Leukemia & Lymphoma v.2015

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Kaplan USMLE® Guided Study Session Leukemia & Lymphoma Facilitator Edition

USMLE® Guided Study Session Topic: Leukemia & Lymphoma

Facilitator Edition

Case 1

A 43-year old woman comes to the office because of progressive fatigue over the last 3 months.

In addition, the patient complains of night sweats, abdominal pain, and low-grade fever. A

complete blood count (CBC) and a blood smear were taken from the patient, which showed a

white count of 200,000/mm3, with differential count including 70% segmented neutrophils and

15% band forms. The absolute numbers of basophils and eosinophils are increased somewhat.

Review of the peripheral smear does not show any blast forms.

Notes:

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Case 1 Discussion Points for Facilitator

Diagnosis

This patient most likely has chronic myelogenous leukemia (CML). Chronic myelogenous

leukemia is primarily a disease of middle age, with a median age of 45 years. The comparatively

few cases occurring in the elderly are more likely to be aggressive than those occurring in

middle-aged adults.

Incorrect Diagnosis

Acute Myelogenous Leukemia (AML): Blast cells would be seen in the peripheral smear in

acute myelogenous leukemia.

Chronic Lymphocytic Leukemia (CLL): The numbers of lymphocytes are increased and the

numbers of other blood cells may be decreased.

Hodgkin disease: May show a modest increase in neutrophils and eosinophils in the blood, but

would not have the dramatic increase seen in this patient.

Polycythemia vera: While to the novice, polycythemia vera and chronic myelogenous leukemia

appear to be obviously different diseases, both cause an increase in many marrow cell lines,

and ambiguous cases do exist. Leukocyte alkaline phosphatase is a helpful test to perform in

these settings, because it is characteristically low in chronic myelogenous leukemia, but high in

polycythemia vera. Also, polycythemia vera does not usually have the Philadelphia

chromosome.

Clinical Presentation

CML has an insidious onset. Clinical presentations are fatigue, fever, night sweats, and weight

loss. Splenomegaly (up to 5 kg) is common in patients with chronic myelogenous leukemia, and

in more than half of the patients, is palpable more than 5 cm below the costal margin at the

time of diagnosis. Splenomegaly may be a very helpful sign on physical examination, since it is

uncommon in reactive leukocytosis. Hepatomegaly can also occur, but is less common.

Pruritus is also common after hot baths/showers from histamine release from basophils

Pathogenesis

This is a cancer of pluripotent marrow stem cells characterized by a proliferation, predominantly

of granulocytes, although other cell lines (megakaryocytes, monocytes, erythrocytes, and even

some T and B cell lines) may also be increased.

The characteristic chromosomal translocation of chronic myelogenous leukemia is t(9;22). This

translocation results in a distinctive abnormal chromosome sometimes called the Philadelphia

chromosome, and is seen in 90-95% of CML cases. The Philadelphia translocation is also seen

in 20-25% of adults with acute lymphoblastic leukemia, 2% of adults with acute myeloid

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leukemia, and 2-10% of childhood acute lymphoblastic leukemia. Some authors think that these

cases may represent variants of chronic myelogenous leukemia in which the "blast

transformation" (which commonly occurs 3-5 years after diagnosis in untreated patients with

chronic myelogenous leukemia) either develops very early in the disease, or later, but in a

patient in whom the chronic phase had been missed clinically.

The t(9;22) Philadelphia translocation links the Abelson oncogene (c-ABL) (normally on

chromosome 9) to the BCR region of chromosome 22. The resulting gene product is a new,

chimeric, protein called protein 219 or BCR-ABL, which has tyrosine kinase activity. In some

manner still not well understood, this gene product then produces the clinical problems we

diagnose as CML.

Diagnostic testing

● initial test : CBC and peripheral smear

● Bone marrow examination

● most accurate test: Cytogenetic studies (Ph chromosome)

Microscopically the bone marrow is hypercellular, with all cell lines increased in number.

Peripheral leukocytosis present, including markedly increased numbers of neutrophils) and

bands and metamyelocytes), and also increased eosinophils and basophils (like the other MPS

The most accurate test us BCR-ABL which can be done by PCR or FISH (fluorescent in-situ

hybridization) on peripheral blood.

CML vs leukemoid reaction: low LAP leukocyte alkaline phosphatase , increase basophils in

CML, splenomegaly and presence of Ph chromosome .

Treatment

● A tyrosine kinase inhibitor, sometimes with chemotherapy

● Sometimes stem cell transplantation

Tyrosine kinase inhibitors such as imatinib mesylate (Gleevec), dasatinib, or nilotinib are

important new drugs that specifically target the abnormal gene product (a tyrosine kinase) of

the BCR-ABL translocation. These drugs are well absorbed after oral administration and can be

used to treat both the chronic phase and blast crisis of CML. It also shows promise in

potentially being used in autologous (self-to-self) bone marrow transplant, where it may be

possible to clear the transplant of leukemic cells in vitro with chemotherapy before reinjecting

the transplant.

Prognosis: In the past, the average life expectancy of CML patients has been 3-5 years, with

most patients dying after a blast crisis develops. The blast crisis may produce either clinical

acute lymphoblastic leukemia or acute myeloid leukemia. This was historically true despite

chemotherapy and any apparent improvements in blood counts with chemotherapy. Bone

marrow transplant is becoming an increasingly preferred treatment modality in those cases in

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which a suitable donor can be found, because it now has a cure rate of approximately 50%.

The mortality rate of t his procedure is 10-20% or less if a matched sibling donor is used and

increases to 30-40% if an unrelated donor is used.

Ph chromosome–negative CML and chronic myelomonocytic leukemia have a worse prognosis

than Ph chromosome–positive CML. Their clinical behaviors resemble a myelodysplastic

syndrome

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Case 2

A 55-year-old man consults a physician because he has been experiencing chronic weakness

and fatigue. Physical examination is notable for the presence of petechiae and a massively

enlarged spleen. A peripheral blood smear was sent, which on review demonstrates anemia,

thrombocytopenia, modest neutropenia, and the presence of small numbers of unusual white

blood cells. These blood cells are small cells with a moderate amount of cytoplasm that are

covered with distinctive cytoplasmic projections that appear to be long microvilli.

Notes:

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Diagnosis

The diagnosis is Hairy cell leukemia. The male to female ratio is 5:1 and the patients are

usually middle aged with a median age of 52.


Hairy cell leukemia is a chronic leukemia that often has an indolent course. It can present with

weakness and fatigue due to anemia, bleeding due to thrombocytopenia, or fever and infections

due to neutropenia. Almost every patient has splenomegaly, which is massive in 4/5 of cases.

