McCance 30 Book

• Leukocyte and lymphoid disorders range from deficiencies in leukocyte quantity/quality to increased numbers.
• Hematologic disorders are often malignancies that can metastasize to the bone marrow, disrupting normal leukocyte production.

Alterations of Leukocyte Function

• Leukocyte function is affected by abnormal white blood cell counts or structural/functional defects.
• Quantitative disorders stem from decreased production in bone marrow or accelerated cell destruction.
• Infections can also cause quantitative alterations in leukocytes.
• Qualitative disorders involve disruptions of leukocyte function.
• Phagocytic cells may lose phagocytic capacity, and lymphocytes may lose their ability to respond to antigens.
• Other leukocyte alterations include infectious mononucleosis and blood cancers like leukemia and multiple myeloma.

Quantitative Alterations of Leukocytes

• Leukocytosis: Higher-than-normal leukocyte count.
• Leukopenia: Lower-than-normal leukocyte count.
• These conditions can affect all or specific leukocyte types.
• Leukocytosis is a normal protective response to stressors like infection, exercise, or emotional changes.
• Pathologic conditions like malignancies and hematologic disorders can also cause leukocytosis.
• Leukopenia is never normal, defined as an absolute blood cell count less than 4000 cells/μL.
• Leukopenia increases the risk for infection, especially when neutrophils are decreased.
• Absolute Neutrophil Count (ANC) is calculated by multiplying the WBC count by the percentage of band and segmented neutrophils.
• Mild ANC: 1000-1500 cells/μL.
• Moderate ANC: 500-1000 cells/μL.
• Severe ANC: <500 cells/μL.

Hodgkin Lymphoma (HL)

• HL is a malignant lymphoma characterized by Reed-Sternberg (RS) cells in the lymph nodes.
• RS cells are necessary for diagnosis but not specific to HL, as they can appear in other conditions.
• HL incidence in developed countries: 2.1/100,000, compared to 0.6/100,000 in less developed countries.
• In the U.S., HL accounts for about 0.5% of all new cancer cases.
• HL commonly affects young adults (15-40 years) and older adults (over 55 years).
• More prevalent in men than women.
• Possible causes include genetic susceptibility, EBV infection, and exposure to occupational toxins.
• HL typically starts in the upper body lymph nodes (neck, chest, armpits).

Physical Findings and Symptoms of Hodgkin Lymphoma

• Enlarged, painless lymph nodes in the neck are often the 1st sign.
• Nodes in cervical, axillary, inguinal, and retroperitoneal areas are commonly affected.
• Local symptoms result from pressure on adjacent structures.
• Mediastinal mass can cause chest pain, difficulty breathing, and cough.
• Abdominal mass can cause abdominal pain and distension.
• Advanced HL symptoms: fever, night sweats, weight loss (>10% of body weight in 6 months).
• "B symptoms" (fever, drenching night sweats, unexplained weight loss) indicate worse prognosis.
• Elevated sedimentation rate, leukocytosis, and eosinophilia are common, while leukopenia occurs in advanced stages.

Splenic Involvement

• Splenic involvement in HL depends on histopathologic type.
• Spleen is involved in 60% of mixed cellularity and lymphocytic depletion HL.
• Spleen involvement is seen in only 34% of lymphocyte predominance and nodular sclerosis types of HL.

Evaluation and Treatment of Hodgkin Lymphoma

• Early detection can be difficult due to variable symptoms.
• Asymptomatic lymphadenopathy can progress undetected for years.
• Evaluation: chest x-rays, lymphangiography, and biopsy.
• Lymph node biopsy showing scattered RS cells and cellular infiltrate highly indicates HL.
• Treatment effectiveness depends on age and disease extent.
• Approximately 75% of individuals with HL are cured with combined radiation and chemotherapy.
• Death rate for HL has fallen more rapidly than for any other malignancy.
• Recent treatments: high-dose chemotherapy with bone marrow/stem cell transplantation.
• Monoclonal antibodies are being developed; nonmyeloablative allogeneic stem cell transplantation can help some individuals.

