require surgical relief of the obstruction (TURP – Transurethral resection of the prostate) secondary to prostatic hyperplasia. - Medical management with drug therapy may also be considered. - Although the cause is unknown, androgens appear to have a central role in its development

Nodular hyperplasia of the prostate

- most common cancer of men over 50 years of age, with the peak prevalence between 65-75 - significant evidence suggests androgens contribute significantly to the development of this cancer. - Hereditary and environmental contributions also have been suggested. - clinically evident carcinomas invade adjacent structures and metastasize via both the lymphatics and the bloodstream. Regional node involvement occurs early. - Osseous metastasis is the most common form of hematogenous spread

carcinoma of the prostate

- represents a useful marker in the management of prostate cancer, - is elevated in both normal prostate and those affected by cancer, prostatitis, or nodular hyperplasia. ___ is of limited value when used as an isolated screening test - value is enhanced considerably when combined with other tests

PSA

- most common tumor is _____, which represents 90% of neoplasms of the bladder. This typically occurs in men between the ages of 50 and 80 years and the dominant presenting manifestation is painless hematuria. - Predisposing factors include cigarette smoking, chronic cystitis, infection with Schistosomiasis, and exposures to various carcinogens - The tumor is preceded by a premalignant precursor lesion which often has a papillary growth pattern, but can also be flat. Tumor cells generally lack cohesion and are shed into the urine

urothelial cell carcinoma

- venereal disease that is produced by a spirochete, Treponema pallidum. - Greater than 24,000 cases reported in the U.S. in 2015. - African Americans affected 30X more often than whites. The peak of incidence is between 20-24 years old, followed by 15-19 years old - infection produces two types of antibodies

syphilis

two types of antibodies produced by sphylis

- syphilitic reagin | - treponemal antibody

simple screening tests for syphilis

- VDRL - RPR - FTA- expensive (more specific)

•painless chancre which arises at the site of entry 9-90 days (mean of 21 days) after exposure. •Glans penis in the male and the •vulva or cervix in females are common sites. Lips, fingers, oropharynx and anus are also possible sites. •. Serologic tests begin to become positive after 1-2 weeks of infection and are positive in the vast majority by 4-6 weeks. Because of the early negativity of the screening tests, •dark-field examination of the exudate is extremely important in the diagnosis of early ___ ___. •____spirochetes can be found within the normal oral flora and this makes the dark-field method of limited use for primary oral lesions. -Spirochetemia occurs during this stage. 50% of the females and 30% of the males either never develop or do not detect the chancre. Chancres heal in 4-6 weeks

primary syphilis

•25% of untreated patients, healing of the chancre is followed within 2 months •presenting with generalized lymph node enlargement combined with widespread mucocutaneous lesions that are maculopapular, scaly or pustular and even involve the palms and soles. -Oral and vaginal areas of localized spongiotic mucositis are called mucous patches. -Elevated large broad plaques (condyloma lata) can form in moist skin areas such as the axillae, inner thighs and anogenital area. -Mucosal condyloma lata are not rare and often noted in the oral cavity, pharynx and external genitalia. -All sites are infectious. The rash can be extremely subtle and may be ignored. All serologic tests are positive

secondary syphilis

•arises in 30% of untreated patients usually after a latent period of 5-20 years. •It may affect any part of the body, but it shows a predilection for the cardiovascular system (80%) and the CNS (10%). The aorta may develop scarring, weakening and dilation secondary to obliterative endarteritis. Brain atrophy produces dementia. •Rubbery gray-white areas of total necrosis (gumma) may be seen most frequently in mucocutaneous tissue and bone. Nasal and palatal bones are not uncommon sites. The gumma is due to hypersensitivity to products of the spirochete and to ischemia from obliterative endarteritis. -Treponemes are difficult to find in ___ ___ and this stage is much less infectious. With treatment, gummas will become areas of scar; the cardiovascular and neural damage is irreversible. -The nonspecific serologic screening tests typically are negative. Once exposed the highly sensitive specific treponemal antibody tests are positive for life

tertiary syphilis

can be divided into three patterns: stillbirth, infantile and late

congenital syphilis

refers to liveborn infants that at birth or within the first few months of life present with clinical lesions similar to those seen in secondary syphilis

infantile syphilis

refers to cases of untreated congenital syphilis of more than 2 years duration. Classic manifestations of this chronic infection include interstitial keratitis of the eyes, saber shins, saddle nose, Hutchinson's incisors, mulberry molars, eighth nerve deafness, gummas and neurosyphilis

late congenital syphilis

1. Interstitial keratitis 2. Hutchinson’s teeth 3. Eighth nerve deafness

Hutchinson's Triad

frequent sexually transmitted disease caused by Neisseria gonorrhoeae, a gram-negative diplococcus. An estimated 800K cases occur annually in the U.S., and this is complicated by the emergence of strains which are resistant to multiple antibiotics. Humans are the only natural reservoir, and spread requires direct contact with the mucosa of an infected person - 80% of the females and 40% of the males are asymptomatic - ascending infection in males results in acute prostatitis, epididymitis or orchitis

Gonorrhea

Ascending infection involving the uterus, fallopian tubes, and ovaries results in

acute salpingitis

Following the acute infection, granulation tissue and fibrosis results in permanent deformities, giving rise to

pelvic inflammatory disease

- Mothers may produce blindness in infants from gonococcal contamination at birth - presently rare because of a prophylactic antibiotic placed in the eyes of all newborns

gonococcal opthalmia neonatorum

- the most common forms of sexually transmitted disease which must be reported to CDC. - Most cases appear related to Chlamydia trachomatis, but a number of other organisms also have been implicated as a possible cause in some cases - The infection is usually milder with fewer complications than gonorrhea but does produce suppuration within the infected area. - Males develop urethritis which may spread into the epididymes; - females develop urethritis and/or cervicitis which may spread into the oviducts and even produce pelvic inflammatory disease. - Infants born of infected mothers may develop conjunctivitis or neonatal pneumonia. - Ceftriaxone combined with doxycycline is the treatment of choice

nongonococcal urethritis and cervicitis

- significant manifestation of chlamydial infection. - This is an immune-mediated process that develops in response to genitourinary or gastrointestinal infections and predominates in patients who are HLA-B27 positive. - It typically presents as a combination of urethritis/cervicitis, arthritis, conjunctivitis, and mucocutaneous lesions

Reactive arthritis (Reiter syndrome)

-a common STD that affects an estimated 50 million individuals in the U.S. and occurs from infection by ______. Most are caused by Type II, with a small percentage related to Type I. . -actively shed during periods of clinically visible lesions. -Primary infections may be asymptomatic; the remainder develop painful focal lesions with dysuria, fever, lymphadenopathy, headache and malaise. -The glans penis or surrounding areas in men and the cervix in women are the usual sites. Involvement of the vagina, vulva and labia may also be seen. -diagnosis is made via a smear or biopsy which will reveal the cytopathologic effects of the virus in epithelial cells (ballooning degeneration of epithelial cells with large, multinucleate “Tzanck cells”). -Without treatment, the clinical manifestations may last 3-6 weeks. -Recurrent presents with periodic vesiculo-erosive lesions that heal in 7-10 days. -More than 80% of the patients with Type II genital herpes have one or more recurrences yearly for several years

genital herpes simplex

- the cause of a number of epithelial proliferations in the genital tract, including condyloma acuminatum, some precancerous lesions and some carcinomas. - Condyloma acuminatum is usually associated with___ types 6 or 11 and typically arises on moist mucocutaneous surfaces. - They present as benign papillary nodules, and frequently appear in clusters. Other types ____ (16, 18, 31, 33, 45, 52, and 58) are found more frequently in epithelial neoplasia, including cervical and oropharyngeal cancer. - The penis and around the anus are the common sites in men - vulva is the most frequent site in females. - Occasional lesions are seen intraorally and it is not uncommon to develop synchronous lesions. - Genital ___ can be transmitted to neonates during vaginal delivery and may result in life-threatening lesions of the upper respiratory tract. - lesions are treated with surgery, laser ablation, cryotherapy, or topical imiquimod. Malignant transformation of condyloma acuminatum can occur but is uncommon

