February 20th, 2010
Pathophysiology
1) progressive systemic sclerosis owing to deposition in tissues of circulating immune complexes that cause systemic manifestations 2) initiating event is unknown 3) mild form occurs in CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfuction, sclerodactyly, telangiectasias
Signs and Symptoms
1) often presents with Raynaud’s phenomenon 2) edema of fingers and hands followed by tightening and thickening of skin 3) ulcerations of fingertips 4) polyarthralgias 5) stone facies/restricted eye and mouth movements 6) dysphagia (esophageal hypomotility) 7) decreased intestinal motiliy with bacterial overgrowth/malabsorption 8) dyspnea on exertion 9) the “sclerodermal renal crisis” of progressive renal failure, microangiopathic hemolytic anemia, and acute onset of uncontrollable hypertension
Characteristic Test Findings
Laboratory – 1) anticentromere antibodies 2) antinuclear antibodies 3) antibodies to SCL-70 (topoisomerase I) 4) presence of male fetal cells 5) decreased CD8 T suppressor cells 6) antibodies against thyroid, salivary glands, and smooth muscle and type I and type IV collagen 7) positive rheumatoid factor
February 19th, 2010
Pathophysiology
1) progressive neurodegenerative disease with selective neuronal loss – caused by an excessive repeat of the CAG nucleic acid sequence in the gene on chromosome 4 that codes for the Huntington protein 2) unclear how altered Huntington protein contributes to the specific symptoms 3) the protein HAP-1, which binds to the Huntingtin protein, possibly contributes to the pathogenesis 4) usual duration from onset of symptoms to death is about 15 years 5) marked by involuntary movements, progressive dementia, striking emotional changes
Signs and Symptoms
1) the greater the expansion, the earlier the onset of disease 2) onset is earlier by 3-4 years if condition is inherited from father 3) usual presenting signs – emotional and cognitive deficits (often by years) 4) most striking sign – choreoathetoid movements
Characteristic Test Findings
Brain biopsy – marked decrease in brain levels of GABA, glutamic acid decarboxylase, and acetylcholine
Histology/Gross Pathology
1) atrophic frontal cortex 2) striking atrophy of caudate nucleus and to lesser degree the putamen 3) lateral ventricles appear enlarged owing to caudate nucleus atrophy 4) protein aggregrations and intranuclear inclusions
Associated Conditions
some pateints also develop a parkinsonism with rigidity in late disease
Biochemistry
1) the normal number of repeats of CAG, which codes for glutamine is 10-35; Huntington’s disease has 40-100 repeats 2) effect is probably an altered protein-protein interaction secondary to the polyglutamate area at the N-terminal of the protein
Inheritance/Epidemiology
1) affected chromosome region is 4p16.3 2) autosomal dominant 3) occurs in 1/15,000 births in affected populations, mostly in western European and Scandinavian descent 4) some spontaneous mutations are known to exist 5) heterozygotes have same severity of disease as homozygotes 6) age of onset is typically 30-50 years
Tips for USMLE
1) other diseases caused by a CAG trinucleotide repeat expansion – Machado-Joseph disease, spinal-bulbar musculat atrophy, olivopontocerebellar disease, dentatorubro-pallidoluysian atrophy (DRPLA) 2) if a brain biopsy shows loss of striatal neurons, think Huntington’s
February 18th, 2010
Pathophysiology
most common types by far are adenocarcinoma and squamous cell carcinoma
Signs and Symptoms
1) difficulty swallowing (dysphagia) – most common presenting symptom 2) pain on swallowing (odynophagia) 3) anorexia 4) cachexia 5) hoarseness (owing to compression of recurrent laryngeal nerve) 6) chronic cough (owing to tracheoesophageal fistula) 7) aspiration pneumonia 8) chest pain
Characteristic Test Findings
Laboratory – 1) hypercalcemia (even in absence of bone metastates) Endoscopy – 2) test of choice for obtaining tissue biopsy
Histology/Gross Pathology
1) occurs in polypoid, ulcerating, and infiltrative forms 2) spread is to regional lymph node basin, draining affected part of esophagus – cervical lymph nodes from upper third, mediastinal lymph nodes from middle third, and celiac and gastric lymph nodes from lower third 3) adenocarcinoma almost always arises from Barrett’s metaplasia 4) adenocarcinoma is located in lower third of esophagus 5) squamous cell carcinoma is more common in upper two thirds of esophagus
Associated Conditions
increased incidence with – 1) Plummer-Vinson syndrome 2) Barrett’s esophagus 3) heavy smoking and alcohol use (squamous carcinoma) 4) achalasia 5) chemical injury with stricture 6) presence of webs, rings, or diverticula 7) large amount of ingested nitrates 8) smoked opiates 9) deficiencies in dietary zinc, molybdenum, and vitamin A
