White Blood Cell Disorders: An Overview

WHITE BLOOD CELL
DISORDERS
RAM KUMAR ADHIKARI
KANTIPUR DENTAL COLLEGE TEACHING HOSPITAL AND
RESERCH CENTRE
BDS 4TH
BATCH /4TH
YEAR
ROLL NO. 17

WHITE BLOOD CELL DISORDERS Page 1
INTRODUCTION
White blood cells (WBCs) or leukocytes originate from pluripotent hematopoietic stem cells in
either bone marrow or lymphoid tissue.
These cells are responsible for the protection of the body against foreign invaders such as fungi,
bacteria, viruses, and parasites.
Leucocytes are of three types:
– Granulocytes
– Monocytes
– Lymphocyte
DEVELOPMENTAL STAGES OF BLOOD CELLS
WHITE BLOOD CELL

GRANULOCYTES
Neutrophils: Primary pathogen-fighting cells
Eosinophils: Help control allergic responses; fight parasites
Basophils: Release heparin, histamine, and other inflammatory mediators.
LYMPHOCYTES
Three types of cells are present and they are:
a. B cells: create antibodies
b. T cells: control immune response; cell-mediated immunity
c. Natural killer cells: kill antigenic cells
MONOCYTES/MACROPHAGES
These are antigen-presenting cells and create inflammatory mediators.
WBC DISORDERS
• Qualitative
Chediak- Higashi syndrome
• Non neoplastic
Leukocytosis
Leukopenia
• Neoplastic
Leukemia
Lymphoma
Multiple myeloma
QUALITATIVE DISORDER
It is caused due to defects in leukocyte function both genetic and acquired lead to increased
vulnerability to infection.
These qualitative defects can be:
• Defects in adhesion: leukocyte adhesion deficiency (LAD type I, defect in leukocyte
integrins).
• Defects in microbial activity: chronic granulomatous disease.
• Defects in phagolysosome function: Chediak-Higashi syndrome.
CHEDIAK-HIGASHI SYNDROME
• It is a autosomal recessive disorder.
• Mutation is in the lysosomal trafficking regulator gene (LYST) on chromosome 1q42–45.
• Abnormal granules in the granulocytes (neutrophils) are present.
• The presence of granules results in neutrophils with decreased chemotactic and antibacterial
activity

Clinical Presentation
• Hypopigmentation of the skin, iris, and hair
• Neutropenia with recurrent infections (especially S. aureus)
• Lymphomas
• Peripheral neuropathy
• Eosinophilic inclusions in myleoblasts
• δ-Storage Pool Defects (SPD)
• Hepato-splenomegaly
• Normal platelet count.
• Oculocutaneous albinism
Oral Manifestation
 Gingival and periodontal disease
 Increased caries incidence
 Oral ulcerations
 Early loss of teeth
Treatment
Bone marrow transplantation is the treatment of choice.
Differential White Cell Count
Neutrophils 2000-7500/mm3 50-60%
Lymphocytes 1500-4000/mm3 20-30%
Monocytes 200-800/mm3 3-7%
Eosinophils 40-400/mm3 1-3%
Basophils 10-100/mm3 ˂1%