HPV

- inflammation of the vulva, can be caused by infection, contact irritant, allergic reaction, or traumatic injury. - A variety of pathogens has been associated and often sexually transmitted. In addition, the moist environment supports fungal infections (Candida albicans). - Contact irritation or allergic reaction may be related to a number of agents, including soaps, perfumes, deodorants, clothing textiles, etc. - Scratching-induced trauma secondary to associated pruritus (itching) may exacerbate the primary condition

Vulvitis

- inflammation of the vagina, is relatively common and results in production of vaginal discharge (leukorrhea). - A variety of organisms have been associated, including bacteria, fungi, and parasites. - Many are commensal organisms that become pathogenic under certain circumstances, such diabetes, systemic antibiotic therapy (which disrupts normal microbial flora), or immunodeficiency. - Candida albicans and Trichomonas vaginalis are frequent offenders

vaginitis

- inflammation of the cervix, is extremely common and is associated with purulent vaginal discharge. - The process may be secondary to specific infections such as candida, trichomonas, chlamydia, gonorrhea, syphilis, HPV, or herpes - more commonly, it arises from nonspecific infections and is seen in virtually every multiparous woman. - It may be acute or chronic. In severe lesions, it is difficult to clinically distinguish from carcinoma and biopsy is required for diagnosis

Cervicitis

- this cancer was the leading cause of cancer deaths in women; but currently, it ranks 14th - The Papanicolaou cytologic test (Pap smear, 1940) is responsible for the increased discovery of these earlier lesions, most of which are cured by effective therapy. - Exfoliated cells collected from the cervix are processed with a special stain (Papanicolaou stain) - 75-95% of cervical cancers present as squamous cell carcinoma. Most (perhaps all) invasive ____carcinomas arise from precursor lesions termed _____. - Not all ____ progress to cancer. The cancer is now known to be the end stage of a continuum of progressively more dysplastic changes in which one slowly progresses on to the next stage; - this progression evolves slowly over the course of many years. ____ is graded I (Mild) – III (Carcinoma in situ); the higher the grade, the greater the likelihood of progression to carcinoma. - Although probable in many instances, progression to carcinoma is not inevitable, even in higher-grade lesions

Cervical intraepithelial neoplasia and carcinoma of the cervix

profuse or prolonged bleeding

menorrhagia

irregular bleeding between periods

metrorrhagia

unusually painful menstrual bleeding

dysmenorrhea

- the presence of endometrial glands and/or stroma in locations other than the uterine lining (10% women in reproductive years, 50% of women with infertility). - most common site is in the pelvis (ovaries, uterine ligaments, tubes and rectovaginal septum). - Less common sites include the peritoneal cavity, umbilicus, lymph nodes, lungs and even heart or bone. - causation is unknown, but the most accepted theory proposes that menstrual endometrium backflows through the fallopian tubes and also somehow enters the local venous and lymphatic systems. - Sites of ____ are functional and undergo cyclic bleeding. - long-standing disease, seepage and organization of the blood leads to widespread fibrosis and adherence of pelvic structures

endometriosis

- hyperplasia of the epithelial lining of the uterus that is thought secondary to an excess of estrogen. - process often arises in perimenopausal women from obesity (estrogen synthesis in fat deposits), failure of ovulation, administration of estrogen or from estrogen-secreting tumors - hyperplasia produces abnormal bleeding; but more importantly, it is a forerunner to carcinoma of this area

endometrial hyperplasia

- benign tumors of myometrial smooth muscle origin. When arising in the uterus, these neoplasms historically have been called fibroids. - arise from the myometrium in 30-50% of women during active reproductive life; this makes ______ the most common benign tumor in females. - cause is unknown, they seem to be estrogen dependent, as evidenced by their rapid growth during pregnancy and the tendency to regress after menopause. Uterine versions are often asymptomatic and discovered during routine pelvic exams. Occasionally, they produce menorrhagia. Multiple ____ are not rare

leiomyomas

- arises from the uterine lining and is the most frequent cancer of the female genital tract in the Western world (due to decreased prevalence of cervical carcinoma secondary to PAP test). - Most cases are diagnosed between the ages of 55-65 and are very uncommon prior to the age of 40. - two clinical settings, each associated with a specific type of ____ carcinoma: perimenopausal women with evidence of estrogen excess and in older women with endometrial atrophy. - majority of these cancers appear to be associated with increased estrogen stimulation with similar risk factors as endometrial hyperplasia. - most common early symptoms are leukorrhea and irregular bleeding, a red flag in postmenopausal women. - Fortunately, these are late-metastasizing cancers, but dissemination can occur to regional nodes and more distant sites like the liver and lungs. - Radiotherapy and surgery are the standard of care with the addition of antiestrogen chemotherapy for disseminated cases. If localized to the body of the uterus, 5-year survival is 90%, but this drops to 20% once it has spread outside of the uterus

endometrial carcinoma

Two types of endometrial carcinoma

endometrioid carcinoma- most common in perimenopausal women serous carcinoma- in older women with endometrial atrophy

- common hormonal disorder affecting 5-10% of females of reproductive age. - generally diagnosed after menarche in teenage girls or young adults. - condition was named due to the presence of multiple _____ follicles in ovaries, resulting in increased size of ovaries and excess production of androgens and estrogens. - seems to be a genetic influence, the cause of this disorder is incompletely understood. - Patients may present with delayed or absent menstruation, oligomenorrhea, hirsutism (increased body hair, acne, fertility problems, and obesity. - women are also at increased risk for type II diabetes and cardiovascular disease. - Neoplasia is the most significant disease with carcinoma of the ovaries accounting for more deaths than cancers of the cervix and endometrium combined. - fifth leading cause of cancer deaths in women

Polycystic ovarian disease

- come in a wide variety of histogenic types. The surface epithelial variants account for 90% of ____cancers, with - less common varieties also produced by the germ cells and sex-cord stroma. Several risk factors for ____cancer have been recognized, - two most prominent being nulliparity and family history (5-10% of cases → Mutations of BRCA genes (BRCA1, BRCA2 = increase risk for____ and _____ cancer). Use of oral contraceptives appears to reduce the risk somewhat. - The clinical presentation of these tumors is remarkably similar. - Most are asymptomatic until they become large enough to cause local pressure symptoms. - prognosis of invasive ___ tumors depends heavily on the stage of the disease at the time of diagnosis. - cancers that have penetrated the capsule, the 10-year survival is less than 15%. - Approximately 22K new cases of ____ cancer will be diagnosed in the US in 2017; of these patients, close to 14K will die of their disease

Ovarian ovarian and breast Ovarian Ovarian

- are tumors which develop from differentiation of totipotential germ cells into mature tissues which represent all three germ layers: ectoderm, mesoderm, and endoderm. - tumors have a tendency to arise in the first two decades of life, and the earlier onset the greater the likelihood of malignancy. - at least 90% of these germ cell neoplasms are benign mature cystic ____. - cysts commonly contain an epidermal appearing cyst lining with adnexal skin appendages (hair follicles, sebaceous glands, sweat glands) - Most are discovered incidentally in young women - often contain hair, bone, cartilage, bronchial or gastrointestinal epithelium, and even teeth

Teratomas of the ovary

- apply to breast alterations which arise as an exaggeration and distortion of the cyclic breast changes that occur normally in the menstrual cycle. - _____changes consist of overgrowths of the fibrous stroma, the epithelial elements or a proliferation of both. - tend to arise during reproductive life but may persist after menopause. - lesions frequently are bilateral and/or multiple. - sometimes produce masses requiring differentiation from cancer. The great majority of these lesions do not predispose to cancer. However, there is a slightly increased risk with florid ductal hyperplasia; and if the hyperplasia is atypical, there is a significant increased risk