Inheritance/Epidemiology
1) worldwide, squamous cell more common; in USA adenocarcinoma predominates 2) increased incidence in lower socioeconomic classes 3) esophageal cancer belt stretches across central Asia with incidence 300 times greater than areas of low incidence
Treatment
1) chemoradiation and surgery (if resectable) 2) anti-angiotenic drugs (endostatin, alpha-IFN) are being tried to stabilize disease 3) prognosis for adenocarcinoma is better than squamous, but overall 5 year survival is 5%
Tips for USMLE
1) if patient is a 56 year-old man with heavy alcohol and smoking history who develops weight loss and difficulty swallowing solids over a 3 month period, think esophageal cancer 2) if patient is a 67 year old man with a 25 year history of poorly controlled severe heartburn who has “pain in this throat” when he swallows, think esophageal cancer
February 18th, 2010
Pathophysiology
1) characterized by proliferation of histiocytes (Langerhans’ cells) 2) considered a variant of Langerhans’ cell histiocytosis (along with eosinophilic granuloma disease and Letterer-Siwe disease 3) mostly affects children 4) usually fairly indolent in nature with an intermediate prognosis between eosinophilic granuloma (best) and Letterer-Siwe (worst)
Signs and Symptoms
1) classic triad (occurs in one third of cases) – exophthalmos, diabetes insipidus, and multiple cystic effects of skull 2) lymphadenopathy 920%) 3) red crusty sores on trunk, hairline, and dorsum of hands and feet 4) bony lesions are typically the most impressive findings
Characteristic Test Findings
Radiology – 1) lytic bone lesions most commonly in the skull and in scapulae, ribs, pelvis, and jaw (causing “floating teeth”) 2) infiltrates in lung fields (20%)
Histology/Gross Pathology
1) Langerhans cells – proliferation and contain racket-shaped Birbeck’s granules 2) nucleus on H and E stain has a “kidney bean” appearance
Associated Conditions
1) hypopituitarism 2) deafness
Inheritance/Epidemiology
1) most commonly affects children age 2-5 years 2) occurs equally in boys and girls 3) makes up 20% of all cases of Langerhans’ cell histiocytosis
Treatment
1) radiation to destroy masses of histiocytes, especially if they are in the retro-orbital area 2) corticosteroids 3) cyclophosphamide 4) diabetes insipidus does not always reverse with treatment
Tips for USMLE
1) if question mentions cells that contain granules shaped like tennis rackets or nuclei that look like kidney beans, think Hand Schuller Christian disease 2) if the question mentions a 5 year-old girl with lytic bone lesions in her skull and exophthalmos, think Hand-Schuller-Christian disease 3) Langerhans cells – another term for histiocyte
February 18th, 2010
Pathophyisology
1) solid tumors (usually adenocarcinoma) that develop from pre-existing adenomas 2) progression from adenomatous polyp to dysplastic lesion to microfoci of adenocarcinoma probably involves activation of an oncogene followed by loss of a tumor-suppressor gene 3) mets typically go to mesenteric nodes and liver
Signs and Symptoms
Right colon cancers – 1) fever 2) fatigue 3) palpitations 4) weight loss 5) angina Left colon cancers – 6) abdominal pain 7) abdominal cramping 8) bloating 9) perforation 10) hematochezia 11) tenesmus 12) small caliber stools
Characteristic Test Findings
Laboratory – 1) positive guaiac test on rectal exam 2) iron-deficient hypochromic microcytic anemia 3) increased CEA 4) mildly increased transaminases or GGT in liver mets Radiology – 5) “apple core” sign on barium enema
Histology/Gross Pathology
1) right colon tumors – typically large and exophytic but do not obstruct feces owing to semiliquid nature 2) left colon tumors – typically cause obstructive symptoms as bowel is formed 3) irregular colonic glands with pleomorphic nuclei
Associated Conditions
increased incidence with polyposis syndromes, Lynch’s syndrome, inflammatory bowel disease (especially ulcerative colitis), alcohol intake, tobacco intake, Streptococcus bovis bacteremia, low-calcium diet, ureterosigmoidoscopy
Biochemistry
associated with – 1) point mutations in k-ras 2) hypomethylation of DNA 3) DNA loss at the tumor-suppressor gene APC on chromosome 5q21 4) loss of DNA at tumor-suppressor gene DDC on chromosome 18 5) mutations in p53-suppressor gene on chromosome 17p
Inheritance/Epidemiology
130,000 new cases in USA each year
Treatment
