USMLE Step 1: Integrated Vignettes: Must-know, high-yield review

CHAPTER 1

Hematopoietic and Lymphoreticular System

Checklist of Processes Within This System

Developmental Disorders

Congenital thymic cyst

Thymic hypoplasia

Accessory spleen

Fanconi anemia

Diamond-Blackfan anemia

Infectious Diseases

Splenic hydatidosis

Infectious mononucleosis

Cat-scratch disease

Malaria

CMV

Inflammatory Diseases

Acquired multilocular thymic cyst

Graft-versus-host disease

Autoimmune Diseases

Autoimmune hemolytic anemia

Immune thrombocytopenic purpura

Trauma

Penetrating splenic injury

Blunt splenic trauma

System-Specific Diseases

Reactive changes in WBCs: leukocytosis and leukopenia

Morphologic changes in RBCs

Shape changes: elliptocytes, spherocytes, target cells, acanthocytes, echinocytes, schistocytes, bite cells, teardrop cells, sickle cells

Red cell inclusions on microscopy: basophilic stipples, Howell-Jolly bodies, Pappenheimer bodies, ring sideroblasts, Heinz bodies

Platelet disorders: thrombocytopenia

Anemias: micro-, macro-, normocytic

Extramedullary hematopoiesis

Lymphadenopathy

Splenomegaly

Neoplasia

Lymphoid neoplasms: mature B cell neoplasms, peripheral T-cell and natural killer neoplasms, Hodgkin lymphoma, B and T lymphoblastic lymphoma/leukemia

Myeloid neoplasms: acute myelogenous leukemia, myelodysplastic syndromes

Myeloproliferative neoplasms: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia

Multiple myeloma

Localized extracutaneous mast cell neoplasms

Splenic lymphangiomas and hemangiomas

Thymomas

Posttransplant lymphoproliferative disorder

Representative Diseases

What follows are clinical vignettes for 10 select diseases within this organ system. First, read the vignette and try to identify the condition. Then, move on to read integrated information on each disease.

Vignette 1

A full-term baby girl is born to a 23-year-old G1P0 mother who did not seek prenatal care. The newborn turns blue shortly after birth; she also has a cleft palate. Within a few hours of birth, she develops muscle spasms. Lab evaluation reveals a low CD3 count and low ionized calcium.

Diagnosis? __________________

Vignette 2

A 54-year-old college professor notices that his face appears red and swollen. Physical examination is also notable for distended veins in his neck. Chest x-ray shows a well-circumscribed anterior mediastinal mass with no evidence of local invasion, lung mass, or lymphadenopathy.

Diagnosis? __________________

Vignette 3

An 8-year-old boy presents to the pediatrician with yellow eyes, pale skin, and dark urine. His mother states that he began having upper respiratory symptoms 2 days ago. She also states that her brother has similar episodes when he gets a cold. CBC is notable for normocytic anemia, elevated bilirubin, and negative fluorescent spot test. Peripheral blood smear reveals Heinz bodies and bite cells.

Diagnosis? __________________

Vignette 4

A father takes his 6-year-old son to the pediatrician because of several dark itchy lesions below the waistband of his shorts and under his socks. He is otherwise healthy. The father states the boy appears to scratch his legs more on hot days. Physical examination reveals many hyperpigmented patches that are most prominent around the waist and ankles.

Diagnosis? __________________

Vignette 5

A 16-year-old boy presents with a high fever for several days. He also reveals that he has lost 10 pounds in the last 2 weeks. Physical examination reveals bilateral nontender lymphadenopathy. Imaging of the chest demonstrates a bulky anterior mediastinal mass.

Diagnosis? __________________

Vignette 6

A 45-year-old woman presents to the ED with a spontaneous nosebleed. She reports 1 week of a fever that has not responded to acetaminophen. She denies cough, shortness of breath, abdominal pain, dysuria, and rash. Physical examination is notable for active bleeding from the nares bilaterally and numerous pinpoint red papules on her lower extremities. Lab evaluation reveals elevated white blood cell count, low hemoglobin/hematocrit, and low platelets.

