Systematic Literature Review – Hodgkin’s Lymphoma Assignment | Get Homework Help

Week 2: Systematic Literature Review This week, you will write a mini-systematic literature review, you will be reviewing two sources. • Remember, for a systematic review, focus your analysis on the treatments, causes, diagnosis, and prognosis presented in the literature. • Next, conduct your research of scholarly articles. You will need to choose two sources to include in this mini-literature review. For this review, be sure to: • Select two relevant and appropriate scholarly articles that address the topic you chose besides your text book. • Present a thorough literature review of both articles by summarizing, synthesizing, and evaluating the materials. • Demonstrate understanding of the content presented in the articles. • Include a critical assessment of the sources. Do not simply include a summary of what you have read. • Incorporate citations into your body paragraphs; incorporate the essential and most relevant supporting evidence eloquently and appropriately. • Present your writing in a clear, organized manner. • Provide a strong introduction and conclusion, including further questions for research. • Use proper APA format with proper citations. Review APA Citations Here • Your literature review should be 1–2 pages in length. Remember, you will need to use APA formatting in your literature review and include a title page and a reference page.

Malignant Disorders of White Blood Cells

Marie L. Kotter, Jacquelyn L. Banasik

CHAPTER OUTLINE

• Classification of Hematologic Neoplasms,215
• Etiology of Myeloid and Lymphoid Neoplasms,216
• General Principles of Management,217
  • Diagnosis of Hematologic Neoplasms, 217
  • Principles of Treatment, 218
  • Prevention and Management of Complications, 219
• Myeloid Neoplasms,221
  • Chronic Myeloid Leukemia, 221
  • Acute Myeloid Leukemia, 222
• Lymphoid Neoplasms,223
  • Chronic Lymphoid Leukemia, 223
  • Acute Lymphoblastic Leukemia/Lymphoma, 223
  • Hairy Cell Leukemia, 224
  • Plasma Cell Myeloma (Multiple Myeloma), 224
  • Hodgkin Disease, 227
  • B-Cell, T-Cell, and NK-Cell Lymphoma (Non-Hodgkin), 229

KEY QUESTIONS

• How do the various types of leukemia, lymphoma, and plasma cell myelomas differ based on the type of malignant transformation?
• How do the clinical presentations, prognosis, and management of types of acute and chronic leukemia differ?
• Why are malignant disorders of white blood cells commonly associated with bone marrow depression?
• How is Hodgkin disease clinically and histologically differentiated from other types of lymphoma?
• What is the purpose and process of staging procedures for lymphomas?
• What clinical and laboratory findings would suggest a diagnosis of plasma cell myeloma?

Leukemia, lymphoma, and plasma cell myeloma (multiple myeloma) are common neoplastic disorders of the bone marrow and lymphoid tissues. Depending on the location and specific types of white blood cells involved, these malignancies can be further divided into a number of specific subtypes. Leukemias can be conceptualized as circulating tumors that are disseminated from the beginning of the disease process and primarily involve the blood and bone marrow. Lymphoma tends to localize in lymph tissues, but is often disseminated to other sites at the time of diagnosis. Plasma cell myeloma is a malignant transformation of B-lymphocyte plasma cells and has a predilection to form localized tumors in bony structures.

Malignancies of the blood-forming tissues and lymphatic structures often present with nonspecific symptoms. Malaise, weakness, unexplained fever, night sweats, and recurrent infections should raise suspicion of malignancy. Enlarged, nontender lymph nodes (lymphadenopathy) are a common finding in lymphoma and some leukemias. Often, white blood cell malignancies are found by chance during routine assessment of the complete blood cell count (CBC). A very high total white blood cell count or the presence of abnormal cell types should precipitate an assessment for hematologic cell malignancy. In general, earlier detection of malignancy is associated with a better prognosis for cure.

Classification of Hematologic Neoplasms

Various classification schemes have been used to group hematologic neoplasms, with clinicians favoring schemes that use clinical findings and pathologists preferring morphologic criteria. With the advent of technologies to identify specific genetic alterations and molecular characteristics of neoplastic cells, the traditional classification systems have become less useful. However, many clinicians and organizations, such as the American Cancer Society, continue to use traditional groupings to collect statistics and to provide information to the public. The approach used in this chapter incorporates the most recent World Health Organization (WHO) classifications for hematologic neoplasms and includes common clinical terminology. A major force behind the adoption of the WHO classification is the recognition that lymphoid leukemias and lymphomas are not separate disorders, but represent different stages of the same biological disease. Thus the major categories of the WHO system are based on the cell type of the neoplasm rather than its location in the body. Neoplasms involving cells of the myeloid lineage (Box 11.1) are separated from those of the lymphoid lineage (Box 11.2). The myeloid lineage includes red blood cells, platelets, monocytes, and granulocytes; the lymphoid lineage includes B cells, T cells, and natural killer (NK) cells (Fig. 11.1). There are four major categories of myeloid neoplasms: myeloproliferative diseases, myelodysplastic/proliferative diseases, myelodysplastic syndromes, and acute myeloid leukemia (AML). There are three major categories of lymphoid neoplasms: B-cell neoplasm, T-cell and NK-cell neoplasm, and Hodgkin disease. The term non-Hodgkin lymphoma is still in clinical usage and refers to lymphomas of B-cell, T-cell, and NK-cell origin. Non-Hodgkin lymphoma includes such a large and diverse group of malignancies that it has little relevance to prognosis or treatment. The WHO classification does not use this term. There are many etiologic, pathogenic, and treatment similarities among the hematologic malignancies, and these are addressed in a general way first, followed by sections concentrating on specific diseases.

Box 11.1

WHO Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

• Chronic myeloid leukemia (CML), BCR-ABL1⁺
• Chronic neutrophilic leukemia (CNL)
• Polycythemia vera (PV)
• Primary myelofibrosis (PMF)
  • PMF, prefibrotic/early stage
  • PMF, overt fibrotic stage
• Essential thrombocythemia (ET)
• Chronic eosinophilic leukemia, not otherwise specified (NOS)
• MPN, unclassifiable
• Mastocytosis

Myeloid/Lymphoid Neoplasms With Eosinophilia and Rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2

• Myeloid/lymphoid neoplasms with PDGFRArearrangement
• Myeloid/lymphoid neoplasms with PDGFRBrearrangement
• Myeloid/lymphoid neoplasms with FGFR1rearrangement
• Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)
• Atypical chronic myeloid leukemia (aCML), BCR-ABL1⁻
• Juvenile myelomonocytic leukemia (JMML)
• MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
• MDS/MPN, unclassifiable

Myelodysplastic Syndromes (MDS)

• MDS with single lineage dysplasia
• MDS with ring sideroblasts (MDS-RS)
  • MDS-RS and single lineage dysplasia
  • MDS-RS and multilineage dysplasia
• MDS with multilineage dysplasia
• MDS with excess blasts
• MDS with isolated del(5q)
• MDS, unclassifiable
• Provisional entity: Refractory cytopenia of childhood
• Myeloid neoplasms with germ line predisposition

Blastic Plasmacytoid Dendritic Cell Neoplasm

Acute Myeloid Leukemia (AML) and Related Neoplasms

• AML with recurrent genetic abnormalities
• AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11
• APL with PML-RARA
• AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A
• AML with t(6;9)(p23;q34.1);DEK-NUP214
• AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
• AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1
• Provisional entity: AML with BCR-ABL1
• AML with mutated NPM1
• AML with biallelic mutations of CEBPA
• Provisional entity: AML with mutated RUNX1
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• AML, NOS
  • AML with minimal differentiation
  • AML without maturation
  • AML with maturation
  • Acute myelomonocytic leukemia
  • Acute monoblastic/monocytic leukemia
  • Pure erythroid leukemia
  • Acute megakaryoblastic leukemia
  • Acute basophilic leukemia
  • Acute panmyelosis with myelofibrosis
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome
  • Transient abnormal myelopoiesis (TAM)
  • Myeloid leukemia associated with Down syndrome

Acute Leukemias of Ambiguous Lineage

• Acute undifferentiated leukemia
• Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
• MPAL with t(v;11q23.3); KMT2Arearranged
• MPAL, B/myeloid, NOS
• MPAL, T/myeloid, NOS

From Arber DA et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391–2404.