NON-NEOPLASTIC DISORDERS
• Leukocytosis
• Leukopenia
REACTIVE LEUCOCYTOSIS
• It is an increase in the number of circulating white blood cells, often due to infection.
• It is relatively non-specific and can be classified on the basis if particular white cell series
affected.
• In response to increased demand, increased number of immature neutrophils called ‘bands’
enters the circulation, a process called a ‘left shift’.
• This is called LEUKEMOID reaction which is often secondary to viral infection.
CAUSES OF LEUKOCYTOSIS
NEUTROPHILIA
• Infection: bacterial, fungal
• Trauma: surgery, burns
• Infarction: myocardial infarct, pulmonary embolus, sickle-cell crisis
• Inflammation: gout, rheumatoid arthritis, ulcerative colitis, Crohn’s disease
• Malignancy: solid tumours, Hodgkin lymphoma
• Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia
• Physiological: exercise, pregnancy
EOSINOPHILIA
• Allergy: hay fever, asthma, eczema
• Infection: parasitic
• Drug hypersensitivity: gold, sulphonamides
• Skin disease
• Connective tissue disease: polyarteritis nodosa
• Malignancy: solid tumors, lymphomas
• Primary bone marrow disorders: myeloproliferative disorders, hyper-eosinophilia syndrome
(HES), acute myeloid leukemia
BASOPHILIA
• Myeloproliferative disease: polycythaemia, chronic myeloid
• Leukaemia
• Inflammation: acute hypersensitivity, ulcerative colitis, Crohn’s disease
• Iron deficiency
MONOCYTOSIS
• Infection: bacterial (e.g. tuberculosis)
• Inflammation: connective tissue disease, ulcerative colitis, Crohn’s disease
• Malignancy: solid tumors

LEUKOPENIA (low white cell count)
 A reduction in the total numbers of circulating white cells is called leukopenia.
 It may be due to a reduction in all types of white cell or in individual cell types (usually
neutrophils or lymphocytes).
 Leucopenia may occur in isolation or as part of a reduction in all three hematological lineages
(i.e. pancytopenia).
Also known as Agranulocytosis / Granulocytopenia
LYMPHOPENIA
Condition in which the lymphocyte count is ˂1 x 103 /mm3
• Inflammation: connective tissue disease
• Lymphoma
• Renal failure
• Sarcoidosis
• Drugs: corticosteroids, cytotoxics
• Congenital: severe combined immunodeficiency
NEUTROPENIA
Neutrophils count is ˂1500/mm3, but dependent on age and race.
• Infection: viral, bacterial (e.g. Salmonella), protozoal (e.g. malaria)
• Drugs: Sulphonamides, penicillins, cephalosporins, ranitidine, zidovudine
• Autoimmune: connective tissue Alcohol
• Bone marrow infiltration: leukaemia, myelodysplasia
• Congenital: Kostmann’s syndrome disease
Clinical Features
• The disease has a sudden onset and is characterized by chills, fever, malaise, and sore throat.
• Within 12–24 hours, signs and symptoms of respiratory and/ or gastrointestinal tract or other
bacterial infections may develop.
• The risk of infections is usually related to the degree of neutropenia.
Oral Manifestation
 Ulceration and necrotizing lesions may
be seen on the:
– Floor of mouth
– Buccal mucosa
– Pharynx or other sites within in
the oral cavity (agranulocytic
angina)
– Gingiva
 Ulcer lacks the surrounding
inflammation and is characterized by
necrosis and foul smell.

 Lesion shows massive growth of microorganism, with relatively poor leukocyte response
(minimal swelling and pus).
 Severe necrotizing gingivitis with periodontal tissue destruction is common.
Laboratory Diagnosis
Laboratory diagnosis can be done with white blood count and bone-marrow aspiration.
Differential Diagnosis
• Cyclic neutropenia
• Necrotizing ulcerative gingivitis
• Myelic aplasia
• Acute leukemia
• Wegener granulomatosis
Treatment
 Antibiotics,
 White blood cell transfusions
 Administration of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage
colony-stimulating factor (GM-CSF) is also beneficial.
Dental Consideration
 Oral infections in patients with severe neutropenia should be considered potentially life
threatening because they can lead to bacteremia and septicemia.
 Ulcers can be treated with topical anesthetics and antiseptic mouth rinses.
 In severe pulpal and periodontal infections broad spectrum antibiotics can be advised until
culture reports are available.
CYCLIC NEUTROPENIA
Definition
Cyclic neutropenia is a rare hematological disorder characterized by regular periodic reduction of
the neutrophil leukocytes.
Etiology
It is a hereditary autosomal dominant trait has been recorded in some cases.

