USMLE Step 3 (Fach) / Oncology (Lektion)

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• Hodgkin lymphoma Epidemiology:- Age: bimodal distribution → 1st peak: 25-30 years→ 2nd peak: 50-70 years- Sex: ♂ > ♀ → Male predominance, especially in pediatric cases→ Exception: ♀ = ♂ in nodular sclerosing HL (most common type) Etiology:- Strong association with Epstein-Barr virus (EBV)  - Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infection, chemotherapy- Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis) Clinical features:- Painless lymphadenopathy→ Cervical lymph nodes (in ∼ 60-70% of patients) > axillary lymph nodes (in ∼ 25-35% of patients) > inguinal lymph nodes (in ∼ 8-15% of patients)  → Mediastinal mass → chest pain, dry cough, and shortness of breath→ Splenomegaly or hepatomegaly may occur if the spleen or liver are involved. - B symptoms: Night sweats, weight loss > 10% in the past 6 months, fever > 38°C (100.4°F)→ The presence of only one of the symptoms – in the case of confirmed HL – is considered positive for B symptoms.- Pel-Ebstein fever: Intermittent fever with periods of high temperature for 1-2 weeks, followed by afebrile periods for 1-2 weeks.- Alcohol-induced pain  - Pruritus (focal or generalized) Stages: Cotswolds modified Ann Arbor systemStage I: Involvement of 1 lymph node area (IN), or 1 extranodal (IE) focusStage II: Confined to one side of the diaphragm: Involvement of ≥ 2 (IIN) lymph node areas or extranodal foci (IIE)Stage III: On both sides of the diaphragm: Involvement of ≥ 2 (IIIN) lymph node areas or extranodal foci (IIIE)Stage IV: Disseminated spread into one or more extralymphatic organs independent of lymph node involvement Diagnostics: Diagnosis of HL is primarily based on medical history and clinical features (B symptoms, localization of lymph node involvement) and is confirmed with lymph node biopsy. Treatment:- Early stage (I and II): combination of chemotherapy and radiation therapy  → The most widely used chemotherapy approach is ABVD: adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine- Advanced stage (III and IV and often II with bulky disease): combination chemotherapy with radiation therapy in select cases→ ABVD→ Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone→ BEACOPP: bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (vincristine), procarbazine, prednisone
• Tumor lysis syndrome The rapid destruction of tumor cells leads to a massive release of intracellular components, which subsequently damage the kidneys and may cause potentially life-threatening renal failure. Etiology: mostly occurs after initiating cytotoxic treatment of ALL, AML, or NHL Pathophysiology: tumor cell lysis → release of intracellular components (e.g., K+, PO43-, nucleic acid) into the bloodstream- Hyperkalemia- Hyperphosphatemia: PO43- binds Ca2+ and forms calcium phosphate crystals that obstruct renal tubules → acute kidney injury- ↓ Ca2+ secondary to PO43- binding → hypocalcemia- ↑ Nucleic acid → conversion to uric acid → hyperuricemia → urate nephropathy and risk of acute renal injury Clinical features:- Nausea, vomiting, and diarrhea- Lethargy- Hematuria- Seizures- Cardiac arrhythmias- Tetany, muscle cramps- Paresthesia  Prophylaxis:- Hydration (most effective preventive measure)- Avoid potentially nephrotoxic drugs such as NSAIDs- In patients with a low to intermediate risk of TLS: allopurinol- In patients with a high risk of hyperuricemia due to TLS (e.g., extremely high WBC): rasburicase→ Recombinant uricase: catalyzes the breakdown of uric acid to allantoin  - Consider alkalinization of the urine   Treatment:- Treat electrolyte abnormalities→ Hyperkalemia: Glucose and insulin (rapid action), Sodium polystyrene sulfonate (delayed action), Last resort: hemodialysis or hemofiltration→ Hypocalcemia: calcium administration→ Hyperphosphatemia: hydration and possibly phosphate binding agents- Rasburicase, if not already given as prophylaxis- Fluid administration with or without loop diuretics to aid renal excretion of uric acid crystals- Renal replacement therapy may be necessary