Survival Rate by Stage

• 5-year survival rate for stages I and II: 90%-95%.
• 5-year survival rate for stage III: 80%-85%.
• 5-year survival rate for stage IV: 75%.
• Stages I and II disease: chemotherapy, radiation therapy, or both.
• Stages III and IV disease or bulky disease: combined chemotherapy (with/without radiation).
• Poorer survival is related to high WBC count (>15,000/μL), low hemoglobin (<10.5 g/dL), low lymphocyte count (<600/μL), and male gender.
• Cure is achievable in 75% of HL cases with current therapies.

Non-Hodgkin Lymphoma (NHL)

• NHL is a diverse group of neoplasms from lymphoid tissue with varied biologic and clinical features.
• Worldwide, NHL accounts for about 3% of the cancer burden.
• NHL incidence in developed countries: 8.6/100,000.
• NHL incidence in less developed countries: 3.6/100,000.
• In the United States, NHL accounts for 4.3% of all new cancer cases.
• NHL incidence rates increased worldwide from 1950 to 2000.

Classification of Non-Hodgkin Lymphoma

• Reclassified in the WHO/REAL scheme into:
  • B-cell neoplasms (including myelomas).
  • T-cell and NK-cell neoplasms.
• Differentiated from HL by lack of RS cells.
• 72,240 cases of NHL with 20,140 deaths are predicted in the US for 2017.
• Median age of diagnosis is 67 years.
• Highest incidence in North America, Europe, Oceania, and some African countries.
• Affects more men than women.
• Increased incidence from the 1950s to 1990s attributed to diagnostic improvements and AIDS-related cancers.
• Mortality from NHL has declined since 1997 due to newer treatment modalities.

Risk Factors for NHL

• Family history of lymphoma.
• Exposure to mutagenic chemicals or irradiation.
• Infection with cancer-related viruses (EBV, human herpesvirus-8, HIV, HTLV-1, hepatitis C).
• Immune suppression related to organ transplantation.
• Gastric infection with Helicobacter pylori increasing risk for gastric lymphomas.
• It is a disease of middle age, usually found in individuals more than 50 years old.

Pathophysiology of Non-Hodgkin Lymphoma

• Described as a progressive clonal expansion of B cells, T cells, or NK cells.
• B cells account for 85%-90% of NHLs.
• Remainder are T cells and, rarely, NK cells.
• A very small percentage originates from macrophages.
• Chromosomal translocations may activate oncogenes, or tumor-suppressor loci may be inactivated by deletion or mutation of chromosomes.
• Some subtypes may have altered genomes due to oncogenic viruses.
• Genetic lesions affecting proto-oncogenes/tumor-suppressor genes result in cell immortalization, increasing malignant cells.
• Specific subtypes can be identified by diagnostic markers related to cytogenic lesions.
• Lymphomas likely originate from mutations in cellular genes (many environmentally induced).
• The most common chromosomal alteration is translocation, disrupting genes at breakpoints.

Tumor Categories

• Categorized by level of differentiation, cell of origin, and rate of cellular proliferation.
• Tumor aggressiveness in B-cell NHLs is predicted by cell growth pattern and size.
• Tumors with a nodular pattern are generally less aggressive than lymphomas with a diffuse pattern of proliferation.
• Small lymphocyte lymphomas are less aggressive than large-cell lymphomas.