Box 11.2

WHO Classification of Lymphoid Neoplasms

Precursor Lymphoid Neoplasms

• Precursor B lymphoblastic leukemia/lymphomas (precursor B-cell ALL)
• Precursor T lymphoblastic leukemia/lymphoma

Mature (Peripheral) B-Cell Neoplasms*

• B cell chronic lymphocytic leukemia/small lymphocytic lymphoma
• B cell prolymphocytic leukemia
• Lymphoplasmacytic lymphoma
• Splenic marginal zone B-cell lymphoma (6 villous lymphocytes)
• Hairy cell leukemia variant
• Plasma cell myeloma/plasmacytoma
• Waldenström macroglobulinemia
• Heavy-chain diseases
• Extranodal marginal zone B-cell lymphoma of MALT type
• Nodal marginal zone B-cell lymphoma (6 monocytoid B cells)
• Follicular lymphoma
• Mantle cell lymphoma
• Epstein-Barr virus positive DLBCL of the elderly
• Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
• Primary mediastinal (thymic) large B-cell lymphoma
• Primary effusion lymphoma
• Burkitt lymphoma/Burkitt cell leukemia

Mature T-Cell and NK-Cell Neoplasms

• Mature (peripheral) T-cell neoplasms
  • T-cell prolymphocytic leukemia
  • T-cell granular lymphocytic leukemia
• Aggressive NK-cell leukemia
• Adult T-cell lymphoma/leukemia (HTLV1⁺)
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy-type T-cell lymphoma
• Hepatosplenic γδ T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Mycosis fungoides
• Sézary syndrome
• Primary cutaneous anaplastic large cell lymphoma
• Peripheral T-cell lymphoma, not otherwise characterized
• Angioimmunoblastic T-cell lymphoma
• Anaplastic large cell lymphomas (ALK positive or ALK negative)

Hodgkin Lymphoma (Hodgkin Disease)

• Nodular lymphocyte predominance Hodgkin lymphoma
• Classical Hodgkin lymphoma
• Nodular sclerosis Hodgkin lymphoma (Grades 1 and 2)
• Lymphocyte-rich classical Hodgkin lymphoma
• Mixed cellularity Hodgkin lymphoma
• Lymphocyte depletion Hodgkin lymphoma

^*B- and T/NK-cell neoplasms are grouped according to major clinical presentations (predominantly disseminated/leukemic, primary extranodal, predominantly nodal).

From Hoffbrand AV, Moss PAH: World Health Organization classification of tumours of the haematopoietic and lymphoid tissues. In Essential haematology, ed 6, Oxford, England, 2011, Blackwell, pp 428–429.

 

FIG 11.1 Division of hematologic neoplasms into myeloid and lymphoid lineages. PV, Polycythemia vera.

Etiology of Myeloid and Lymphoid Neoplasms

As in other malignant processes, the exact cause of hematologic neoplasms is unknown. The basic mechanism of malignant transformation involves mutation of cells, which disrupts growth control and differentiation pathways. These processes are thought to be similar to those described for solid tumors (see Chapter 7). A number of specific genetic mutations have been found for several hematologic malignancies. In some cases, these specific mutations indicate prognosis of the disease, and in others they may provide a target for therapy. Monoclonal antibodies have been developed to attach to products of some of these mutated genes, thus allowing therapy to be more targeted to the abnormal cells.

Viruses have long been suspected as mutagenic agents in some neoplasms, particularly retroviruses and herpesviruses. Close associations have been found between a small number of viruses and particular malignancies. For example, human T-cell leukemia virus (HTLV-1) is linked to the development of adult T-cell lymphoma/leukemia, and human immunodeficiency virus (HIV) is linked to B-cell lymphomas. Epstein–Barr virus (EBV) has been implicated in both Hodgkin disease and Burkitt lymphoma. Effective immune surveillance is thought to keep proliferation in check and prevent progression in immunocompetent individuals.

Radiation exposure is an important etiologic factor for leukemia and lymphoma. Because of the relatively high turnover of hematologic cells, they are more susceptible to radiation-induced damage than most other cell types. An acute whole-body dose of radiation, like that which occurs with nuclear explosions, is known to increase the risk of leukemia. In Japanese survivors of the atomic bomb, the estimated lifetime risk of leukemia is 0.85%, sixfold higher than the norm. There are substantial uncertainties about the risk of low-level, long-term exposure to radiation. The average annual exposure from usual sources, including cosmic rays and medical procedures, is very low and is estimated to account for less than 5% of leukemia cases.

Despite intensive scrutiny only a small number of chemicals have been shown unequivocally to increase the risk of hematologic malignancies. Benzene has been implicated in numerous studies, as has cigarette smoking. Other suggested carcinogens have failed to be confirmed, including exposure to hair dye, alcohol, and marijuana. On the other hand, a study from the Children’s Cancer Group found a link between high maternal intake of products high in bioflavonoids (beans, fresh vegetables, and fruit) and an increased incidence of infant leukemia. These bioflavonoids were enzyme inhibitors (topoisomerase II inhibitors) that caused DNA cleavage and chromosome translocations. Many of the antineoplastic drugs used to treat cancers, especially the alkylating agents, are significant factors in the development of posttreatment hematologic neoplasia. Any drugs that suppress the bone marrow or immune function are also believed to predispose to the emergence of malignancies.

A number of disease conditions have been linked to the development of leukemia, although the mechanisms are unclear. A reduction or alteration in normal hematopoiesis, as occurs in such disorders as Fanconi anemia and aplastic anemia (see Chapter 13), is associated with a higher incidence of leukemia. A higher risk also has been noted in some genetic diseases, including Down syndrome and Klinefelter syndrome (see Chapter 6).

General Principles of Management

Diagnosis of Hematologic Neoplasms

Manifestations of hematologic neoplasms vary somewhat, depending on the cell type involved. Common manifestations are shown in Box 11.3. Clinical symptoms are related to bone marrow suppression and organ dysfunction secondary to leukemic infiltration. Bone marrow suppression results in varying degrees of leukopenia, anemia, and thrombocytopenia. These three deficiencies cause the most common clinical manifestations and may prompt the patient to seek care.

Box 11.3

Common Manifestations of Hematologic Malignancies

History

• Fever
• Weight loss
• Night sweats
• Itching (pruritus)
• Fatigue
• Bone pain (sternum, tibia, femur, back)
• Abdominal fullness
• Bleeding episodes (epistaxis, menorrhagia)
• Bruising, petechiae
• Frequent infections
• Headache, nausea, vomiting

Physical

• Enlarged spleen
• Enlarged liver
• Enlarged lymph nodes
• Hyperplasia of gums

Laboratory

• Anemia or polycythemia
• Thrombocytopenia or thrombocythemia
• Leukopenia or leukocytosis
• Blasts on peripheral blood smear
• Elevated uric acid level
• Elevated alkaline phosphatase level
• Hypercalcemia

Anemia, with a hematocrit level of 25% to 30% or a hemoglobin level of 8 to 10 g/dL, may manifest with pallor, fatigue, malaise, shortness of breath, and decreased activity tolerance. The severity of symptoms is determined by the rate of red blood cell decrease, as well as the absolute deficiency. Chronically low hemoglobin and hematocrit values may be better tolerated than a drastic drop in these measurements. Depending on symptoms, transfusion may be indicated when the hematocrit level falls below 30%.

Thrombocytopenia, with a platelet count less than 20,000 cells/µL, can manifest as petechiae, easy bruising, bleeding gums, occult hematuria, or retinal hemorrhages. Spontaneous intracranial bleeding can occur and may be fatal. In general, the risk of bleeding increases proportionately to the fall in platelet count. Platelet transfusion may be given when the risk of bleeding is high.

Insufficient numbers of functional leukocytes leave the patient at high risk for development of infection, and the CBC is routinely monitored. Neutropenia is an absolute neutrophil count less than 500 cells/µL, and an affected patient requires protective isolation (neutropenic precautions) to prevent infection. Infections may be caused by bacterial, viral, fungal, or protozoal organisms. Often, the microorganisms are of the opportunistic variety. That is, they are part of the patient’s own flora, which normally do not cause disease unless the host’s immune system becomes incompetent. It is very difficult to protect patients from their own flora, and infection is the most common cause of death in the immunocompromised leukemic patient. The presence of infection is suspected if fever develops. Infections are managed aggressively with antibiotic agents to prevent development of life-threatening sepsis.

Infiltrative manifestations include lymphadenopathy, joint swelling and pain, weight loss, anorexia, hepatomegaly, and splenomegaly. Sternal tenderness is frequently present in chronic myeloid leukemia (CML). Gingival hyperplasia occurs in AML. Meningeal involvement is frequently encountered in children with acute lymphoid leukemia (ALL). Central nervous system (CNS) infiltration can occur with any type of leukemia and may be difficult to manage because of the poor ability of chemotherapeutic agents to cross the blood–brain barrier. CNS involvement can present with increased intracranial pressure, seizures, or changes in mental ability. Increased intracranial pressure should be suspected in the leukemia patient who complains of nausea, vomiting, headache, and visual changes.

A key aspect of diagnosis is the evaluation of a peripheral blood sample. Blood cell number and morphologic evaluation are indicative; however, definitive diagnosis is usually made after bone marrow aspiration or lymph node biopsy. Malignant cells can be subtyped according to genetic and molecular characteristics to better determine prognosis and choice of treatment.

Principles of Treatment

To make informed treatment decisions, patients and their families need information about the nature and prognosis of their disease, as well as about the risks and benefits of various treatment options. Many treatment protocols are experimental, and the outcomes may be uncertain. Sometimes the side effects of treatment, as well as its limited efficacy, will weigh in favor of palliative care. Treatment decisions are complex and stressful for all concerned. A great deal of support must be available during the diagnostic, treatment, and monitoring phases.