Fibrocystic changes

- most common benign tumor of the female breast and usually appears in prepubertal girls and young women, with the peak prevalence in the third decade. - result from increased estrogen. - tumors are encapsulated and comprised of both glandular epithelium and fibrous tissue. - usually appear as a solitary, discrete, freely movable nodule (1-10 cm in diameter). - Biopsy is mandatory to verify its benign nature

fibroadenoma

-arises from the glandular (and ductal) structures of the breast, and many histologic variants are seen. -_____ carcinoma was the number one cause of cancer deaths in women until 1986, when the increased prevalence of smoking caught up with females and lung cancer became number 1. Of those women that develop _____cancer (253,00 US cases in 2017), approximately one fourth will die of their disease. It is the 2nd leading cause of cancer related death in women (41,000 deaths in US for 2017). -Genetic factors, environmental influences (e.g. Exposure to ionizing radiation, diet, reproductive patterns, nursing habits, etc.) and hormonal influences (e.g. Prolonged exposure to exogenous estrogens) have been implicated in the etiology. -About 10% of_____cancers are thought to be related to specific inherited mutations. In those cases related to specific inherited mutations (Majority seen with BRCA1, BRCA2 genes), the cancers appear in women under 40 years of age and more often are bilateral. -lifetime risk of female _____cancer is one in eight with 75% occurring in individuals over the age of 50. -lesions are freely movable, discrete, non-tender masses and most are found by self-examination. -most are identified in the upper outer quadrant but lower inner quadrant and central lesions have lowest 5 yr survival (tumors tend to be larger by the time of detection). -tumor has a tendency to become adherent to the body wall with fixation of the lesion. -Adherence to the overlying skin results in retraction or dimpling of the nipple (often the first indication of a lesion). -Tumor blockage of the lymphatics can result in thickened skin which resembles the surface of an orange (peau d’orange)

breast cancer

- can be classified as ductal carcinoma (arising from ductal epithelium) or lobular carcinoma (arising from glandular acini). - Both have noninvasive precursor stages, termed ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), in which the neoplasm has not penetrated the basement membrane and thus has not invaded or infiltrated the connective tissue stroma

classifications of breast carcinoma

oalmost always associated with a pituitary adenoma omay produce symptoms by hormone production or by local mass effect ♣compression of optic nerve leading to visual disturbances increased intracranial pressure

hyperpituitarism

type of associated syndrome- ACTH and other POMC-derived peptides

Cushing syndrome | Nelson syndrome

type of associated syndrome- GH

gigantism | acromegaly

type of associated syndrome- prolactin

galactorrhea and amenorrhea | sexual dysfunction and infertility

type of associated syndrome- prolactin and GH

-combined features of prolactin and GH excess

type of associated syndrome- TSH

-hyperthyroidism

type of associated syndrome- FSH, LH

hypgonadism, mass effects and hypopituitarism

causes: ononfunctional pituitary adenoma oIschemic necrosis, most commonly from Sheehan’s syndrome (postpartum infarct). Need over 75% of anterior lobe to be destroyed for clinically significant effects. oAblation of pituitary by surgery or radiation odestruction by adjacent tumor manifestations oPituitary dwarfism (GH) oAmenorrhea and infertility in women and decreased libido, impotence, and lack of pubic/axillary hair in men (gonadotropin) oNo post-partum lactation (prolactin) oHypothyroidism (TSH) Hypoadrenalism (ACTH

hypofunction (hypopituitarism)

•Oxytocin- no significant clinical abnormalities •Antidiuretic hormone (ADH) oFunctions in kidneys to promote resorption of free water diabetes insipidus

Posterior lobe pathology

•Caused by an adenoma in the anterior lobe that secretes growth hormone •Occurs before closure of the epiphyseal plates (growth plates) in the long bones •Clinical features: •Generalized increase in the size of the body •Arms and legs are disproportionately long Treatment: surgical removal of the adenoma •Prognosis: fair to good

Gigantism

•Increased growth hormone secretion (also due to an adenoma) •After closure of the epiphyseal plates (skeletal maturity) •Clinical features: •Enlarged bones of the hands, feet, and face •Prognathism, development of a diastema •Hypertension and congestive heart failure may be seen •Treatment: same as gigantism (remove adenoma) Prognosis: Guarded—due to complications of hypertension and congestive heart failure

Acromegaly

Potential causes: •Failure of pituitary gland to produce growth hormone •Lack of response to growth hormone by the patient’s tissues Clinical features: •Short stature •Small jaws and teeth •Treatment: if lack of production of growth hormone is the problem, then hormone replacement therapy works Prognosis: Good (if replacement therapy works)

Pituitary dwarfism

oGraves disease (Diffuse toxic hyperplasia) (#1 cause) oingestion of excessive exogenous thyroid hormone (TH) ohyperfunctional multinodular goiter ohyperfunctional thyroid adenoma TSH-secreting pituitary adenoma (Rare)

Hyperthyroidism

Clinical manifestations oHypermobility (increased activity—can’t sit still) oG-I hypermobility, malabsorption and diarrhea oTachycardia, palpitations, irritability oNervousness, tremor, irritability, proximal myopathy oWide, staring gaze with eyelid lag oExophthalmos (bulging of the eyes) with Graves’ disease oHeat intolerance and excessive sweating oSoft, warm, flushed skin oWeight loss despite increased appetite

Hyperthyroidism

•Abrupt onset of hyperthyroidism usually triggered by stress •Patients can die of cardiac arrhythmia if untreated – A medical emergency •Treatment: Depends on the cause. Reactive iodine can be used to destroy overactive thyroid tissue Prognosis: Good (If identified and treated properly) •Diagnosed by elevated TH and decreased TSH (primary hyperthyroidism)

Thyroid storm

female predominance, F:M 7:1 Common, 1.5-2% of US women •hyperthyroidism; exophthalmos (40%); skin lesions opretibial myxedema, scaly thickening of skin overlying shins •autoimmune, significant genetic component oAutoantibodies to TSH receptor; constantly stimulated •pathology odiffuse enlargement of the thyroid on gross examination ohyperplasia of follicles with lymphoid infiltrates oIncrease in serum free TH, decreased serum TSH

Grave's disease

oPrimary or secondary oCommon causes oAblation by surgery or radiation therapy oHashimoto thyroiditis (Autoimmune destruction) Iodine deficiency

Hypothyroidism

♣Develops in childhood ♣Rare now due to iodine supplementation in diet ♣Impaired development of skeleton and CNS ♣Coarse facial features ♣Short stature ♣Severe mental retardation Protruding tongue

Cretinism

♣Develops in older children and adults ♣Generalized apathy and mental sluggishness (mimics depression) ♣Cold-intolerance, obese ♣Coarse facial features, enlargement of tongue, deepening of voice, constipation, late cardiac effects ♣Accumulation of mucopolysaccharide-rich edema

myxedema

diagnosis of what type of thyroid dysfunction: oMeasure serum TSH oincreased in primary due to loss of feedback inhibition oNot increased in cases caused by primary hypothalamic or pituitary disease oTreatment: Thyroid hormone replacement therapy (Synthroid) oPrognosis: Good unless treatment is delayed. The damage to skeletal and nervous systems could be permanent

hypothyroidism

ofemale predominance, 10:1 to 20:1 ousually older women osignificant genetic component oMost common cause of hypothyroidism where dietary iodine is sufficient oAutoimmune; progressive destruction of parenchyma with inflammatory infiltrates oInvolves CD4+, CD8+, and NK cells oinitially euthyroid, with progression of disease most patients will become hypothyroid oPainless thyroid enlargement with hypothyroidism oSome cases are preceded by transient hyperthyroidism oPatients usually at risk for other autoimmune diseases and B-cell Non-Hodgkin lymphomas No established risk of development of thyroid neoplasm

hashimoto thyroiditis

•Most common manifestation of thyroid disease •Diffuse and multinodular ___ reflect impaired synthesis of thyroid hormone oMost often due to dietary deficiency, though some cases are idiopathic oImpairment of TH synthesis  increase in serum TSH  hypertrophy and hyperplasia of thyroid follicular cells  gross enlargement of gland •Most common clinical features are due to mass effects oCosmetic problem oAirway obstruction oDysphagia oCompression of vessels •Hyperfuctional, “toxic’ ____ oIn a minority of patients, the a “toxic” nodule may develop in a long-standing, non-toxic ______ Hyperthyroidism

