Hematologic Malignancies

Chapter 14 Hematologic Malignancies



Dana M. Carne, Thomas A. Brown, MD, Sonali J. Shah




Insider’s Guide to Hematologic Malignancies for the USMLE Step 1


Hematologic malignancies are easy points on Step 1 if you study for these topics correctly. This chapter is included to focus you on the most high-yield points to take away for boards. Before you read through this chapter, you should skim the following list of tips to help you gain the maximum number of points on your examination:



image Know all of the chromosomal translocations mentioned in this chapter and First Aid. Board exams love to test students on these points.


image Pay careful attention to patient ages whenever they are given in the clinical history. Age can be very helpful in distinguishing various types of hematologic malignancies. You should especially memorize the age ranges for the most common types of leukemias. Acute lymphoblastic leukemia (ALL) occurs between the ages of 0 to 15, acute myelogenous leukemia (AML) occurs between the ages of 15 to 59, chronic myelogenous leukemia (CML) occurs between the ages of 40 to 59, and chronic lymphocytic leukemia (CLL) occurs after the age of 60 years. Keep in mind that boards will provide you with classic presentations for diseases, so memorizing particular rules like this one for the USMLE can be extremely helpful.


image Many high-yield images derive from this section. You should know how to diagnose different leukemias and lymphomas from images of peripheral blood smears or bone marrow aspirates. You should also know how to recognize Auer rods and Reed-Sternberg cells, two especially high-yield images covered in this section.


image When learning the various hematologic malignancies, focus on the information that helps you differentiate these cancers from one another. Sometimes, this is all you need to know for boards. A great example is hairy cell leukemia, for which you should know that these cells have hairlike projections and stain positively with tartrate-resistant acid phosphatase (TRAP). These are the two most unique facts about hairy cell leukemia, and at least one of them is guaranteed to be provided in any question stem you may receive on this topic. It’s as simple as that. Use the information in this chapter (especially the tables) to guide what you should take away from each individual disease.



Basic concepts



1 What are the two principal lineages along which leukocytes differentiate?


The lymphoid lineage gives rise to B and T lymphocytes as well as natural killer (NK) cells, and the myeloid lineage gives rise to the granulocytes (eosinophils, basophils, neutrophils), monocytes, platelets, and erythrocytes (i.e., the nonlymphoid cells). Cells of the innate immune system derive from the myeloid lineage, but cells of the adaptive immune system derive from the lymphoid lineage. The exception to this rule is NK cells, which are considered to be players in the innate immune system.



2 What categories of hematologic malignancy arise from the lymphoid lineage?




image The lymphomas, including Hodgkin’s lymphoma and the various types of non–Hodgkin’s lymphoma (NHL)


image The lymphocytic leukemias, including acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL)


image Tumors of plasma cells (antibody-secreting B cells), which include multiple myeloma and lymphoplasmacytic lymphoma


Note: All lymphoid neoplasms arise from a single transformed cell and are consequently phenotypically monoclonal.



3 What is the general distinction between lymphoma and leukemia?


Leukemia generally indicates significant bone marrow involvement with neoplastic cells (and often significant peripheral blood involvement). Lymphoma indicates a mass originating in the peripheral tissues (lymph nodes). However, this line is often blurred because lymphomas can evolve to infiltrate the marrow (a leukemic picture), and malignancies otherwise identical to leukemias may start out as peripheral tissue masses similar to lymphomas. Currently, leukemia or lymphoma refers to the usual tissue distribution of neoplasms of a particular cell type.



4 What is the distinction between small cell lymphocytic lymphoma (SLL) and (B-cell) chronic lymphocytic leukemia (B-CLL)?


B-CLL and SLL are essentially the same entity with the exact same cell type, immunophenotype, and genetic alteration. They are therefore typically referred to as simply SLL/B-CLL, without designating a specific diagnosis. The distinction is that when the peripheral blood lymphocytes reach a certain level, then the disease is considered “leukemic.” This is a fantastic example of the blur between leukemias and lymphoma.