Diagnosis? __________________

Vignette 7

A 68-year-old man presents for an annual physical examination. He reports mild fatigue for several months but attributes this to just getting older. Lab evaluation reveals microcytic anemia, undetectable ferritin, and thrombocytopenia.

Diagnosis? __________________

Vignette 8

A 26-year-old woman presents to her primary care physician complaining of 1 year of heavy menses. On physical examination there are several red pinpoint macules on the buccal mucosa and there are ecchymoses on the extremities. Platelet count is 18,000/μL.

Diagnosis? __________________

Vignette 9

A 50-year-old male smoker presents to the ED with a severe headache and dizziness. CBC is significant for hemoglobin 18.5 g/dL and urinalysis is positive for blood. Abdominal imaging reveals a renal mass.

Diagnosis? __________________

Vignette 10

A 25-year-old man is playing with a new rescue cat he recently brought home. A few days later he develops a swollen red lesion on his left hand. Two weeks later he develops painful swelling in his left axilla and a fever.

Diagnosis? __________________

Vignette 1

A full-term baby girl is born to a 23-year-old G1P0 mother who did not seek prenatal care. The newborn turns blue shortly after birth; she also has a cleft palate. Within a few hours of birth, she develops muscle spasms. Lab evaluation reveals a low CD3 count and low ionized calcium.

Pathogenesis. 22q11.2 deletion syndrome is also known as DiGeorge syndrome and velocardiofacial syndrome. It is caused by a microdeletion on chromosome 22 on the long (‘q’) arm at the 11.2 locus. This deletion leads to abnormal fetal development of 3rd and 4th pharyngeal pouches, which are involved with the development of the thymus and parathyroid glands. Most patients are heterozygotes; the disorder is usually sporadic but can be familial with autosomal dominant inheritance. It is one of the most common syndromes with multiple anomalies.

Clinical Presentation. The syndrome phenotype is highly variable. Children with the syndrome typically present with some combination of cardiac malformation, thymic hypoplasia with immunodeficiency, and hypocalcemia due to hypoparathyroidism. It is the most common syndrome associated with cleft palate. Cardiac malformations include tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch, all of which cause cyanosis in the newborn period; ventricular septal defect (VSD) is the most common heart anomaly. Immunodeficiency can be mild or severe. Cognitive deficits are common, and there is an increased rate of psychiatric disorders including schizophrenia. Children with milder manifestations of DiGeorge may not be identified until later in childhood when they experience recurrent infections. Some cases may go undetected.

Diagnostic Studies.

•Molecular testing of amniotic fluid (prenatal) or blood (postnatal) for 22q11.2 deletion via FISH (fluorescence in situ hybridization) analysis

•Echocardiogram identifies specific cardiac anomalies

•Chest x-ray can identify absence of thymic shadow

•Low CD3(+) T-cell count confirms immunodeficiency

•Low ionized/free calcium with inappropriately low parathyroid hormone

•Pulse oximetry identifies hypoxemia even in the absence of frank cyanosis

Morphologic Features.

•Gross examination: heart malformations (tetralogy of Fallot, truncus arteriosus, or interrupted aortic arch), cleft palate

•Microscopic: depletion of T-cell zones of lymphoid organs

Differential Diagnosis. Any of the syndromic features can be present in isolation. Patients with prenatal exposure to ethanol or retinoids can have a DiGeorge-like phenotype, but will lack the 22q11.2 deletion. HIV can also cause isolated T-cell deficiency, but congenital HIV would not be associated with heart malformations or hypocalcemia.

Treatment and Outcomes.

•Stem cell or thymic transplant for severely immunosuppressed children

•Surgical repair of cleft palate and cyanotic heart malformations; facial reconstructive surgery

•Calcium replacement therapy administered with activated vitamin D

•Prognosis and life expectancy depend on severity of cardiac malformation and immunosuppression

Physiology Correlation. In response to low ionized calcium in the blood, the parathyroid glands secrete parathyroid hormone (PTH). PTH increases serum calcium by acting in the kidneys and the bones. In the kidneys, PTH binds to calcium channels in the distal tubule, causing them to open and allow more calcium reabsorption. In the bone, PTH binds to osteoblasts, causing them to activate osteoclasts. Increased osteoclastic activity releases calcium and phosphate from the bone, termed resorption.