• Multiple myeloma Multiple myeloma: diffuse infiltration of the bone marrowPlasmacytoma: extramedullary solitary mass that may affect bones or soft tissue Epidemiology:- Sex: ♂ > ♀ (3:2)- Peak incidence: 50-70 years   Classification: Based on immunoglobulin type- IgG: 50% of multiple myelomas- IgA: 25% of multiple myelomas- Bence Jones myeloma (free light chains excreted in urine): 20% of multiple myelomas Clinical features:- Often asymptomatic- Bone pain – especially back pain (most common symptom), spontaneous fractures- Symptoms of hypercalcemia- Mild fever, night sweats, weight loss- Weakness and anemia- Increased risk of infection- Increased risk of petechial bleeding- Foamy urine, caused by Bence Jones proteinuria International Staging System (ISS) Stage I: β2 microglobulin < 3.5 mg/L AND albumin ≥ 3.5 g/dLStage II: β2 microglobulin 3.5-5.5 mg/L OR β2 microglobulin < 3.5 mg/L AND albumin < 3.5 g/dLStage III: β2 microglobulin > 5.5 mg/L Diagnostics: The following tests are required for patients with suspected MM- Serum protein electrophoresis (best initial test): monoclonal gammopathy with M protein- Urine protein electrophoresis: Bence Jones proteins- Bone marrow biopsy (confirmatory test)- Laboratory tests (CBC and biochemistry) to assess for hypercalcemia, anemia and renal insufficiency- Imaging to assess for bone lesions: low‑dose whole‑body CT (WBLD-CT) Treatment:- Asymptomatic patients: watch and wait, unless patients have ≥ 60% clonal cells, excessive free light chains or ≥ 1 bone lesion- Symptomatic patients→ Standard and intermediate riska) HSCT eligible: induction therapy followed by autologous HSCTb) HSCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)→ High-risk patients should be enrolled in clinical trials- Osteolysis and bone pain: Bisphosphonates; Radiation therapy of osteolytic regions- Pancytopenia with anemia and increased risk of infection: Blood transfusions; Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (EPO)
• Multiple myeloma – Complications Hypercalcemic crisis   AL amyloidosis: light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes. Myeloma cast nephropathy (myeloma kidney)- Most common cause of renal injury and renal failure in patients with MM- Pathophysiology: Light chains are directly toxic to renal tissue and protein complex (cast) formation in the distal nephron leads to tubular obstruction- Clinical findings: fatigue, peripheral edema and dyspnea, oliguria- Diagnostics: → ↑ BUN, ↑ Creatinine; dipstick negative for protein  → Confirmed by a markedly positive urine sulfosalicylic acid test and/or urine protein electrophoresis- Treatment: → Treatment of multiple myeloma (chemotherapy) and hypercalcemia (fluids and bisphosphonates)→ Forced diuresis and removal of offending agents (e.g., NSAIDs)→ If progression to end-stage renal disease (ESRD) occurs: dialysis, plasmapheresis or transplantation. Secondary plasma cell leukemia- Leukemic course secondary to multiple myeloma- Diffuse spreading of abnormal cells and distribution of large amounts of plasma cells into the circulatory system- Rare; occurs in 2–3% of cases
• Monoclonal gammopathy of undetermined significance (MGUS) Characterized by complete or incomplete monoclonal immunoglobulins detectable in patient serum without accompanying clinical symptoms Epidemiology:- Prevalence: ∼ 3% in individuals 45-75 years of age.- The most common type of plasma cell dyscrasia Diagnostic criteria:- Paraproteins: monoclonal immunoglobulins detectable in serum < 30 g/L- Bone marrow: < 10% of plasma cells in bone marrow- No evidence of organ damage or multiple myeloma-associated disease (see CRAB mnemonic) Evaluation: MGUS usually precedes multiple myeloma.   Treatment: none required (watch and wait)
• Waldenstrom's macroglobulinemia A type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies. It mostly occurs in old age and has a good prognosis, as it is a type of indolent lymphoma. Clinical presentation:- Impaired platelet function → hemorrhagic diathesis with petechial bleeding- Normochromic anemia- Raynaud's phenomenon- Formation of cold agglutinins (IgM) with hyperviscosity syndrome  - Impaired acral blood flow- Impaired vision, hearing, and renal function- Lymph node enlargement possible- Constitutional symptoms (e.g., fatigue, headache) Diagnosis:- ↑ ESR, ↑ uric acid, ↑ LDH, and ↑ alkaline phosphatase- Bone marrow biopsy and aspirate: abnormal plasma cells with Dutcher bodies (periodic acid-Schiff positive, intranuclear inclusions of IgM deposits) Treatment:- Only indicated in symptomatic patients- Causative: CD20 antibodies (e.g., rituximab)- Hyperviscosity syndrome: plasmapheresis
• Bone lesions and associated malignancy Osteolytic: Myeloma, kidney, lung, breast, GI Osteoblastic: Prostate, breast (may be mixed), germ cell, ovary, uterus