Pathogenesis

Hairy cell leukemia cells are an abnormal type of mature B lymphocytes. Unlike many

leukemias, these cells are often present in circulating blood in small numbers, although

involvement of the spleen is more prominent. It is a rare B-cell neoplasm that causes an

indolent disease.

Bone marrow aspiration is often unsuccessful due to a dry tap; core biopsy will show the tumor

cells with abundant cytoplasm infiltrating a fine fibrillar network. The hairy cell leukemia cells are

sensitive to purine analogues (cladribine) and interferons. Granulocyte colony stimulating factor

(filgrastim) is used to reduce the neutropenia that may produce life-threatening susceptibility to

infections (gram-negative rods, atypical mycobacteria, disseminated fungal,

and Pneumocystis ).

Diagnostic testing

● Initial test: CBC (peripheral smear showing hairy cells).

● Accurate test: immunophenotyping by flow cytometry.

Strong positivity for tartrate-resistant acid phosphatase (TRAP) is a classic finding in hairy cell

leukemia cells, and you may see an item about this on a USMLE question. However, you

should also be aware that this test is no longer available at many centers.

Immunophenotyping of peripheral blood has mostly replaced the (less sensitive) TRAP test for

diagnosis, and is thought to be capable of making the correct diagnosis in this setting in over

90% of cases, even when only very small numbers of circulating leukemia cells are present.

Monoclonal Bly-7 is both sensitive and specific for hairy cell leukemia cells.

Treatment

The treatment of hairy cell leukemia (HCL) has dramatically improved with the development of

newer, more effective antineoplastic agents, such as cladribine. Cladribine is considered to be

the treatment of choice for this condition. This is a relatively nontoxic drug that provides benefit

in approximately 95% of all cases and a complete remission in more than 80% of these cases.

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In general, response rates are long-lasting, with few patients relapsing in the first several years.

Interferon and splenectomy are rarely used today to treat this condition. With respect to the

pharmacology of this agent, cladribine is indicated for the treatment of active HCL as defined by

clinically significant anemia, neutropenia, thrombocytopenia, or disease related symptoms.

Patients often experience long-term remission with chemotherapy, and late relapses (after 5-10

years) often respond a second time to the same chemotherapy.

LEUKEMIAS

Disease Characteristics Pathology

Acute

Lymphocytic

Leukemia (ALL)

60-70% occur in childhood, peak

age 4; rare over age of 50

Poor prognosis in adults, 50% of

children are cured

Most likely leukemia to involve CNS

Most cells are pre-B cells,; T-cell

variants occur, usually affecting

boys and causing thymic mass that

may compress the trachea

Present with lymphadenopathy,

bone pain, hepatosplenomegaly

Fatigue fever, epistaxis, gingival

petechiae, ecchymoses 2º to

thrombocytopenia; may have

subarachnoid or cerebral

hemorrhage

Smear: lymphoblast are prominent;

mature WBCs rare

CD10 (CALLA) is the diagnostic surface

marker; terminal deoxynucleotidyl

transferase (TDT) positive in both B-cell

and T-c ell ALL and negative in AML

Favorable prognostic factors are

● Age 3 to 9 yr

● WBC count <25,000/μL (<

50,000/μL in children)

● French-American-British

(FAB) L1 morphology

● Leukemic cell karyotype with

> 50 chromosomes and

t(12;21)

● No CNS disease at diagnosis

Acute

Myelogenous

Leukemia (AML)

20% of acute leukemia in children,

most common acute leukemia in

adults

signs and symptoms resemble ALL,

except usually present with

lymphadenopathy or splenomegaly

AML: t(15;17); acute promyelocytic

leukemia: t(1;12) treat with all trans

retinoic acid

Primary cell type variable; French

American and British (FAB)

Classification: (M0 – M7)

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Chronic

Myelogenous

Leukemia (CML)

Middle age but my occur in children/

young adults

Fatigue, fever, night sweats, and

weight loss

Splenomegaly giving abdominal

discomfort

2/3 covert to AML, 1/3 to B-cell ALL

Philadelphia chromosome (Ph1),

t(9;22): bcr:abl translocation is

pathognomonic, present in 95% of

cases

Prognosis in CML is worse in Ph1-

negative patients

Marked leukocytosis

Low to absent leukocyte alkaline

phosphatase

Elevated serum vitamin B12 and vitamin

B12 binding protein

High uric acid levels (due to rapid cell

turnover)

Chronic

Lymphocytic

Leukemia

Over 60 years of age

Asymptomatic or fatigue and weight

loss; lymphadenopathy ad

hepatosplenomegaly later findings

Higher incidence of visceral

malignancy

Median survival with treatment is 5

years but varies widely; prognostic

factor is extent of disease

Lymph node histology indistinguishable

from diffuse, well-differentiated

lymphocytic lymphoma

Classic cell: CD5 B cell

Cells do not undergo apoptosis

Hairy Cell

Leukemia

Rare disease; cell express tartrate-

resistant acid phosphatase

Present with hepatosplenomegaly,

pancytopenia common

Prognosis: May now be cured with

2-chloro-deoxyadenosine (2CdA),

and apoptosis inducer

Leukemic cells have “hair-like”

cytoplasmic projections visible on phase-

contrast microscopy

Cells express some B-cell antigen

Acute T-cell

Leukemia/Lymph

oma (CD4 T cell)

Endemic in Japan

Lymphadenopathy,

hepatosplenomegaly, skin

involvement, and hypercalcemia

Poor prognosis,; however, many

infected patients do not progress to

Caused by human T-cell

leukemia/lymphoma virus (HTLV1);

exposure to the virus may be decades

earlier

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disease

Myelodysplastic

Syndromes

Proliferative stem cell disorders-

maturation defect

Gray one between benign

proliferation and frank acute

leukemias

One-third of these patients later

develop frank acute myelocytic

leukemia

Presents as pancytopenia in elderly

patients

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Case 3

A 17-year-old boy is taken by his mother to his pediatrician because he has had chronic fatigue of two months duration, which has been accompanied by intermittent low-grade fevers. On questioning, the boy reports that he has had one episode of intense itchiness and two episodes of waking up with night sweats during this period. Physical examination is remarkable only for a fever of 37.6 C (99.7 F). A chest x-ray film shows marked mediastinal widening without masses or other lesions in the lung fields. Blood studies show moderate polymorphonuclear leukocytosis, lymphocytopenia, and eosinophilia. The patient is sent for mediastinoscopy with biopsy. During this procedure, a small incision is made immediately above the sternum and a rigid tube is inserted into the chest cavity for visualization of the mediastinum by video camera.