The management of hematologic malignancies relies primarily on the use of combination chemotherapy to eradicate malignant cells and stem cell transplant to rescue and restore bone marrow function. In some cases radiation and tissue-specific drug therapy may be indicated. Unfortunately, the treatment regimen usually causes many serious side effects that must be monitored and treated.

The goal of chemotherapy is to induce long-term remission, that is, the absence of any detectable neoplastic cells in the body. A complete remission (CR) is defined as a return to normal hematopoiesis with normal red blood cell, neutrophil, and platelet counts and no detectable neoplastic cells. For leukemia, the bone marrow must have less than 5% blasts, which are the most immature bone marrow cells, and be maintained for at least 4 weeks. CR is not synonymous with cure. Therefore most treatment protocols include several cycles of chemotherapy to eradicate the undetected cells. The choice of antineoplastic agents varies with the type of neoplasia and the stage of clinical disease. Most chemotherapeutic agents work by disrupting some aspect of DNA synthesis or cell replication and induce apoptosis (cell death; see Chapter 4). In general, rapidly dividing cells are more susceptible to apoptosis because they have less time for repair. Neoplasms with genetic defects that impair apoptotic pathways may be more difficult to eradicate and require more intense therapy. Unfortunately, these high doses are toxic to normal stem cells as well and can produce fatal bone marrow failure. Therefore to effect a cure, high-dose chemotherapy is often followed by bone marrow “rescue” with transplantation of functional stem cells.

Chemotherapy usually includes two or three treatment phases: (1) remission induction phase, (2) postremission or consolidation phase, and (3) remission maintenance phase. The aim of treatment during the remission induction phase is to eliminate all detectable neoplastic cells and achieve a CR. Postremission consolidation therapy begins after CR is attained in an attempt to eliminate the population of undetected cells that may have escaped initial induction phase treatment. Maintenance phase treatment is used in the management of some neoplasms to prolong the remission interval. Intermittent chemotherapy may be continued for 2 to 3 years after initial induction of remission. Drugs that target the neoplastic cells specifically, such as monoclonal antibodies or molecular therapies, are generally less toxic than other agents and may be used for long-term maintenance in patients with residual disease.

In children and adults, the CNS can act as a sanctuary for neoplastic cells in diseases such as ALL and AML. This makes conventional routes of chemotherapy unsuccessful, because they do not permit drugs to cross the blood–brain barrier efficiently. Chemotherapeutic agents administered into the cerebrospinal fluid via lumbar puncture (intrathecal route) can effectively eliminate leukemic cells in the CNS. This therapy carries significant risk for temporary or permanent neurologic damage. A number of different chemotherapeutic agents can be administered safely by the intrathecal route, including methotrexate.

Prevention and Management of Complications

Maintenance of adequate nutrition in patients with hematologic malignancy is a major challenge. Anorexia, weight loss, nausea, vomiting, and stomatitis are common findings, especially during the treatment phase. Children and adolescents receiving chemotherapy may experience significant growth delay, and measures to maintain protein and caloric intake are necessary. Newer antiemetic agents have been helpful in reducing nausea, vomiting, and anorexia associated with chemotherapy and should be considered in patients experiencing these symptoms.

Infection is the most troublesome complication for the patient who is immunosuppressed by either disease or treatments. Constant vigilance in prevention, early detection, and rapid management of infections can profoundly affect the outcome of chemotherapy. The length of time that a patient remains neutropenic can be shortened with the use of growth factors to stimulate bone marrow production of granulocytes.

Bone marrow transplantation has been an important part of the management of certain leukemias for many years. The intense chemotherapy used to induce remission can lead to bone marrow failure. Stem cells can be reintroduced into the host’s bone marrow by bone marrow transplantation. The transplanted cells are given intravenously; they find their way to the host’s bone marrow, where they establish residence and begin to produce functional white blood cells, red blood cells, and platelets. A close match between donor and host is necessary for a successful transplantation. Otherwise, the transplanted cells can mount an immune attack on the host’s tissues—a life-threatening problem called graft-versus-host disease (see Chapter 10). In past years, the transplant was obtained by aspiration from the marrow of a suitable donor, and this may still be done in some cases. Peripheral stem cell transplantation allows stem cells to be harvested from the circulating bloodstream. This procedure can be used to collect stem cells from the patient’s own blood to be stored and then reinfused after chemotherapy and irradiation. This type of transplant is called autologous, whereas a transplant from a closely matched relative is called allogeneic (Fig. 11.2). Use of autologous transplants eliminates the problem of graft-versus-host disease and reduces transplant-related mortality, but the potential for disease recurrence is higher than with allogeneic transplants.

 

FIG 11.2 Procedures for allogeneic and autologous stem cell transplantation. For nonmyeloblative (reduced intensity) allogeneic stem cell transplantation, lower doses of chemotherapy, with or without radiotherapy, are used. (From Rodak B et al: Hematology: clinical principles and application, ed 4, Philadelphia, 2012, Saunders.)

It has been noted that in AML and CML, transplantation with allogeneic cells is much more successful in curing leukemia than is autologous transplantation. Transplanted cells in the allograft are thought to detect and kill leukemic cells in a process termed graft versus leukemia. Autologous transplants are appropriate in some cases, especially when a matched donor is not available, because they may extend life even though cure is unlikely. Autologous transplants are well tolerated and cause fewer complications than allografts. Methods to purify a patient’s collected peripheral blood by selectively removing neoplastic cells are available to reduce the risk of reintroducing malignant cells during autologous transplantation. Increased availability of stem cell transplants allows patients to undergo more intensive chemotherapy, aimed at cure rather than palliation, based on the knowledge that bone marrow rescue is possible.

Anemia is a common complication of leukemia and chemotherapy. Red blood cell production by the bone marrow is suppressed, but the size and shape of red blood cells present in the blood are normal. This is called normocytic, normochromic anemia. Administration of erythropoietin growth factors can enhance red blood cell production and moderate anemic episodes. However, patients frequently require red blood cell transfusion therapy to maintain adequate red blood cell counts. Patients with frequent or significant bleeding episodes are also predisposed to severe anemia, and efforts to prevent bleeding will help minimize anemia.

Platelet deficiency (thrombocytopenia) with resultant hemorrhage can be a life-threatening complication of leukemia and chemotherapy. In patients at high risk of bleeding, fresh frozen plasma or pooled platelets may be given to inhibit bleeding. Patients must be protected from trauma and may be placed on activity restrictions.

Pain is a common complication of the diagnostic and treatment protocols used in the cancer patient as well as of the disease process itself. Pain most commonly involves the bones and joints, and is due to pressure caused by infiltration and accumulation of neoplastic cells in the bone marrow. Hemarthrosis (bleeding into joints) can cause acute episodes of joint pain. Chemotherapy may help reduce bone pain, as the number of neoplastic cells is reduced drastically. Patients are subjected to numerous painful procedures during diagnosis, treatment, and monitoring. Frequent collection of blood and bone marrow samples, placement of intravenous access lines for drug administration, and manifestations of unpleasant drug side effects all contribute to the pain experience. Nausea and mouth pain (stomatitis) are frequent complaints during chemotherapy. Pain management with a variety of strategies, including narcotic and nonnarcotic drugs, distraction, and biofeedback, is generally helpful. (See Chapter 47 for a discussion of pain and pain management.)

Epithelial cells, with normally high rates of turnover, are particularly susceptible to damage by radiation and chemotherapy. Sloughing of skin and mucous membranes and hair loss (alopecia) are common. Loss of skin and mucous membrane integrity increases the risk of infection and can contribute significantly to the pain and discomfort of treatment. Abnormalities in growth, development, and fertility are complications of particular concern in children undergoing radiation and chemotherapy.

Key Points

• Classification of the types of leukemia is based on cell type involved (lymphoid or myeloid) and degree of cell maturation. Common myeloid neoplasms include Chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and acute myeloid leukemia (AML). Common lymphoid neoplasms include chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), plasma cell myeloma, Hodgkin disease, and various forms of non-Hodgkin lymphoma.
• Risk factors for the development of hematologic neoplasms include exposure to chemical, viral, and radiation mutagens; consequences of chemotherapy drugs; and effects of immunodeficiency disorders.
• Common manifestations of hematologic neoplasia are due to insufficient production of normal white blood cells, red blood cells, and platelets, as evidenced by leukopenia, anemia, and thrombocytopenia. Anemia manifests as pallor, fatigue, dyspnea, and decreased activity tolerance. Thrombocytopenia causes petechiae, bleeding gums, hematuria, and prolonged bleeding time. Leukopenia manifests as frequent, recurrent infections. Other manifestations may occur with infiltration of tissues and organs. These include weight loss, anorexia, lymphadenopathy, bone pain, and central nervous system (CNS) dysfunction.
• Chemotherapy is the mainstay of management for most hematologic neoplasms. Several courses may be needed to kill neoplastic stem cells. Most chemotherapeutic agents interfere with some aspect of DNA replication and cell division to induce apoptosis (programmed cell death).
• Treatment is associated with a number of potential complications, including anemia, infection, and bleeding. Rapidly dividing hair cells and mucous membranes are also affected, leading to alopecia and stomatitis. Transfusion of blood products or stimulation of endogenous production with colony-stimulating factors and erythropoietin may be necessary. Bone marrow transplantation may be undertaken in some cases to restore stem cell function.

