PANCE Blueprint Hematology (5%)

Acute and chronic lymphocytic leukemia (Lecture)

Patient with acute lymphocytic leukemia (ALL) will present as → a 5 y/o child with bone pain, bleeding, and fever. His mom notes that the patient has been less active and has had recurrent upper respiratory infections over the past several months. Clinical examination reveals diffuse lymphadenopathy. His CBC demonstrates anemia and leukopenia, and the blood smear shows peripheral blasts. Bone marrow biopsy demonstrates 30% lymphoblasts.

Patient with chronic lymphocytic leukemia (CLL) will present as → a 60-year-old male complains of fatigue. On physical exam he has painless cervical lymphadenopathy and hepatosplenomegaly. His blood tests demonstrate severe anemia, decreased neutrophil count, and immature B cells that broke apart during the peripheral smear.

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Acute lymphocytic leukemia (ALL)CHILD + lymphadenopathy + bone pain + bleeding + fever in a CHILD, bone marrow > 20% blasts in bone marrow

  • In acute leukemia, there’s uncontrolled proliferation of partially developed WBCs (blast cells) which build up in the blood over a brief period of time
  • ALL results from a proliferation of cells from the lymphoid line (vs. the myeloid line in AML) and is classified into T-cell ALL, where there’s proliferation of T-cell precursors, and B-cell ALL (70-80% of cases), where there’s proliferation of B-cell precursors
  • Caused by chromosomal translocations (12,21) and (9,22)
  • Population: Children - most common childhood malignancy peak age 3-7
  • Symptoms of ALL include fatigue, because of the anemia, easier bleeding, because of thrombocytopenia, and more frequent infections, because of the leukopenia
  • Abnormal lymphoblasts in ALL can also infiltrate the lymph nodes and other lymphatic tissue, so it’s also called acute lymphoblastic lymphoma
  • A key clinical symptom in T-cell ALL, is that the abnormal lymphoblasts migrate to the thymus like normal T-cells do and cause thymus enlargement which can present as a mass, or growth in the mediastinum.
  • Highly responsive to chemotherapy (remission > 90%)

Chronic Lymphocytic Leukemia (CLL): Middle age/elderly patient, often asymptomatic (seen on blood tests), fatigue, lymphadenopathy, and splenomegaly

  • Population: Adults - peak age 50 y/o
  • Not caused by one particular mutation but results from a variety of chromosomal mutations that affect lymphocytes, in particular B cells
  • Just like with the blast cells in ALL, partially mature B-cells can move into the lymphatic tissues and cause lymphadenopathy. B cells in these nodes will accumulate to form “lymphomas”, which is why CLL is sometimes called small lymphocytic lymphoma
  • These abnormal B Cells are likely to produce autoantibodies resulting in immune thrombocytopenia and autoimmune hemolytic anemia
  • Hairy cell leukemia is a special but rare type of CLL linked with a mutation in the BRAF gene. The affected B-cell have hair-like projections, giving them a fuzzy appearance
  • Up to 70% of persons with CLL are asymptomatic at diagnosis and when symptoms do appear, they are typically nonspecific and include easy fatigability and weight loss. Some patients can present with lymphadenopathy and hepatosplenomegaly
  • Diagnostic studies: SMUDGE CELLS on peripheral smearmature lymphocytes
  • Treatment with observation, if lymphocytes are > 100,000 or symptomatic treat with chemo
How can you differentiate AML from ALL?
To differentiate between AML and ALL one must identify the blast cells as either myeloblast or lymphoblasts in a specially stained smear. Myeloblasts are usually large cells with nuclei containing fine chromatin and prominent nucleoli. Lymphoblasts are relatively smaller cells with coarse chromatin, which are clumped together and have small nucleoli. Lymphoblasts have very little cytoplasm, which has glycogen granules. In addition, immunophenotyping is done to detect certain markers, for example, TdT, which is a DNA polymerase that’s present only in the nucleus of the lymphoblast, is a marker for lymphoblasts, and CD10 is a surface marker for pre-B cells.