Goiter

osolitary thyroid nodules may be detected in 2-4% of the general population omost nodules are non-neoplastic disease (1% are carcinomas) oNodules in young patients are more likely to be neoplastic oNodules in males are more likely to be neoplastic ogenetic and environmental factors oexposure to radiation in first 2 decades

thyroid neoplasms

osolitary nodules, 3-5 cm in diameter ogrossly separated from the normal thyroid by a thin, discrete capsule omicroscopically composed of follicles with varying amounts of colloid

follicular adenoma

oaccounts for >85% of thyroid cancers o3rd-5th decade, F>>M o60-70% are multifocal osome cases related to radiation exposure oMany have mutations in the RET proto-oncogene oPathology omicroscopically characterized by papillary projections odistinctive nuclear changes onuclear clearing, aka “orphan annie nuclei” onuclear grooves onuclear inclusions onuclear enlargement oIndolent lesions, 10-year survival rates >95% poor prognostic features include extrathyroidal extension and elderly

papillary thyroid carcinoma

oaccounts for 5-15% of thyroid cancers oOlder age than papillary; areas with dietary iodine deficiency ogrossly may resemble an adenoma with a discrete capsule oMust see invasion through the capsule or into the blood vessels

follicular carcinoma

oRare <5%; typically presents as rapid enlargement in a long standing goiter oextremely poor prognosis

anaplastic thyroid carcinoma

ouncommon, accounts for 5% of thyroid cancer oderived from the parafollicular (C) cells omay be sporadic or familial (component of MEN syndromes) oAll have mutation in the RET proto-oncogene oIncreased serum calcitonin

medullary thyroid carcinoma

•An important cause of hypercalcemia •Excessive secretion of parathyroid hormone (PTH) •Two types oPrimary: an autonomous spontaneous overproduction of PTH oSecondary: a secondary phenomenon in patients with chronic renal failure •Treatment: Surgical removal of hyperplastic parathyroid glands. Kidney transplant may be beneficial in patients with _____ secondary to renal failure. Prognosis: Usually good

Hyperparathyroidism

oCommon endocrine disorder generally affecting adults oCaused by ____ adenomas or hyperplasia --> hypercalcemia oClinical features oMore common in women (4:1); often clinically silent Classic constellation of symptoms ♣Painful bones: Fractures associated with osteoporosis ♣Renal stones ♣Abdominal groans: Constipation, peptic ulcers, and gallstones ♣Psychic moans: Refers to depression, lethargy and seizures oWeakness and fatigue oBrown tumor of hyperparathyroidism can develop in the jaws, extravasated blood cells oGround glass appearance – alteration in trabecular density, seen in jaws oMetastatic calcifications ♣Deposition of calcium in throughout body, including blood vessels Currently, routine blood tests taken for other reasons often detect clinically silent ______

primary hyperparathyroidism

Renal failure is most common cause oDecreased phosphate excretion  hyperphosphatemia  depresses serum calcium levels  stimulates parathyroid glands (which become hyperplastic) •Normally kidneys would increase Vit D synthesis to increase Ca absorption in gut to compensate •But because they aren’t working, there is decreased renal synthesis of Vitamin D and reduced intestinal absorption of calcium •Symptoms are dominated by renal failure •Same manifestations as primary ____but usually less severe •Bone changes- renal osteodystrophy Serum calcium remains near normal because the compensatory increase in PTH sustains serum calcium

Secondary hyperparathyroidism

Uncommon Etiology osurgical removal of parathyroids (inadvertently during thyroidectomy or other neck dissection) ocongenital absence (DiGeorge’s syndrome) oauto-immune disease •Clinical manifestations oHypocalcemia oIncreased neuromuscular excitability oCardiac arrhythmias Increased intracranial pressure and seizures

Hypoparathyroidism

•Group of metabolic disorders resulting in hyperglycemia (excessive amounts of glucose in the blood) due to defects in insulin secretion, insulation action, or both •In 2015, over 30 million Americans affected (7 % of population) with ¼ undiagnosed, with 84 million pre-diabetics •Vasculopathy with long-term complications involving kidneys, eyes, nerves Leading cause of end-stage renal disease (ESRD), blindness, and amputation

-diabetes mellitus

``` •Type 1 o 5% of cases o Severe insulin deficiency • Type 2 Caused by a combination of peripheral resistance to insulin action and an inadequate response to insulin secretion by the beta cells ```

- diabetes mellitus classification - Type I- juvenile onset or insulin dependent - Type II- adult onset or non-insulin dependent

Which type of DM? oSymptoms appear once 90% of beta cells have been destroyed, usually by age 20 oPolyuria oPolydipsia oPolyphagia with weight loss oKetoacidosis •With fat as primary energy source: excess ketones in blood, low blood pH Can lead to diabetic coma •Absolute lack of insulin secondary to autoimmune destruction of beta cells •Abrupt onset •Patients require insulin from outside sources to survive or kidney/pancreas transplantation Prognosis is guarded due to many complications

-type I

Which type of DM? oUsually present after age 40, but not always oPolyuria and polydipsia may occur oDiagnosis usually made by routine blood or urine tests oEnhanced susceptibility of infections, periodontal disease •Results from a collection of multiple genetic defects, each contributing its own predisposing risk and modified by environment. •Peripheral tissues cannot respond properly to insulin (insulin resistance) •Beta cell dysfunction results in inadequate insulin secretion in the face of insulin resistance and hyperglycemia. Disposing factors oObesity ♣80% of these type DM patients are obese ♣60% of the obese exhibit glucose intolerance ♣Obesity in children is implicated in development of DM as adults ♣Exercise and weight loss can reverse insulin resistance and clinical evidence of disease oPregnancy oStress •Treatment: Weight loss, improve diet, oral hypoglycemic drugs, insulin Prognosis is fair. Patients have complications similar to those seen in another type. However, the disease is usually not as severe. the other type of DM patients are more likely to die of the disease than these patients

type II

Which organ do you see these manifestations of DM in? -Reduction of the number and size of islets oHeavy inflammatory infiltrate Amyloid deposition

pancreas

DM related pathosis: oResponsible for 80% of DM-related deaths oAtherosclerosis is severe and accelerated oMyocardial infarction and stroke oGangrene of lower extremities is 100-fold increased over normal population oThickened basement membrane, especially around small blood vessels (microangiopathy)

vasculopathy

o2nd leading cause behind vascular diseases, leads to HTN and ESRD oGlomerular lesions ♣Diffuse glomerulosclerosis ♣90% of diabetics within 10 years; not specific to diabetics ♣Microangiopathy around glomerular capillaries and deposition of matrix ♣Proteinuria, total renal failure oNodular glomerulosclerosis ♣15-30% of long-term diabetics; specific to diabetics ♣Ball-like deposition of matrix at the periphery of the glomerulus ♣Total renal failure ♣Renal atherosclerosis Pyelonephritis

-diabetic nephropathy

o4th leading cause of blindness oMicroangiopathy and microaneurysms oRetinal detachment and vision loss

retinopathy

oCan affect the peripheral sensorimotor nerves | Autonomic neuropathy causing disturbances in bowel and bladder function, impotence

diabetic neuropathy

* Uncommon (<2% of all pancreatic neoplasms) * Most are from the exocrine pancreas * may be functional or nonfunctional

islet cell tumors

Beta cell tumor, hyperinsulinism, most are adenomas Hypoglycemia quickly occurs from fasting or exercise Many are asymptomatic, 5-10% malignant Nervousness, confusion, stupor Surgical excision

insulinoma (insulin secreting islet cell tumor)

Arise in duodenum, peripancreatic tissues, or pancreas gastric acid hypersecretion 90-95% of recalcitrant peptic ulcers

Gastrinoma

Pancreatic islet cell tumor, hypersecretion of gastric acid, severe peptic ulcers Most are malignant (60%), surgical resection

Zollinger-Ellison Syndrome

Causes oMost commonly by excess administration of exogenous glucocorticoids oPrimary adrenal hyperplasia or neoplasm (e.g. adrenal adenoma) oPrimary pituitary source ♣ACTH oversecretion by pituitary microadenoma ♣Known as Cushing disease oEctopic ACTH secretion by neoplasm, e.g. lung Signs and symptoms Short Term ♣weight gain and hypertension ♣“Moon facies” (accumulation of fat in the face) ♣“Buffalo hump” (accumulation of fat in the posterior neck and back) Long Term ♣Decreased muscle mass, weakness ♣Diabetes ♣Osteoporosis ♣Cutaneous striae, hirsutism ♣Mental disturbances: mood swings, depression, psychosis ♣Menstrual irregularities •Treatment: depends on the cause Prognosis: good

Hypercortisolism