Clinical features
• The disease is usually manifested in childhood,
• The reduction of neutrophils occurs regularly in a 21-day cycle.
• Patients typically may complain of:
– Low-grade fever and Headache
– Malaise
– Anorexia
– Arthralgias
– Cervical lymphadenopathy
– Gastrointestinal disorders
Oral Manifestation
 Oral lesions present as a painful ulcer covered by a whitish membrane and surrounded by an
erythematous halo.
 Localized gingivitis is also a common finding.
LEUKEMIA
 It is a malignant disorders of the
hematopoietic stem cell
compartment,
 It is associated with increased
numbers of white cells in the bone
marrow and/or peripheral blood.
 It is derived from Greek word (Greek
leukos, “white”; aima, “blood”)
 This neoplastic proliferation in
marrow results in diminished
production of normal erythrocytes,
granulocytes, and platelet.
Epidemiology
 Incidence 10/100 000 p.a.
 Males > females

o 3:2 in acute leukemia
o 2:1 in chronic lymphocytic leukemia
o 1.3:1 in chronic myeloid leukemia
 Acute leukemia occurs at all ages.
 Acute lymphoblastic leukemia shows a peak of incidence in children aged 1–5 years.
 All forms of acute myeloid leukemia have a striking rise over the age of 50.
 Chronic leukemia’s occur mainly in middle and old age
Risk Factors for Leukemia
Ionizing radiation
• After atomic bombing of Japanese cities (myeloid leukemia)
• Radiotherapy for ankylosing spondylitis
• Diagnostic X-rays of the fetus in pregnancy
Cytotoxic drugs
• Especially alkylating agents (myeloid leukemia, usually after a latent period of several years)
• Industrial exposure to benzene
Retro viruses
• One rare form of T-cell leukemia/lymphoma appears to be associated with a retrovirus similar
to the viruses causing leukemia in cats and cattle.
Genetic
• Identical twin of patients with leukemia
• Down’s syndrome and certain other genetic disorders
Immunological
• Immune deficiency states (e.g. hypo-gammaglobulinaemia)
CLASSIFICATION OF LEUKEMIA
• Lymphocytic leukemia (“lymphoblastic”)
• Acute lymphoblastic
• Chronic lymphoblastic
• Myelogenous leukemia (“myeloid” or “non-lymphocytic”)
• Acute myeloid
• Chronic myeloid
ACUTE LEUKEMIA
 It is of two types:
Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
• There is failure of cell maturation in acute leukemia.

• Proliferation of immature cells leads to an accumulation of useless cells which take up more and
more marrow space at the expense of the normal hematopoietic elements.
 In adults- AML:ALL=4:1
 In children-AML:ALL=1:4
• Acute leukemias have increased number of immature cells called blasts in peripheral
circulation.
Immature cells called blasts in peripheral blood film
WHO CLASSIFICATION OF ACUTE LEUKEMIA
 Acute myeloid leukemia (AML) with recurrent genetic abnormalities
AML with t (8; 21) gene product AML/ETO
AML with eosinophilia in v (16) or t (16; 16), gene product CBFβ/MYH11
Acute promyelocytic leukemia t(15;17), gene product PML/RARA
AML with 11q23 abnormalities (MLL)
 Acute myeloid leukaemia with multilineage dysplasia
e.g. Following a myelodysplastic syndrome
 Acute myeloid leukaemia and myelodysplastic syndromes, therapy-related
e.g. Alkylating agent or topoisomerase II inhibitor
 Acute myeloid leukaemia not otherwise specified
e.g. AML with or without differentiation,
 Acute myelomonocytic leukaemia,
Erythroleukaemia,
Megakaryoblastic leukemia,
Myeloid sarcoma
 Acute lymphoblastic leukaemia (ALL)
Precursor B ALL
Precursor T ALL