Pharmacology Correlation. Vitamin D is ingested in one of 2 inactive forms: D2 (ergocalciferol) or D3 (cholecalciferol). Both forms are converted in the liver to 25-OH vitamin D, which is subsequently converted to the final active form 1, 25-dihydroxyvitamin D (calcitriol) in the kidneys by α1-hydroxylase. Calcitriol increases blood calcium levels by increasing calcium absorption from the GI tract and the distal tubules of the kidney. Calcitriol works in conjunction with PTH by increasing production of calbindin, a calcium binding protein, within the tubular epithelial cells to facilitate reabsorption.

Vignette 2

A 54-year-old college professor notices that his face appears red and swollen. Physical examination is also notable for distended veins in his neck. Chest x-ray shows a well-circumscribed anterior mediastinal mass with no evidence of local invasion, lung mass, or lymphadenopathy.

Pathogenesis. A thymoma is a benign epithelial neoplasm arising in the thymus. It represents about half of all tumors arising in the anterior mediastinum. Because thymomas release immature T-cells into the circulation, this neoplasm is associated with autoimmune disorders. About a third of patients with thymoma also have myasthenia gravis (MG).

Clinical Presentation. Thymoma typically presents in decades 4 or 5 of life. Patients may experience signs and symptoms of superior vena cava syndrome, including facial plethora and swelling, distension of neck veins, and upper extremity swelling. Other symptoms of a mediastinal mass may include chest pain or dyspnea. Patients may also present with symptoms of MG, including facial or limb weakness; thymic abnormalities are present in 75% of all AChR antibody–positive MG patients. A minority of patients with thymoma are asymptomatic and the tumor is an incidental finding during imaging studies.

Diagnostic Studies.

•Chest CT or MRI can confirm the presence of a mediastinal mass and determine whether resection is possible.

•If MG is suspected, the edrophonium test is only administered if antibody and electrodiagnostic test results are negative.

•AchR antibodies are positive in most patients with a thymoma and MG.

Morphologic Features.

•Gross examination: firm gray-white mass ranging in size up to 20 cm. Cytologically benign thymomas may be noninvasive or invasive.

•Microscopic: The tumors are morphologically heterogeneous and consist of a mixture of thymic epithelial cells without atypia and lymphocytes. Perivascular clearing (a hypocellular area around venules) is a predominant feature of one of the subtypes. Thymic carcinomas (5% of thymomas) are usually squamous cell carcinomas.

Differential Diagnosis. In adults, most mediastinal tumors are anterior and malignant. Thymic carcinoma will show signs of invasion on chest imaging. If resected, it will be infiltrative rather than circumscribed. Lymphomas can involve the mediastinum but usually demonstrate extramediastinal involvement. Germ cell tumors of the mediastinum can be associated with elevated hCG and/or AFP.

Treatment and Outcomes.

•Thymectomy if possible

•Chemotherapy and/or radiation if mass is unresectable

•Most patients with a resectable mass have an excellent prognosis and rarely have recurrences

Physiology Correlation. Superior vena cava (SVC) syndrome develops when the SVC is compressed by a mediastinal or lung mass. When the SVC is compressed, blood flow from all veins that empty into the SVC (including brachiocephalic, jugular, and subclavian veins) is obstructed. Thus the anatomical sites drained by these veins become congested with blood, leading to swelling, redness, and prominent veins in the head, upper extremity, and upper chest.

Pharmacology Correlation. Acetylcholinesterase (AChE) inhibitors such as pyridostigmine or neostigmine are cholinergic agonists commonly used to treat MG. AChE normally breaks down acetylcholine at the neuromuscular junction. When AChE is blocked, the concentration of acetylcholine increases in the neuromuscular junction, temporarily overcoming the inhibitory action of the anti-AChR antibodies.