Myeloid Neoplasms

Myeloid neoplasms result from transformation and proliferation of a precursor stem cell in the bone marrow (Fig. 11.3). The progeny of the aberrant stem cell clone accumulate in the bone marrow and are released into the circulation. In many cases, the abnormal stem cell is multipotent and causes the overproduction of more than one cell type, resulting in myeloproliferative disease. The cells produced in myeloproliferative diseases are usually functional and have a normal morphologic appearance. The common myeloproliferative diseases are CML, PV, and ET, referring, respectively, to an excess of granulocytes, red blood cells, and platelets. These insidious and indolent disorders have few clinical symptoms and are commonly discovered on routine CBC analysis. Common features of CML, PV, and ET include involvement of a multipotent hematopoietic progenitor cell; hypercellularity of marrow; overproduction of one or more functional blood cells; chromosomal abnormalities involving chromosomes 1, 8, 9, 13, and 20; and eventual spontaneous conversion to AML or development of marrow fibrosis.

 

FIG 11.3 Maturation pathways of myeloid cells showing the different types of leukemia associated with various stages of development. M1, M2, and M3 types result in granulocytic leukemia; M4 has characteristics of monocytic and granulocytic leukemia; M5 is monocytic; M6 is associated with erythroid leukemia; and M7 is associated with megakaryocytic leukemia. RBC, Red blood cell.

In contrast to the myeloproliferative diseases, the myelodysplastic syndromes and AML are characterized by neoplastic cells that are morphologically and functionally abnormal. The prognosis for myelodysplastic syndromes and AML is poor, and intensive treatment is necessary to extend life. AML and CML are described next. A discussion of PV and ET can be found in Chapters 13 and 14, respectively.

Chronic Myeloid Leukemia

Pathogenesis and clinical manifestations.

CML represents approximately 15% of all cases of leukemia in the United States. The average age of onset is between 40 and 50 years, and CML occurs only occasionally in childhood and adolescence. The majority of CML cases are characterized by malignant granulocytes that carry a unique chromosomal abnormality, the Philadelphia chromosome (Ph⁺). The Philadelphia chromosome is formed because of a balanced translocation between chromosomes 9 and 22 (Fig. 11.4). The translocation causes two genes to be juxtaposed, resulting in a new fusion gene called bcr-abl. This mutation is thought to be critical in the development of CML. Molecular studies have revealed that the protein product of the fusion gene is a functional enzyme that spurs cell proliferation and reduces apoptotic cell death. CML is unusual among human cancers because a single oncogene (bcr/abl) is capable of conferring a malignant state. Numerous mutations are necessary for development of most other cancers (see Chapter 7). The cells in CML are more mature than those found in AML, as noted by the greater degree of nuclear segmentation (Fig. 11.5).

 

FIG 11.4 Balanced translocation between chromosomes 9 and 22 results in the formation of a Philadelphia chromosome. The translocation causes two genes, abl and bcr, to become juxtaposed, resulting in a fusion gene. This fusion gene, bcr-abl, is thought to be essential for the development of chronic myeloid leukemia.

 

FIG 11.5 Peripheral blood smear from a patient with chronic myeloid leukemia (CML). Note that a greater degree of neutrophil segmentation is found in CML than in acute myelogenous leukemia (see Fig. 11.6), reflecting a more advanced stage of development. (From Hoffman R, et. al. Hematology: basic principles and practice, ed 6, Philadelphia, 2013, Saunders.)

The usual clinical presentation of CML includes a high granulocyte count on the CBC and splenomegaly. Symptoms, when present, may include fatigue, weight loss, diaphoresis, bleeding, and abdominal discomfort from the enlarged spleen.

Prognosis and treatment.

CML does not respond well to chemotherapy. Although most patients will achieve a temporary remission, the overall survival time is poor. In untreated patients the median survival is about 2 years. After discovery of the fusion protein (bcr/abl), drugs targeted to inhibit its action were developed (e.g., imatinib). The goal of anti-bcr/abl therapy is to reduce the number of leukemic cells with the bcr/abl phenotype to undetectable levels. It is not known whether imatinib can cure CML or what duration of treatment is necessary to permanently suppress the leukemic cell population. Some patients with CML have developed drug resistance against imatinib, and research is ongoing. The only known curative treatment is allogeneic bone marrow transplantation from a suitable donor. It is believed that the donor cells detect and kill the host’s leukemic cells. Even with a human leukocyte antigen (HLA)–identical sibling donor, the probability of transplant-related mortality is about 25%, and the likelihood of long-term disease-free survival is 50% to 60%. Transplant-related mortality is about 50% if the HLA-matched donor is unrelated. Bone marrow transplantation with cells harvested from the patient’s own blood (autografting) during the early stages of CML may also be done, but it is less effective in curing the disease. For those not able to undergo stem cell transplantation, standard chemotherapy during the chronic phase may be instituted. Once CML has progressed to the blast phase, essentially becoming AML, the prognosis is poor, regardless of treatment, with an expected median survival of 3 to 4 months.

Acute Myeloid Leukemia

Pathogenesis and clinical manifestations.

AML is primarily a disease of adults, comprising 80% of cases of acute leukemia in this population but accounting for only 20% of the cases of acute leukemia of childhood. The median age at presentation is 64 years. Like CML, AML is a malignant disorder associated with transformation of a myeloid stem cell. The bone marrow aspirate must have more than 20% blasts to be classified as AML. AML can present in a variety of ways because of the potential for myeloid stem cells to produce different cell types. Thus AML has a number of subtypes. Acute granulocytic leukemia is the most common type of disorder, and the term is often used interchangeably with AML. Myeloblastic cells have a large, nonsegmented nucleus and fine chromatin (Fig. 11.6). AML is also subtyped according to genetic abnormalities. Worse outcomes are noted with loss of P53 or RB tumor suppressor gene function. Most are chromosomal translocations or inversions. If cytogenetic class is not apparent, then AML is classified by morphologic characteristics, including myeloid cell of origin and degree of differentiation or maturation. Correct classification increases the accuracy of prognosis and may influence the choice of treatment.

 

FIG 11.6 Peripheral blood smear showing typical cells of acute myelogenous leukemia. (From Eric Jeandidier et. al, A cytogenetic study of 397 consecutive acute myeloid leukemia (AML) cases identified three with a t(7;21) associated with 5q abnormalities and exhibiting similar clinical and biological features, suggesting a new, rare AML entity. Cancer Genetics, 2012;205(7):365–372.)

AML presents in a manner very similar to that of ALL, and the two are difficult to distinguish by clinical findings alone. Acute leukemia causes bone pain, anemia, thrombocytopenia, and increased susceptibility to infection. The skin, the genitourinary and gastrointestinal systems, and the respiratory tract are common infection sites. The onset of symptoms is abrupt, with most patients seeking care within a few weeks of disease onset. The prognosis is much worse for AML than for ALL, with fewer than 50% of children and only about 25% of adults achieving long-term survival. An exception is the promyelocytic subtype of AML. Although it accounts for only 10% to 15% of AML cases, acute promyelocytic leukemia (APL) deserves special consideration because it is the most curable of all AML subtypes, with a 70% to 80% 5-year disease-free survival. APL is characterized by a chromosomal translocation between chromosomes 8 and 21, which forms a fusion gene called PML/RARα. The PML/RARα protein binds to a repressor complex in the cell nucleus and inhibits myeloid cell differentiation. RARα is a retinoic acid receptor that can be induced to release its inhibitory hold on differentiation when all–trans-retinoic acid (ATRA) is administered. Addition of ATRA to the chemotherapy management of patients with APL significantly improves disease-free survival (see Table 11.1 for a comparison of acute and chronic leukemias).

TABLE 11.1

Comparison of Acute and Chronic Leukemias
	Acute	Chronic
Age	All ages	Adult
Clinical onset	Sudden	Insidious
Course of untreated disease	Weeks to months	Months to years
Predominant cell	Blasts, some mature forms	Mature forms
Anemia	Mild to severe	Mild
Thrombocytopenia	Mild to severe	Mild
WBC count	Variable	Increased

Adopted from McKenzie S: Clinical laboratory hematology, Upper Saddle River, NJ, 2004, Pearson, p 482.

Prognosis and treatment.

Treatment protocols for AML are increasingly incorporating the cytogenetic profile of the leukemic cells to individualize therapy and monitor response. Traditionally the management of AML has two phases: remission induction and consolidation/postremission. A CR is attempted in the remission induction phase, with an attempt to eliminate any undetected residual leukemic cells during the consolidation/postremission phase. Patients with AML who are able to complete only one or two cycles of their chemotherapy because of toxicity almost invariably have recurrence of leukemia even when CR was achieved. To induce remission, most protocols use two cycles of a combination of agents. Postremission therapy commonly includes high-dose Ara-C in younger patients, whereas the elderly require lower-dose regimens. Drug treatment is constantly being evaluated and altered to obtain better outcomes. With the advent of allogeneic stem cell transplantation, the chances for a cure may improve; however, procedure-related mortality is 10% to 25%. New therapies using monoclonal antibodies to detect and destroy leukemic cells have been used and show promise for improving outcomes in AML.