ALL

  • CBC: pancytopenia (anemia, thrombocytopenia, leukopenia)
  • Peripheral blood smear demonstrates peripheral blasts. Blast cells in the peripheral smear may approach 90% of the white blood cell (WBC) count
  • Bone marrow aspiration and biopsy: with > 20% blasts
  • Histochemical studies, cytogenetics, and immunophenotyping studies help distinguish the blasts of ALL from those of AML or other disease processes

CLL

  • CBC: pancytopenia (anemia, thrombocytopenia, leukopenia) with an increase in the absolute number (>5,000) of lymphocytes in the peripheral blood
  • The peripheral blood smear of patients with CLL demonstrates lymphocytosis (small mature lymphocytes) and often shows smudge” cells, which are immature B cells that have broken apart during the smear
  • Evaluation of the bone marrow is not usually necessary
Smudge cells are fragile B cells that often smudge during slide preparation

Smudge cells are fragile B cells that often smudge during slide preparation - seen in CLL

Acute Lymphoblastic Leukemia (ALL): Chemotherapy

  • Highly responsive to combination chemotherapy with a remission of > 90%.
  • Stem cell transplant if relapse.

Chronic Lymphoblastic Leukemia (CLL): Observation if indolent

  • Chronic - treat with chemo

osmosis Osmosis
Acute leukemia
Chronic leukemia
Picmonic
Chronic lymphocytic leukemia (CLL)

chronic-lymphocytic-leukemia-cll_5045_1466637131

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. Most patients are older than 60 years of age and there is a 2 to 1 male predominance. In CLL, lymph nodes are diffusely effaced by an infiltrate of small lymphocytes. The peripheral blood also contains large numbers of small round lymphocytes with minimal cytoplasm. Some of these cells often come disrupted in the process of making smears and produce smudge cells that are characteristic of CLL. The bone marrow is almost always involved. Unlike most other lymphoid malignancies, chromosomal translocations are relatively rare. Patients are often asymptomatic at diagnosis and when symptoms do appear, they are typically nonspecific and include easy fatigability and weight loss. Some patients can present with lymphadenopathy and hepatosplenomegaly. Hypogammaglobulinemia is also common and contributes to disruption of normal immune function. CLL is also associated with warm autoimmune hemolytic anemia, which is often caused by the attachment of IgG antibodies to red blood cells.

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Acute Lymphoblastic Leukemia (ALL)

IM_Acute_Lymphoblastic_Leukemia_ASSETS_

Acute lymphoblastic leukemia (ALL) is a neoplasm of immature B and T cells (pre B and pre T cells), which are referred to as lymphoblasts. About 85% of ALLs are B cell tumors and typically manifest in children less than 15 years of age. The less common T cell ALLs tend to present in adolescents as a thymic lymphoma in the mediastinum. In these cancers, the bone marrow is typically hypercellular and packed with lymphoblasts, which replace the normal elements within the bone marrow. Therefore, common symptoms include fatigue due to anemia and bleeding due to thrombocytopenia. Neoplastic infiltration of bone marrow can also cause bone pain from marrow expansion and infiltration of the subperiosteum. Immunostaining for terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase that is expressed only in pre B and pre T lymphoblasts is positive in more than 95% of cases. Majority of these B-cell tumors also express the common acute lymphoblastic leukemia antigen (CALLA). Approximately 90% of ALLs demonstrate chromosomal changes, most commonly hyperploidy of chromosomes. These chromosomal aberrations are thought to cause the dysregulation of the expression and function of transcription factors that are required for normal B and T cell development. A fraction of B cell tumors contain a translocation of genes 12;21 involving the genes TEL and AML1, two genes required in very early hematopoiesis. This translocation is associated with better prognosis. This tumor is known to spread to the CNS and testes. With aggressive chemotherapy, about 95% of children with ALL obtain complete remission.