``` causes: oSodium retention, Potassium excretion -Hypertension and hypokalemia ♣Primary oVery rare oHyperplasia, neoplasm, idiopathic oDecreased levels of plasma renin ♣Secondary oAldosterone release in response to activation of renin-angiotensin system Increased levels of plasma renin ```

hyperaldosteronism

♣Primary or ♣Secondary •Decreased stimulation of adrenals from deficiency of ACTH ♣Don’t appear until at least 90% of adrenal gland has been destroyed ♣Manifestations •Weakness •Fatigue GI disturbances (anorexia, nausea, vomiting, weight loss, diarrhea

hypoadrenalism

In patients maintained on exogenous corticosteroids, rapid withdrawal of steroids or failure to increase steroids in response to an acute stress can precipitate an adrenal crisis Vomiting, abdominal pain, hypotension, coma, death Can also be caused by adrenal hemorrhage or stress in a patient with existing Addison's

acute adrenocortical insufficiency

•Progressive destruction of adrenal cortex •Serum ACTH may be elevated  skin and mucosal pigmentation •Destruction of cortex prevents response to ACTH •Potassium retention, sodium loss, hyperkalemia, hyponatremia, volume depletion, and hypotension Causes oAutoimmune destruction of steroid-producing cells ♣Most common, 60-70% of cases oTB oAIDS oMetastatic disease •Clinical features •Progressive weakness—easily fatigued •GI disturbances: nausea, vomiting, anorexia, weight loss, diarrhea •Hyperpigmentation—often involves the oral mucosa •A craving for salt Treatment: Corticosteroid replacement therapy Prognosis: Guarded. Can result in death if not recognized and treated properly

Addision's Disease

•Any disorder of hypothalamus of pituitary that reduces output of ACTH •Symptoms similar to Addison’s disease oBut no skin/mucosa pigmentation

secondary adrenocortical insufficiency

oneoplasm of chromaffin cells, F > M, 30-60 yrs. Chromaffin cells produce epinephrine. oHypertension, tachycardia, tremor, headache oSurgically correctible orule of 10's: 10 % bilateral, extra-adrenal, malignant, familial syndromes large polygonal cells with variable pleomorphism