Key Points

• Chronic myeloid leukemia (CML) is a myeloproliferative disorder that primarily affects adults, has an insidious onset, and responds poorly to chemotherapy. Most cases of CML are characterized by the presence of a gene translocation (Philadelphia chromosome) that produces a fusion gene called bcr-abl. The product of this gene is thought to be responsible for producing the malignancy. This molecular abnormality is the target of new drug therapies to eliminate neoplastic cells. The prognosis of CML remains relatively poor, but may be improved with allogeneic bone marrow transplantation in which transplanted cells destroy leukemic cells.
• AML affects adults primarily, has an acute onset, responds fairly well to treatment, and has a prognosis somewhat worse than that of ALL. AML is usually a malignancy of granulocytes, although other myeloid cell types may be affected. Several gene abnormalities have been identified in AML that may indicate better or worse prognosis. The median survival of patients younger than 60 years is 30% to 40% at 4 years.

Lymphoid Neoplasms

The lymphoid neoplasms include malignant transformations of B cells, T cells, and NK cells. When present in blood and bone marrow, lymphoid neoplasms are called leukemias, and when they are localized in lymphoid tissues, they are called lymphomas. The location of lymphoid neoplasms is a consequence of the stage of the disease. The WHO classification uses cell type rather than stage to classify the lymphoid neoplasms, resulting in some difficulty with the traditional conceptualization of leukemias and lymphomas. The factors that determine whether a particular neoplastic cell will present as leukemia or as lymphoma are not presently known. Subcategories of the B-cell and T-cell/NK-groups are based on the maturity of the neoplastic cells (see Box 11.2). The precursor cell neoplasms are characterized by cells that have arrested development in the early blast stage, whereas the mature cell neoplasms are more differentiated and often located in peripheral sites (Fig. 11.7).

 

FIG 11.7 Maturation pathways of T and B lymphocytes showing the stages at which lymphocyte development is typically arrested in leukemia. Different markers are present on the surface of B cells and T cells at progressive stages of development, which are helpful in identifying the neoplastic cell type and maturity.

Chronic Lymphoid Leukemia

Pathogenesis and clinical manifestations.

CLL accounts for about 30% of all cases of leukemia in the United States. In 95% of cases, a malignant B-cell precursor is at fault. Only 5% of cases of CLL are associated with T-cell transformation, but this type is more aggressive. In general, B-cell CLL follows an indolent course, which is usually asymptomatic. Often CLL is found by accident on routine blood count examinations. When CLL becomes symptomatic, patients may experience fatigue, weight loss, and anorexia. Because the leukemic B cells do not produce antibodies normally, an increased susceptibility to certain types of infection may occur. Malignant lymphocytes invade lymphoid tissues and bone marrow, disrupting function. Lymphoid invasion often presents as enlarged, painless lymph nodes (lymphadenopathy) or enlarged spleen (splenomegaly). Bone marrow infiltration reduces the production of other cells, including red blood cells and platelets. A typical slide of a bone marrow aspirate from a patient with CLL is shown in Fig. 11.8. Note the preponderance of lymphoid cells. CLL cells are characterized by defective apoptosis and therefore have extended life spans. They are derived from mature peripheral B cells (see Table 11.2 for a comparison of acute and chronic leukemias).

 

FIG 11.8 Bone marrow aspirate showing small lymphocytes with condensed nuclear chromatin typical of chronic lymphocytic leukemia, B-cell type. (From Henderson ES et al, editors: Leukemia, ed 7, Philadelphia, 2003, Saunders, color plate 11-28.)

TABLE 11.2

Comparison of Acute Lymphocytic (ALL) and Acute Nonlymphocytic Leukemia (ANLL)
	ALL	ANLL
Age	Common in children	Common in adults
Hematology results	Anemia, neutropenia, thrombocytopenia	Anemia, neutropenia, thrombocytopenia
Cell morphology	Small to medium lymphoblasts, fine chromatin, indistinct nucleoli	Medium to large myeloblasts, distinct nucleoli, clear chromatin, Auer rods
Cytochemistry	PAS positive, peroxidase negative, Sudan black B negative	PAS negative, peroxidase positive, Sudan black B positive

PAS, Periodic acid–Schiff reaction.

Adopted from McKenzie S: Clinical laboratory hematology, Upper Saddle River, NJ, 2004, Pearson, p 487.

Prognosis and treatment.

Certain genetic mutations confer better or worse prognosis. A mutation in the variable region of the immunoglobulin gene (IgV) is associated with a median survival of 24 years or more; those without this mutation have a median survival of less than 8 years. CLL cell types demonstrating short telomere lengths and P53 dysfunction have poor outcomes. Because the average age of patients with CLL is about 65 to 70 years, those with indolent disease may not be treated; they are more likely to die of another disorder rather than CLL. Patients with cell types likely to progress rapidly may receive chemotherapy to induce remission. Those without complete response may consider stem cell transplantation to prolong the duration of remission.

Acute Lymphoblastic Leukemia/Lymphoma

Pathogenesis and clinical manifestations.

ALL is a malignant disorder of the lymphoid cell lineage. The great majority of cases are the result of malignant transformation of B cells (80%), with the remainder involving T cells. The abnormal cells resemble immature lymphocytes, called lymphoblasts (Fig. 11.9). Most lymphoblastic neoplasms present as leukemias, but lymphoblastic lymphomas are thought to be the same disease at a different stage. B-cell leukemias are categorized into cytogenetic groups based on common chromosomal translocations. One of these transformations results in the bcr/abl fusion gene discussed previously in the context of CML. Three other types of translocations also form fusion genes that produce abnormal signaling components. These gene derangements have different prognoses and may respond differently to alternative treatment protocols.

 

FIG 11.9 Peripheral blood smear showing typical cells of acute lymphocytic leukemia. (From Onciu M: Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009;23(4):655–674.)

Lymphoblasts do not mature and accumulate in large numbers in the blood and bone marrow. At least 20% of the bone marrow cells must be leukemic lymphoblasts to meet the diagnostic criteria for ALL. The space occupied by the accumulation of leukemic cells in the bone marrow prohibits the production of normal red blood cells, platelets, and leukocytes. Circulating blasts are poorly functioning cells and do not provide effective immunocompetence (see Table 11.2 for a comparison of ALL and acute nonlymphocytic leukemia [ANLL]).

ALL primarily affects children. It is the most common malignancy and the second-leading cause of death in this population. The peak incidence occurs between the ages of 3 and 7 years. A second peak occurs in middle age. The onset of symptoms is abrupt, with common complaints of bone pain, bruising, fever, and infection. Children may refuse to walk, and their parents may report loss of appetite, fatigue, and abdominal pain. The spleen, liver, and lymph nodes may be enlarged from leukemic infiltration. A small number of children (3%) may present with CNS signs from leukemic infiltration of brain tissues.

Prognosis and treatment.

ALL is highly curable in the pediatric population, but less so in adults. The 5-year survival rate is 85% in children and 30% to 50% in adults. Certain forms of ALL are more responsive to therapy. For example, children with the pre–B-cell type have a 90% cure rate, whereas those with mature B-cell or immature T-cell leukemia have a poorer prognosis.

Chemotherapy is used for remission induction. Postremission chemotherapy with or without stem cell transplantation is indicated for most patients. In general, adults with ALL require more intense therapy than children to achieve complete remission (CR). Monoclonal antibodies may be used in patients whose tumors express specific antigens.

Hairy Cell Leukemia

Pathogenesis and clinical manifestations.

Hairy cell leukemia is a rare, chronic type of leukemia. The disease represents about 2% of adult leukemias, but it is of interest because of its highly treatable nature. The median age at presentation is about 55 years, and there is a 5-to-1 predominance of males. Hairy cell leukemia has a B-cell phenotype and is characterized by the presence of peculiar cells with hairlike projections on their surface (Fig. 11.10). At diagnosis, patients have hairy cells in the peripheral blood as well as reduced numbers of granulocytes, platelets, and red blood cells. Splenomegaly is a common finding, being present in 90% of patients.

 

FIG 11.10 Peripheral blood smear showing cells typical of hairy cell leukemia. (From Skarin AT: Atlas of diagnostic oncology, ed 4, Philadelphia, 2010, Saunders.)

Prognosis and treatment.

Treatment may be instituted when a patient becomes symptomatic with an enlarged spleen, recurrent infection, bleeding disorder, or anemia. An appropriate chemotherapeutic protocol produces CR rates of 80%.

Plasma Cell Myeloma (Multiple Myeloma)

Pathogenesis and clinical manifestations.

Plasma cell myeloma, also known as multiple myeloma, is a malignant disorder of mature, antibody-secreting B lymphocytes, called plasma cells. Malignant plasma cells have a predilection to invade bone and form multiple tumor sites. Other tissues may be targeted also, including lymph nodes, liver, spleen, and kidneys. Plasma cell myeloma occurs exclusively in the adult population, usually affecting individuals older than 40 years, with a median age at presentation of 65 years. Men are affected more often than women.