CLINICAL FEATURE
• Anemia
Shortness of breath on effort, excessive tiredness, weakness
• Leucopenia
Recurrent infections
• Thrombocytopenia
Bleeding and bruising (particularly acute promyelocytic leukemia)
• Marrow infiltration
Bone pain
Examination may be unremarkable, but features include:
 Pallor
 Fever (due to infection, not the disease itself)
 Petechiae, purpura, bruises, fundal hemorrhage
 Lymphadenopathy, hepatosplenomegaly
 Violaceous skin
 Testicular enlargement
 Cranial nerve palsies occasionally found
ORAL MANIFESTATION
The most common oral lesions are:
 Ulceration
 Spontaneous gingival hemorrhage,
 Petechiae,
 Ecchymoses,
 Tooth loosening, & delayed wound healing.
Gingival enlargement is a characteristic pattern, frequently seen in patients with myelomonocytic
leukemia.
Candidiasis and herpetic infections are relatively common oral complications of leukemia.

INVESTIGATIONS
Blood Count
Blood film
Blast cells almost invariably seen
The presence of Auer rods in the cytoplasm of blast cells indicates a myeloblastic type of leukemia
Bone marrow aspirate
Increased cellularity,
Reduced erythropoiesis,
.
Chest X-ray
Mediastinal widening often present in T
lymphoblastic leukemia
Cerebrospinal fluid examination
Management
The aim of treatment is to destroy the leukemic clone of
cells without destroying the residual normal stem cell
compartment from which repopulation of the
hematopoietic tissues will occur.
There are three phases:
• Remission induction
• Remission consolidation
• Remission maintenance

Remission Induction
• In this phase, the bulk of the tumor is destroyed by combination chemotherapy.
• The patient goes through a period of severe bone marrow hypoplasia,
• Requiring intensive support and
• Inpatient care from a specially trained multidisciplinary team.
Remission Consolidation
• If remission has been achieved, residual disease is attacked by therapy during the consolidation
phase.
• It consists of a number of courses of chemotherapy, again resulting in periods of marrow
hypoplasia.
• In poor-prognosis leukemia this may include bone marrow transplantation.
Remission Maintenance
• If the patient is still in remission after the consolidation phase for ALL, a period of maintenance
therapy is given, consisting of a repeating cycle of drug administration.
• This may extend for up to 3 years if relapse does not occur and is usually given on an outpatient
basis.
In patients with ALL it is necessary to give prophylactic treatment to the central nervous system, as
this is a sanctuary site where standard therapy does not penetrate.
Supportive Therapy
Aggressive and potentially curative therapy which involves periods of severe bone marrow failure
would not be possible without adequate and skilled supportive care.
The following problems commonly arise.
Anemia
• Anemia is treated with red cell concentrate transfusions.
Bleeding
 Thrombocytopenic bleeding requires platelet transfusions.
 Prophylactic platelet transfusion should be given to maintain the platelet count above 10 × 10
9/L.
Infection
• Fever (> 38 °C) lasting over 1 hour in a neutropenic patient indicates possible septicemia.
• Parenteral broad-spectrum antibiotic therapy is essential.
• Empirical therapy is given with a combination of an aminoglycoside (e.g. gentamicin)
and a broad-spectrum penicillin (e.g. piperacillin / tazobactam).
• Oral and pharyngeal monilial infection is common. Fluconazole is effective for the treatment of
established local infection.
• Herpes simplex infection is treated with acyclovir.

Bone Marrow Transplantation
• In patients with high-risk acute leukemia, allogeneic BMT can improve 5-year survival from
20% to around 50%.
FAB CLASSIFICATION OF ACUTE MYELOGENOUS LEUKEMIA (AML)