• Light-chain amyloidosis (AL-amyloidosis) Most common form of amyloidosis in developed nations Etiology: associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenstrom macroglobulinemia) Pathophysiology: increased production of the light chains of immunoglobulins → deposition of AL (amyloid light chain) protein in various organs Clinical presentation: rapidly progressive clinical course  - Heart: restrictive cardiomyopathy, atrioventricular block- Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus- Tongue: macroglossia → obstructive sleep apnea- Autonomic nervous system: autonomic neuropathy- Gastrointestinal tract: malabsorption- Bleeding disorders
• Reactive amyloidosis (AA-amyloidosis) Etiology: secondary disease- Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)- Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)- Certain tumors (e.g., renal cell carcinoma, lymphomas) Pathophysiology: chronic inflammatory process → increased production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs Clinical features:- Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus- Adrenal glands: primary adrenal insufficiency- Liver and spleen: hepatomegaly, splenomegaly- Gastrointestinal tract: malabsorption
• Hemodialysis-associated amyloidosis Amyloid protein: β2-microglobulin→ Aβ2M amyloid protein Etiology: Long-term hemodialysis  Organ most commonly affected: Joints and tendons
• Breast cancer Predisposing factors:- Breast cancer in the contralateral breast; history of ovarian, endometrial, or colorectal cancer- Increased estrogen exposure: Early menarche, late menopause, Nulliparity, First full-term pregnancy after age 35 years, Exogenous estrogen intake: hormone replacement therapy after menopause  - BRCA1 or BRCA2 gene mutations  - Positive family history (e.g. affected first-degree relatives)- Positive history of breast conditions (e.g., fibrocystic change, fibroadenoma) with cellular atypia- Previous radiation treatment in childhood - Lifestyle factors: low-fiber and high-fat diet, smoking, alcohol consumption, obesity in postmenopausal women   Associated genetic diseases:- Li-Fraumeni syndrome (Sarcoma, Breast, Leukemia and Adrenal Gland cancer syndrome (SBLA))→ Autosomal dominant inherited mutation of the p53 tumor suppressor gene (TP53)→ Multiple malignancies at an early age: breast cancer, osteosarcoma, leukemia, lymphoma, brain tumor, adrenocortical carcinoma- Peutz-Jeghers syndrome Diagnostics:- < 30 years and low probability: Reassess 3-10 days after menstruation- < 30 years and high probability: Ultrasound- > 30 years: Mammography→ Fine-needle aspiration Treatment:- Early stage disease→ Breast-conserving therapy (BCT): lumpectomy followed by radiation therapy→ Intraoperative lymph node evaluation  → Adjuvant systemic therapy- Gestational breast cancer→ Surgery is the treatment of choice (radiation therapy is contraindicated during pregnancy)→ Adjuvant chemotherapy only in the second and third trimester.- DCIS: breast-conserving therapy or mastectomy- LCIS: life-long surveillance and chemoprevention with hormone therapy (e.g., tamoxifen)
• Breast cancer screening Mammography: every 2 years in average-risk women aged 50-74 years  - Two views of the breast are obtained: mediolateral oblique and craniocaudal High-risk women:- BRCA1/BRCA2 mutation-positive women  - Women with a first-degree relative with a BRCA1/BRCA2 gene mutation- Women who have a family history of breast cancer  - Women with a history of chest radiation therapy (between age 10-30 years)- Women with personal or family history of familial cancer syndromes (e.g., Li-Fraumeni syndrome, Cowden syndrome)- Women ≥ 35 years of age with previous invasive breast cancer or carcinoma in situ→ Genetic counseling→ Annual mammography and MRI  → Prophylactic surgery
• Lung cancer – Paraneoplastic syndromes NSCLC + SCLC:- General paraneoplastic manifestations: cachexia, increased risk of thrombosis (and lung embolism!)- Dermatomyositis- Acanthosis nigricans NSCLC:- Hypercalcemia of malignancy (squamous cell carcinoma)- Gynecomastia (large cell carcinoma)- Hypertrophic osteoarthropathy (also known as Pierre-Marie-Bamberger disease)  - Clubbing of the fingers and toes- Swelling and pain in joints and long bones  - Hypercoagulability and thrombophlebitis migrans (adenocarcinoma)- Nonbacterial verrucous endocarditis (adenocarcinoma) SCLC:- Cushing syndrome- Syndrome of inappropriate antidiuretic hormone secretion(SIADH)- Lambert-Eaton syndrome (similar clinical features as myasthenia gravis)- Paraneoplastic cerebellar degeneration- Peripheral neuropathy