Vignette 3

An 8-year-old boy presents to the pediatrician with yellow eyes, pale skin, and dark urine. His mother states that he began having upper respiratory symptoms 2 days ago. She also states that her brother has similar episodes when he gets a cold. CBC is notable for normocytic anemia, elevated bilirubin, and negative fluorescent spot test. Peripheral blood smear reveals Heinz bodies and bite cells.

Pathogenesis. Glucose-6 phosphate dehydrogenase deficiency (or G6PD deficiency) is an X-linked recessive disorder of RBC metabolism. There are hundreds of variants. At the subcellular level there is an inability to produce enough NADPH to reduce glutathione. RBCs which lack G6PD are sensitive to oxidative stress, resulting in periodic hemolysis. The disease is common in males of African and Mediterranean origin.

Clinical Presentation. Patients present with anemia, hyperbilirubinemia, methemoglobinemia, and hemoglobinuria. Triggers for hemolysis include infection, ingestion of fava beans, and exposure to oxidizing medications. Patients usually do not have chronic, baseline hemolysis.

Diagnostic Studies.

•CBC shows normocytic anemia (MCV 80–100)

•Elevated total and direct bilirubin (extravascular hemolysis)

•Fluorescent spot test: negative due to NADPH deficiency

•Quantitative biochemical G6PD assay. Measurement during acute hemolysis may cause false negative results.

Morphologic Features.

•Peripheral blood smear: Heinz bodies (oxidized hemoglobin), bite cells

Differential Diagnosis. Sickle cell disease (SCD) also causes hemolysis in individuals of African and Mediterranean origin. Patients with SCD usually have chronic baseline hemolysis, unlike G6PD-deficient patients. Their peripheral blood smear shows sickled cells, not bite cells. Hemoglobin electrophoresis reveals abnormal hemoglobin S.

Treatment and Outcomes.

•Treatment of underlying infection if applicable

•Avoidance of medications that trigger hemolysis

•Discontinuation of inciting medications

•Hydration of patient during hemolytic episode

•Normal life expectancy

Physiology Correlation. G6PD synthesizes NADPH and reduced glutathione (GSH) in the hexose monophosphate shunt; they provide protection against antioxidants. In the absence of G6PD, RBCs are sensitive to oxidative stress. As hemoglobin oxidizes, it precipitates into Heinz bodies that are cleared by the spleen, leaving ‘bite’ cells.

Pharmacology Correlation. Primaquine, a quinoline derivative, is an antimalarial drug that can be used for primary prophylaxis or treatment. It attacks not only the intraerythrocytic form of the parasite but also intrahepatic parasites (hypnozoites) and gametocytes. Primaquine, along with other oxidizing medications such as methylene blue, sulfa drugs, and nitrofurantoin, should be avoided in patients with G6PD deficiency.

Vignette 4

A father takes his 6-year-old son to the pediatrician because of several dark itchy lesions below the waistband of his shorts and under his socks. He is otherwise healthy. The father states the boy appears to scratch his legs more on hot days. Physical examination reveals many hyperpigmented patches that are most prominent around the waist and ankles.

Pathogenesis. Cutaneous mastocytosis is a condition characterized by increased numbers of mast cells in the skin due to a mutation in the KIT gene. The excess mast cells degranulate, releasing histamine, which causes intense pruritus. The most common form of the condition is urticaria pigmentosa.

Clinical Presentation. Cutaneous mastocytosis is usually seen in children who present with severe pruritus after exposure to triggers such as local irritation or heat, like the child in vignette 4 who is most affected at the site of tight-fitting clothing. Bullae or pigmented macules/patches may develop. Darier’s sign is typically positive; upon stroking an area of the skin, erythema, urticaria, and pruritus develop at the site within minutes.

Diagnostic Studies.

•Elevated serum tryptase

•CBC is normal

•Molecular testing reveals mutation of the KIT gene

Morphologic Features.

