Chapter 23: Disorders of White Blood Cells
What three groups of white blood cells (WBCs) are found in the peripheral circulation?
What are the three types of granulocytes?
- neutrophils (90%)
What are the three types of lymphocytes?
- T lymphocytes (thymus mediated)
- B lymphocytes (bursa derived)
- natural killer (NK) cells
What is the primary function of neutrophils?
They defend against bacterial infections through phagocytosis and enzymatic destruction.
What is the primary function of basophils?
They mediate allergic reactions through release of their cytoplasmic granules.
What are the primary functions of eosinophils?
They mediate allergic reactions and also defend against parasitic infections.
What is the primary function of T lymphocytes?
They mediate delayed, cellular immunity.
What is the primary function of B lymphocytes?
They mediate immediate, humoral immunity.
What are the primary functions of monocytes?
They are involved in phagocytosis, inflammation, and serve as antigen-presenting cells.
What are monocytes serving as antigen-presenting cells in lymph nodes called?
What are monocytes serving as antigen-presenting cells in skin and mucosa called?
What are monocytes in tissue that phagocytose microbes called?
Where are most WBCs are produced primarily?
What are the three "pools" formed by WBCs located in the bone marrow?
- mitotic (immature precursor cells)
- maturing (cells undergoing maturation)
- storage (functional cells, released as needed)
What are the two "pools" formed by WBCs circulating in the peripheral blood?
- marginal (adhering to vessel walls)
What substances are responsible for the growth of committed granulocyte–monocyte stem cells?
colony-stimulating factors (CSFs)
What are the three locations throughout the body where lymphocytes are primarily localized?
- lymph nodes
- mucosa-associated lymphoid tissue (MALT)
What molecules function in antigen binding to B cells?
What molecule functions in antigen presentation to T cells?
major histocompatibility complex (MHC)
Which type of T cell do MHC class I molecules present antigens to?
CD8+ (cytotoxic) T cells
Which type of T cell do MHC class II molecules present antigens to?
CD4+ (helper) T cells
What is the estimation of the percentage of each WBC type per microliter of blood called?
differential WBC count
What is the normal relative abundance of each WBC type expected on a differential WBC count?
- neutrophils (50% to 60%)
- lymphocytes (20% to 34%)
- monocytes (3% to 7%)
- eosinophils (1% to 3%)
- basophils (<1%)
What is the term for an increase in the number of circulating WBCs (greater than 11,000/µL)?
What is the term for a reduction in the number of circulating WBCs (less than 4400/µL)?
What are three potential causes of physiologic leukocytosis?
- emotional stress
What are three potential causes of pathologic leukocytosis?
What type of leukocytosis is caused by pyogenic infections or cellular necrosis?
What is a “shift to the left”?
Increase numbers of immature neutrophils (bands ) in response to a bacterial infection.
What type of leukocytosis is caused by tuberculosis, syphilis, and viral infections?
What type of leukocytosis is caused by protozoal infections?
What type of leukocytosis is caused by allergies or parasitic infections?
What form of leukopenia involves a cyclic depression of circulating neutrophils about every 21–28 days?
What gene is mutated in cyclic neutropenia?
neutrophil elastase gene (ELA2)
What is cancer of the WBCs that affects the bone marrow and circulating blood called?
Which leukemias involve exponential proliferation of a clonal myeloid cell?
Which leukemias involve exponential proliferation of a clonal lymphoid cell?
Which leukemias are rapidly progressive, resulting from accumulation of immature, nonfunctional WBCs?
Which leukemias have a slower onset, allowing for production more mature, functional WBCs?
What are the four main types of leukemia?
- acute myelogenous leukemia (AML)
- acute lymphocytic leukemia (ALL)
- chronic myelogenous leukemia (CML)
- chronic lymphocytic leukemia (CLL)
What are three potential risk factors for the development of leukemia?
- ionizing radiation
- chemical exposure (e.g. benzene)
- viral infections (e.g. EBV)
Which leukemia is a neoplasm of immature myeloid cells?
acute myelogenous leukemia (AML)
What age group is most commonly affected by AML?
This is a leukemia of adults; mean age of affected persons in the United States is 65 years.
What group of clonal disorders of hematopoietic stem or progenitor cells may evolve into AML?
What are four genetic disorders that increase the risk for AML?
- Down syndrome
- Klinefelter syndrome
- Fanconi anemia
- von Recklinghausen disease
What are five signs and symptoms of AML?