• Pancreatic cancer Epidemiology:- Sex: ♂ > ♀ - More common in African Americans Risk factors:- Smoking  - Chronic pancreatitis- High alcohol consumption  - Type 2 diabetes- Obesity- Occupational exposure to chemicals used in the dry cleaning and metal working industries- Cirrhosis of the liver- H. pylori infection; excess stomach acid Clinical features:- Belt-shaped epigastric pain which may radiate to the back- Jaundice→ Courvoisier sign: enlarged gallbladder and painless jaundice  → Pale stools, dark urine, and pruritus- Weight loss, nausea, weakness, poor appetite- Diarrhea (possibly steatorrhea secondary to exocrine pancreatic insufficiency)- Superficial thrombophlebitis (in 10% of cases, also called Trousseau syndrome or thrombophlebitis migrans)- Thrombosis (e.g., phlebothrombosis, splenic vein thrombosis)  - Impaired glucose tolerance (rarely)   Diagnostics:- Tumor markers: CA 19-9 and CEA- First test: usually either contrast-enhanced abdominal CT or ultrasound → if ultrasound reveals a pancreatic mass → subsequent CT   Treatment:- Pancreatic head carcinoma: pancreaticoduodenectomy ("Whipple procedure")- Pancreatic body and tail carcinoma: Resection of the left side of the pancreas with splenectomy- Neoadjuvant or adjuvant chemoradiotherapy- Cholestasis: ERCP with stent implantation  
• Hepatocellular carcinoma (HCC) Epidemiology:- Fifth most common malignancy worldwide- Highest incidence in Southeast Asia and Africa   Etiology:- Liver cirrhosis (80% of cases)- Chronic hepatitis B or C virus infection  - Nonalcoholic steatohepatitis (NASH)  - Hemochromatosis- Wilson's disease- Alpha-1 antitrypsin deficiency- Schistosomiasis- Glycogen storage disease- Chronic ingestion of food contaminated with aflatoxin   Clinical features:- Weight loss, cachexia- Hepatomegaly and right upper quadrant tenderness  - Ascites and jaundice Diagnostics:- ↑ Serum alpha-fetoprotein (AFP)- Laboratory studies consistent with hepatitis and cirrhosis (e.g., ↑ LFTs, positive hepatitis serologies, ↓ coagulation factors)- Paraneoplastic syndromes: erythrocytosis, hypoglycemia, hypercalcemia - Ultrasound: first test  - Abdominal CT (confirmatory test) Treatment:- Surgical resection  - Liver transplantation  - Ablative therapies (mostly palliative, but can also be curative) result in shrinking and scarring of the tumor Follow-up:- Vaccination against HBV in high-risk individuals- Surveillance with ultrasound in patients with cirrhosis or chronic hepatitis B
• Renal cell carcinoma Risk factors:- Smoking  - Acquired cystic kidney disease as a result of ESRD  - Renal pelvic stones- Obesity- Hypertension- Immunodeficiency- Chronic hepatitis C infection- Sickle cell disease  - Exposure to cadmium, asbestos, petroleum by-products, Chemotherapeutic agents (e.g., cisplatin) during childhood  - Chronic analgesic use (especially acetaminophen, and aspirin) Hereditary renal cell carcinomas - Von Hippel-Lindau syndrome  - Hereditary papillary renal cell carcinoma (HPRCC)  - Tuberous sclerosis   Types:- Clear cell carcinoma (most common)- Papillary- Chromophobic- Oncocytic- Collecting duct carcinoma (Bellini duct carcinoma) Clinical features: Patients become symptomatic when the tumor has reached a large size (usually > 10 cm) and/or if metastases are present.  - Hematuria is the most common presenting symptom.  - Anemia (common): pallor, lethargy- Dragging/colicky flank pain  - Potentially palpable renal mass  - Constitutional symptoms: weight loss, fatigue, night sweats, fever  - Paraneoplastic syndromes: Hypertension, Hypercalcemia, Polycythemia, Secondary hypercortisolism, Limbic encephalitis- Reactive amyloidosis- Symptoms of local spread: Varicocele, Budd-Chiari syndrome Diagnostics:- Best initial test: abdominal CT scan with contrast   Treatment:- Treatment of choice: Surgical resection of the tumor via open, robotic, or laparoscopic surgery.Stage I: cryoablation, thermal ablation, partial nephrectomy, or simple nephrectomy  Stage II-IV: radical nephrectomy  - Palliative treatment: Arterial embolization, External beam radiotherapy- Immunomodulatory and/or targeted therapy:→ Interferon-α (immunotherapy)→ Recombinant cytokines (e.g., interleukin-2)→ Tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, pazopanib)Chemotherapy is not used to treat RCC because RCC is highly resistant to chemotherapeutic agents! This occurs because tumor cells express MDR-1 (multidrug resistance protein-1).