Notes:

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Diagnosis

The diagnosis is Hodgkin lymphoma. A neoplastic transformation of lymphocytes particularly in

the lymph node characterized by the presence of Reed-Sternberg cells on histology and to

spread in an orderly centripetal fashion to contagious areas of lymph nodes.


Hodgkin lymphoma has a bimodal age group distribution (late 20s and older than 50). Patients

usually present with painless enlargement of lymph nodes. B-cell symptoms (“B”

symptoms)include fever (that comes and goes/ Pel-Ebstein fever), weight loss, and night

sweats. Bad prognosis is proportional to number of Reed-Stenberg cells present. Survivors of

chemotherapy and radiotherapy have increased risk for secondary non-Hodgkin lymphoma or

acute leukemia.

Pathogenesis

The cells shown are Reed-Sternberg cells, and they are very likely seen in a photograph or in a

verbal description on the USMLE. Reed-Sternberg (RS) cells are typically binucleate (or

contain bilobed nuclei) with prominent "owl's eyes" nucleoli. These cells must be identified

before the diagnosis of Hodgkin disease can be made. The RS cell and RS variants express

CD30 (Ki-1), a lymphoid activation antigen. CD15 (Leu-M1), a granulocyte antigen, is also

uniformly positive in RS cells.

Reed-Sternberg cells seen in a background of mixed normal cells, including eosinophils,

indicate Hodgkin disease. There are around 7000 new cases of Hodgkin disease annually. The

disease has a bimodal age distribution with peaks in adolescence to young adulthood and old

age. It has contagious spread from one node to next with spleen involved before liver.

Histological subtypes of Hodgkin disease include lymphocyte predominant, nodular sclerosis,

mixed cellularity, and lymphocyte-depleted.

Note: Although cells resembling Reed-Sternberg cells on hematoxylin and eosin stained

tissues can be uncommonly seen in a wide variety of settings (including some non-Hodgkin

lymphomas and some tumors), for the USMLE, you can probably safely assume that any time

large, binucleate cells with prominent nucleoli are described, they are Reed-Sternberg cells and

the disease is Hodgkin disease.

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Variants of Hodgkin Disease

1. Lymphocyte predominance

(best prognosis) 3%

Sea of lymphocytes, few RS cells, variable number of

histiocytes, little fibrosis, and no necrosis

It is associated with Epstein Barr virus (40% of cases)

2. Nodular sclerosis 67% More common in women

Mediastinal, supraclavicular, and lower cervical nodes

Mixture of lymphocytes, histiocytes, a few eosinophils,

plasma cells, and RS cells. Collagen bands create nodular

pattern; RS cells called lacunar cells

3. Mixed cellularity 25% Mixture of neutrophils, lymphocytes, eosinophils, plasma

cells, and histiocytes

Large number of RS cells

4. Lymphocyte depletion

(worst prognosis)

Rare lymphocytes, many RS cells with variable eosinophils,

plasma cells, and histiocytes

Diffuse fibrosis may be seen

Diagnostic testing

● initial test : Lymph node biopsy

● Chest x-ray

● CT of chest, abdomen, and pelvis

● CBC, alkaline phosphatase, LDH, liver function tests, albumin, Ca, BUN, and creatinine

● PET for staging and MRI if neurologic symptoms are present

● Sometimes bone marrow biopsy

AN excisional lymph node biopsy is the essential first step in determining the diagnosis. After

the initial diagnosis is determined, the most important step is to determine the extent of the

disease because the stage will determine the nature of the therapy (radiation versus

chemotherapy). A chest x-ray or chest CT scan, abdominal CT scan, or MRI are used to

determine if the disease is localized to the supraclavicular area. CT scanning is sensitive

enough to detect any involved lymph nodes. A bone marrow biopsy is used to definitely

determine if the disease is truly localized. Pet scan can be used to determine the content of

some enlarged nodes. CBC shows anemia, high WBC, platelet count, eosinophilia. An

elevated

LDH indicates an adverse prognosis.

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Treatment

● Chemotherapy

● Radiation therapy

● Surgery

● Sometimes hematopoietic stem cell transplantation

In the Ann Arbor staging of Hodgkin and non-Hodgkin lymphoma, stage I involves one lymph

node only; stage II involves two or more lymph nodes on the same side of the diaphragm, stage

III involves the lymph nodes, spleen, or both, on both sides of the diaphragm (with subclass 1

above the renal vessels and subclass 2 in the lower abdomen), and stage IV shows extranodal

involvement in sites such as bone marrow, lung, and liver. "A" is added if the patient is free of

systemic symptoms and "B" is added if he has systemic symptoms such as weight loss, intense

pruritus, fever, and night sweats. "B" symptoms are more common in higher stage disease.

Radiotherapy alone to an extended field can be used to treat some stage I and IIA disease;

combined chemotherapy and radiotherapy or chemotherapy alone are usually used for patients

with higher stages. Even in advanced disease, complete remission can be obtained in up to 70-

80% of patients, and more than half of those who survive are disease-free at 10 to 15 years.

Most patients with Hodgkin disease, including those with advanced stages of the disease, are

best treated with combination chemotherapy using doxorubicin, bleomycin, vincristine and

dacarbazine (ABVD. This particular combination therapy has been proven to be the more

effective and less toxic than traditional therapies, such as mechlorethamine, vincristine,

procarbazine and prednisone (MOPP). Specifically, ABVD causes less secondary leukemia

and less reproductive sterility than MOPP. Several other shorter and more intensive regimens

have shown great promise in the treatment of Hodgkin disease.

Complications of treatment: Chemotherapy, increases the risk of leukemia, which typically

develops after > 3 yr. Both chemotherapy and radiation therapy increase the risk of malignant

solid tumors (eg, breast, GI, lung, soft tissue).

most common side effects:

● doxorubicin: cardiotoxicity.

● vincristine: neuropathy.

● cisplatin: renal and ototoxicity.

● bleomycin: lung fibrosis.

● cyclophosphamide: hemorrhagic cystitis and cancer ; prevent with mesna .

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Step 1 Questions

1. A 69-year-old man comes to the physician because of a 2-month history of weight loss, fatigue and night sweats. He has lost approximately 6.8 kg (15 lb). Physical examination shows multiple, painless, palpable cervical and axillary lymph nodes. The spleen is palpable 3 cm below the costal margin. Laboratory studies show lymphocytosis; hemoglobin is 10.8 g/dL.