As with other forms of neoplasia, the exact etiologic process of plasma cell myeloma is unknown, but abnormalities in chromosome structure and number are commonly found. The malignant plasma cells all belong to a single clone, and the excessive antibodies they produce are identical monoclonal antibodies. These accumulate in the bloodstream and can be detected by serum protein electrophoresis. Normally, serum antibodies are of many forms (polyclonal) and show a varied distribution of size on the electrophoresis test. In plasma cell myeloma, there is a large amount of one type of antibody, which forms a characteristic spike (Fig. 11.11). Excessive production of light-chain antibody fragments by malignant plasma cells results in their accumulation in blood and urine. When found in urine, these light-chain fragments are called Bence Jones protein. In addition to helping confirm the diagnosis, Bence Jones protein is important to the pathogenesis of plasma cell myeloma because it can accumulate in the kidneys and cause kidney damage. Malignant plasma cells tend to accumulate in bone, where they enhance osteoclastic activity and produce bone lesions. Pathologic fractures, especially compression fractures of the vertebral column, are common. Bone destruction releases calcium into the bloodstream, with resultant hypercalcemia.

 

FIG 11.11 Serum protein electrophoresis comparing abnormal myeloma protein in the γ region typical of benign monoclonal gammopathy (A) with the large quantity of monoclonal antibody (spike) γ typical of plasma cell myeloma (B). (From Skarin AT: Atlas of diagnostic oncology, London, 2003, Gower Medical, pp 536–537.)

Most of the clinical manifestations of multiple myeloma are due to bone and renal damage. The diagnosis of plasma cell myeloma is suspected based on the monoclonal antibody peak, the presence of Bence Jones protein, hypercalcemia, and evidence of bone lesions. The diagnosis is confirmed by bone marrow biopsy. Normally, the plasma cell component of the marrow comprises about 5%. In multiple myeloma, plasma cells may occupy 30% to 95% of the bone marrow (Fig. 11.12). A minimum of at least 10% to 15% of bone marrow plasma cells is necessary for the diagnosis of plasma cell myeloma. The likelihood of bone marrow dysfunction increases as the plasma cell component increases. Normal production of erythrocytes, platelets, and leukocytes can be impaired to varying degrees.

 

FIG 11.12 Bone marrow aspirate from a patient with multiple myeloma showing a large number of abnormal plasma cells with multiple nuclei and cytoplasmic droplets. (From Kocjan G: Diagnostic cytopathology essentials. Churchill Livingstone, 2013, Elsevier.)

The onset of plasma cell myeloma is generally slow and insidious. A premalignant stage is apparent in some individuals who have excess production of monoclonal antibodies but no evidence of bone lesions or Bence Jones protein in the urine. This stage is called monoclonal gammopathy of undetermined significance (MGUS). Approximately 25% of patients with MGUS progress to malignant disease. Affected individuals remain asymptomatic until the disease is fairly advanced. The asymptomatic stage often lasts for many years after malignant transformation. During this time the only complaint may be frequent infections. Diagnosis during the asymptomatic phase is usually made because protein in the urine or high serum calcium levels are found on routine examination. Bone pain is usually the first symptom. Sometimes the evaluation of a fracture or back pain leads to the identification of myeloma. Anemia, recurrent infections, and bleeding tendencies are suggestive of bone marrow depression.

Renal insufficiency is a complication experienced by approximately 50% of patients with plasma cell myeloma. Impairment of renal function is due to a combination of factors, including hyperproteinemia, high levels of Bence Jones protein, hypercalcemia, and hyperuricemia. Renal function may continue to decline over time, culminating in end-stage renal disease (chronic renal failure).

Bone involvement is a consistent feature of plasma cell myeloma. Radiologic studies of ribs, spine, skull, and pelvis show a characteristic “honeycomb” appearance, attributable to lucid areas of demineralized bone (Fig. 11.13). Minimal trauma is likely to result in fractures. Sometimes fractures occur with no known trauma; these are called pathologic fractures.

 

FIG 11.13 Vertebral body (A) and skull (B) radiographs showing the characteristic “honeycomb” appearance of demineralized bone associated with multiple myeloma. (Courtesy Marvin J. Stone, MD, Sammons Cancer Center, Baylor University Medical Center, Dallas, TX.)

Prognosis and treatment.

Antineoplastic agents may be used to induce and maintain a remission in plasma cell proliferation. The best chemotherapy regimen has not yet been determined. The remission induction rate is about 60%, with a median survival of about 3 years after initiation of therapy. High-dose chemotherapy followed by allogeneic bone marrow transplantation is becoming more common and offers a better CR rate. However, the death rate associated with transplantation is high (approximately 40% to 50%). Autologous stem cell transplantation is considered to be the optimal initial therapy for most patients. Pharmacologic management of renal dysfunction is often necessary.

Chronic bone pain is a common problem in the myeloma patient that may require use of multiple remedies. Narcotic and nonnarcotic pain relievers are often necessary. Localized application of radiation to bone lesions may reduce bone pain in some cases.

Key Points

• Chronic lymphoid leukemia (CLL) is a neoplastic transformation of a mature, peripheral B cell that affects adults primarily and has an insidious onset. CLL is usually asymptomatic. Disease in certain genotypes is associated with long survival times and does not require therapy; in other cases, disease is progressive and may be managed with stem cell transplantation or administration of monoclonal antibodies.
• Acute lymphoid leukemia (ALL) affects children primarily, has an acute onset, responds well to therapy, and has a good prognosis. ALL is associated with transformation of precursor “blasts” in the bone marrow. ALL often manifests with bone pain, infections, and a tendency for bleeding. A significant number of children with ALL have CNS involvement, and intrathecal chemotherapy is necessary.
• Plasma cell myeloma is due to malignant transformation of antibody-secreting B lymphocytes. It primarily affects older adults. The onset of symptoms is insidious, with most patients experiencing a 4- to 10-year period of clinical latency. Some patients have a preneoplastic phase called MGUS. When present, symptoms include bone pain, pathologic fractures, anemia, thrombocytopenia, leukopenia, and renal insufficiency. Malignant plasma cells all secrete the same monoclonal antibody, and detection of this antibody in the blood or urine (Bence Jones protein) aids in diagnosis.

Hodgkin Disease

Hodgkin disease represents about 30% of all cases of malignant lymphoma, accounting for approximately 8500 new cases annually in the United States. It occurs across the age continuum, with half of cases occurring in persons between the ages of 20 and 40 years. The overall incidence of Hodgkin disease is higher in males, who have a worse prognosis. The overall 5-year survival rate for treated Hodgkin disease, including all stages, is about 85%.

Pathogenesis and clinical manifestations.

Hodgkin disease is a malignant disorder of the lymph nodes characterized by the presence of Reed-Sternberg cells on histologic examination. Reed-Sternberg cells originate from B cells in the germinal centers of lymph nodes. Reed-Sternberg cells are malignant, but they tend to grow and spread in a predictable manner. This predictability differentiates Hodgkin disease from other types of lymphoma. Hodgkin disease usually metastasizes along contiguous lymphatic pathways (Fig. 11.14). EBV is frequently found in the genome of transformed Reed-Sternberg cells and is thought to be important in the pathogenesis of Hodgkin disease. The malignant cells are clonal, originating from a single mutant precursor cell, and usually present in a single node or localized chain of nodes. In addition to malignant Reed-Sternberg cells, inflammatory cells accumulate within the node (Fig. 11.15) such that Reed-Sternberg cells constitute only a small minority (2%) of the cells in the lymph node tumor.

 

FIG 11.14 Schematic drawing showing the orderly, contiguous, and predictable spread of Hodgkin disease. (Redrawn and modified from Rosenberg SA: Hodgkin disease: no stage beyond cure. Hosp Pract 1986;21(8):97. After original illustrations by Bunji Tagawa.)

 

FIG 11.15 Hodgkin/Reed-Sternberg cells. (From Vandenberghe P: Noninvasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced-stage Hodgkin’s lymphoma by sequencing of circulating cell-free DNA: a technical proof-of-principle study. Lancet Haematol 2015;2(2):e55–e65.)

There are two types of Hodgkin disease: (1) the rare lymphocyte predominance type, which accounts for 5% of cases, and (2) the classical type (cHD) representing the other 95%. The classical type can be divided further into four subtypes according to the relative number of reactive cells in the tumor. The histologic pattern does not seem to predict the prognosis. The stage of Hodgkin disease is more relevant.

Clinical manifestations of Hodgkin disease are dependent on the site of origin, as well as on the stage of dissemination. Lymphomas often are asymptomatic in the early stages. The usual clinical presentation includes painless lymphadenopathy that may be accompanied by fever, night sweats, pruritus, weight loss, and malaise. Usually enlargement occurs in lymph nodes above the diaphragm, with the cervical nodes being the most common site (Fig. 11.16). Other supradiaphragmatic nodes are the supraclavicular, axillary, and mediastinal nodes. Less commonly, nodes below the diaphragm are the primary site. The inguinal nodes are the most common subdiaphragmatic site. As the disease spreads from the site of origin, other lymph nodes and lymphatic tissues may become involved, including the spleen and bone marrow. Staging procedures are performed to determine the extent of metastasis at the time of diagnosis. Staging dictates the treatment modality best suited to provide the patient with the greatest chance for long-term survival.