Note: Smudge cells are a characteristic feature of CLL on a peripheral smear.



5 What categories of hematologic neoplasms arise from the myeloid lineage?




image Acute myelogenous leukemia (AML), which has multiple subclassifications


image Myelodysplastic syndromes, all potential precursors of AML


image Myeloproliferative disorders, including polycythemia vera (PV), chronic myelogenous leukemia (CML), and essential thrombocythemia


image Histiocytoses (of monocyte-macrophage origin)


Note: All myeloid neoplasms arise from a transformed hematopoietic progenitor cell. Features of these neoplasms often overlap, confusing medical students and physicians alike. They may also infiltrate the bone marrow, resulting in anemia, thrombocytopenia, and leukopenia. Additionally, both ALL and CLL, as well as many types of lymphoma, can have significant bone marrow involvement.



6 What is the distinctive feature of acute myelogenous leukemia on bone marrow biopsy?


A substantial amount of the bone marrow is replaced by relatively undifferentiated blast cells that resemble one (or more) of the early steps of myeloid differentiation. Consequently, there are multiple subclassifications of AML, depending on which early cell type predominates (e.g., acute promyelocytic leukemia, acute myelomonocytic leukemia, acute megakaryocytic leukemia).




Step 1 Secret


The most important form of acute myelogenous leukemia (AML) to know for boards is the M3 subtype, which is characterized by circulating granulocytes and myeloblasts containing Auer rods. Auer rods are peroxidase-positive inclusion bodies in the cytoplasm of the neoplastic cells that are pathognomonic for this condition. Release of these Auer rods can result in disseminated intravascular coagulation (DIC), which is associated with the M3 subtype of AML.


The M3 form of AML is marked by a characteristic t(15,17) translocation that involves the retinoic acid receptor. Fortunately, this disease responds to treatment with all-trans-retinoic acid.



7 What is the distinctive feature of myelodysplastic syndromes?


In these diseases, a mutant stem cell that can give rise to all cell types of the myeloid lineage replaces the bone marrow (partly or wholly). However, this mutant stem cell produces cells of the myeloid lineage in an ineffective manner. Consequently, anemia, thrombocytopenia, and leukopenia are seen, from both ineffective hematopoiesis and replacement of bone marrow. Moreover, the myelodysplastic syndromes may evolve into AML.


Dysplastic changes of myelodysplastic syndrome include Pelger-Huet cells with “aviator” nuclei (bilobed polymorphonuclear cells) and ring sideroblasts. This syndrome is associated with BCL2 mutation as well as methylation (and inactivation) of tumor suppressor genes.



8 What is the distinct feature of the myeloproliferative disorders?


In these diseases, a transformed hematopoietic progenitor cell causes a pathologically increased production of one of the final products of the myeloid lineage (granulocytes, erythrocytes, platelets). In other words, myeloproliferative disorders differ from other neoplastic leukocytic disorders in that they cause an overproduction of mature cells. Examples are polycythemia vera (increased red blood cell [RBC] production), essential thrombocytosis (increased platelet production), and CML, which results in an increased number of granulocytes.


Note: CML is unique among the myeloproliferative disorders in that it has a characteristic genetic defect: a chromosomal translocation (t9:22), known as the Philadelphia chromosome.



9 What are the histiocytoses?


A histiocyte is a tissue macrophage found within the interstitium. The histiocytoses are disorders involving uncontrolled proliferation of histiocytes. For Step 1, students need be familiar only with Langerhans cell histiocytosis (also known as histiocytosis X), which, depending on age at presentation and clinical course, is classified as Letterer-Siwe disease, Hand-Schüller-Christian disease, or eosinophilic granuloma. A characteristic feature of histiocytosis X is Birbeck granules in the cytoplasm, which you can easily recognize on Step 1 because they look like miniature intracellular tennis rackets.