A peripheral blood smear is shown. Which of the following is the most likely diagnosis? A. Acute lymphocytic leukemia B. Acute myelogenous leukemia C. Chronic lymphocytic leukemia D. Hairy cell leukemia E. Multiple myeloma 2. A 55-year-old man comes to the physician because of increased fatigue and exertional dyspnea. Laboratory studies and cytogenetic studies confirm leukemia. Genetic testing shows a t(9;22) translocation. Which of the following findings is most likely in this patient? A. Increased lymphocyte count B. Increased neutrophil count C. Numerous lymphoblasts D. Numerous myeloblasts E. Pancytopenia

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3. A 67-year-old man with a history of leukemia develops disseminated intravascular coagulation. A bone marrow biopsy shows hypergranular promyelocytes, some of which contain multiple, reddish, rodlike structures. A diagnosis of acute promyelocytic leukemia is made. Which of the following translocations is most likely responsible for this patient’s illness? A. t(4;11) B. t(6;9) C. t(8;14) D. t(8;21) E. t(15;17) 4. A 17-year-old boy is brought to the physician because of intermittent fever and increased abdominal girth. An abdominal x-ray indicates the presence of an ileocecal mass, which is identified as a lymph node on CT scan of the abdomen. Cytogenetic studies of the lymph node confirm lymphoma with a t(2;8)(p12;q24) translocation. Which of the following is the most likely diagnosis? A. Burkitt lymphoma B. Mantle cell lymphoma C. Multiple myeloma D. Small cell (non-Burkitt lymphoblastic) lymphoma E. Small cleaved-cell lymphoma

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5. A 27-year-old woman comes to the physician because of abdominal discomfort and weight loss. Pelvic examination shows a left-sided ovarian mass. The mass is resected, and histologic examination shows small lymphocytes, interspersed with macrophages surrounded by clear spaces. Which of the following is the most likely genetic abnormality associated with this patient's condition? A. abl-bcr hybrid B. bcl-2 activation C. c-myc activation D. t(9,22) E. t(14,18) 6. A 62-year-old man comes to the physician because of a mass in his neck, intermittent fevers, and an unintentional 11-kg (24-lb) weight loss. Physical examination shows a 1.5-cm nontender mass at the angle of the jaw and an enlarged spleen. Laboratory studies show a hemoglobin of 11 g/dL and a hematocrit of 33%. A photomicrograph of a biopsy specimen of the neck mass is shown.

Which of the following sets of laboratory findings is most likely in this patient?

A.

B.

C .

D .

E.

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7. A 53-year-old woman comes to the physician because of a 2-month history of fatigue and early satiety; she has had a 10 kg (22 lb) weight loss during this period. Laboratory studies shows leukocytosis and thrombocytosis. A peripheral blood smear is shown. There are large numbers of neutrophils and increased numbers of normal-appearing eosinophils and basophils. No blast forms are seen.

Which of the following cytogenetic abnormalities is associated with this condition? A. Bcl-2 activation B. c-Myc activation C. t(8,14) D. t(9,22) E. t(14,18) 8. A 23-year-old woman who is a college student comes to the physician because of a fever, fatigue, and difficulty swallowing. Physical examination shows exudative tonsillitis and cervical lymphadenopathy. A peripheral blood smear shows mild anemia and lymphocytosis, with about 30% of the lymphocytes exhibiting atypical features, and mild thrombocytopenia. A serum sample causes the agglutination of red blood cells. Which of the following is most likely to be found in this patient? A. Cold agglutinins B. Downey cells C. Koilocytes D. Negri bodies E. Owl's-eye inclusions

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Step 1 Explanations

1. The correct answer is C. This patient is presenting with the characteristic signs and symptoms of chronic lymphocytic leukemia (CLL), a disease of older individuals. The condition is indolent and is often asymptomatic for long intervals. It may present as an isolated lymphocytosis on routine blood count, or with fevers, night sweats, and lymphadenopathy in an elderly man. The image above shows pale red erythrocytes, large numbers of very dark blue, mature lymphocytes, and pink, crushed lymphocytes (called "smudge cells"). Smudge cells, which reflect the fragility of B-CLL cells when the smear is made, are considered characteristic of CLL. They also have prognostic importance, with a greater number portending a worse prognosis. Acute lymphocytic leukemia (ALL) (choice A) and acute myelogenous leukemia (AML) (choice B) are both found in younger populations. Large numbers (>30%) of myeloid blasts are found in the peripheral smear of AML patients. Hairy cell leukemia (choice D) presents in elderly men with splenomegaly, abdominal fullness, and fatigue. Hairy cells are seen in the bone marrow, spleen, and blood. Diagnosis is made by a positive tartrate-resistant acid phosphatase test and immunophenotyping. Multiple myeloma (choice E) is a malignant neoplasm of plasma cells that arises in the bone marrow. It is most commonly found in elderly men who present with anemia, bone pain, pathologic fractures, or Bence-Jones proteinuria. Remediation:

● Chronic lymphocytic leukemia is an indolent disorder of malignant lymphocyte clonality (usually B cell).

● It commonly presents in older individuals with signs and symptoms of immunosuppression and bone marrow failure.

● Characteristic "smudge cells" and lymphocytosis are seen on peripheral smear.

2. The correct answer is B. The t(9;22) translocation (Philadelphia chromosome), results in a bcr-abl fusion gene that encodes a protein with tyrosine kinase activity. It is the hallmark of chronic myeloid leukemia (CML). CML typically presents with markedly increased numbers of circulating neutrophils and metamyelocytes, with lesser numbers of eosinophils and basophils and a small number of blasts. The disease follows an indolent course, and usually progresses to an accelerated phase with increased numbers of circulating blasts only after several years. An increased lymphocyte count (choice A) would be seen in chronic lymphocytic leukemia (CLL), another indolent leukemia. Increased numbers of blasts (choices C and D) are seen in the late stages of CML and CLL, or in the acute leukemias. The Philadelphia chromosome is occasionally associated with acute lymphoblastic leukemia and acute myeloblastic leukemia, but these are diseases of children and young adults.

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Pancytopenia (choice E) is most typical of the myelodysplastic syndromes (MDS), in which ineffective hematopoiesis of a pluripotent stem cell produces abnormal development of all cell types. No specific chromosomal abnormality is associated with MDS. Remediation:

● The (9;22) translocation (Philadelphia chromosome) is the hallmark for CML.

● In CML, there is a marked increase in cells in the granulocytic lineage.