•Microscopic: numerous mast cells (mononuclear cells with heavy basophilic granulation) in the epidermis which stain positive for tryptase

Differential Diagnosis. Children with localized pruritus are much more likely to have atopic dermatitis or irritant dermatitis than cutaneous mastocytosis. These disorders are more likely to cause an eczematous-type rash with thick, scaling skin rather than discrete lesions. Diffuse urticaria or pruritus are more likely to reflect an allergic condition than mastocytosis. Systemic mastocytosis can also involve the skin, but is defined by involvement of several organ systems; laboratory abnormalities often include anemia and thrombocytopenia.

Treatment and Outcomes.

•Anaphylaxis is a rare occurrence (treatment with epinephrine injection).

•Antihistamines, specifically H1 blockers (diphenhydramine, cetirizine, loratadine), can be useful for treating pruritus.

•Avoidance of triggers is an important part of recovery.

•Resolution over time is expected with few to no long-term sequelae.

Physiology Correlation. Type I, or immediate type, hypersensitivity reactions require at least 2 exposures to the allergic trigger: initial exposure that sensitizes the individual, and subsequent exposure that triggers the hypersensitivity reaction. After the initial exposure, type 2 helper T cells (Th2 cells) stimulate B cells to synthesize IgE that binds to mast cell Fc receptors. Upon re-exposure, the allergic trigger causes the IgE chains to crosslink, which stimulates the bound mast cells to degranulate. The release of histamine, heparin, and other mast cell granule contents results in local allergic-type symptoms including urticaria, rhinitis, and bronchoconstriction within a few hours of the exposure.

Pharmacology Correlation. Antihistamines, specifically H1 antagonists, block the action of histamine that is released from mast cells by competitively inhibiting at the histamine receptor sites. They can be useful in treating urticaria and pruritus associated with cutaneous mastocytosis. H1 antagonists for urticaria include diphenhydramine, cetirizine, loratadine, and fexofenadine. The most common side effect is sedation, particularly with diphenhydramine.

Vignette 5

A 16-year-old boy presents with a high fever for several days. He also reveals that he has lost 10 pounds in the last 2 weeks. Physical examination reveals bilateral nontender lymphadenopathy. Imaging of the chest demonstrates a bulky anterior mediastinal mass.

Pathogenesis. T-cell lymphoblastic lymphoma is a clonal neoplasm arising from T-lymphoid precursor cells. Many cases are associated with gain-of-function mutations in the NOTCH1 gene. The NOTCH1 protein is normally a receptor involved with proliferation and maturation of T-lymphocytes in the thymus. Mutant NOTCH1 promotes overgrowth of T-cells by upregulating transcription factors such as c-myc, which increases the risk of development of a malignant clone.

Clinical Presentation. T-cell lymphoblastic lymphoma most often affects adolescents or young adults; it is slightly more common in males. Patients often present with typical B symptoms including fever, night sweats, and weight loss. Approximately 50% present with a mediastinal mass.

Diagnostic Studies.

•Chest CT or MRI demonstrates mediastinal mass and extensive lymphadenopathy

•Biopsy of lymph node or mediastinal mass

•Lumbar puncture is performed to rule out CNS involvement

Morphologic Features.

•Microscopy, lymph node/mediastinal mass: sheets of mitotically-active blasts with high nuclear-to-cytoplasmic ratio that obliterate normal lymphoid architecture

•Microscopy, bone marrow: < 25% blasts that are positive for TdT, CD7 , CD2, and CD3, and negative for MPO (by immunohistochemical stain or flow cytometry)

Differential Diagnosis. If a patient’s bone marrow demonstrates >25% blasts, lymphoblastic leukemia rather than lymphoma is diagnosed. Many mediastinal masses start with a t:

•Terrible lymphoma (i.e., lymphoblastic lymphoma)

•Thymoma

•Teratoma

•Thyromegaly (goiter)

Thymomas are usually well-circumscribed and not associated with widespread lymphadenopathy. Teratomas may be heterogeneous on imaging with bony and fatty components. Thyroid enlargement is usually evident on physical examination