- bone pain (leukemic infiltration)
- malaise, pallor, dyspnea (anemia)
- bleeding (thrombocytopenia)
- infections (granulocytopenia)
- enlargement of tonsils, lymph nodes, spleen, and gingiva (leukemic infiltration)
What are five tests used to diagnose leukemia?
- peripheral blood smear
- bone marrow aspirate
- cytochemical staining
- cytogenetic analyses
What type of stain is used for peripheral blood and bone marrow?
What are three laboratory findings for AML?
- at least 20% myeloblasts in blood or marrow
- positive stain for myeloperoxidase
- CD13, CD33, CD34, CD65, and CD117
How is AML subclassified?
It it divided into eight subtypes (M0 to M7) based on cell surface molecules and chromosomal abnormalities.
Which leukemia is a neoplasm of immature lymphoid cells?
acute lymphoid leukemia (ALL)
What age group is most commonly affected by ALL?
This is a leukemia of children; it accounts for 25% of all neoplasms in children and 80% of leukemias.
What chromosomal abnormalities are associated with ALL?
- Down syndrome (trisomy 21)
- Philadelphia chromosome [t(9;22)]
How does the presence of the Philadelphia chromosome affect the prognosis of ALL?
Patients with this chromosomal abnormality have a poorer prognosis in ALL.
The signs and symptoms of AML are largly similar to ALL. What is one important distinction of ALL?
There is a higher propensity toward CNS disease; patients may present with cranial nerve deficiencies.
What are three laboratory findings for ALL?
- massive numbers of lymphoblasts
- terminal deoxynucleotidyl transferase (Tdt)
- CD10 (CALLA), CD19, CD22, and HLA-DR
How is ALL subclassified?
It is divided into three subtypes (L1, L2, L3) based on the type and size of neoplastic lymphocytes:
- L1 (cells small and homogeneous)
- L2 (cells pleomorphic and often large)
- L3 (cells medium and homogeneous)
What are the three phases of chemotherapy for leukemia?
- consolidation (intensification)
- maintenance (remission)
What is the purpose of the first phase of chemotherapy for leukemia?
The first phase induces a state of remission by killing tumor cells with cytotoxic agents.
What is the purpose of the second phase of chemotherapy for leukemia?
The second phase focuses on consolidating the kill of remaining leukemic cells.
What is the purpose of the third phase of chemotherapy for leukemia?
The third phase provides maintenance therapy to prevent expansion of any remaining leukemic cell mass.
What are three criteria for complete remission in acute leukemia?
- platelet count >100,000/µL
- neutrophil count >1000/µL
- bone marrow specimen <5% blasts
What treatment for acute leukemia is usually reserved for patients younger than 45 years of age and for children and young adults who relapse?
bone marrow transplantation (BMT)
What are areas in the body where chemotherapeutic agents cannot reach leukemic cells called?
What is the most important sanctuary in patients with ALL?
What are four oral manifestations of acute leukemias?
- gingival enlargement
- gingival bleeding
- oral infection
What is a localized mass of leukemic cells on the hard or soft tissues of the oral cavity called?
granulocytic sarcoma (chloroma)
Which leukemia is a neoplasm of mature myeloid cells?
chronic myelogenous leukemia (CML)
What age group is most commonly affected by CML?
This is a leukemia of adults; median age at diagnosis is 64 years, and the incidence increases with age.
What chromosomal abnormality is associated with CML?
There is reciprocal translocation of the ABL gene from chromosome 9 and the BCR gene of chromosome 22.
What is the ABL gene?
Abelson leukemia virus gene
What is the BCR gene?
breakpoint cluster region gene
What is the chromosome produced by the t(9;22) translocation in CML called?
Philadelphia (Ph) chromosome
Besides CML, which other leukemia is Philadelphia chromosome associated with?
What is the effect of the ABL-BCR gene formed by t(9;22) translocation in CML?
Translocation contributes to increased tyrosine kinase activity and myeloid proliferation.
What are the three phases of CML?
- chronic phase (3 to 5 years)
- accelerated phase
- blast phase (or crisis)
Which phase of CML are most patients in at the time of diagnosis?
More than 90% of patients, when first diagnosed, are in the chronic phase of the disease.
What explains the increase in complications after CML transitions from the chronic phase to the blastic phase?
During the chronic phase of CML, leukemic cells are still functional; after transformation to the blastic stage, the cells are immature and nonfunctional.
What defines the blast phase of CML?
There must be 30% or more leukemic blast cells in the peripheral blood or marrow.
