Quiz Questions 7

Question 1

Acute Lymphocytic Leukemia is more common in adults. Treatment involves non-cell cycle dependent agents like steroids and asparaginase.

True or false

Answer 1

false

ALL is far more common in childhood than in adults.

Question 2

Alkylating agents associated AML occurs after:

• 2 years
• 10 years
• 5 years
• 8 years

Answer 2

5 years

Treatment related acute leukemias and treatment related myelodysplastic syndromes are diseases which are difficult to treat and have an extremely poor prognosis. Those caused by alkylating agents tend to occur about 4-6 years from the beginning of treatment and involve aberrations in chromosomes 5 and 7. Patients who receiving topoisomerase I inhibitors often develop treatment related MDS earlier (1-3 years) and have more complex chromosomal abnormalities (11q23).

• 2 years
• The occurrence of treatment associated AML at 2 years or earlier may be seen in patients who have received topoisomerase inhibitors.
• 10 years
• Although treatment related AML can occur at a late date, this is not typical.
• 8 years
• Although treatment related AML can occur at a late date, this is not typical.

Question 3

In APL – pathophysiology involves formation of a fusion protein PML-RARA which enhances gene transcription and promotes differentiation of cells.

True or false

Answer 3

false

The PML-RARA fusion protein suppresses gene transcription and blocks cell differentiation. This fusion protein is a consequence of the characteristic t(15;17). Of therapeutic importance, is that all-trans-retinoic acid (ATRA) relieves the blockade and promotes differentiation.

Question 4

Chromosomal abnormality associated with acute promyelocytic leukemia is:

• T(9,11)(p22;q23)
• T(8,21)(q22;q22)
• Inv (16)(p13q22)
• T(15,17)(q22;q12)

Answer 4

T(15,17)(q22;q12)

This translocation is typically associated with M3 leukemia (acute promyelocytic leukemia, APL).

• T(9,11)(p22;q23)
• This translocation is most often associated with M5 leukemia (acute monoblastic leukemia).
• T(8,21)(q22;q22)
• This translocation is most often associated with M2 leukemia (acute granulocytic leukemia with granulocytic maturation).
• Inv (16)(p13q22)
• This translocation is most often associated with M4 leukemia (acute myelomonocytic leukemia).

Question 5

Patients with Polycythemia vera present with Splenomegaly and elevated Erythropoietin levels.

True or False

Answer 5

false

The major abnormal findings on physical examination include splenomegaly, facial plethora (ruddy cyanosis), and hepatomegaly which occurred in 36- 70, 67, and 40 percent of patients. Other physical findings which might be helpful in pointing to a diagnosis of PV include the following: Injection of the conjunctival small vessels and/or engorgement of the veins of the optic fundus, excoriation of the skin, which might be extensive, suggesting the presence of severe pruritus, stigmata of a prior arterial or venous thrombotic event (e.g., stroke, deep vein thrombosis, superficial thrombophlebitis), and Gouty arthritis and tophi. Laboratory findings include an elevated hemoglobin/hematocrit and red blood cell mass in virtually all patients, a platelet count >400,000/microL in 60 percent, and a white blood cell count >12,000/microL in 40 percent. Bone marrow cellularity was increased in 90 percent of patients, and storage iron was absent from the marrow in 94 percent. 81% of patients are reported to have subnormal serum erythropoietin levels.

• true
• Although patients with polycythemia vera (also known as polycythemia rubra vera) may have splenomegaly, they typically have low or undetectable serum erythropoietin levels

Question 6

Which of the following is the Major Criteria for diagnosis of PV (polycythemia vera)?

• Hgb > 18.5 in Men
• Red Cell mass Elevated at by 20%
• Hgb > 15 in women
• Jak-2 Mutation negative
• Epo level that is subnormal

Answer 6

Hgb > 18.5 in Men

The diagnosis of PV requires the presence of both major criteria and one minor criterion, or the presence of the first major criterion together with two minor criteria. WHO Revise Criteria for PV Major criteria: 1. Hemoglobin >18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume (>25% of the mean normal predicted) and 2. Presence of JAK2 617V>F or other functionally similar mutation such as JAK2 exon 12 mutation Minor criteria: 1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation; 2. Serum erythropoietin level below the reference range for normal; and 3. Endogenous erythroid colony formation in vitro.

• Red Cell mass Elevated at by 20%
• One of the major criteria for the diagnosis of polycythemia (PV) is that the red cell volume is increased >25% of the mean normal predicted.
• Hgb > 15 in women
• In females, a hemoglobin >16.5 gm/dL is a major criteria for the diagnosis of PV.
• Jak-2 Mutation negative
• JAK2 mutation is typically present in a patient with PV.
• Epo level that is subnormal
• Although the serum erythropoietin levels are typically low in patients with PV. This finding is not a major criteria.