Note: The term “eosinophilic” refers to the characteristic pink protein staining and not the cell type.



10 What is the relationship between myelofibrosis and the myeloproliferative diseases?


Myelofibrosis is simply fibrosis of the bone marrow with collagen. It has multiple causes, such as radiation, drugs, and chemicals, but is most commonly idiopathic. It can also occur as a result of the myeloproliferative disorders. Myelofibrosis is most likely due to signaling by abnormal megakaryocytes. The resulting fibrosis can impair hematopoiesis, resulting in hypocellular bone marrow and pancytopenia, which can unfortunately be rapidly fatal. The body tries to compensate for this deficiency with extramedullary hematopoiesis.


Myelofibrosis is marked by “teardrop RBCs,” which result from damage to the RBC structure as these cells try to escape the fibrotic bone marrow. If you see these cells on a peripheral blood smear, you should immediately associate this finding with myelofibrosis.



11 How does the leukocyte alkaline phosphatase level help differentiate reactive leukocytosis from a true leukemia?


Reactive leukocytosis (leukemoid reaction; left shift) is a pronounced increase in white blood cell (WBC) count with infection and is associated with high levels of leukocyte alkaline phosphatase (LAP). In contrast, the abnormally large increase in WBCs seen in leukemia is typically associated with low levels of LAP because the neoplastic cells cannot produce this enzyme. This is an important distinction to look out for on boards.



12 Quick review! Cover the right column in Table 14-1 and attempt to list the cell type and pertinent high-yield facts regarding the hematologic malignancies in the left column



Table 14-1 Leukemia Lineages








































Disorder Cell Type/Comments
Lymphoid Lineage
Acute lymphoblastic leukemia Precursor B or T lymphocytes (lymphoblasts)
Chronic lymphocytic leukemia/small lymphocytic lymphoma B cells, smudge cells on peripheral smear
Hodgkin’s lymphoma Reed-Sternberg cells
Lymphoplasmacytoma Plasma cells (mature B cells—IgM-secreting); a common cause of Waldenström’s macroglobulinemia
Multiple myeloma Plasma cells (mature B cells—IgG- and IgA-secreting)
Non-Hodgkin’s lymphoma Multiple types, which generally are classified according to site in lymph node they resemble (e.g., follicular, mantle zone, marginal zone)
Myeloid Lineage
Acute myelogenous leukemia Cells of early myeloid lineage
Histiocytosis Langerhans cell (of monocyte-macrophage origin)
Myelodysplastic syndromes Hematopoietic stem cell with ineffective hematopoiesis that replaces bone marrow
Myeloproliferative syndromes Clonal expansion of a multipotent hematopoietic stem cell, ultimately giving rise to excess numbers of one or more final products of the myeloid lineage

IgA, IgG, IgM, immunoglobulins A, G, and M.



13 Quick review! Cover the right column in Table 14-2 and attempt to define the hematologic terms in the left column



Table 14-2 Hematologic Terminology





















Term Definition
Leukemia Malignant proliferation of blood cells within the bone marrow and circulatory system
Leukemoid reaction Abnormally high WBC count, similar to that occurring in various forms of leukemia, but not as the result of leukemia (typically in response to infection)
Lymphoma Proliferating mass of lymphocytic cells: B cells (most common), T cells, NK cells
Myelofibrosis Fibrosis of bone marrow, often causing extramedullary hematopoiesis that results in hepatosplenomegaly
Myelophthisic anemia Anemia that arises from a space-occupying lesion that displaces normal hematopoietic elements

NK, natural killer; WBC, white blood cell.



14 What are the genetic alterations in the following non-Hodgkin’s lymphomas?


See Table 14-3.