How does the presence of the Philadelphia chromosome affect the prognosis of CML?
Patients with this chromosomal abnormality have a better prognosis in CML.
What are five signs and symptoms of CML?
Up to half of patients are asymptomatic, but if symptoms do occur they may include:
- upper left quadrant pain
- weight loss
- night sweats
What are three laboratory findings of CML?
- WBC >50,000/µL, basophilia, eosinophilia
- positive for Ph chromosome (90%)
- high LDH and low leukocyte ALP
What is the preferred treatment for CML?
tyrosine kinase inhibitors (e.g. imatinib)
What treatment for CML is generally are recommended for younger patients?
stem cell transplants
How do chronic leukemias differ from acute lekemias in oral manifestations?
Chronic leukemias are less likely to demonstrate oral manifestations compared with acute forms.
Which leukemia is a neoplasm of mature lymphoid cells?
chronic lymphocytic leukemia (CLL)
What type of lymphocytes are mainly affected by CML?
CD5+ B lymphocytes
What age group is most commonly affected by CML?
This is the most common type of leukemia in adults; median age at diagnosis is 71 years.
What ethnicity is most commonly affected by CML?
It is more common in Jewish people from Russian or Eastern European ancestry.
What four chromosomal abnormalities are associated with CLL?
- 3q deletion (40%–50%)
- 11q deletion (15%–20%)
- trisomy 12 (15%–20%)
- 17p deletion (5%–10%)
What are five signs and symptoms of CLL?
Most patients are asymptomatic at presentation, but when symptoms do occur, they include:
- weight loss
- infections (hypogammaglobulinemia)
What are three laboroatry findings of CLL?
- mature lymphocytes >5000/µL
- small, round lymphocytes with scant cytoplasm
- CD3, CD19, CD20, CD21, CD23, and CD24
What are the three stages of CLL?
- stage A (two or fewer lymph node groups, no anemia or thrombocytopenia)
- stage B (three or more lymph node groups, no anemia or thrombocytopenia)
- stage C (anemia and thrombocytopenia, any number of lymph node groups)
What is the treatment for CLL?
It is incurable and treatment has little effect on survival; monoclonal antibody targeting agents and corticosteroids may be used for symptomatic patients.
What cancer of the lymphoid organs and tissues presents as discrete tissue masses?
What are the three common types of lymphoma?
- Hodgkin lymphoma (HL)
- non-Hodgkin lymphoma (NHL)
- Burkitt lymphoma
Why are lymphomas of special importance in dental management?
Because initial signs often occur in the mouth (e.g. Waldeyer ring) and in the head and neck region.
What is considered to be one of the most curable forms of cancer?
Hodgkin lymphoma (HL); the current cure rate for HL is about 90%.
Which lymphoma is a neoplasm of B lymphocytes?
Hodgkin lymphoma (HL)
What is the characteristic tumor cell of HL?
What age group is most commonly affected by HL?
This is the most common lymphoma in young adults; it has two peaks of incidence; one in early adulthood and another in the fifth decade of life.
What virus is frequently is present in malignant lymphocytes of HL?
What is the oncogenic protein encoded by EBV?
latent membrane protein 1
What are five signs and symptoms of HL?
- painless, enlarged, rubbery, lymph nodes
- weight loss
- night sweats
What is the main laboratory finding of HL?
The diagnosis is based on bone marrow aspirate showing large, multinucleated Reed-Sternberg cells.
What are the four classic pathologic variants of HL?
- nodular sclerosing (65%)
- mixed cellularity (12%)
- lymphocyte-depleted type (2%)
- lymphocyte-predominant type (3%)
What is the group of symptoms associated with poorer survival rates in HL or NHL called?
What are the "B symptoms" of HL or NHL?
- weight loss (>10%)
- night sweats
- persistent fever (>38 °C)
What are the four stages of HL?
- involvement of one lymph node region or a single extralympatic site
- involvement of multiple lymph nodes or extralympatic sites on same side of diaphram
- involvement of multiple lymph nodes or extralympatic sites on both sides of diaphram
- diffuse extralympatic disease (e.g. in liver, bone marrow, lung, or skin)
What chemotherapeutic drug regimen is given to prevent relapse in patients who have received radiation therapy for HL?
ABVD chemotherapy, also known as salvage therapy:
Which lymphoma comprises a large group of lymphoproliferative disorders of B- or T-cell origin?
non-Hodgkin lymphoma (NHL)
Which cells are most commonly affected by NHL?