CHRONIC LEUKEMIA
Onset of chronic leukemia is insidious with the course (untreated) of the disease running up to 2-6
years.
The chronic leukemias have:
• a slower onset of symptoms,
• a better prognosis, and
• more mature WBCs than do acute leukemias.
Two types
1. Chronic myelocytic leukemia
2. Chronic lymphoid leukemia
CHRONIC MYELOID LEUKEMIA
Chronic Myelogenous Leukemia (CML) is defined as, “a malignant cancer of the bone marrow. It causes
rapid growth of the blood-forming cells (known as myeloid precursors) in the bone marrow,
peripheral blood, and body tissues.”
• CML represents about 14% of all occurrences of leukemias.
• Patients who have CML are said to be in one of the following three phases (in order of
occurrence):
o the chronic phase (between 1 and 15% blasts)
o the accelerated phase (between 15% - 30% blasts)
o the blast phase (more than 30% blasts).
• Median age range at presentation is 40-60 years.
• Up to 30% of patients are aged >60 years
• Slightly higher incidence in males (1.3:1)
• At presentation
o 50% diagnosed by routine laboratory tests
o 85% diagnosed during chronic phase
Clinical Features
• Symptomatic anemia (e.g. shortness of breath)
• Abdominal discomfort due to splenomegaly weight loss
• Fever, sweats, in the absence of infection
• Headache (occasionally) due to hyperleucocytosis
• Bruising, bleeding (uncommon).
Signs
 Pallor
 Splenomegaly, often massive
 Lymphadenopathy (uncommon, when found suggests blast crisis)
 Retinal hemorrhage due to leucostasis.
Oral Manifestations
 Petechial hemorrhages of the posterior hard palate and soft palate
 Ulceration due to an impaired immune defense

 Oral candidiasis
 Herpetic ulcers
 Gingival enlargement and
 Periodontal bone loss secondary to immune alteration and infiltration by leukemic cells may be
presenting features.
Investigations
Blood count.
• WBC raised (usually > 100 × 109/L),
Blood film.
• Neutrophilia
Bone marrow aspirate.
• Increased cellularity, increased myeloid precursors.
Fluorescein-in-situ hybridization (FISH)
Management
Imatinib
First line treatment for the chronic phase
Stem Cell Transplantation (SCT)
Allogeneic haemopoietic stem cell transplantation can cure approximately 70% of chronic phase
CML patients.
CHRONIC LYMPHOCYTIC LEUKAEMIA
CLL is a neoplastic disease characterized by proliferation and accumulation (blood, marrow and
lymphoid organs) of morphologically mature but immunologically dysfunctional lymphocytes
Epidemiology
• Most common leukemia of Western world.
• Less frequent in Asia and Latin America.
• Male to female ratio is 2:1.
• Median age at diagnosis is 65-70 years.
• Uncommon (10%) in patients under 50 years
Etiology and Pathogenesis
• The cause of CLL is unknown.
• There is increased incidence in farmers, rubber manufacturing workers and tire repair workers.
• Genetics factors have been postulated to play a role in high incidence of CLL in some families.
Clinical Features
The majority of patients are asymptomatic at presentation.
Common symptoms are:
• Recurrent infection
• Anemia due to hemolysis or marrow infiltration

• Painless lymphadenopathy
• Left upper quadrant discomfort (from splenomegaly).
The commonest findings on examination are:
• Anemia
• Fever (due to infection)
• Generalized lymphadenopathy (may involve single area)
• Hepatosplenomegaly, sometimes massive.
• However, none of these may be present.
INVESTIGATIONS
 Blood count.
 Blood film.
o Small or medium sized lymphocytes.
o May see smudge cells in vitro.
 Bone Marrow smear (cytological examination)
Differential Diagnosis
 Infectious causes
 Bacterial (tuberculosis)
 Viral (mononucleosis)
 Malignant causes
 B-cell
 T-cell
 Hairy-cell leukaemia
 Waldenstrom macroglobulinemia
 Large granular lymphocytic leukaemia