1) surgical resection of the involved half of colon with adjacent mesentery and liver mets, if possible 2) if lymph nodes are involved, chemotherapy with 5-FU (inactivates thymidylate synthase) and leucovorin 3) evaluation of entire colon before surgery to insure no other lesions 4) screening colonoscopy now recommended every 10 years in normal patients and every 3-5 years if colon cancer has occurred 5) possible chemoprevention with NSAIDs/aspirin/Cox-2 inhibitors and folic acid is being tested
Tips for USMLE
1) in any patient with an unexplained iron deficiency anemia over the age of 50 years, consider colon cancer 2) right-sided tumors – rarely cause obstruction owing to liquid consistency of feces but do commonly ulcerate and cause chronic blood loss 3) typically, CEA levels are drawn every 3-6 months (if initially elevated, the level will fall to baseline after resection) to indicate possible recurrence
February 18th, 2010
Pathophysiology
1) type of B cell lymphoma 2) occurs in an “endemic” form in equatorial Africa and Papua New Guinea and a “sporadic form” in the rest of the world
Signs and Symptoms
1) sporadic – onset is usually in adolescence or early adulthood and sites affected are usually abdominal 2) endemic – onset is usually by age 7 years and sites affected are the abdomen and jaw (usually) 3) metastases occur to the CNS
Histology/Gross Pathology
1) small, noncleaved cell with round to oval nucleus 2) high mitotic rate 3) “starry sky” pattern
Associated Conditions
1) endemic – strongly associated with infection with EBV 2) 1,000 times increased incidence in HIV 3) tumor lysis syndrome and related hyperuricemia, lactic acidosis, hyperkalemia, and renal injury
Biochemistry
1) EBV-stimulated B cell proliferation is shut down by T suppressor cells 2) endemic – T suppressor cells are impaired by malaria infection
Inheritance/Epidemiology
1) associated with three gene translocations – 8/14, 8/2, and 8/22 2) the effect of these translocations is to put the c-myc oncogene physically next to genes that control transcription of immunoglobulin heavy or light chains 3) parts of Africa – 90% of cases are associated with Ebstein Barr virus 4) Japan – 90% of cases are associated with HTLV-1 5) USA – 10% of cases are associated with EBV 6) 90% of sporadic cases occur in men 7) median age of sporadic cases is 31 years 8) considered the most rapidly progressive of all lymphoid malignancies
Treatment
1) cyclophosphamide-based combination chemotherapy 2) prophylactic therapy to CNS 3) cure rates of 70% if prompt initiation of chemotherapy
Tips for USMLE
four key steps in endemic cases are – 1) EBV infection 2) T suppressor cells shut down by malaria infection 3) c-myc gets next to immunoglobulin gene through translocation (8/14, 8/2, or 8/22 and turns it on) 4) B cells proliferate wildly
February 17th, 2010
Pathophysiology
1) aggressive type of bone neoplasm affecting mostly adolescents 2) considered a type of primitive neuroectodermal tumor of childhood, even though the original neoplastic transformation is probably mesenchymal in origin (possibly in the bone marrow) 3) also occurs in soft tissue 4) 90% of cases associated with the 11/22 chromosome translocation
Signs and Symptoms
1) pain at affected site 2) adjacent soft tissue mass 3) fever 4) most commonly affects long bones (especially humerus, tibia, and femur) 5) metastases are via blood system and go to lungs (most commonly), other bones, and bone marrow 6) patients sometimes give history of mass and pain arising after area has received a trauma
Characteristic Test Findings
Laboratory – 1) leukocytosis Radiology – 2) classic finding is onion peel on plain radiograph owing to reactive periosteal bone 3) soft tissue mass on MRI
Histology
February 15th, 2010
Pathophysiology
1) hereditary polyposis coli syndrome with large and small bowel carpeted by adenomatous polyps 2) occurs in association with other tumors and hypertrophic tissue
Signs and Symptoms
1) thousands of adenomatous polyps in large and small bowel (usually do not develop until after puberty) 2) mesenteric desmoid tumors 3) epidermoid inclusion cysts (sebaceous cysts) especially on face 4) soft tissue tumors (lipomas and fibromas) 5) congenital retinal hypertrophy 6) cancer of ampulla of Vater
Histology/Gross Pathology
polyps are adenomas
Associated Conditions
100% of patients develop adenocarcinoma of bowel before age 40 years
Inheritance/Epidemiology
1) autosomal dominant (occasionally occurs as sporadic condition) 2) deletion of APC gene on long arm of chromosome 5
Treatment
total colectomy with ileoanal anastomosis
Tips for USMLE
if a 6 year old girl develops multiple epidermoid inclusion cysts on her face, has hypertrophic renal tissue, but has no polyps on upper and lower barium studies, think Gardner’s
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Colon Cancer