Question 7

All of the following are true about primary myelofibrosis (PMF) EXCEPT:

• Normal spleen size
• Patients aged > 60 yrs
• Uric acid can be elevated
• Peripheral blood smear shows –tear drop cells and nucleated RBC

Answer 7

Normal spleen size

PMF is the least frequent among the MPNs (MPNs). One study reported an estimated incidence of 1.5 per 100,000 per year. PMF occurs mainly in middle aged and elderly patients. The median age at presentation is 67 years. Approximately 5 and 17 percent of the patients are diagnosed before the age of 40 and 50 years, respectively. The condition is rare in childhood. The most common presenting complaint is that of severe fatigue, occurring in 50 to 70 percent of patients. Symptoms due to an enlarged spleen have been described in 25 to 50 percent of patients, while a smaller number note weight loss and 5 to 20 percent experience other signs of a hypermetabolic state such as low-grade fever and night sweats. Approximately 15 to 30 percent are asymptomatic, with the diagnosis being made during investigation of splenomegaly (occurring in at least 90 percent of patients), hepatomegaly (40 to 70 percent), or abnormal blood findings. Enlargement of the spleen and liver are due to the marked extramedullary hematopoiesis associated with PMF. Patients with PMF may have nonspecific abnormalities in a variety of laboratory tests. These include: elevations in the serum concentrations of alkaline phosphatase, lactate dehydrogenase, uric acid, leukocyte alkaline phosphatase, and vitamin B12. The increase in alkaline phosphatase may be due to liver involvement or bone disease, the increase in lactate dehydrogenase may result from ineffective hematopoiesis, hyperuricemia is due to enhanced turnover of hematopoietic tissue and can cause gout or uric acid stones, and the increase in serum vitamin B12 reflects an increased neutrophil mass. Anemia with hemoglobin less than 10 g/dL is seen in approximately 50 percent of patients with PMF and 20 percent present with a hemoglobin less than 8 g/dL. The peripheral smear is quite characteristic, showing anisocytosis (i.e., red cells of varying size), poikilocytosis (i.e., red cells of varying shape), teardrop-shaped red blood cells (dacrocytes), nucleated red blood cells, and variable degrees of polychromasia. The platelet and white blood cell (WBC) counts are variable in PMF. Marked leukocytosis (WBC >30,000/µL) and thrombocytosis (platelet count >500,000/µL) occur at diagnosis in approximately 11 and 13 percent of patients, respectively, while leukopenia and thrombocytopenia are seen in 8 and 26 percent, respectively [8,24]. The variable leukocyte count reflects variation in the number of neutrophils. Immature cells from the neutrophilic series are always present as part of the leukoerythroblastic blood picture and myeloblasts may be seen in the peripheral smear; usually amounting to less than 5 percent of the total WBC count Hypersegmented neutrophils may also be seen). Thrombocytopenia becomes more common with disease progression. Platelets may be abnormally large with altered granulation; in addition, fragmented megakaryocytes are also seen on the peripheral smear. Abnormal platelet function is common although the

• Patients aged > 60 yrs
• The median age at presentation is 67 years. Approximately 5 and 17 percent of the patients are diagnosed before the age of 40 and 50 years, respectively. The condition is rare in childhood.
• Uric acid can be elevated
• Hyperuricemia is due to enhanced turnover of hematopoietic tissue and can cause gout or uric acid stones.
• Peripheral blood smear shows –tear drop cells and nucleated RBC
• The peripheral smear is quite characteristic, showing anisocytosis (i.e., red cells of varying size), poikilocytosis (i.e., red cells of varying shape), teardrop-shaped red blood cells (dacrocytes), nucleated red blood cells, and variable degrees of polychromasia.

Question 8

When a patient presents with a new Budd-Chiari Syndrome (thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava), the hypercoagulable testing should include testing for myeloproliferative disorders.