Treatment
• Decision about treatment depends on clinical stage, prognostic factors and patient’s condition
Indications to treatment:
 III/IV stage according to Rai’s classification
 Progressive disease (rapidly increasing lymphadenopathy, infections, general symptoms)
 Leukemia cell doubling time <6 (12) months
 Rapidly increasing organomegaly
 Secondary anemia, neutropenia, thrombocytopenia because of bone marrow infiltration
 Richter’s syndrome
Monotherapy
Glucocorticoids
Alkylating agents-Chlorambucil
Purine analogues
Combination chemotherapy
Chlorambucil/Cyclophosphamide + Prednisone
• Monoclonal antibodies (monotherapy and in combination) Alemtuzumab (anti-CD52) =
CAMPATH
• Splenectomy (hypersplenism)
• Radiotherapy (massive lymphadenopathy)
• Hematopoietic stem cell transplantation (SCT)
HAIRY CELL LEUKAEMIA (HCL)
• HCL is a clonal proliferation of abnormal B (or
very rarely T) cells which accumulate in the
bone marrow and spleen.
• Rare disease,
• Median age at presentation is 52 years old
• Male to female ratio is 4 : 1
• Name relates to the appearance of the cells on a
blood film and in the bone marrow – they have
an irregular outline owing to the presence of
filament-like cytoplasmic projections.
Clinical Features
 Anemia
 Fever
 Weight loss
 Splenomegaly occurs in 80% of cases
 Lymphadenopathy is uncommon
 Neutropenia
 Thrombocytopenia
 Low monocyte counts are found.

Treatment
• Cladribine and Pentostatin have specific activity in this condition
• Rituximab is used in cases who do not respond to the above drugs.
ORAL MANIFESTATIONS OF LEUKEMIA
Signs and Symptoms Related to Depression of Marrow Function:
 Pallor
 Anemia
 Petechiae
 Ecchymosis
 Gingival bleeding owing to thrombocytopenia
 Infections owing to neutropenia
 Opportunistic infections like: candidiasis, mucormycosis
 Herpes simplex infection
Signs and symptoms related to infiltration of leukemic cells
• Gingival and salivary gland enlargement
• Pain less cervical lymphadenopathy
• Involvement of developing tooth crypt
Signs and symptoms related to treatment of
leukemia
• Oral ulcerations due to chemotherapy and
/or radiation
• Dental anomalies in children
• Lichenoid lesions
• Desquamative gingivitis due to graft
versus host reaction
• Dental anomalies encountered are
microdontia, dental agenesis, and
arrested root development.
Radiographic Findings
The changes include:
 Loss of lamina Dura
 Displacement of teeth
 Loss of the crypt outline around the unerupted teeth
 Widened periodontal ligament
 Loss of cancellous bone trabeculae

Four periapical radiographs of the left mandible illustrating multifocal areas of bone destruction and
widening of portions of the periodontal ligament space (note the mesial surface of the distal root of the first
molar) characteristic of infiltration of the mandible with leukemia
Oral and Dental Considerations
 As the oral signs and symptoms are common, the dentist may be the first clinician to suspect the
disease.
 Preoperative precautions should include screening for hepatitis B and HIV.
 Preventive oral healthcare is essential and where indicated conservative dental treatment may be
possible.
 Management of chronic dental infections in patient with hematologic malignancies ideally should
be based on data that correlates examination findings with outcomes of treatment.
 The dentist should:
 Always discuss with the medical practitioner if any dental treatment is required. A
thorough history is needed prior the dental treatment (information on the underlying
disease, time of the diagnosis, modalities of treatment and etc.)
 Hematological information is needed before any invasive procedures (such as extractions)
as leukemia patients have higher bleeding tendencies and they are liable to infections.
 When oral surgical procedures are anticipated, a platelet count of at least 50 x10 9 /l and
absolute neutrophils count of at least 0.5 x10 9 /l are sought by the provider to comfortably
assure effective hemostasis and reduce the risk of postoperative bacterial infection.
 Preventive oral care is important in leukemia patients. Early intervention is important to
reduce the possible complications.
o Frequent topical fluoride applications
o Fissure sealants on the molars to reduce dental caries.
o Dietary advice to the patient
o Give proper tooth brushing instructions to both patient and parents.
 Antibiotic cover is needed before any surgery to prevent any postoperative infection.
 Root canal treatment is preferred over extractions to reduce the risk for oral and systemic
complications
 Dental treatment should be performed as a traumatically as possible to prevent any injuries to
the soft tissues.