More than 80% of these neoplasms are of B-cell origin.
What are the four major categories of NHL?
- precursor (immature) B-cell neoplasms
- peripheral (mature) B-cell neoplasms
- precursor (immature) T-cell neoplasms
- peripheral (mature) T-cell and NK cell neoplasms
What chromosomal abnormalities are associated with NHL?
Translocations or mutations in genes that regulate lymphocyte growth (BCL6) or survival (BCL2).
What bacterial infection can contribute to gastric lymphoma of NHL?
What are three oncogenic viruses associated with several types of NHL?
- Kaposi sarcoma herpesvirus (KSHV)
What are five signs and symptoms of NHL?
- painless lymph node swelling
- weight loss
- night sweats
How does NHL differ from HL in regards to nodal enlargement the disease is first detected?
HL often begins with a single focus of tumor, NHL usually is multifocal when first detected.
What are lymphomas develop outside of lymph nodes called?
What is the main laboratory finding of NHL?
Excisional biopsy of the involved lymph node showing tumorous cells of B, T, or NK cell lineage.
What are the two most common types of NHL?
- follicular lymphoma
- diffuse large B-cell lymphoma (DLBCL)
What is the CHOP-R chemotherapeutic drug regimen used to treat NHL?
What is the CVP-R chemotherapeutic drug regimen used to treat NHL?
What is the FCR chemotherapeutic drug regimen used to treat NHL?
What are three oral manifestations of HL or NHL?
- cervical lymphadenopathy
- extranodal tumors
- intraoral lymphoma (Waldeyer ring)
What are four oral complications of radiation therapy, often seen in HL or NHL?
- burning mouth symptoms
- xerostomia (>25 Gy)
- osteoradionecrosis (>50 Gy)
Which lymphoma is a mature B-cell lymphoma expressing surface immunoglobulin, usually IgM?
What age group is most commonly affected by Burkitt lymphoma?
It is the most common lymphoma of childhood; it affects children and young adults
What are the three types of Burkitt lymphoma?
- sporadic (nonendemic)
- immunodeficiency associated
Where is endemic Burkitt lymphoma most common?
Where is nonendemic Burkitt lymphoma most common?
All Burkitt lymphomas are associated with translocation of what gene?
What are the three possible translocation of the c-myc gene that occur in Burkitt lymphoma?
- t(8;14) (most common)
What virus is common found in endemic tumors of Burkitt lymphoma?
Why is Burkitt lymphoma of special concern in terms of its tumor growth?
This malignancy is very aggressive and grows very rapidly; tumors can double in size every 3 days.
Where are four places tumors are commonly found in endemic Burkitt lymphoma?
- jaw (especially in young patients)
- adrenal glands
Where are tumors are commonly found in nonendemic Burkitt lymphoma?
What is the primary laboratory finding of Burkitt lymphoma?
Numerous atypical B (CD10) lymphocytes interspersed with lightly stained histiocytes (“starry sky” pattern).
Where do osteolytic jaw lesions commonly occur in Burkitt lymphoma?
Distal to the last mandibular molar.
What are five chemotherapeutic drugs used to treat Burkitt lymphoma?
The disease responds well to high-dose chemotherapy:
- cyclophosphamide, plus
- vincristine, or
- doxorubicin, or
- methotrexate, or
Which form of Burkitt lymphoma is most commonly associatd with oral manifastations?
The endemic form often presents as a rapidly expanding tumor of the maxilla or mandible.
What lymphoproliferative disorder results from overproduction of cloned malignant plasma cells?
multiple myeloma (MM)
What condition, consisting of increased numbers of plasma cells with no other clinical manifestations, may precede MM?
monoclonal gammopathy of undetermined significance (MGUS)
What chromosomal abnormality is associated with MM?
Translocations involving the immunoglobulin heavy chain locus (IgH) at 14q32.
What is the mechanism of the bone resorption at tumor sites in MM?
There is overproduction of cytokines (e.g. IL 1α, RANKL) which stimulate osteoclasts to resorb bone.
What are the top two causes of death in MM?
- renal failure
Why is renal failure a complication of MM?
Tubular damage occurs due to urinary excretion of immunoglobin light chains (Bence-Jones proteins) or deposition of amyloid.
Why is renal infection a complication of MM?
Because of diffuse hypogammaglobulinemia caused by decreased production of normal antibodies.
What are five signs and symptoms of MM?