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Question 1
A 60-year-old presents with fatigue and splenomegaly. CBC reveals the following: WBC- 24,000/microliter, Hgb- 13.5 g/dl, Hct- 40%, MCV- 87 fL, MCHC- 34 g/dl, MCH- 28 pg, and platelets- 380,000/mL. The differential reveals neutrophils- 11%, lymphocytes- 80%, monocytes- 8%, and basophils- 1%. What is the most likely diagnosis?
A
Acute lymphocytic leukemia
Hint:
Acute lymphocytic leukemia is more common in children and presents with blasts in the peripheral blood
B
Acute myelogenous leukemia
Hint:
Acute myelogenous leukemia presents with pancytopenia and presence of blasts in the peripheral blood.
C
Chronic lymphocytic leukemia
D
Chronic myelogenous leukemia
Hint:
Chronic myelogenous leukemia presents with elevated WBC count, marked left shift in the myeloid series of cells, and positive for Philadelphia chromosome.
Question 1 Explanation: 
Chronic lymphocytic leukemia presents with a WBC count greater than 20,000/microliter and an absolute lymphocyte count of greater than 5000/microliter.
Question 2
A 3-year-old girl presents for her well-child visit. The physician notes pallor and bruising. On physical examination, the vital signs are normal, but there is a generalized lymphadenopathy and hepatosplenomegaly. A complete blood count (CBC) reveals a white blood cell (WBC) count of 33,000/ mm3 and a platelet count of 81,000/ mm3. The peripheral blood smear shows blasts, and the lactate dehydrogenase activity is elevated. CBC shows blasts as well as hypochromic red blood cells. The most common leukemia among children is which of the following?
A
acute myelogenous leukemia (AML)
Hint:
AML is the most common leukemia in adults, but it is less common in children.
B
acute lymphocytic leukemia (ALL)
C
chronic myelogenous leukemia (CML)
Hint:
CML is very rare in children, occurring in approximately 2% of childhood leukemia cases.
D
chronic lymphocytic leukemia (CLL)
Hint:
CLL is also unusual in children.
E
equal numbers of AML and ALL
Question 2 Explanation: 
Seventy-three percent of childhood leukemia is ALL. AML is the most common leukemia in adults, but it is less common in children. CML is very rare in children, occurring in approximately 2% of childhood leukemia cases. CLL is also unusual in children.
Question 3
Most cases of ALL are diagnosed between which of the following age ranges?
A
birth and 2 years
Hint:
See B for explanation
B
2 and 3 years
C
12 and 15 years
Hint:
See B for explanation
D
8 and 12 years
Hint:
See B for explanation
E
5 and 15 years
Hint:
See B for explanation
Question 3 Explanation: 
The peak incidence for ALL is between 2 and 3 years of age.
Question 4
Which ethnic group has the highest frequency of ALL?  
A
white
Hint:
The frequency for whites is 30 to 40 per 1 million,
B
Hispanic
C
African American
Hint:
African Americans is approximately one-third the rate of whites.
D
Asian
E
no ethnic variation
Question 4 Explanation: 
Hispanics have a frequency of 43 per 1 million. The frequency for whites is 30 to 40 per 1 million, and that for African Americans is approximately one-third the rate of whites.
Question 5
Which of the statements regarding ALL is true?
A
the peak age at onset is 12 years
Hint:
The peak incidence for ALL is between 2 and 3 years of age.
B
at the time of diagnosis, most patients have a thrombocytosis
Hint:
Most patients with ALL will have a decreased hemoglobin level and platelet count at the time of diagnosis
C
CBC with differential is the most useful initial test
D
a chest radiograph is the most useful initial test
Hint:
A chest radiograph should be obtained to search for a possible mediastinal mass.
Question 5 Explanation: 
The most useful initial test to perform in patients suspected of having ALL is a CBC with differential. In most cases, there will be an increase or decrease in at least one or two cell types. The WBC count may be decreased, normal, or elevated, and the differential will show a neutropenia. Blasts may be seen on the peripheral smear. Most patients with ALL will have a decreased hemoglobin level and platelet count at the time of diagnosis. The diagnosis of ALL is confirmed by a bone marrow examination showing more than 25% lymphoblasts. A chest radiograph should be obtained to search for a possible mediastinal mass. With combination chemotherapy, the prognosis of ALL is very good.
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References: Merck Manual · UpToDate (ALL) (CLL)

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