 

FIG 11.16 Hodgkin disease (stage IIA). Marked enlargement of cervical lymph nodes is present in this patient. It is usually painless and may be confined to only one area or may affect two or more areas. (From Skarin AT: Atlas of diagnostic oncology, London, 2003, Gower Medical, p 482.)

Prognosis and treatment.

The staging protocol commonly used today was first adopted in 1971 at the Ann Arbor symposium and modified later in 1989 at the Cotswold meeting (Box 11.4). The same procedure is also used for staging non-Hodgkin lymphomas. This protocol uses the presence or absence of certain clinical symptoms as well as the locations of affected nodes to determine the clinical stage of disease. The four stages are shown in Fig. 11.17. The letter A denotes the absence of clinical symptoms, whereas the letter B is used when symptoms are present at the time of staging. These symptoms include loss of more than 10% of body weight, unexplained fevers, and night sweats. The clinical stage (CS) is based on history, physical examination, and noninvasive procedures such as computed tomography (CT) scanning. The pathologic stage (PS) is determined by the results of invasive procedures such as laparotomy and tissue biopsy. The stage dictates the treatment modalities used. In general, localized tumors are more amenable to application of radiation therapy, whereas disseminated disease responds better to systemic chemotherapeutic agents. Because Hodgkin disease often is detected while localized, radiation therapy is commonly used, with good results (Fig. 11.18).

Box 11.4

Ann Arbor Staging System for Lymphomas With Cotswold Modifications*

Stage I

Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer ring)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm. The number of anatomic regions is indicated by a subscript (e.g., II₃).

Stage III

Involvement of lymph node regions or structures on both sides of the diaphragm

• III₁: with or without splenic, hilar, celiac, or portal nodes
• III₂: with paraaortic, iliac, mesenteric nodes

Stage IV

Involvement of extranodal site(s) beyond that designated “E”

The site is indicated by a letter code followed by a plus sign (+)

Modifying Characteristics

For Stages I to III

E: Involvement of a single, extranodal site contiguous or proximal to known nodal site

For All Stages

A: No symptoms

B: Fever (temperature >38°C), drenching sweats, weight loss (>10% body weight over 6 months)

X: Bulky disease

• >One-third widening of mediastinum
• >10 cm maximal dimension of nodal mass

^*Clinical stage (CS) is based on history, physical examination, laboratory studies, and CT scans. Pathologic stage (PS) is based on tissue sampling obtained through invasive procedures such as laparotomy and biopsy.

 

FIG 11.17 Depiction of the locations of malignant cells in the various stages of lymphoma using the Ann Arbor staging system. (From Skarin AT: Atlas of diagnostic oncology, London, 2003, Gower Medical, p 479.)

 

FIG 11.18 Typical radiation fields for lymphoma. Different fields of radiation may be used depending on the location of disease.

Patients with nonbulky, stage IA or IIA disease may be candidates for radiation as sole therapy. However, a relatively high rate of relapse has been noted, and combined chemotherapy with limited-field radiation is often used. Patients with bulky disease, “B” symptoms, or stage III and IV disease require chemotherapy with or without radiation. In early-stage disease, appropriate treatment produces a 90% 10-year disease-free survival. More aggressive chemotherapy is indicated for patients with advanced Hodgkin disease.

B-Cell, T-Cell, and NK-Cell Lymphoma (Non-Hodgkin)

The malignancies included in the classification of non-Hodgkin lymphoma are those that do not have the characteristic Reed-Sternberg cells found in Hodgkin disease. The majority of cases of non-Hodgkin lymphoma arise from lymph nodes, but they can originate in any lymphoid tissue. With the exception of a few subtypes, most cases of non-Hodgkin lymphoma occur in older adults (95%), and males are at a slightly higher risk than females. The incidence of non-Hodgkin lymphoma is on the rise, particularly in areas with large AIDS populations. More than 72,000 new cases of non-Hodgkin lymphoma are diagnosed annually in the United States. The lifetime risk of developing this disease is about 1 in 50.

Most cases of non-Hodgkin lymphoma arise from B cells, T cells, or NK cells. Some of the more common types of non-Hodgkin lymphoma are summarized in Table 11.3. The prognosis and recommended treatment protocols vary according to type. A general schema for grouping non-Hodgkin lymphoma according to indolent or aggressive types is in common usage. Generally, indolent disease is associated with longer survival times, whereas aggressive lymphomas tend to be disseminated at presentation and carry a generally poorer prognosis. As a group, the non-Hodgkin types of lymphoma are more likely to spread early and unpredictably in comparison with Hodgkin disease.

TABLE 11.3

Summary of Major Types of Lymphoid Leukemias and Non-Hodgkin Lymphomas
Diagnosis	Cell of Origin	Genotype	Salient Clinical Features
Neoplasms of Immature B and T Cells
B-cell acute lymphoblastic leukemia/lymphoma*	Bone marrow precursor B cell	Diverse chromosomal translocations; t(12;21) involving RUNX1 and ETV 6 present in 25%	Predominantly children; symptoms relating to marrow replacement and pancytopenia; aggressive
T-cell acute lymphoblastic leukemia/lymphoma	Precursor T cell (often of thymic origin)	Diverse chromosomal translocations, NOTCH1mutations (50%–70%)	Predominantly adolescent males; thymic masses and variable bone marrow involvement; aggressive
Neoplasms of Mature B Cells
Burkitt lymphoma*	Germinal-center B cell	Translocations involving MYCand lg loci, usually t(8;14); subset EBV-associated	Adolescents or young adults with extranodal masses; uncommonly presents as “leukemia”; aggressive
Diffuse large B-cell lymphoma†	Germinal-center or postgerminal center B cell	Diverse chromosomal rearrangements, most often ofBCL6 (30%), BCL2 (10%), or MYC (5%)	All ages, but most common in older adults; often appears as a rapidly growing mass; 30% extranodal; aggressive
Extranodal marginal zone lymphoma	Memory B cell	t(11;18), t(1;14), and t(14;18) creating MALT1-IAP2, BCL10-IgH, and MALT1-IgH fusion genes, respectively	Arises at extranodal sites in adults with chronic inflammatory diseases; may remain localized; indolent
Follicular lymphoma†	Germinal-center B cell	t(14;18) creating BCL2-IgHfusion gene	Older adults with generalized lymphadenopathy and marrow involvement; indolent
Hairy cell leukemia	Memory B cell	Activating BRAF mutations	Older males with pancytopenia and splenomegaly; indolent
Mantle cell lymphoma	Naive B cell	t(11;14) creating CyclinD1 –IgH fusion gene	Older males with disseminated disease; moderately aggressive
Multiple myeloma/solitary plasmacytoma†	Postgerminal-center bone marrow homing plasma cell	Diverse rearrangements involving IgH; 13q deletions	Myeloma: older adults with lytic bone lesions, pathologic fractures, hypercalcemia, and renal failure; moderately aggressive  Plasmacytoma: isolated plasma cell masses in bone or soft tissue; indolent
Small lymphocytic lymphoma/chronic lymphocytic leukemia	Naive B cell or memory B cell	Trisomy 12, deletions of 11q, 13q, and 17p	Older adults with bone marrow, lymph node, spleen, and liver disease; autoimmune hemolysis and thrombocytopenia in a minority; indolent
Neoplasms of Mature T Cells or NK Cells
Adult T-cell leukemia/lymphoma	Helper T cell	HTLV-1 provirus present in tumor cells	Adults with cutaneous lesions, marrow involvement, and hypercalcemia; occurs mainly in Japan, West Africa, and the Caribbean; aggressive
Peripheral T-cell lymphoma, unspecified	Helper or cytotoxic T cell	No specific chromosomal abnormality	Mainly older adults; usually presents with lymphadenopathy; aggressive
Anaplastic large-cell lymphoma	Cytotoxic T cell	Rearrangements of ALK(anaplastic large cell lymphoma kinase) in a subset	Children and young adults, usually with lymph node and soft-tissue disease; aggressive
Extranodal NK/T-cell lymphoma	NK-cell (common) or cytotoxic T cell (rare)	EBV-associated; no specific chromosomal abnormality	Adults with destructive extranodal masses, most commonly sinonasal; aggressive
Mycosis fungoides/Sézary syndrome	Helper T cell	No specific chromosomal abnormality	Adult patients with cutaneous patches, plaques, nodules, or generalized erythema; indolent
Large granular lymphocytic leukemia	Two types: cytotoxic T cell and NK cell	Point mutations in STAT3	Adult patients with splenomegaly, neutropenia, and anemia, sometimes, accompanied by autoimmune disease

^*Most common tumors in children

^†Most common tumors in adults.

EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; Ig, immunoglobulin; NK, natural killer.

Modified from Kumar V et al, editors: Pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders, p 591.

Pathogenesis and clinical manifestations.

The etiologic process of non-Hodgkin lymphoma is thought to be similar to that of other malignant transformations. The tumor cells are all derived from a single mutant precursor cell and are clonal. Viruses are suspected in the development of some types of lymphoma. In particular, Burkitt lymphoma is strongly associated with the presence of EBV. Adult T-cell lymphomas are associated with infection by HTLV-1. The overall 5-year survival rate for all types of non-Hodgkin lymphomas combined is about 70%.

Most patients with non-Hodgkin lymphoma present with advanced disease (stage III or IV). Clinical manifestations may include painless lymphadenopathy, fever, night sweats, weight loss, malaise, and pruritus (similar to Hodgkin disease). A comparison of the features of Hodgkin disease and non-Hodgkin lymphoma is shown in Table 11.4. Extranodal involvement occurs early in the course of non-Hodgkin lymphoma, and patients may present with infiltrative disease of the skin, gastrointestinal tract, bone, or bone marrow. Complications occur more frequently than in Hodgkin disease. Two of the most serious oncology emergencies are obstruction of the superior vena cava and spinal cord compression. Infection, bone metastasis, and joint effusions are also common. Staging of non-Hodgkin lymphoma is done in the same way as for Hodgkin disease, and the classification system is not different. Earlier clinical stages are associated with the best prognosis for survival.

TABLE 11.4

Clinical Differences in Hodgkin Disease and Non-Hodgkin Lymphoma
Characteristic	Hodgkin Disease	Non-Hodgkin Lymphoma
Pattern of spread	Contiguous spread	Noncontiguous spread
Extranodal disease	Uncommon	More common involvement of gastrointestinal tract, testes, bone marrow
Site of disease	Mediastinal involvement common	Mediastinal involvement less common
	Bone marrow involvement uncommon	Bone marrow involvement common
	Liver involvement uncommon	Liver involvement common
Extent of disease	Often localized	Rarely localized
B symptoms	Common	Uncommon

Prognosis and treatment.

The effectiveness of therapy for non-Hodgkin lymphoma is variable. Favorable outcomes are likely in stage I and II disease. However, non-Hodgkin lymphoma is likely to present as stage III or IV disease, which has a poor prognosis. Therapeutic management is determined by the clinical stage, histologic type, patient age, and bone marrow integrity at the time of diagnosis. Radiation, chemotherapy, and tissue-specific therapies such as monoclonal antibodies and bone marrow transplants may all be applicable.

Key Points

• Hodgkin disease is characterized by malignant transformation of B cells in lymph nodes, called Reed-Sternberg cells. The spread of malignant cells occurs along predictable, contiguous pathways. Most commonly, a single cervical lymph node is involved initially, with slow progression to nearby nodes.
• Non-Hodgkin lymphoma constitutes a diverse group of malignant diseases of lymphoid tissue. The characteristic Reed-Sternberg cell of Hodgkin disease is not present. Non-Hodgkin lymphoma is unpredictable in its spread and is often disseminated at diagnosis.
• Manifestations of Hodgkin disease and non-Hodgkin lymphoma are similar. These include painless lymph node enlargement, fever, night sweats, and weight loss. Early-stage disease is often asymptomatic.
• Staging is done to determine the degree of dissemination of disease. When affected lymph nodes are localized to one area (stage I) or one side of the diaphragm (stage II), the prognosis for cure is very good. Dissemination to lymph nodes above and below the diaphragm (stage III) or to extralymphatic organs or tissues (stage IV) carries a poorer prognosis.
• Radiation of the involved field is commonly used for malignant lymphoma in early stages. More disseminated disease may be treated with chemotherapeutic protocols. Non-Hodgkin lymphoma is routinely treated with chemotherapy because the disease is often well advanced at the time of diagnosis. Treatment may lead to bone marrow suppression and may predispose the patient to anemia, thrombocytopenia, and leukopenia.

Summary

Malignant disorders of white blood cells are classified according to cell type and fall into two major categories: myeloid neoplasms and lymphoid neoplasms. Myeloid neoplasms commonly present as leukemia and usually involve transformation of granulocytes. Lymphoid neoplasms may present as leukemia, lymphoma, or plasma cell myeloma. Leukemia is a malignant neoplasm of immature stem cells that is characterized by diffuse replacement of the bone marrow by neoplastic blasts. In most cases the leukemic cells overflow into the bloodstream, where they may be seen in large numbers. These cells may also infiltrate the liver, spleen, lymph nodes, and other tissues throughout the body. Lymphoma is characterized by malignancy of cells found in lymphoid tissues and usually arises in the lymph nodes. Hodgkin disease is a special category of malignant lymphoma that is characterized by the presence of Reed-Sternberg cells. Hodgkin disease is more predictable in its spread than the non-Hodgkin types of lymphoma, and it is generally curable in the early stages. Non-Hodgkin lymphoma types comprise a large number of different disorders that involve malignant transformation of B cells, T cells, or NK cells. As with Hodgkin disease, earlier stages are more easily cured. However, the non-Hodgkin lymphomas tend to be unpredictable in their dissemination, and the prognosis is less certain. Plasma cell myeloma is a malignant transformation of mature, antibody-secreting B cells. Malignant plasma cells are monoclonal, and all produce identical antibodies, which accumulate in the blood. These cells have a predilection to settle in skeletal structures, where they cause bone demineralization and destruction. Hypercalcemia, bone fractures (pathologic fractures), and renal damage are common complications of plasma cell myeloma. Treatment for the various types of hematologic neoplasms continues to evolve, and excellent disease-free survival is commonly achieved when the disease is diagnosed in the early stages.

Resources

Etiology and Classification of Hematologic Neoplasms

Henderson ES, Lister TA, Greaves MF. Leukemia. ed 7. Saunders: Philadelphia; 2002.

Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press: Lyon, France; 2001.

Lowenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic leukemia. Hematology. 2003;82–101; 10.1182/asheducation-2003.1.82.

McKenzie SB, Williams L. Clinical laboratory hematology. Pearson Education: Upper Saddle River, NJ; 2015 [3/E].

National Cancer Institute.  https://seer.cancer.gov/statfacts/.

Ross JA, Potter JD, Reaman GH, et al. Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): a report from the Children’s Cancer Group. Cancer Causes Control. 1996;7(6):581–590.

Tessoulin B, Eveillard M, Lok A, et al. p53 dysregulation in B-cell malignancies: More than a single gene in the pathway to hell. Blood Rev. 2017 [S0268-960X(16)30059-5. doi: 10.1016/j.blre.2017.03.001].

Myeloid Neoplasms

American Cancer Society. Cancer facts and figures, 2015. Author: Atlanta, GA; 2003.

Aster JC. The hematopoetic and lymphoid systems. Kumar V, Abbas AK, Fausto N, Mitchell R. Robbins basic pathology. ed 8. Saunders: Philadelphia; 2007:421–478.

Barille-Nion S, et al. Advances in biology and therapy of multiple myeloma. Hematology. 2003;248–278; 10.1182/asheducation-2003.1.248.

Henderson ES, Lister TA, Greaves MF. Leukemia. ed 7. Saunders: Philadelphia; 2002.

Hoffbrand AV, Moss PAH. The World Health Organization (WHO) classification of the tumors of haematopoietic and lymphoid tissues. Essential haematology. ed 6. Blackwell: Oxford, England; 2011.

Keating MJ, et al. Biology and treatment of chronic lymphocytic leukemia. Hematology. 2003;153–175; 10.1182/asheducation-2003.1.153.

Linker CA. Blood. Tierney LM, McPhee SJ, Papadakis MA. Current medical diagnosis and treatment. ed 46. McGraw-Hill: New York; 2007:493–547.

McKenzie SB, Williams L. Clinical laboratory hematology. Pearson Education: Upper Saddle River, NJ; 2015 [3/E,].

Melo JV, Hughes TP, Apperley JF. Chronic myeloid leukemia. Hematology. 2003;132–152; 10.1182/asheducation-2003.1.132.

Spivak JL, et al. Chronic myeloproliferative disorders. Hematology. 2003;200–224; 10.1182/asheducation-2003.1.200.

Lymphoid Neoplasms

Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31:1860–1861.

Diehl V, Stein H, Hummel M, et al. Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory and relapsed disease. Hematology. 2003;225–247; 10.1182/asheducation-2003.1.225.

Iacobucci I, Mullighan CG. Genetic Basis of Acute Lymphoblastic Leukemia. J Clin Oncol. 2017;35(9):975–983.

Lister TA, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol. 1989;7(11):1630–1636.

Rytting ME, Jabbour EJ, O’Brien SM, Kantarjian HM. Acute lymphoblastic leukemia in adolescents and young adults. Cancer. 2017; 10.1002/cncr.30624.

Vose JM, Chiu BCH, Cheson BD, et al. Update on epidemiology and therapeutics for non-Hodgkin’s lymphoma. Hematology. 2002;241–262; 10.1182/asheducation-2002.1.241.