Table 14-3 Genetic Alterations in Non-Hodgkin’s Lymphoma















Non-Hodgkin’s Lymphoma Genetic Alterations
Burkitt’s lymphoma Translocation between chromosomes 8 and 14, involves c-myc activation on chromosome 8; often associated with HIV infection; EBV infection common in African Burkitt’s (patients present with jaw mass)
Sporadic form is associated with pelvic and abdominal lesions
Look for characteristic “starry sky” appearance of Burkitt’s type, due to sheets of neoplastic lymphocytes infiltrated with occasional macrophages
Follicular lymphoma Translocation between chromosomes 14 and 18 involving BCL2 activation (antiapoptosis gene)
Associated with painless, generalized lymphadenopathy, primarily in adults
Mantle cell lymphoma Translocation between chromosomes 11 and 14, which increases cyclin D expression and promotes cell cycle progression
Associated with CD5 expression
Usually fatal, occurs in adults
Cells resemble mantle zone cells that surround follicular centers

EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.



15 What are some characteristics of the other non-Hodgkin’s lymphomas?


See Table 14-4.


Table 14-4 Characteristics of Non-Hodgkin’s Lymphoma (NHL)















NHL Type Description
Cutaneous T-cell lymphoma Caused by a T-cell dyscrasia, unlike most NHLs, which are B cell in origin
Examples are mycosis fungoides and Sézary syndrome
T-cell lymphomas are associated with cutaneous lesions
Diffuse large B-cell lymphoma Very aggressive lymphoma occurring mostly in older adults but sometimes in children
Associated with BCL6 overexpression, which silences p53
Early stage is responsive to treatment
Marginal zone lymphoma (MALToma) Begins as reactive polyclonal B cell proliferation, culminating in monoclonal B-cell neoplasm


16 Quick review with high-yield word associations: Cover the right column of Table 14-5 and attempt to list the associated diseases



Table 14-5 High-Yield Word Associations

































Description Disease
>30% myeloid blasts in bone marrow Acute myelogenous leukemia (AML)
8:14 translocation Burkitt’s lymphoma
14:18 translocation involving BCL2 Follicular lymphoma
Auer bodies Acute myelogenous leukemia
Bence Jones proteinuria Multiple myeloma
Massive splenomegaly, B-cell proliferation, and presence of tartrate-resistant acid phosphatase in B cells Hairy cell leukemia
Philadelphia chromosome Chronic myelogenous leukemia (CML)
Reed-Sternberg (lacunar) cells Hodgkin’s lymphoma
Smudge cells on peripheral blood smear Chronic lymphocytic leukemia (CLL)



Case 14-1


A 65-year-old man is evaluated for recent-onset of low back pain, despite a negative history of trauma or injury to the back. The pain is moderately severe and has been waking him at night. He also reports a 10-lb weight loss in recent months as well as fatigue and recurrent sinus infections. The physical examination is significant only for focal tenderness to palpation at the level of the T12 vertebra.



1 What is the differential diagnosis for back pain in an older patient?


The differential diagnosis is quite broad and includes musculoskeletal back pain (muscle strain, herniated disk), vertebral compression fracture, malignancies (primary or metastatic), abdominal aortic aneurysm, and an infectious cause such as osteomyelitis, abscess, or tuberculosis (Pott’s disease).


For boards, you need to have a high index of suspicion for malignancy, particularly in an older individual with constitutional complaints such as unintentional weight loss and fatigue, back pain that is waking the patient at night (one of the “alarm” symptoms of back pain), and recurrent infections. Malignancies to consider in an older man include metastatic prostate cancer and multiple myeloma.




Case 14-1 continued:


An x-ray film of the skull for evaluation of his sinus infections is shown in Figure 14-1. Serum protein electrophoresis reveals an M spike. A urine dipstick test is negative for proteinuria, but a 24-hour urine protein collection reveals marked proteinuria.


image

Figure 14-1 X-ray film of skull from patient in Case 14-1.


(From Abeloff MD, Armitage JO, Niederhuber JE, et al: Clinical Oncology, 3rd ed. Philadelphia, Churchill Livingstone, 2004.)

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Apr 7, 2017 | Posted by in NURSING | Comments Off on Hematologic Malignancies

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