3. The correct answer is E. Acute promyelocytic leukemia (M3 by the FAB classification) is associated with a t(15;17) (q22;q11) translocation. The reddish-appearing structures are Auer rods. Disseminated intravascular coagulation can occur in this disorder due to the release of procoagulant substances from the leukemic cells, especially during treatment. The t(4;11)(q21;q23) translocation (choice A) is associated with acute lymphocytic leukemia (ALL) and undifferentiated leukemia. The t(6;9)(p23;q34) translocation (choice B) is found in subtypes of AML with basophilia (M1, M2, M4). Burkitt leukemia, which is related to Burkitt lymphoma, is associated with t(8;14) (q24;q32) (choice C). The t(8;21) (q22;q22) translocation (choice D) is seen in M2 leukemia, also known as AML with maturation, and some M4 (AML with granulocytic and monocytic maturation). Remediation:

● Acute promyelocytic leukemia (M3 by the FAB classification) is associated with a t(15;17) (q22;q11) translocation and characterized by Auer rods.

● Disseminated intravascular coagulation can occur due to the release of procoagulant substances from the leukemic cells, especially during treatment.

4. The correct answer is A. Burkitt lymphoma is actually associated with three translocations. The common variant t(8;14)(q24;q32), involves the oncogene myc on chromosome 8 and the heavy immunoglobulin chain on chromosome 14. The other two variants are: t(8;22)(q24;q11), involving myc and the lambda light chain immunoglobulin site; and t(2;8)(p12;q24), involving the kappa light chain and myc. Mantle cell lymphoma (choice B), multiple myeloma (choice C), and small (not cleaved) cell lymphoma (choice D) are associated with the t(11;14)(q13;q32) translocation involving bcl -1 and the heavy chain site. Small cleaved-cell lymphoma (choice E) is associated with t(14;18)(q 32;q21), involving the immunoglobulin chain site and bcl-2. Remediation:

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Chromosomal translocations that have been associated with Burkitt lymphoma are: t(8;14), t(2;8), and t(8;22). They all involve the myc gene. 5. The correct answer is C. The disease is Burkitt lymphoma (the major clue is the "starry-sky" pattern described), which occurs as a jaw lesion in epidemic form in Africa (associated with Epstein-Barr virus) and in a sporadic form that usually involves the pelvic or abdominal organs. Burkitt lymphoma is associated with c-myc activation due to a t(8,14) translocation that places the c-myc-containing segment of chromosome 8 near an actively transcribed gene for immunoglobulin heavy chains. t(9,22) (choice D) and abl-bcr hybrid (choice A) are associated with chronic myeloid leukemia (CML). t(14, 18) (choice E) and bcl-2 (choice B) are associated with follicular lymphomas, not Burkitt lymphoma. Remediation:

● Burkitt lymphoma has a “starry-sky” appearance microscopically.

● Burkitt lymphoma is associated with a c-myc activation due to a t(8,14) translocation.

6. The correct answer is A. The patient has Hodgkin disease, and the large binucleate eosinophilic cells in the image are the characteristic Reed-Sternberg cells. This patient also has anemia, as evidenced by his decreased hemoglobin and hematocrit values. Anemia of chronic disease is common in patients with Hodgkin disease. Anemia of chronic disease can be seen in the settings of chronic infection, inflammation, or cancer. Typical findings include microcytic or marginally normocytic anemia (hence the low MCV in the correct choice) and abnormal iron metabolism characterized by low total iron-binding capacity, normal/high ferritin, and low/normal serum iron. The combination of low MCV, low serum iron, and high total iron-binding capacity (choice B) is more characteristic of iron deficiency anemia, in which the body’s iron stores are reduced and total iron binding increases as the body tries to accumulate more iron. Low MCV with normal serum iron and normal iron-binding capacity (choice C) is characteristic of thalassemia minor; patients with this disorder do not usually need multiple transfusions and therefore do not develop excess iron loads. This pattern can also be seen in patients with lead poisoning, unless coexistent iron deficiency (which is common in children exposed to lead paint) is also present, in which case serum iron would be low and total iron-binding capacity would be high. Low MCV, high serum iron, and normal-to-decreased total iron-binding capacity (choice D) are typical of sideroblastic anemias, in which abundant iron is available to developing erythrocytes but is not used effectively. The abundant iron leads to decreased total iron-binding capacity as the body compensates by downregulating iron-binding capacity. High MCV with normal serum iron and normal total iron-binding capacity (choice E) is more characteristic of nutritional megaloblastic anemias secondary to folate or vitamin B12deficiency.

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In these anemias, DNA synthesis lags behind cytoplasm formation so that mitosis is relatively delayed, and the erythrocytes are larger than normal. Iron metabolism is not usually directly affected. Remediation:

● Anemia of chronic disease can be seen with chronic infection, inflammation, or cancer.

● The anemia is usually microcytic; there is typically low total iron-binding capacity, normal/high ferritin, and low/normal serum iron.

7. The correct answer is D. The disease described is chronic myelogenous leukemia (CML), which usually affects adults between 40 and 59 years of age. The clinical hallmark of CML is the uncontrolled production of maturing granulocytes, which are predominantly neutrophils, but eosinophils and basophils are also seen. CML is associated with the Philadelphia (Ph) chromosome, which is actually a translocation involving chromosomes 9 and 22 that produces an BCR-ABL hybrid fusion protein. The fusion protein commonly possesses an oncogenic dysregulated kinase activity and is the hallmark of CML. Diagnosis involves identifying the Ph chromosome or its products, the BCR-ABL fusion mRNA, or the BCR-ABL protein. Bcl-2 activation (choice A) and a t(14,18) (choice E) translocation are features of follicular lymphomas. In follicular lymphoma, the Bcl-2 oncogene is translocated from 18 to the Ig heavy chain locus on chromosome 14. The Bcl-2 protein differs from oncogenes (which promote cellular proliferation) and tumor suppressor genes (which inhibit cell growth), in that the Bcl-2 protein blocks apoptosis, leading to prolonged cell survival. c-Myc activation (choice B) and a t(8,14) (choice C) translocation are features of Burkitt lymphoma. Remediation:

● Suspect chronic myelogenous leukemia (CML) in patients with systemic complaints (fatigue, malaise, sweating, weight loss), early satiety, thrombocytosis, and an elevated white blood cell count with predominant neutrophils.

● The "gold standard" for the diagnosis of CML is demonstration of the Philadelphia chromosome [t(9,22) translocation] or identifying the BCR-ABL fusion mRNA or the BCR-ABL fusion protein.