 Fixed and removable orthodontic appliances are not recommended for patients with poor oral
hygiene.
 Pre-shedding deciduous teeth should be left to exfoliate naturally and patient should not play with
it with his/her tongue to reduce bacteremia.
 Leukemia patients should maintain their oral hygiene by:
o Brush twice daily using a soft toothbrush to reduce the risk of significant bleeding and
infection of the gingival.
o Attending the dental appointments regularly to monitor their oral condition.
o Remove plaque effectively to prevent formation of dental caries
o Rinse after meal to avoid accumulation of plaque/food debris.
LYMPHOMA
The lymphomas are malignant tumors of lymphoid tissue, characterized by the abnormal
proliferation B or T cells in lymphoid tissue.

CLASSIFICATION OF LYMPHOMA
• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma
HODGKIN’S LYMPHOMA (HL)
Introduction
• Hodgkin lymphoma (formerly called Hodgkin's disease) is a group of cancers characterized by
Reed-Sternberg cells in an appropriate reactive cellular background.
• An important clinical feature is its tendency to arise within lymph node areas and to spread in
an orderly fashion to contiguous areas of lymph nodes.
• Late in the course of the disease, vascular invasion leads to widespread hematogenous
dissemination.
• Hodgkin lymphoma has a bimodal age distribution with one peak in the 20s and 30s, and
a second peak over the age of 50.
Classification
• Nodular lymphocyte- predominant Hodgkin’s lymphoma
• Classical Hodgkin’s lymphoma:
• Nodular sclerosis HL
• Lymphocyte-rich HL
• Mixed cellularity HL
• Lymphocyte-depleted HL
Epidemiology
Incidence
Approximately 4 new cases/100 000 population/year
Sex ratio
Slight male excess (1.5:1)

Age
Median age 31 years; first peak at 20–35 years and second at 50–70 years
Etiology
• Unknown
• More common in patients from well-educated backgrounds and small families
• Three times more likely with a past history of infectious mononucleosis but no causal link to
Epstein–Barr virus infection proven
General symptoms
• Fever
• Weight loss
• Loss of appetite
• Night sweats
• Pruritus
• Lethargy
Local Symptoms
• The appearance of a painless
lymphadenopathy is typical, usually
in the area of the neck, which slowly
expands.
• The lymph nodes are hard, not
painful, movable relative to the skin,
and often adhere to each other.
• A considerable portion of the
patients have systemic symptoms,
called B symptoms, which become
evident before the lymphadenopathy
is discovered.
• These include noninfectious fever above 38 °C (Pel-Ebstein fever) periodicity of
7-10 days, loss of weight (10% in six months), and night sweats.
Signs of HL
• Lymph node enlargement
• Cachexia
• Anemia
• Splenomegaly
• Hepatomegaly
• Jaundice rarely

Investigations
 Lymph node biopsy is required for a definitive diagnosis.
 Hodgkin lymphoma, mixed cellularity
(lymphocytes, histiocytes, lacunar cells, in
the center a Sternberg giant cell).
 Liver biochemistry is often abnormal, with
or without liver involvement.
 Serum lactate dehydrogenase; raised level
is adverse prognostic factor.
 Chest X-ray may show mediastinal widening,
with or without lung involvement
 Positron emission tomography (PET) is
increasingly being used for staging,
assessment of response and direction of
therapy.
Clinical stages of lymphomas according to Ann Arbor’s classification (Cotswold
modifications)
Stage I: involvement of one lymph node region or one lymphatic organ (spleen, thymus, Waldeyer
ring).
Stage II: involvement of two or more lymph node regions on one side of the diaphragm.
Stage III: involvement of lymph node regions on both sides of the diaphragm.
Stage IV: involvement of one or more extra lymphatic organs (bone marrow, liver, etc).
Management
• Radiotherapy
• Short course of chemotherapy (ABVD):
• Adriamycin,
• Bleomycin,
• Vinblastine and
• Dacarbazine