- “punched-out” bone lesions
- amyloid deposition in soft tissues
- pneumonia (hypogammaglobulinemia)
- bone pain (spine, ribs, and sternum)
What are five labortory findings of MM?
- elevated serum calcium
- increased immunoglobulins in the blood
- Bence-Jones proteins in urine
- anemia, neutropenia, thrombocytopenia
- monoclonal (M) protein band (electrophoresis)
What three immunoglobulins are most commonly detected in MM?
What are labortory findings of MM indicate renal involvement?
- increased blood urea nitrogen (BUN)
- increased serum creatinine
What are labortory findings of MM indicate a poorer prognosis?
- decreased serum albumin level
- increased β2-microglobulin
What is the role of thalidomide in the treatment of MM?
It is an immunomodulating agent that inhibits angiogenesis and secretion of TNF-α and IL-6.
What is the role of bortezomib in the treatment of MM?
It is a proteasome inhibitor which blocks proteases required for the accumulation of regulatory proteins important in cell cycle control.
What drug is given to manage anemia in MM?
What drug is given to manage bone loss in MM?
What are three oral manifestations of MM?
- osteolytic lesions (“punched-out”)
- soft tissue lesions
- soft tissue deposits of amyloid
Why is it important for the dentist to attempt to identify leukemia through history and clinical examination before starting any treatment?
Because patients with leukemia:
- may experience serious bleeding complications
- may have altered healing of surgical wounds
- are prone to postsurgical infection
What is the appropriate course of action when a dental patient displays the classic signs or symptoms of leukemia, lymphoma, or MM ?
They should be promptly referred directly to a physician.
What two screening tests should be ordered for patients suspected to have leukemia?
- CBC with differential
- blood smear for cell morphologic study
What is the appropriate course of action when screening tests for lekemia are ordered by the dentist and one or more results are abnormal?
The patient should be promptly referred for medical evaluation and treatment.
What are the three phases of dental management in patients undergoing medical therapy for a WBC disorder?
- pretreatment assessment
- oral health care during medical therapy
- posttreatment management
What four components should be included in the pretreatment assessment for patients with WBC disorders?
- extraoral examination
- intraoral examination
- panoramic film
- blood laboratory findings
What four components should be included in the pretreatment care for patients with WBC disorders?
- oral hygiene instructions
- treatment of caries
- treatment of pulpal disease
- any extractrations
What is the minimum period of time that must be allowed between the time of a dental extraction and initiation of chemotherapy or radiotherapy?
10 to 14 days (3 weeks preferred)
What condition causes the mucosa to become red, raw, and tender, often developing 7 to 10 days after initiation of chemotherapy?
What are four treatments for mucositis?
- oral hygiene to minimize infection
- bland mouth rinse to clean the ulcer
- benzocaine for pain relief
- antimicrobial rinses (e.g. chlorhexidine)
What condition increases risk for infection after initiation of chemotherapy?
Which form of leukemia is more prone to oral infections?
Oral infection is more of a problem in acute leukemia because the cells are immature and nonfunctional.
What is an important consequence of neutropenia that may complicate diagnosis of oral infections?
The swelling and erythema usually associated with oral infection are often less distinctive.
What are three reasons why opportunistic infections are common in patients with leukemia?
- malignant leukocytes are immature
- chemotherapy is immunocompromising
- use of broad-spectrum antibiotics
What is a common oral opportunistic infection in patients with leukemia?
What is a common viral opportunistic infection in patients with leukemia?
herpes simplex virus (HSV)
What is the minimum platelet count before performance of invasive dental procedures?
What common sequela of BMT or stem cell transplantation occurs when donor T cells react against histocompatibility antigens of the host?
How is graft-versus-host disease prevented in patients who are preparing for BMT?
They undergo T-cell depletion of the graft and prophylactic treatment with immunosuppressive agents.
Which chemotherapeutic drug is associated with paresthesias?
Which chemotherapeutic drug is associated with gingival overgrowth?
Which chemotherapeutic drug is associated with pigmentation of the hard palate?
How can chemotherapy during childhood affect future dental health?
- restricted growth of the jaws leads to micrognathia, retrognathia, or malocclusion
- damage to the teeth can manifest as blunted roots, dilacerations, microdontia, or hypodontia
Can patients with WBC disorders who are in a state of remission can receive dental treatment?
Yes; they can receive most indicated dental treatment.
Can patients with WBC disorders who have advanced disease receive dental treatment?
No; they should receive emergency care only.
When is risk for infection greatest following splenectomy, indicating antibiotic prophylaxis?