8. The correct answer is B. The syndrome represented by this clinical vignette is infectious mononucleosis. Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis; cytomegalovirus (CMV) is responsible for heterophile-negative mononucleosis. EBV is the most common cause of mononucleosis in the United States. Diagnosis is made by the finding of heterophile antibodies (antibodies that agglutinate animal erythrocytes by binding to the Paul-Bunnell antigen). Downey cells are atypical reactive lymphocytes (CD8+ lymphocytes) that may comprise up to 70% of the white cells in a CBC. Cold agglutinins (choice A) are antibodies that agglutinate red blood cells at 4ºC (39.2ºF). They

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can be found in some cases of mononucleosis, but they are nonspecific. They are also observed in other conditions (e.g., Mycoplasma pneumoniae infection and autoimmune hemolytic anemia). Koilocytes (choice C) are found in cells infected with human papillomavirus. They are characterized by perinuclear vacuolization and an enlarged nucleus. Negri bodies (choice D) are found in neurons infected with the rabies virus and represent sites of virus assembly. Owl's-eye inclusions (choice E) are found in cells infected with CMV. CMV would be the next most likely choice as the cause of mononucleosis; however, the present case states that the patient is heterophile antibody-positive (serum that agglutinates red blood cells). CMV, as stated above, is responsible for heterophile-negative mononucleosis. Remediation:

● College student with sore throat and lymphadenopathy = infectious mononucleosis

● Heterophile-positive (antibodies agglutinate animal red blood cells) finding means the cause is Epstein-Barr virus; heterophile-negative means the cause is cytomegalovirus

● In the circulation of a patient with infectious mononucleosis, up to 70% of the complete blood count is comprised of atypical CD8+ (killer) T lymphocytes (Downey cells).

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Step 2 Questions 1. A 56-year-old man was recently diagnosed with lymphoma. He is being treated with chemotherapy using cyclophosphamide, doxorubicin, prednisone, and vincristine. He is currently on his second of four cycles of chemotherapy. He noticed last week that he had some burning during micturition and dark colored urine. He is now unable to empty his bladder. He is referred to the emergency department. On examination in the emergency department, he is in moderate distress. His temperature is 37.3 ºC (99.1 ºF), blood pressure is 175/93 mm Hg, and pulse is 115/min. There is palpable cervical adenopathy. His lungs are clear to auscultation and his heart has no murmurs. Abdomen is soft in the upper quadrants, but there is a 8 x 8 cm mass in the suprapubic region, that is slightly tender to palpation. Genital examination shows blood clots at the urethral meatus, and the testicles are descended bilaterally. Rectal examination shows good anal tone with a mildly enlarged, smooth prostate. Hematocrit is 31% and creatinine is 0.8 mg/dL. Urinalysis shows 3-4 WBC/hpf, full field RBC, and leukocyte esterase negative. Which of the following is the most likely explanation for this patient’s hematuria? A. Bladder cancer B. Cyclophosphamide use C. Benign prostatic hyperplasia D. Urinary tract infection E. Vincristine use

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2. A 72-year-old man complains of increased nausea and itching for the past few days. He denies fever, chills, shakes, chest pain, or shortness of breath. He was diagnosed recently with non-Hodgkin lymphoma and he completed his first cycle of chemotherapy 10 days ago. He has a diminished oral intake. As part of his workup for lymphoma, he underwent several CT scans with contrast, which revealed abdominal lymphadenopathy. His vital signs are stable. Examination is unremarkable. Laboratory studies show:

Na: 137 mEq/L

K: 4.5 mEq/L

Cl: 100 mEq/L

Ca: 5.0 mg/dL

HCO3: 24 mEq/L

BUN: 56 mg/dL

Creatinine: 6.0 mg/dL

Uric acid: 14/mg/dL

Phosphate: 8.0 mg/dL Which of the following is the most likely cause of these laboratory findings? A. Dehydration B. Interstitial nephritis C. Renal infarct D. Tumor lysis syndrome E. Ureteral obstruction

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3. A 25-year-old woman is admitted to the hospital for treatment of non-Hodgkin lymphoma that presented with fevers, night sweats, weight loss and cervical lymphadenopathy. She is found by CT scan to have advanced disease which is confirmed with PET scan and mediastinoscopy with biopsy. After much consultation, she is started on an experimental chemotherapeutic protocol. She tolerates the protocol well and reports no major adverse events. However by the fourth day of her treatment, her urine output is 30 cc/hour and her laboratory results reveal the following:

Hemoglobin: 10.5 g/dL

Hematocrit: 32%

Leukocyte count: 4,000/mm3

Platelets: 140,000/mm3

Sodium: 137 mEq/L

Potassium: 5.1 mEq/L

Chloride: 100 mEq/L

Bicarbonate: 22 mEq/L

BUN: 65 mg/dL

Creatinine: 4.5 mg/dL

Despite aggressive fluid administration for 2 hours with several fluid boluses, her laboratory values were essentially unchanged. Urine output is now 26 cc/hour. Which of the following is most likely responsible for these findings? A. Bleomycin B. Cisplatin C. Cytarabine D. Dexamethasone E. Doxorubicin

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4. A 60-year-old woman explains to her primary care physician that she has been having daily temperature elevations to 100ºF (37.8ºC). In addition, for the past 3 weeks she has had no energy, and now, over the past week, she has been waking up at night sweating. On examination she has sternal tenderness on palpation and her spleen is palpated 4 cm below the left costal margin. CBC shows 70,000 white blood cells with a predominance of mature myeloid cells. There are 1% blasts seen. Hematocrit is 38% and platelets are 400,000/µL. Which of the following is the most appropriate next step in management? A. Admit to the hospital for cultures and broad-spectrum IV antibiotics B. Look for smudge cells on the peripheral smear C. Perform CT scan of the thorax and abdomen D. Perform FISH on peripheral blood to find the bcr-abl protein E. Start treatment with imatinib mesylate 5. A 35-year-old woman comes to the physician because of a mass in her right axilla for 5 weeks. During the past week she has seen 2 small masses on the left side of her neck, and she has had 2 episodes of night sweats. She has had no fevers or weight loss. Her maternal aunt died of breast cancer at age 56 years. Examination shows 2 firm, nontender, mobile lymph nodes, 2- to 3-cm, in the left anterior cervical chain and right axilla. The lungs are clear to auscultation. Cardiac examination shows a normal S1 and S2; no murmurs are heard. There is no abdominal tenderness or hepatosplenomegaly. A biopsy specimen of the axillary node is shown.