February 15th, 2010
Pathophysiology
1) neoplasm of B cell lymphocytes with presence of Reed-Sternberg cells 2) classical variants – nodular sclerosis (most common), lymphocyte-rich, mixed cellularity, and lymphocyte poor
Signs and Symptoms
1) nontender lymphadenopathy, especially cervical and axillary (usual presenting sign) 2) splenomegaly 3) episodic fevers (Pel-Ebstein fevers) 4) night sweats 5) weight loss 6) pruritus 7) pain on alcohol ingestion
Characteristic Test Findings
Laboratory – 1) mild anemia 2) neutrophilia and eosinophilia 3) increased sed rate 4) decreased circulating lymphocytes Radiology – 5) osteolytic bone destruction
Histology/Gross Pathology
1) Reed-Sternberg cells – have binucleated, mirror-imge morphology (most common in mixed cellularity variant) 2) Hodgkin’s cells – look like Reed-Sternberg cells but have only one nuclei (commonly seen in all variants) 3) “popcorn cells” with multiple nuclei and scant cytoplasm (most common in lymphocyte predominant variant) 4) cut surface of lymph nodes have “fish flesh” appearance 5) enlargement in spleen of white pulp only
Associated Conditions
1) increased risk with ataxia-telangiectasia (100 times), HIV/AIDS, infection with Ebstein Barr (EBV), rheumatoid arthritis, and HLA-B18 2) post-treatment patients have increased risk of – acute myelogenous leukemia (5%) and large-cell lymphoma (5%)
Biochemistry
marked by deficient delayed-type hypersensitivity reactions (deficient T cell function)
Inheritance/Epidemiology
1) 8000 new cases in USA each year 2) more common in whites and males 3) bimodal age distribution at diagnosis (in 20s and 80s) 4) young patients – nodular sclerosing variant most common 5) old patients and third-world countries – mixed cellular most common 6) young women – nodular sclerosing most common 7) best prognosis – nodular sclerosing and then lymphocyte predominant
Treatment
1) radiation and/or chemotherapy 2) some stage 2 patients and all stage 3 and 4 patients receive a “staging laparotomy” of splenectomy, liver biopsy, lymph node biopsy, and bone marrow biopsy
Tips for USMLE
1) if Reed-Sternberg is mentioned, think Hodgkin’s 2) if question mentions a 21 year-old male with fevers and enlarged but nontender neck nodes, think Hodgkin’s 3) 20-40% of Hodgkin’s patients have proliferation of Ebstein-Barr infected cells 4) Hodgkin’s cells occur in diseases other than Hodgkin’s disease
February 14th, 2010
Pathophysiology
1) structure is an abnormal placenta 2) two forms are described – complete mole and partial mole 3) complete mole – when an ovum that lacks DNA is fertilized 4) partial moles – from fertilization of a normal ovum with two sperm or from fertilization of a normal ovum with one abnormal sperm (46 or 69 chromosomes) 5) partial moles have a fetus that dies before 10 weeks, with fetal tissue usually present
Signs and Symptoms
1) usually presents at 11-25 weeks 2) striking uterine enlargement 3) heavy bleeding 4) passage of grape-like tissue fragments
Characteristic Test Findings
Laboratory – 1) strikingly elevated HCG with a rapid rate of increase Radiology – 2) “snow storm” appearance on ultrasound
Histology/Gross Pathology
Complete mole – 1) placenta has markedly swollen chorionic villi that look like grapes 2) no embryo is present 3) very few if any vessels in villi 4) varying stages of trophoblastic proliferation; atypia with syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast all occurring Partial mole – 5) some normal and some swollen and abnormal villi (but much less in number than in complete mole) 6) some blood vessels 7) trophoblastic proliferation is focal only
Associated Conditions
1) hemorrhage 2) infection 3) perforation of uterus 4) embolism 5) choriocarcinoma in 2% of complete moles (does not occur in partial moles) 6) if the mole has invaded the underlying myometrium or has penetrated through it to the broad ligament, there is a 25-40% chance of spread to distant sites, especially the lungs
Inheritance/Epidemiology
1) complete mole – all genes are of paternal origin (46XX) 2) risk is related to maternal age with a bimodal distribution (< 15 years and > 40 years) 3) risk for occurrence in Asian women is 25 times greater than in white women 4) risk for recurrence is increased 20 times after first mole
Treatment
1) suction curettage of uterus with close follow-up of HCG levels 2) chemotherapy is required if HCG remains elevated 3) hysterectomy if no further pregnancies are planned
Tips for USMLE
1) complete moles have no fetal parts; partial moles usually have fetal parts 2) choriocarcinoma is a risk following complete moles only
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