pheochromocytoma

``` •Types I, 2A, and 2B •Tumors of multiple endocrine organs oMedullary Thyroid Carcinoma oPheochromocytoma oParathyroid oPituitary oPancreas •RET proto-oncogene •Type 2B notable for early orofacial manifestations oMucosal neuromas (tongue, labial commisure) oLarge, blubbery lips oMarfanoid body habitus Early onset medullary carcinoma of thyroid ```

Multiple Endocrine Neoplasia Syndromes

-aka brittle bone disease -group of hereditary conditions characterized by abnormal development of type I collagen, -Four major variants of this disorder are known and associated with variable severity. -Autosomal dominant (most common) and autosomal recessive forms are seen with multiple bone fractures being the primary associated pathosis. -severe forms, extreme bone fragility leads to death in utero or shortly after passage through the birth canal. -milder forms, the fractures don’t appear until childhood (may be confused with child abuse) and don’t shorten life significantly. -Other interesting but inconsistent findings include blue sclera and opalescent teeth which resemble dentinogenesis imperfecta. -Management includes minimizing factors that cause fractures. Prognosis depends on the type of OI and expression of the gene

Osteogenesis Imperfecta

-aka marble bone disease group of rare hereditary disorders characterized by deficient osteoclastic activity with resultant defective bone remodeling. -Both autosomal dominant and autosomal recessive forms are seen with an associated variable presentation and severity. -Affected patients present with significantly thickened, heavily mineralized and abnormally brittle bone, prone to fractures. -pancytopenia is common leading to anemia, thrombocytopenia, leukopenia, and an increased prevalence of infections such as osteomyelitis. -Compression on the cranial foramina and nerve roots creates nerve palsies (blindness, deafness) in many patients. -bone marrow transplantation can provide recipients with fully functional osteoclasts. -May be complicated by GVHD

Osteopetrosis

- increased porosity of the skeleton resulting from reduced bone mass with an associated increased bone fragility and increased prevalence of fractures. - process may be localized (such as cases of disuse in an immobilized extremity) or generalized. - Generalized ______ can arise secondarily to a wide variety of pathoses. - primary- process most commonly is associated with aging and is distinctly common in postmenopausal females with associated reduced estrogen (2-3X more frequent). - About 25% of women sustain fractures by age 65 and 50% by age 90. - most common form of acquired, metabolic bone disease (10 million in US, 44 million osteopenia). - _____ fractures affect more women than heart attack, stroke and breast cancer combined - Over 95% of the cases are primary and appear to be related to reduced estrogen in females and lower androgens in males - Common sites of involvement include the vertebral bodies, pelvis, femoral neck, and other weight-bearing bones - primary therapy to slow bone loss includes adequate dietary calcium intake, vitamin D supplementation, and regular weight-bearing exercise. This approach works best when initiated prior to age 30 to maximize the peak bone mass

Osteoporosis

- aka osteitis deformans - fairly common bone disorder characterized by repetitive episodes of frenzied, regional osteoclastic activity and bone resorption (osteolytic stage), followed by exuberant osteoblastic activity and bone formation (mixed osteoclastic-osteoblastic stage), and finally by an apparent exhaustion of cellular activity (osteosclerotic stage). - net effect is a gain in bone mass; but the newly formed dense bone is disordered, structurally weak and prone to fracture. - These processes produce skeletal deformation caused by accumulation of excessive amounts of abnormal, unstable bone - histopathologic features form a mosaic pattern of bone. - Radiographically, the bone shows a mixture of radiolucent-radiopaque areas referred to as a cotton-wool pattern - possible complications include leontiasis ossea - diagnosis is made secondary to the radiographic and microscopic appearances combined with demonstration of elevated levels of urinary hydroxyproline (⇑bone resorption) and serum alkaline phosphatase (⇑bone apposition). - Most patients have mild symptoms which can be controlled by calcitonin or bisphosphonates and analgesics

Paget disease

- infection spreading through the medullary spaces of a bone. Bacteria can colonize the spaces within bone, normally through one of three pathways. 1. Hematogenous spread 2. Contiguous infection (i.e. odontogenic infections) 3. Direct traumatic introduction (i.e. compound fractures, surgical procedures) - Hematogenous _____ is caused most frequently by Staphylococcus aureus; while mixed infections, often with anaerobes, are seen in those secondary to trauma or dental problems

osteomyelitis

characterized by progressive replacement of normal bone by fibrous tissue intermixed with unorganized, woven bone. This may reflect disordered bone maturation with arrest at an immature stage of woven bone due to a specific mutation. Three clinical patterns are seen

Fibrous dysplasia

70% of all cases. It usually manifests in childhood and often becomes stationary at puberty. The most common sites of involvement in descending order of frequency are the ribs, femur, tibia, jaws, calvarium, and humerus

Monostotic fibrous dysplasia

Jaffe-Lichtenstein Syndrome: Multiple bones are affected, and the involvement often tends to be unilateral. This pattern accounts for about 25% of the cases, often arises at an earlier age, and can continue to cause problems during adulthood. Frequently affected bones are craniofacial bones (including jaws), femur, tibia, humerus, and pelvis. Café-au-lait pigmentations are variable but not rare; related endocrine abnormalities are absent

Polyostotic fibrous dysplasia without endocrine involvement

McCune-Albright syndrome: This pattern is the least common, represents around 3% of all cases, and typically is accompanied by melanin pigmentation of the skin (café-au-lait spots) and endocrine abnormalities. Although precocious sexual development is the most common endocrine abnormality, other disorders such as hyperthyroidism, excess growth hormone, and primary adrenal hyperplasia may be seen. Females are affected much more than males. The process often is unilateral and affects the majority of the bones on the altered side -of immature woven bone and this pattern has been termed Chinese characters. When radiographically examined with film capable of high detail (dental films), the affected area will appear as an ill-defined area of increased radiopacity described as ground glass

Polyostotic fibrous dysplasia in association with endocrinopathies

- bone and osteoid producing malignancy. - most common primary malignant tumor of bone(other than lymphoproliferative diseases) - most patients are younger than age 20 (mean age 18yrs). - metaphyseal region of long bones in the extremities is the most frequent site (60% occurring in the knee vs 8 % in the jaws). - painful enlarging mass is the most frequent clinical presentation; - pathologic fracture can also be the first sign of disease. - radiographic appearance is generally that of a large, destructive, mixed radiolucent-radiopaque lesion that may present with a “sunburst” appearance. - formation of an acute angle between the neoplastic bone and the cortex (Codman’s triangle). - Diagnosis requires histologic evidence of direct production of osteoid by malignant mesenchymal cells

Osteosarcoma

- most common disorder of the joints - degeneration of the articular cartilage.The process may be primary (arises without obvious predisposing factors) or secondary (arises in a previously deformed joint). - not primarily an inflammation of the joints but may become secondarily inflamed as the process progresses. - most important factors appear to be aging and mechanical effects - early stages, the cartilage cap develops vertical fissures. With time, these fissures extend through the full thickness to the subchondral bone. - portions of the cartilage are eroded completely with exposure of the underlying bone. - Fragments of dislodged bone and cartilage often float free in the joint space and form “joint mice”. - At the margins of the joint, small bony outgrowths termed osteophytes arise and help to further inflame the surrounding synovial membrane. - The initial symptoms typically develop after the age of 50 and include crepitus (grating or popping sensation), joint stiffness and deep, aching pain, especially in the morning. - Repeated use of the joint tends to aggravate the pain. - signs and symptoms develop slowly and usually affect only one or a few joints. As the disease progresses, pain, deformity and limitations of motion become apparent - fusion of the joint does not occur. - Fortunately, most people are without severe disability. - Aside from complete inactivity, there is no way to prevent or halt the progression. - Although the process can stabilize, it generally is slowly progressive. - Treatment includes NSAIDs, intrajoint hyaluronic acid, cortisone shots, physical therapy, braces to wear, and joint replacement

Osteoarthritis

- disorder caused by tissue accumulation of excessive amounts of uric acid. - High levels of uric acid in these patients can cause supersaturation of the blood, crystallization of the uric acid and production of recurrent bouts of arthritis. - Elevation of the serum uric acid may result from overproduction or reduced excretion of uric acid or from both. In most cases, the process is due to an idiopathic overproduction of uric acid. - high uric acid in body fluids leads to precipitation of urate crystals that trigger a chain of events that culminate in joint injury. - released crystals activate complement and cause chemotaxis of neutrophils. - Dying neutrophils and reacting macrophages release destructive lysosomal enzymes and inflammatory mediators

Gout

arises upon precipitation of urate crystals in the synovial fluid and membranes. These crystals elicit an acute inflammatory response until the crystals resolubilize. Although any joint may be affected, the great toe is affected in close to 90%. Peripheral joints like the hands and feet are affected more frequently, most likely secondary to reduced solubility of urate in these cooler joints

Acute gouty arthritis

secondary to repeated episodes of acute attacks. Crystals become encrusted on the articular surface and even penetrate deeply into surrounding bone and soft tissue. Each deposit is known as a tophus and is diagnostic of ___. Erosion and progressive destruction of the joint occurs secondary to tophi and resembles advanced osteoarthritis

Chronic gouty arthritis

- After the joints, the kidney is the most frequently affected organ. Renal conditions such as pyelonephritis, nephrosclerosis, tubular deposition of crystals, intertubular deposition of crystals and uric acid renal stones are seen secondary to _____. - Advanced arteriosclerosis, hypertension and obesity also are positively associated with ___. - exhibits a male predominance and rarely produces symptoms prior to 30 years of age. - onset of symptoms is abrupt and followed by asymptomatic intervals and recurrent episodes of arthritis. - increased numbers of joints are involved with eventual development of permanent joint deformity. D - rugs (NSAIDs, corticosteroids, colchicine, allopurinol) are available to abort or prevent ____attacks. Diet modification can also aid in management of ______

Gout

- X-linked recessive disorder caused by the absence of a structural protein termed dystrophin - seen in about 1/3500 live male births. - Absence or abnormality of dystrophin is associated with impaired contractile activity and a variety of other derangements in both skeletal and cardiac muscle. - seen more inmale offspring of carrier females. - Rare cases occur from mutations de novo or in females. - affected muscles undergo progressive degeneration, and the process begins in the pelvis and shoulder girdles with eventual spread to the extremities. - initial signs appear in childhood and present as difficulty in standing, walking, and getting out of a chair. - leg muscles are often enlarged secondary to pseudohypertrophy (replacement of lost muscle with fibrofatty tissue). - Signs and symptoms typically begin around three to five years of age. - in teens, most patients are confined to wheel chairs - death usually ensues before age 30 due to cardiac involvement, weakness of muscles necessary for respiration, or from pneumonia secondary to aspiration of food associated with difficulties in swallowing. - diagnosis is confirmed from the family history, clinical presentation, elevated serum muscle enzymes, by electromyography, and biopsy

Duchenne muscular dystrophy

- autoimmune disease which results in destruction of acetylcholine receptors - most active muscles generally are the most severely affected, such as the muscles involved in eye movement, facial expression, chewing, swallowing and respiration. - disease can arise at any age and exhibits a female predominance. - pts exhibit an increased prevalence of other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome. I - strong association with thymus abnormalities. - Approximately 65% will demonstrate thymic hyperplasia, while another 15% will exhibit a thymoma. - In both instances, the altered thymus tissue demonstrates myoid cells which antigenically resemble acetylcholine receptors. - muscles affected have about a 70-90% reduction in the number of acetylcholine receptors - initial involvement are the muscles of the eyelids (ptosis: drooping of eyelids) and the muscles controlling eye movement (diplopia: double vision). In addition, involvement of the muscles of facial expression, speech and mastication is not rare. Difficulty in chewing food or holding the head upright is not rare. - signs and symptoms are first seen as a failure of contraction after sustained effort; - progresses to loss of contractility even after extensive rest. - helped by thymectomy in cases of thymus hyperplasia and removal of the tumor in those with a thymoma. - In addition, medications such as cholinesterase inhibitors and corticosteroids have been proven to be beneficial in many cases. - respiratory compromise was a major cause of death; due to improved therapies, the current 5-year survival is 95%

myasthenia gravis

see 12-24 h after irreversible hypoxic/ischemic insult. See shrinkage of the cell body, pyknosis of the nucleus, loss of nucleolus, loss Nissl substance, red cytoplasm, break down in bloodbrain barrier with acute injuries

acute "red neurons"

a. Increased fluid content within brain parenchyma (trauma, hypoxia, tumor, infection) b. Common form of secondary brain damage, occurs in 75% of patients with brain injury c. Major cause of elevated intracranial pressure. d. Clinical Classic indications of raised intracranial pressure are headache, vomiting and papilledema (swelling of optic disc) e. Presents as swollen gyri, narrowed sulci, compressed ventricles, brain shifting f. Vasogenic edema-blood brain barrier disruption and increased vascular permeability-note fluid shift from vascular component to the brain. g. Cytotoxic edema-increased intracellular fluid secondary to neuronal glial or endothelial cell membrane injury e.g. hypoxic or metabolic damage.