Which of the following is the most likely associated finding on further workup? A. Acid-fast bacilli B. Atypical lymphocytes C. Bilateral hilar adenopathy D. Calcifications on mammography E. Mediastinal adenopathy F. Upper lobe cavitation

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6. A 55-year-old man comes to the physician because he "bleeds too much" every time he brushes his teeth. For the past three days, he has not been feeling well and has been also complaining of headaches and chest pain. He has been trying to workout lately but as soon as he starts walking, he feels very fatigued and has to stop. His temperature is 39 ºC (102 ºF), blood pressure is 130/80 mm Hg, pulse is 110/min, and respirations are 20/min. Heart: II/VI systolic ejection murmur is heard on auscultation, Lungs: bilateral ronchi; skin: scattered petechiae over the thorax and extremities; neurological exam: patient is oriented in person, time, and place; strength: 4/5 throughout, reflexes: 2/5. Laboratory reports include:

Hemoglobin 7.1 gm/dL

Platelets 30,000/mm3

White blood cells 11,800/mm3

Peripheral blood: numerous blasts

Bone marrow biopsy: hypercellular with 35% blasts

Blast cells: presence of rod-shaped structures in the cytosol

Myeloperoxidase: positive

Chest X-ray: scattered infiltrations on the base, bilaterally

Which of the following is the most likely diagnosis?

A. Acute lymphocytic leukemia

B. Acute myelogenous leukemia

C. Aplastic anemia

D. Chronic myelogenous leukemia

E. Myelofibrosis

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Step 2 Explanations

1. The correct answer is B. This patient has hemorrhagic cystitis secondary to the administration of cyclophosphamide. The same result can occur with the use of ifosfamide. These chemotherapeutic agents are metabolized by the body to a breakdown product called acrolein. Acrolein is responsible for the development of the hemorrhagic cystitis. It does this by causing the bladder epithelium to slough and then form a thin, vascular, easily friable, new mucosal lining. The prevention of cyclophosphamide-induced hemorrhagic cystitis can be accomplished if 2-mercaptoethane sodium sulphonate (MESNA) is given together with the cyclophosphamide. MESNA works by binding with acrolein in the bladder to form an inert thioether that is passed innocuously in the urine. This patient’s hematuria is so severe that he has developed urinary retention, explaining his distress, elevated blood pressure, and a palpable, distended bladder in the suprapubic area. Patients who are given cyclophosphamide have a ninefold increased risk for developing bladder cancer. The lag time between termination of treatment and development of urothelial cancer has been observed to be between 9 months and 11 years. The bleeding that may occur with bladder cancer can be similar to this patient's bleeding. In this scenario, it is unlikely that the bleeding is related to a new bladder cancer (choice A). Vincristine (choice E) is not associated with the development of hemorrhagic cystitis or gross hematuria. It is possible to develop gross hematuria with a urinary tract infection. There is not usually, however, an association with the passage of clots. Patients also have urinary frequency and burning and, the urinalysis should be nitrite or leukocyte esterase-positive (choice D). Benign prostatic hyperplasia (BPH; choice C)is usually not associated with gross hematuria, but it can occur in severely enlarged prostates. BPH can present with obstructive and irritative symptoms. Microscopic hematuria is a more common finding. Remediation: Hemorrhagic cystitis (HC) secondary to the administration of cyclophosphamide is the most common type of HC. Efforts, like good hydration and the administration of MESNA should be made to avoid this complication 2. The correct answer is D. This patient has tumor lysis syndrome (TLS) from lymphoma treatment, and this is confirmed by the hyperphosphatemia, hypocalcemia, and hyperuricemia seen in his laboratory values. The most likely cause of the acute renal failure is the acute precipitation of uric acid crystals in the collecting tubules secondary to tumor lysis. In anticipation of this complication, for prophylaxis, patients should be given allopurinol or rasburicase and aggressive intravenous hydration. Once tumor lysis develops, treatment consists of normalizing electrolyte disturbances, rasburicase, IV fluids, and diuretics. Dialysis should be considered in patients with severe disease or with disease that is unresponsive to these measures. Dehydration from anorexia (choice A) is a possibility. In fact, treatment for TLS includes aggressive intravenous hydration. However, dehydration does not account for the profoundly abnormal uric acid, phosphate, and serum calcium.

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Interstitial nephritis (choice B) could occur in the setting of a new medication; however, serum urate would not be elevated. Urine eosinophils should be measured if this diagnosis is suspected. Renal infarct (choice C) as an embolic phenomenon is less likely in this patient. Ureteral obstruction (choice E) secondary to a mass effect from the tumor is a possibility. Urine output and renal ultrasound would need to be obtained. Obstruction, however, does not account for this patient's laboratory findings. Remediation: Tumor lysis syndrome should be suspected in a patient with hyperphosphatemia, hypocalcemia, and hyperuricemia. Once tumor lysis develops, treatment consists of normalizing electrolyte disturbances, rasburicase, IV fluids, and diuretics. 3. The correct answer is B. Cisplatin is one of the more nephrotoxic chemotherapeutic agents and requires aggressive fluid administration during treatment. Even with continuous infusion of cisplatin (less likely to cause renal damage than bolus dosing) and with aggressive hydration, nephrotoxicity is common. The present patient has clear signs of acute renal failure (her elevated BUN and creatinine with decreased urine output). Urine output should be at least 0.5-1.0/cc/kg/hour (30-60 cc/hour in a 60-kg person). Her urine output should also have increased after fluid boluses if she had normal renal function. Although she has slightly decreased hemoglobin, leukocyte and platelet counts, this can be considered an expected side effect of her chemotherapy and is not related to her renal failure. The most important side effects associated with chemotherapy drugs are: Bleomycin (choice A) and busulfan: retroperitoneal and pulmonary fibrosis Vincristine and vinblastine: peripheral neuropathy Cyclophosphamide: hemorrhagic cystitis Cisplatin: deafness, renal failure Cytarabine (choice C): eye problems; prevent with topical steroids Dexamethasone(choice D): does not cause renal damage. Doxorubicin(choice E) cardiomyopathy; always check ejection fraction before treatment Remediation: It is imperative that you know the common chemotherapeutic agents and their side effects. This is very high-yield for the USMLE. Cisplatin is associated with renal failure and deafness. 4. The correct answer is D. From the findings and the predominance of myeloid cells on laboratory results, you should have a strong suspicion of chronic myelogenous leukemia (CML). The disease remains stable often for years before it transforms to a higher-grade malignancy, and it is most commonly a disease of the elderly. Patients typically present with fatigue, night sweats, low-grade fever (hypermetabolic from overproduction of white cells), and splenomegaly. On examination there may be sternal tenderness from marrow overexpansion. CML is characterized by the Philadelphia chromosome, which is a reciprocal translocation between the long arms of chromosomes 9 and 22. A fusion gene, bcr-abl, is created, producing an abnormal

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protein. The gold-standard in diagnosing CML is either detection of the bcr-abl gene in the peripheral blood by FISH (fluorescent in-situ hybridization) (see image below) or cytogenetic studies for the Philadelphia chromosome. This is required in order to make the diagnosis.