True or False

Answer 8

true

The myeloproliferative neoplasms can be broadly classified as essential thrombocythemia (ET), polycythemia Vera (PV), idiopathic (or primary) myelofibrosis (PMF), chronic myelocytic leukemia (CML), and myeloproliferative neoplasms (MPN) not otherwise specified (NOS). As with most other kinds of active malignancies patients with MPN appear to have an increased risk of thrombosis. This risk varies with severity of the disease. For example, patients with CML in the chronic phase have little risk of thrombotic complications, but this risk appears to increase as the disease enters the accelerated or blastic phase. Greater than 95% of patients with PV have a mutation of JAK2, a component of the JAK-STAT pathway; approximately 50% of patients with ET or PMF have a JAK2 mutation. The MPNs, particularly PV and ET, are characterized by thrombotic complications. These complications include both arterial and venous thrombosis and microcirculatory disorders such as erythromelalgia and visual and neurologic symptoms. Hyperviscosity may play a contributing role. A high percent of patients with idiopathic hepatic (e.g., Budd-Chiari syndrome) or portal vein thrombosis, but not those with idiopathic lower extremity DVT, have had in vitro evidence (e.g., spontaneous erythroid colony growth in the absence of erythropoietin, presence of the JAK2 mutation, clonal karyotypic abnormalities on bone marrow examination) suggestive of an occult myeloproliferative neoplasm Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disorder of bone marrow stem cells. Affected patients generally have chronic intravascular hemolysis with episodes of gross hemoglobinuria accompanied by leukopenia and thrombocytopenia. PNH is also associated with an approximately 40 percent prevalence (in the United States and Europe) of venous thrombosis in the intra-abdominal venous network (mesenteric, hepatic, portal, splenic, and renal veins) and cerebral vessels, as opposed to deep vein thrombosis or pulmonary embolism. The indications for the evaluation of patients with a thrombosis for the presence of a hypercoagulable state remains controversial. Many clinicians feel that it is less likely that a patient greater than 50 years of age will have a congenital cause of thrombosis and others feel that all patients with a first time thrombosis should be fully evaluated. The likelihood of a patient with idiopathic thrombosis outside of the splanchnic system and with no other signs of a MPN, being JAK2 mutation+ is approximately 1:300. For this reason, routine screening for this mutation in patients with arterial thrombosis, venous thrombosis, or cerebral vein thrombosis, in the absence of splanchnic venous thrombosis (i.e., Budd-Chiari syndrome or portal vein thrombosis) or overt myeloproliferative disease is not recommended. Never-the-less, the initial presentation of patients with MPN can be that of thrombosis and if all other more commonly evaluated causes of idiopathic thrombosi

Question 9

What is the frequency of JAK-2 mutation in Essential thrombocythemia (also called essential thrombocytosis) patients?

• 25%
• 40%
• 55%
• 50%

Answer 9

50%

Greater than 95% of patients with PV have a mutation of JAK2, a component of the JAK-STAT pathway; approximately 50% of patients with ET or PMF have a JAK2 mutation.

Question 10

First line treatment in patients with Essential thrombocythemia and who are at a high risk for a thrombotic event is:

• Aspirin alone
• Warfarin alone
• Hydroxyurea
• Anagrelide alone
• Phlebotomy alone

Answer 10

Hydroxyurea

Most patients with ET enjoy a normal life expectancy without associated disease-related complications. In morphologically and cytogenetically defined ET (i.e., patients in whom PV, CML, MDS, and PMF have been excluded), the delayed development of either acute myeloid leukemia (AML) or post-ET myelofibrosis (post-ET MF) ranges from 2-17% and 4- 9%, respectively and thrombotic risk was 22%. Risk factors for inferior survival include: low hemoglobin level (60 years of age. Therefore, cytoreductive therapy is indicated in these high-risk patients (i.e., age >60 years or history of prior thrombosis).

• Aspirin alone
• Aspirin alone is not the ideal treatment of high risk patients.
• Warfarin alone
• Although warfarin is an effective way of preventing the thrombotic complications associated with ET, its inconvenience and associated complications make it less desirable.
• Anagrelide alone
• Anagrelide is a drug available for the treatment of ET. Unfortunately, patients treated with this drug have a higher risk of arterial thrombosis and conversion to myelofibrosis than those receiving aspirin alone.

Question 11

Megakaryocyte numbers are reduced in the bone marrow of Essential Thrombocytosis patients.

True or False

Answer 11

false

Diagnosis requires meeting all four criteria. WHO criteria for ET 1. Sustained platelet count ≥450 x 109/L*; 2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis; 3. Not meeting WHO criteria for PV•, PMF¦¤, CML◊, MDS§ or other myeloid neoplasm; 4. Demonstration of JAK2 617V>F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis∗

Question 12

Which of the following is the goal of Hematocrit in PV (polycythemia vera)?