Cerebral edema

a.Choroid plexus produces CSF. In continuity with ependyma, intraventricular fibrovascular cores lined by epithelial cells. b.accumulation of excessive CSF within ventricular system c.During infancy-increased CSF will result in increased head circumference. In an adult/non infant (skull in no longer “flexible” due to suture closure), note expansion of the ventricles and increased intracranial pressure. Causes: •Decreased CSF resorption (CSF flow obstructed by: tumor, hemorrhage or inflammation i.e. meningitis) Increased CSF production (tumors of the choroid plexus; rare_

Hydrocephalus

Type of herniation: Unilateral or asymmetric expansion of the cerebral hemisphere displaces cingulated gyrus under falx cerebri-may compress anterior cerebral artery

Subfalcine (cingulated)

Type of herniation: Medial aspect temporal lobe compressed-CN III compromised-pupils dilate and impairment ocular movements-may also compress posterior cerebral artery-affecting visual cortex-Duret Hemorrhage-midbrain bleeds

Uncinate (transtentorial)

Type of herniation: Displacement cerebellar tonsils through foramen magnum-life threatening as the brain stem becomes compromised as the breathing and cardiac regulatory centers are located in the medulla oblongata

Tonsillar herniation

Altered consciousness brought about by sudden change in momentum of head-e.g. moving head hits a rigid surface. b. Neurologic changes-note transient neurologic dysfunction, loss of consciousness, respiratory arrest, loss of reflexes-develop amnesia for the event-neurologic recovery complete

Concussion

Damage occurs at the point of contact

Coup injury

Note damage at site diametrically opposed. If head stable-coup injury, if head is mobile-may see both

Contrecoup injury

dural arteries most frequently the mid-meningeal artery •Usually associated with a skull fracture •Dura separates from blood accumulation. Rupture of a meningeal artery- arterial bleeding •“Lucid interval”, then progressive loss of consciousness Neurosurgical emergency Need PROMPT DRAINAGE as this is a life-threatening condition.

Epidural hematoma

•Brain can move but venous sinuses are fixed •Blood between dura and arachnoid membrane •See this in the elderly (chronic) with brain atrophy (bridging veins are stretched out) and infants (acute – Whiplash injury, Shaken baby syndrome) (bridging veins are thin-walled) Usually note slowly progressive neurologic dysfunction-remove blood and organizing granulation tissue

Subdural hematoma

third leading cause of death in the U.S.

Cerebrovascular disease

acute onset, non-epileptic, neurological deficit that lasts > 24 hours.

working definition of stroke

1Grossly & histologically normal: first 12 hours 2.24-36 hours (acute): Red neurons and neutrophil infiltration into the brain parenchyma 3.3rd – 5th day (subacute): Involved tissue becomes softer in consistency. Macrophages with foamy cytoplasm begin to infiltrate 4.1 month: Soft, irregular, cavitated lesion, loss of brain tissue. 6 months (chronic): Smooth walled cavity

Evolution of a brain infarct

______ is the most common underlying cause of primary parenchymal hemorrhage. b. Accelerated atherosclerosis in larger vessels and hyaline arteriolosclerosis in smaller vessels weakens the vessel walls. c. Subsequently note wall rupture and hemorrhage, which is most common in the regions of the basal ganglia, followed by pons, thalamus and cerebellum. d. Can be clinically devastating if it affects large portions of brain and extends into ventricular system. e. Severe headache, hemiparesis, hemisensory loss

Hypertension | Hypertensive cerebrovascular disease and intraparenchymal hemorrhage

a.Defined as abrupt onset extravasation of blood in space between arachnoid and pia (arterial bifurcations of the circle of Willis) mater due to rupture of vessels in arachnoid space. b.Often are spontaneous, but could also be precipitated by traumatic injury. c.Chief complaint of patient “Worst headache of my life”. d.Ruptured berry (saccular) aneurysm (of major brain arteries) is the most common cause of non-traumatic hemorrhage. e.Most aneurysms arise from branches of the middle cerebral, internal carotid and the junction between the anterior cerebral and anterior communicating arteries. f.Probably represents an acquired, degenerative process, aggravated by hypertension. g.______ _______ i.e. blood in CSF may be seen together with intraparenchymal hemorrhage

Subarachnoid hemorrhage

Infections resulting in inflammation of the leptomeninges and subarachnoid space. Brain is swollen. Purulent exudate under subarachnoid space, over the cerebral hemispheres. Purulence within the ventricles b. Acute purulent ____ is caused by pyogenic bacteria e.g. E. coli, group B streptococci, H. influenza, Neisseria meningitidis). c. Chronic lepto_______ is caused by both bacterial e.g Mycobacterial tuberculosis and fungal e.g. Cryptococcus neoformans organisms. d. Risk factors to develop include: extremes of age, poor hygiene, crowded living conditions, and debilitation. e. Symptoms include neck stiffness, neurologic impairment, headache, photophobia. f. Lumbar puncture: increased pressure; bacteria, PMNs, necrotic cellular debris, decreased glucose in the CSF

acute bacterial meningitis

a. > 2-3 weeks of headache, lethargy, nausea & vomiting b. Cranial nerve palsies, epilepsy c. Gelatinous exudate, may appear nodular. d. Histology: Lymphocytes, macrophages, and multinucleated giant cells form granulomas. Mycobacteria may be demonstrable by acid fast stain

Tuberculous meningitis (chronic meningitis)

a. Spherical budding yeast, found in soil and bird excrement b. Low grade fever, debility, headache c. Slimy exudate, capsular material d. Both healthy and immunocompromised hosts (e.g. HIV+) can be affected

Cryptococcal meningitis (chronic meningitis)

a. Usually caused by bacteria which include streptococci, staphylococci and anaerobic organisms. b. Cavity contains pus, surrounded by a thick wall of granulation tissue and fibrosis c. 50% are spread from adjacent infections (dental, ear or sinus). Streptococcus milleri is most common identified organism. d. Usually solitary, may be multiple. e. Clinical features: headaches, fever, neck rigidity, increased intracranial pressure and focal neurologic deficits. f. Extremes of age is a poor prognostic factor, mortality is approximately 20%

Brain abscess

a. Diffuse inflammation of the brain parenchyma caused by a number of viral agents e.g. HSV most common, HIV, cytomegalovirus and also many arthropod-borne encephalitis viruses. b. Clinical symptoms: headache, neck stiffness, pyrexia (fever) and focal seizures. c. Without treatment, usually fatal. d. Microscopically can note perivascular lymphocytosis, microglial nodules and neuronophagia. May also note viral inclusions e.g. Cowdry A and Negri bodies

Encephalitis

Consistent with what neuro disease? a. Microscopically note Neuritic (senile) plaques (aggregates of thickened, tortuous processes with central amyloid deposits) and neurofibrillary tangles (filamentous aggregates within neuronal cytoplasm)

Alzheimers

Consistent with what neuro disease? Diagnostic microscopic features: Intracytoplasmic eosinophilic inclusion bodies known as Lewy bodies, within pigmented neurons of the substantia nigra and locus ceruleus

Parkinson's disease

tumors of CNS account for 20% of

pediatric cancers; arise in posterior fossa

70% of adult CNS cancers arise in

cerebral hemisphere above tentorium

a.Astrocytomas (infiltrating) comprise 80% of adult tumors. Symptoms include seizures, headaches and focal neurologic deficits. b.In adults, mostly affects the cerebral hemisphere c.Pilocytic astrocytoma (Grade I) → Astrocytoma (Grade II) → Anaplastic astrocytoma (Highly cellular with mitotic figures, Grade III) → Glioblastoma (Necrosis and microvascular proliferation, Grade IV). Glioblastoma → note endothelial cell proliferation. d.Clinical features-may remain “silent” until increase in growth. Treatment consists of surgical resection, then radiation and chemotherapy. ~ 15 month survival. Pilocytic astrocytoma: Less aggressive, often in pediatric patients, usually located in the cerebellum

Gliomas

a.Patients often have several years of neurologic symptoms including seizures. b.Mostly cerebral hemisphere. c.Well circumscribed, often calcified. Cells with uniform, round nuclei and perinuclear halo (fried egg look) Generally better prognosis than astrocytoma

Oligodendroglioma

a.Arise most often next to ependymoma-lined ventricles-including obliterated central canal of the spinal cord. b.Typically occurs near the 4th ventricle. c.May manifest with hydrocephalus secondary to obstruction of the ventricle. May also have CSF dissemination. d.Well-circumscribed lesions, arising from ventricular wall. Elongated cells with processes radiating around blood vessels (perivascular pseudorosettes) Generally low-grade lesions (Usually Grade II

Ependymoma

a. Derived from the arachnoid matter b. Female predominance c. Firm, lobulated lesions with a pushing border into underlying brain d. Microscopically: cellular whorls and psammoma bodies are common

Meningioma

a.Primarily seen in pediatric patients in cerebellum (by definition). b.Rapid growth with cells disseminating through CSF. May block CSF flow-note hydrocephalus. c.Cells form Homer-Wright rosettes Very aggressive (Grade IV tumor) but radiosensitive. Surgical excision and radiation. Five year survival as high as 75%

Medulloblastoma

: flat, circumscribed area <5 mm

macule

flat, circumscribed area >5mm

patch

elevated lesion <5 mm

papule

elevated lesion > 5 mm

plaque

discrete pus-filled lesion

pustule

fluid-filled lesion <5 mm

vesicle

fluid-filled lesion >5 mm

bulla

CLINICAL FEATURES Erythematous, edematous, and pruritic papules and plaques (wheals) Individual ___ last <24 hours (just a few hours), but episodes can continue for weeks Localized or generalized PATHOGENESIS Mast cell degranulation increased dermal vascular permeability dermal edema Immediate Type I (IgE) hypersensitivity rxn Inciting factor: medications (opiates, abx) TREATMENT Antihistamines

Urticaria- hives

CLINICAL FEATURES Pruritic inflammatory erythematous papules and scaly plaques Can become vesicular and crusted over time, skin thickens due to acanthosis Spongiotic dermatitis on histo: epidermal edema, perivascular lymphocytic infiltrate, and mast cell degranulation

Acute Eczema

Type of Eczema- autoimmune related Genetic predisposition Atopic triad of asthma, allergies, and eczema More common in childhood, outgrow as adult

Atopic Eczema

Type of Eczema- contact exposure to an allergen Type IV hypersensitivity rxn: CD4+T lymphocyte mediated Poison ivy, neosporin

Allergic Contact

Type of eczema- abnl reaction to ultraviolet light

photoeczematous

Hypersensitivity reaction most often due to medication/drug and certain infections Common meds: sulfonamides, PCN, NSAIDs, hydroquinone Infections: HSV and mycoplasma On spectrum of Stevens Johnson (more mucosal involvement and wider surface area) and toxic epidermal necrolysis (TEN- full thickness epidermal necrosis) CLINICAL FEATURES “targetoid” lesions Multiple features with macules, papules, vesicles with central pallor Can lead to epidermal desquamation if progresses

Erythema multiforme

Chronic inflammatory dermatosis in 1-2% of US population Associated with heart disease and 10% can develop psoriatic arthritis Autoimmune, T-cell mediated rxn Can be localized to specific areas or generalized and severe (erythroderma) CLINICAL FEATURES erythematous salmon-pink colored plaques with silvery scale extensor elbows, knees, scalp, gluteal cleft nail thickening and dystrophy Koebner: induce lesion by local trauma Auspitz sign: punctate bleeding when overlying scale is removed Histopathology: Epidermal thickening (acanthosis) with incr epidermal cell turnover but lack of maturation Epidermal hyperplasia Downward extension of rete ridges Parakeratotic scale

Psoriasis

Infectious dermatoses- Staph Aureus, can be Strep pyogenes Contagious, more commonly in kids, spread through direct contact Starts as small macule often perioral/perinasal Enlarges with honey-colored crust (dried serum) Treat with antibiotics with good Staph coverage

Impetigo

Type II hypersensitivity reaction IgG autoantibodies bind to desmoglein type I and type 3 intercellular desmosomal proteins Disrupted intercellular adhesion causes blistering DIF: intercellular IgG deposition along keratinocyte cell membranes (fish-net)

Pemphigus

IgG deposits throughout epidermis Rare disease of elderly women>men Mucosal and skin involvement Pressure points on trunk, groin, axillae, face Intraoral involvement Flaccid blisters that easily rupture leaving denuded skin with extensive erosions and crusting Treatment: immunosuppressants +/- systemic steroids

Pemphigus vulgaris

: IgG deposits in superficial layers of epidermis

Pemphigus foliaceus

Red, rough patches on chronically sun exposed skin (mainly head/neck, lips, dorsal hands) More common in fair-skinned and blond/red heads Histo: cytologic atypia with hyperplasia of basal cells with overall epidermal thinning Can rarely evolve into squamous cell carcinoma, particularly with TP53 mutation from UV DNA damage Treatment: cryotherapy (liquid nitrogen), topical chemotherapy agents

Actinic Keratosis/Cheilitis

Forms in basal layer of epidermis 2nd most common type of skin cancer UV light exposureDNA mutations, loss of DNA repair, leading to cell damage TP53 mutation HRAS and Notch receptor mutations Red scaly plaques Over time, become invasive, nodular, and ulcerate Men>women Squamous atypia through epidermis Invasive when penetrates through BM Metastasis- Mucosal>cutaneous Thickness of lesion and depth of invasion into dermis Size >2 cm Ulceration High risk locations such as head/neck, particularly lips, ears, around eyes Treatment of choice is tumor resection If detected early, simple excision If more aggressive, can be done by Mohs surgical technique (tumor removed layer by layer, evaluated histopathologically in real time, with additional layers taken for residual tumor; repair of defect)

Squamous cell carcinoma

Risk factors for what cancer? UV exposure: chronic and accumulated Fair complexion, red/blond hair Chronic inflammation: chronic ulcers, old burns Radiation Arsenic ingestion and chemical carcinogens Immunosuppression: organ transplants and chemotherapy HPV infection Xeroderma pigmentosum: Auto recessive

Squamous cell carcinoma

Most common type of skin cancer Pearly pink, translucent papules with telangiectasias; can become nodular and ulcerate Superficial: multifocal growth in epidermis Nodular: downward invasion to dermis Can be locally aggressive but rarely metastasizes Histopathology Arise in basal layer of epidermis Palisading nests of basaloid cells with hyperchromatic nuclei surrounded by fibrotic stroma

Basal cell carcinoma

Risk factors for which cancer? Fair complexion and red/blond hair UV exposure: intermittent/intense over chronic Radiation Genetic disorder: Basal Cell Nevus Syndrome (Gorlin Syndrome) with PTCH gene mutation in Hedgehog tumor suppressor pathway

Basal cell carcinoma

benign neoplasm of melanocytes Congenital or acquired BRAF mutation as common factor in nevi Cellular senescence: migration of ___from DEJ into dermis

Melanocytic nevi (moles)