Clinical Manifestations

• Symptoms usually begin as localized or generalized lymphadenopathy.
• Common sites affected: cervical, axillary, inguinal, and femoral chains.
• Swelling is generally painless, with nodes enlarged over months or years.
• Other sites of involvement: nasopharynx, GI tract, bone, thyroid, testes, and soft tissue.
• Some individuals have retroperitoneal/abdominal masses, causing abdominal fullness, back pain, ascites, and leg swelling.
• Lymphomas are classified as low, intermediate, or high grade.
• Low-grade lymphoma (indolent) has a slow progression.
• Individuals commonly present with painless, peripheral adenopathy.
• Spontaneous regression of nodes may occur, mimicking infection.
• Night sweats with elevated temperature, weight loss, and extranodular involvement are common in advanced stages.
• Cytopenia, reflecting bone marrow involvement, is often seen.
• Hepatomegaly is common; splenomegaly is present in 40% of individuals.
• Fatigue and weakness are more prevalent with advanced stages.
• Intermediate- and high-grade lymphomas are more aggressive and have a more varied clinical presentation.
• High-grade lymphoma may also be termed aggressive.
• Adenopathy is common, with >⅓ of individuals having extranodal involvement in the GI tract, skin, etc.
• Night sweats with increased temperature and weight loss occur in 30%-40% of individuals.
• Some individuals have retroperitoneal/abdominal masses, abdominal fullness, back pain, ascites, and leg swelling.
• Hepatomegaly and splenomegaly are often present.

Evaluation and Treatment of Non-Hodgkin Lymphoma

• Biopsy is the primary means for diagnosis.
• Staging identifies treatment and prognosis.
• In addition to biopsy, CT scans of the neck, chest, abdomen, and pelvis and bilateral bone marrow aspirate examination are performed.
• Noncontiguous lymph node involvement is common, unlike HL.
• The Ann Arbor staging system is most commonly used to stage NHL.
• Treatment depends on cell type (B or T), tumor stage, histologic status, symptoms, age, and comorbidities.
• Treatment is usually initiated at diagnosis unless low-grade indolent lymphomas are widely disseminated, in which case observation may be most appropriate.
• Success of treatment depends on the lymphoma type, disease stage, cell type, organ involvement outside lymph nodes, age, and body's reaction to disease (e.g., fever, night sweats, weight loss).
• Treatment with chemotherapy alone or with radiation therapy is common.
• Low-dose chemotherapy followed by autologous stem cell transplantation.
• Rituximab, a monoclonal antibody against antigen CD20 on B cells, is effective for B-cell lymphomas and some autoimmune diseases.
• Radioimmunotherapy combines radiation therapy with monoclonal antibody therapy to improve remission rates.
• Individuals with NHL can survive for extended periods with survival rates (1 year, 77%; 5 years, 59%; and 10 years, 42%) less than for Hodgkin lymphoma.
• High-grade NHL is seen with increasing frequency in persons with AIDS and has an extremely poor prognosis.

Burkitt Lymphoma

• Burkitt lymphoma is a B-cell non-Hodgkin lymphoma with unique clinical and epidemiologic features.
• It accounts for 30% of childhood lymphomas worldwide.
• Highly aggressive and fastest-growing human tumor.
• Burkitt lymphoma types: endemic, sporadic, and immunodeficiency-related.
• Endemic Burkitt lymphoma commonly occurs in Africa and is linked to the EBV.
• Sporadic Burkitt lymphoma occurs worldwide.
• Immunodeficiency-related Burkitt lymphoma is most often seen in individuals with AIDS.
• Endemic cases usually involve a rapidly growing tumor of the jaw and facial bones.
• In the United States, Burkitt lymphoma is rare, usually involves the abdomen, and is characterized by extensive bone marrow invasion and replacement.

Pathophysiology

• EBV is associated with almost all cases (over 90%) of Burkitt lymphoma.
• Suppression of the immune system increases susceptibility to EBV.
• The B cell undergoes chromosomal translocations, resulting in overexpression of the C-MYC proto-oncogene and loss of control of cell growth.
• The most common translocation (75% of individuals) is between chromosomes 8 and 14.

Clinical Manifestations

• In non-African Burkitt lymphoma, the most common presentation is abdominal swelling.
• Manifestations of most tumors occur at extranodal sites.
• More advanced disease involves the eye, ovaries, kidneys, or glandular tissue, and presents with type B symptoms.
• Common manifestations include nausea and vomiting, loss of appetite or change in bowel habits, gastrointestinal bleeding, symptoms of an acute abdominal condition, intestinal perforation, and renal failure.