• 40%
• 55%
• 45%
• 30%

Answer 12

45%

If the truth be told, the optimal hematocrit in PV is not known with certainty. However, there are several small clinical trials which indicate that C is best answer for this question. These studies showed the following: 1. Cerebral blood flow was decreased with Hcts >46%. Decreasing the Hct from 53% to 45% increased cerebral blood flow by 73% and reduced whole blood viscosity by 30%. 2. In a retrospective review in patients with PV treated with phlebotomy with or without chemotherapy, there was a positive correlation between vascular occlusive episodes and hematocrit, with a suggested optimum hematocrit of less than 50 percent. 3. Reduction of hematocrit to less than 50 percent resulted in significant improvement in choroidal and retinal blood flow and a reduction in the subsequent incidence of transient blindness in patients with PV

• 40%
• Induced anemia is not a goal in the treatment of patients with PV.
• 55%
• In a retrospective review in patients with PV treated with phlebotomy with or without chemotherapy, there was a positive correlation between vascular occlusive episodes and hematocrit, with a suggested optimum hematocrit of less than 50 percent. Reduction of hematocrit to less than 50 percent resulted in significant improvement in choroidal and retinal blood flow and a reduction in the subsequent incidence of transient blindness in patients with PV.
• 30%
• Induced anemia is not a goal in the treatment of patients with PV.

Question 13

Splenic marginal zone lymphoma is associated with which of the following infections:

• Hepatitis B
• Hepatitis C
• C. jejuni
• Borrelia burgdorferi
• H. Pylori

Answer 13

Hepatitis C

Hepatitis C is commonly associated with splenic marginal zone lymphoma, usually treatment of underlying infection leads to improvement in the lymphoma.

• Hepatitis B
• There is no know relationship between hepatitis B and MZL.
• C. jejuni
• C. jejuni is associated with intestinal lymphoma.
• Borrelia burgdorferi
• Borrelia infection is associated with cutaneous lymphoma.
• H. Pylori
• H pylori are associated with gastric MALT lymphomas.

Question 14

Hodgkin’s disease is characterized by which of the following pathological findings:

• Reed Sternberg cell
• Diffuse large B cells
• Small round sheets of lymphocytes
• Popcorn cells

Answer 14

Reed Sternberg cell

Reed Sternberg cell is pathognomonic of Hodgkin’s lymphoma and is characterized by abundant slightly basophilic cytoplasm and at least two nuclei. The nuclei have an eosinophilic nucleolus surrounded by a peri-nuclear halo.

• Diffuse large B cells
• Three morphologic variants are commonly seen: centroblastic, immunoblastic, and anaplastic. Most cases of DLBCL are centroblastic, having the appearance of medium-to-large-sized lymphocytes with scanty cytoplasm. Oval or round nuclei containing fine chromatin are prominently visible, having two to four nucleoli within each nucleus. Immunoblasts have significant basophilic cytoplasm and a central nucleolus. A tumour can be classified as immunoblastic if greater than 90% of its cells are immunoblasts. The third morphologic variant, anaplastic, consists of tumour cells which are generally very large with a round, oval, or polygonal shape and pleomorphic nuclei, and may resemble Hodgkin cells or Reed-Sternberg cells.
• Small round sheets of lymphocytes
• This finding is consistent with chronic lymphocytic leukemia or small lymphocytic lymphoma. These are the same disease. CLL presents with peripheral blood involvement and small lymphocytic lymphoma presents with node or tissue involvement.

Question 15

Richter’s transformation involves:

• Change of an indolent lymphoma into a high grade, aggressive lymphoma
• Bleeding into lymphoma leading to enlargement
• CNS spread of lymphoma causing symptoms
• Hyperuricemia, hyperkalemia and renal insufficiency from breakdown of lymphoma cells

Answer 15

Change of an indolent lymphoma into a high grade, aggressive lymphoma

Involves transformation of an indolent lymphoma into a high grade, aggressive lymphoma like DLBCL. Characterized by sudden lymphadenopathy, new B symptoms and BM involvement. Tumor Lysis syndrome is characterized by sudden breakdown of tumor cells which causes hyperuricemia, hyperkalemia, hyperphosphatemia, uric acid crystallization in urine and renal failure.

• Bleeding into lymphoma leading to enlargement
• Bleeding into lymph nodes is not a characteristic of Richter’s syndrome.
• CNS spread of lymphoma causing symptoms
• Patients with Richter’s syndrome have an aggressive disease and CNS involvement may occur during its course; however, this is not a characteristic of the syndrome.
• Hyperuricemia, hyperkalemia and renal insufficiency from breakdown of lymphoma cells
• While this combination of abnormalities may occur as part of the so-called tumor lysis syndrome (TLS), they are not a constant in patients with Richter’s syndrome.

Question 16

The gene commonly translocated in Burkitt’s lymphoma is:

• cMyc
• Cyclin D1
• Bcl-2
• MLL

Answer 16

cMyc

cMyc present on chromosome 8 is commonly translocated in Burkitt’s lymphoma.

• Cyclin D1
• Cyclin D1 translocations are seen in Mantle cell lymphoma.
• Bcl-2
• Bcl-2 translocations are seen in follicular lymphoma.
• MLL
• MLL re-arrangements are uncommon in lymphomas but are commonly seen in acute leukemia.