``` Junctional Nests at dermal-epidermal junction Compound Nests at DEJ and dermis Intradermal +/- cellular senescence Nests primarily dermal (intradermal) ```

Growth pattern of Nevi

Marker for melanoma, not precursor Vast majority will not transform into melanoma BRAF mutation common, NRAS mutation Size >5 mm in size Pigment variegation Border irregularity Familial Dysplastic Nevus Syndrome Dysplastic nevi >100s with strong melanoma risk Cytologic atypia of melanocytes on histopath

Dysplastic Nevi

Skin cancer derived from melanocytes 3rd most common type of skin cancer, but can be highly aggressive and more likely to metastasize if untreated Early detection critical and can be curative Delayed detection can lead to metastasis and poor prognosis Clinical signs Rapid change in size of prior nevus with asymmetry Color change and/or variability Itching/pain associated in a lesion New onset pigmented lesion esp in adults Irregular borders ABCDEs (Asymmetry, Border irregularity, Color change, Diameter, Evolution Histopathology Melanocytes are irregular in size and shape with prominent nucleoli Radial and vertical growth seen histologically Atypical mitoses common Specific special stains, such as HMB-45, can help detect melanocytes Tx Early detection Routine skin exams, biopsy of any suspicious appearing lesions Wide local excisions for Breslow depth <1 mm Sentinel lymph node biopsy for depth >1mm Chemotherapy/Immunomodulators/Radiation and numerous clinical trials

Melanoma

Risk factors for what kind of cancer Fair complexion and red/blond hair UV exposure: blistering childhood sunburns Family history of melanoma and moles Dyplastic nevi Can occur on any cutaneous surface as well as mucosal (oral/anogenital) and ocular, meningeal, and esophageal involvement

Melanoma