Evaluation and Treatment

• Tumors in the jaw and facial bones, enlarged lymph nodes, and bone marrow containing malignant B cells indicate Burkitt lymphoma.
• Aggressive multidrug regimens (combination chemotherapy) is the mainstay of treatment.
• Adjuvant monoclonal antibody therapy with rituximab (anti-CD20) may improve outcomes.

Lymphoblastic Lymphoma

• Lymphoblastic lymphoma (LL) is a relatively rare variant of NHL (2%-4%).
• It accounts for about 20% of cases of NHL in children and adolescents.
• Faster-growing type of NHL: increased numbers of lymphoblasts in lymph nodes and thymus gland.
• Lymphoblasts can spread to other areas of the body.
• Most cases (over 85%) are of T-cell origin, the remainder arising from B cells.
• Similar to acute lymphoblastic leukemia; may be considered a variant.

Pathophysiology

• Arises from a clone of relatively immature T cells that becomes malignant in the thymus.
• Frequently associated with translocations, primarily of the chromosomes that encode for the T-cell receptor (chromosomes 7 and 14).

Clinical Manifestations

• First sign: painless lymphadenopathy in the neck.
• Peripheral lymph nodes in the chest become involved in about 70% of individuals.
• Very aggressive tumor; presents as stage IV in most people.
• T-cell LL associated with a mediastinal mass (up to 75%).
• The mass results in chest pain and may cause compression of bronchi or the superior vena cava.
• Bone marrow infiltration occurs in about half of those affected.
• Many individuals express type B symptoms (fever, night sweats, and significant weight loss).

Evaluation and Treatment

• Combined chemotherapy with multiple drugs is the most common therapeutic approach.
• In early stages, the response rate is high with increased survival.
• 5-year survival in children: 80%-90%; 45%-55% in adults.
• Though easily treated, there is a high relapse rate: 40%-60% of adults.

Conditions That Mimic Lymphomas

• Mimicking conditions: tuberculosis (TB), syphilis, systemic lupus erythematosus, lung cancer, and bone cancer.
• Lymphomas: localized lymphadenopathy.
• Infectious precursors to malignant lymphomas: more generalized lymphadenopathy with systemic signs and symptoms.

Plasma Cell Malignancies

• Plasma cell: the end-stage cell of the humoral immune response.
• Immunocompetent B cells undergo proliferation and differentiation into antibody-producing plasma cells when stimulated by antigens and cytokines from T helper cells.
• Antigen-reactive B cells have undergone rearrangement of immunoglobulin heavy-chain variable region genes (V, D, J) and may develop into plasma cells that secrete IgM or selectively rearrange the immunoglobulin heavy-chain genes to switch to secretion of IgG, IgA, or IgE
• Some cells may undergo malignant transformation, leading to plasma cell malignancies.
• Common characteristic: secretion of complete or partial immunoglobulin molecules.

Multiple Myeloma

• Multiple myeloma (MM; plasma cell myeloma) is a clonal plasma cell cancer characterized by the slow proliferation of tumor cell masses in the bone marrow associated with lytic bone lesions.
• Uncommon variants: solitary myeloma (plasmacytoma) and smoldering myeloma.
• Most MMs secrete large amounts of monoclonal proteins resembling intact immunoglobulins.
• MM is the third most common blood cancer in the United States.
• Incidence reported has doubled in the past two decades.
• The number of new cases in the United States is estimated at greater than 30,280 with more than 12,590 deaths for 2017.
• Occurs in all races, but the incidence in blacks is about twice that of whites.
• Rarely occurs before 40 years; peak age of incidence between 65 and 70 years.
• Slightly more common in men than women.
• Other risk factors: exposure to radiation or certain chemicals, including pesticides, and a history of MGUS or plasmacytoma.
• Neoplastic cells reside in the bone marrow and are usually not found in the peripheral blood.
• Occasionally spreads to other tissues, especially in advanced stages.