In blast crisis (>30% immature precursor cells), patients have bone-marrow failure and will present with bleeding or infection that necessitates hospitalization and broad-spectrum antibiotics(choice A). Smudge cells in peripheral blood (choice B) is characteristic of chronic lymphocytic leukemia (CLL), not CML, and will show a predominance of lymphocytic cells on peripheral blood. Imatinib mesylate (choice E), also known by the trade name Gleevec®, is a specifically designed inhibitor of tyrosine kinase produced by the Philadelphia chromosome. It results in control of the chronic phase in almost all patients, is very well tolerated, and is the drug of choice in treating CML. There would be no reason to perform a CT scan of the thorax and abdomen (choice C) in this patient. Remediation: The gold-standard in diagnosing CML is either detection of the bcr-abl gene in the peripheral blood by FISH or cytogenetic studies for the Philadelphia chromosome. To confirm the diagnosis, one of these 2 tests should be performed on any patient with highly suspicious signs and symptoms of CML. 5. The correct answer is E. This patient has Hodgkin disease, which is a neoplastic transformation of lymphocytes particularly in the lymph nodes characterized by the presence of Reed-Sternberg cells on histology (the image shows classic Reed-Sternberg cells). The neoplastic cells express CD15 and CD30 and do not express CD3 or CD45. Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. Patients may also develop what are labeled "B" symptoms, which are drenching night sweats, 10% weight loss, and fevers. Cervical, supraclavicular, and axillary lymphadenopathy are the most common initial signs of the disease, but lymphadenopathy may develop anywhere in the body. Extralymphatic sites, such as splenic, skin, gastric, lung, CNS, or any other organ may possibly be involved. Extralymphatic involvement is more common with non-Hodgkin lymphoma. An

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excisional lymph node biopsy is the essential first step in determining the diagnosis. Thereafter it is imperative to determine the extent of the disease, because the stage will determine the nature of the therapy. A chest x-ray film or chest CT scan (which may show mediastinal unilateral or bilateral lymphadenopathy), abdominal CT with PET scan, or MRI scan are used to determine the spread of disease. A lymph node biopsy specimen positive for acid-fast bacilli (choice A) and upper lobe cavitation (choice F) would be found in a patient who has tuberculosis. Patients who have pulmonary TB present with cough, sputum, fever, and an abnormal lung examination; weight loss and night sweats are common. Any part of the body may be involved, although the lymph node is the most common extrapulmonary site; other frequent sites of involvement include meninges, gastrointestinal tract, and genitourinary tract. Mononucleosis is a common, acute infectious process, usually affecting young people and caused by the Epstein-Barr virus (EBV). Patients may have pharyngitis with exudates and petechiae. Generalized lymphadenopathy, splenomegaly, and hepatomegaly may also be present. A preliminary diagnosis of EBV may be made by the presence of typical symptoms plus atypical lymphocytes (choice B) in the peripheral blood. Serologic testing, although not always necessary, confirms the diagnosis. Bilateral hilar adenopathy (choice C) is a classic finding on a chest x-ray film of a patient suffering from sarcoidosis. It is more common in African American females and is characterized by chronic cough, arthritis, uveitis, and fever/night sweats. Lymph node biopsy specimen shows noncaseating granulomas. Although this patient's age and family history put her at higher risk for developing breast cancer, which could present with right breast calcifications on mammography (choice D), the diagnosis of Hodgkin disease becomes clear with the presence of Reed-Sternberg cells on histology. Remediation:

● Hodgkin disease is characterized by the presence of Reed-Sternberg cells on histology.

● Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. A chest x-ray film or chest CT scan may show mediastinal lymphadenopathy.

● The neoplastic cells in Hodgkin disease express CD15 and CD30.

6. The correct answer is B. The clinical presentation is consistent with acute myelogenous leukemia (AML). The most common presentation results from effects of the leukemic blast cells crowding out the normal marrow cells, resulting in symptoms of pancytopenia, even if the total white blood cell count is normal. Fatigue from anemia is the most common presenting complaint. Bleeding from thrombocytopenia occurs. Infection from the underproduction or abnormal function of white blood cells also occurs. The CBC is the first clue to the diagnosis. The white cell count can be low, normal, or elevated. A bone marrow biopsy showing greater than 30% blasts confirms the diagnosis of acute leukemia. AML is characterized by the presence of Auer rods (rod-shaped structures in the cytosol), myeloperoxidase, and esterase. The initial chemotherapy for AML is cytosine arabinoside (AraC) and either daunorubicin or idarubicin.

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Acute lymphocytic leukemia (ALL); (Choice A) is most common in children (from newborn to 14-years-old). The clinical presentation is similar to that of AML. ALL is characterized by the presence of the common ALL antigen (CALLA) and terminal deoxynucleotidyl transferase (TdT). Chronic myelogenous leukemia (CML); (Choice D) is characterized by the massive overproduction of myeloid cells. The most common symptoms are fatigue, night sweats, and low-grade fever. Neoplastic bone marrow precursors in this condition are still capable of differentiating along myeloid lines, so that most circulating leukemic cells appear as mature white blood cells. CML is a myeloproliferative disorder, so the platelet count and erythrocyte count are usually normal or even increased. Infection and bleeding are uncommon because the white cells and platelets retain the majority of their functions. Leukocytosis in CML is usually striking, often higher than 200,000/mm3. The leukocyte alkaline phosphatase score (LAP) is diminished. Basophilia is characteristic of CML. The Philadelphia chromosome, result of a balanced translocation between 9q and 22q, is present in 95% of cases. Aplastic anemia (Choice C) most commonly presents with bleeding from thrombocytopenia, but may present with a combination of the findings associated with deficiencies in all three-cell lines. Fatigue from anemia and infections from neutropenia may also occur. Pancytopenia on a CBC is the first test. The bone marrow is empty of almost all precursor cell as well as evidence of primary metastatic cancer, infections, or fibrosis. The marrow is fat filled with no abnormal cells seen. There are circulating blasts on peripheral blood. Myelofibrosis (Choice E) is the growth and proliferation of abnormal bone marrow stem cells, resulting in the replacement of bone marrow with fibrous connective tissue. It could present with splenomegaly with portal hypertension and splenic infarcts. Normocytic anemia with the distinctive teardrop cells is characteristic. Thrombocytosis also occurs in 50% of cases. Remediation: Acute myelogenous leukemia usually presents with fatigue (anemia), bleeding (thrombocytopenia) and infection (underproduction or abnormal function of white blood cells). In the laboratory, the presence of Auer rods, myeloperoxidase, and esterase confirms the diagnosis.

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Leukemia & Lymphoma v.2015