• Ovarian cancer Genetic predisposition:- BRCA1/BRCA2 mutation  - HNPCC syndrome  - Peutz-Jeghers syndrome Risk factors:- Elevated number of lifetime ovulations (the contraceptive pill appears to have a protective effect)- Infertility/low number of pregnancies- Early menarche and late menopause- PCOS Epithelial tumors:- Cystadenoma/cystadenocarcinoma- Mucinous- Endometrioid carcinoma Germ cell tumors:- Teratoma- Yolk sac tumor: often malignant; occurs mainly in childhood and adolescence- Dysgerminoma: most common malignant ovarian tumor in young women (20-30 years)- Non-gestational choriocarcinoma: rare and extremely malignant Sex cord-stromal tumors of the ovary:- Estrogen producing: granulosa cell tumor and theca cell tumor   - Androgen producing: Sertoli-Leydig cell tumor: Primarily affects women aged 30-40 years- Ovarian fibroma: Benign, although may cause Meigs' syndrome Clinical features:- Abdominal pain and ascites- Cancer cachexia- Possible disruption of menstrual cycle- Dyspnea due to malignant pleural effusion- Abdominal or pelvic mass- Complication: tumor can cause ovarian torsion → tissue infarction → surgical emergency Diagnostics:- Hypercalcemia due to paraneoplastic synthesis of PTHrP- Epithelial ovarian tumor: CA-125- Yolk sack tumor: alpha-fetoprotein- Non-gestational choriocarcinoma: beta hCG- Granulosa cell tumor: inhibin B- Imaging: Transvaginal ultrasound is the gold standard, but abdominal or rectal ultrasound may also be conducted.Fine needle aspiration cytology is absolutely contraindicated in ovarian tumors because it increases the risk of spreading tumor cells to the peritoneum!
• Pancoast tumor A peripheral lung carcinoma (predominantly NSCLC) that is located in the superior sulcus of the lung; often involves the cervical sympathetic nerves and brachial plexus. Clinical features:- Severe, localized pain in the axilla and shoulder  - Horner syndrome- Atrophy of arm and hand muscles  - Edema of the arm, facial swelling, morning headaches  
• Uveal melanoma Risk factors:- Congenital ocular/oculodermal melanocytosis and uveal nevus  - Light skin color- Light color of the iris- Choroidal nevus  - Iris nevus- Cutaneous nevus Choroid or ciliary body melanomaInitially asymptomatic  Late symptomsVision loss due to tumor growth into the optical axisVisual field defects, floaters, and/or photopsia due to tumor-related retinal detachmentBlurred vision due to tumor growth in the ciliary bodyIris melanomaTypically discovered earlier than choroidal or ciliary body melanoma because of visible signsDistortion of pupil shapeA new brown nodule on the iris that becomes visible, or growth of a previous noduleBlurred visionTransscleral melanoma with extension into the orbitPainVision lossCataractProptosis Diagnostics:- Fundoscopy- Ultrasonography  - Fluorescein angiography  - Staging: Liver function tests, CT/MRI, Chest x-ray Treatment:- Observation: for small, asymptomatic tumors  - Radiation therapy: Brachytherapy; Iodine-125 (gamma rays); Ruthenium-106 (beta rays); Charged-particle radiation therapy  → Indicated in circumpapillary lesions (i.e., lesions encircling the optic nerve)- Enucleation: in advanced findings  

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