Pathophysiology

• Multiple myeloma is a biologically complex disease with significant heterogeneity reflected by a wide range of genetic alterations and individual differences in clinical response and survival of individuals receiving the same treatment.
• Genetic mutations in different pathways alter the intrinsic biology of the plasma cell, generating the features of myeloma.
• Genetic mutations affect genes that impact cell growth and division. Affecting cell growth and division. Resulting in excessive proliferation of plasma cells.
• Many myelomas are aneuploid.
• Chromosomal translocations are responsible for development of myeloma in most individuals.
• The primary translocation involves the immunoglobulin heavy chain on chromosome 14, which relocates to sites containing genes that cell-cycle.
• A progression of further secondary genetic alterations causes development to an aggressive multiple myeloma.
• The precise timing and reason for the genetic alteration and accumulation are unknown but probably occur initially late in B-cell development after exposure to antigen.
• Malignant plasma cells arise from one clone of B cells, producing abnormally large amounts of one class of immunoglobulin.
• The malignant transformation may begin early in B-cell development, possibly before encountering antigen.
• These cells return either to the bone marrow or to other soft tissue sites.
• Myeloma cells in the bone marrow directly secrete hepatocyte growth factor and parathyroid hormone–related peptide and adhere to stromal cells, inducing their production of several cytokines.
• The antibody produced is usually defective. Contains truncations, deletions, and other abnormalities. It is frequently referred to as a paraprotein.
• M protein becomes the most prominent protein in the blood in 80% of individuals with myeloma.
• Leads to diminished or absent normal antibodies.
• The excessive amount of M protein also may contribute to many of the clinical manifestations of the disease.
• The myeloma may produce free immunoglobulin light chain (Bence Jones protein) that is present in the blood and urine in approximately 80% of individuals and contributes to damage of renal tubular cells.

Clinical Manifestations

• Common presentations include: hypercalcemia, renal failure, anemia, and bone lesions.
• Hypercalcemia and bone lesions result from infiltration of the bone by malignant plasma cells and stimulation of osteoclasts to reabsorb bone.
• Destruction of bone tissue causes pain, pathologic fractures.
• Bones most commonly involved: vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula.
• Spinal cord compression occurs in about 10% of individuals because of weakened vertebrae.
• Additional symptoms: weakness, fatigue, weight loss, anorexia, easy bruising or bleeding, and trouble breathing along with pain.
• Amyloid proteins can increase in number. Amyloid proteins stick together, called amyloidosis. Affecting peripheral nerves and organs. Manifestations: extreme exhaustion, purple spots on the skin, enlarged tongue, diarrhea, edema, tingling, and numbness in legs and feet.
• Proteinuria observed in 90% of individuals, renal failure, anemia.
• High concentration of paraprotein in the blood may lead to hyperviscosity syndrome.
• Suppression of the humoral (antibody-mediated) immune response results in repeated infections.
• Organisms commonly involved are encapsulated bacteria that are particularly sensitive to the effects of antibody.
• Infection is the leading cause of death from MM.
• MM is often preceded by Monoclonal gammopathy of undetermined significance (MGUS).
• Present in ~1% of general population, or 3% of those > 70 years old.
• Pesticides are associated with increased risk.
• About 2% of individuals with MGUS progress to malignant plasma cell disorders.
• MM may advance first to asymptomatic MM and then to symptomatic MM.

Evaluation and Treatment

• Diagnosis: symptom assessment, radiographic and laboratory studies, and bone marrow biopsy.
• Quantitative measurements of immunoglobulins (IgG, IgM, IgA) are performed.
• Serum electrophoretic analysis reveals increased levels of M protein.
• M protein is monoclonal and each molecule has the same electric charge.
• Bence Jones protein is observed in the urine or serum using immunoelectrophoretic analysis or in the serum using enzyme-linked immunosorbent assay (ELISA).