In relapsed disease
High dose of chemotherapy and peripheral stem cell transplantation
COMPLICATIONS OF TREATMENT
Due to Radiotherapy:
Second malignancies - solid tumors, IHD, Hypothyroidism and lung fibrosis
Due to Chemotherapy:
Myelosupperssion, nausea, infection, alopecia and AML
Due to both of them:
NHL & infertility
NON-HODGKIN’S LYMPHOMA
Malignant tumors of the lymphoid system classified separately from Hodgkin’s lymphoma.
• 30% of T cell origin.
• 70% are of B cell origin
Epidemiology
Incidence
12 new cases/100 000 people/year
Sex ratio
Slight male excess
Etiology
• No single causative abnormality described
• Lymphoma is a late manifestation of HIV infection
• Are associated with EBV, human herpes virus 8 (HHV8) and human T-cell lymphotropic virus
(HTLV) infection
• Gastric lymphoma associated with Helicobacter pylori
• t(14:18) translocation in follicular lymphoma results in the deregulated expression of the BCL-2
gene product, which inhibits apoptotic cell death
• Congenital immunodeficiency states and in immunosuppressed patients after organ
transplantation
Lymphomas may be grouped by how quickly they are likely to grow:
INDOLENT
• (Also called low-grade) lymphomas grow slowly.
• They tend to cause few symptoms.
AGGRESSIVE
• (Also called intermediate-grade and high-grade) lymphomas grow and spread more
quickly.
• They tend to cause severe symptoms.
• Over time, many indolent lymphomas become aggressive lymphomas.

Clinical Features
Peripheral lymphadenopathy
Most patients present with painless, superficial
lymph node enlargement.
Systemic symptoms (B symptoms)
Fever, sweats and weight los
Extra-nodal presentation
This is more common than in HL and may
involve the gastrointestinal tract, lung, brain,
testes, thyroid and skin.
Abdominal involvement
May reveal hepato-splenomegaly.
Skin involvement (T cell lymphomas)
Presents as mycosis fungoides and Sézary syndrome
Oropharyngeal involvement occurs rarely
Oral Manifestation
Clinically, oral lymphoma presents as a diffuse,
painless swelling, which may or may not be
ulcerated
Most commonly affected area:
 soft palate,
 posterior part of the tongue,
 gingiva, and
 the tonsillar area
Investigations
1. Routine bone marrow aspiration and trephine.
2. Immunophenotyping of surface antigens
• distinguish T and B cell tumours.
• This may be done on blood, marrow or nodal material.
3. Immunoglobulin determination.
• Some lymphomas are associated with IgG or IgM paraproteins, which serve as
markers for treatment response.
4. Measurement of uric acid levels.
• aggressive high-grade NHLs are associated with very high urate levels,
• can precipitate renal failure when treatment is started.
5. HIV testing.
• This may be appropriate if risk factors are present

Management
Low-Grade NHL
• Asymptomatic patients may not require therapy.
• Indications for treatment include marked:
– Systemic symptoms,
– Lymphadenopathy causing discomfort or disfigurement,
– Bone marrow failure or
– Compression syndromes.
• The options are:
Radiotherapy
• This can be used for localized stage I disease, which is rare.
Chemotherapy
• Most patients will respond to oral therapy with chlorambucil, which is well
tolerated but not curative.
• More intensive intravenous chemotherapy in younger patients produces better
quality of life but no survival benefit.
Monoclonal antibody therapy.
• Humanized monoclonal antibodies can be used to target surface antigens on tumor cells,
and induce tumor cell apoptosis directly.
• Rituximab in combination with cyclophosphamide, vincristine and prednisolone (R-CVP) is
recommended as first-line therapy.
Transplantation
• Particular interest is on the role of high-dose chemotherapy and bone marrow
transplantation in patients with relapsed disease.
High-Grade NHL
Chemotherapy
The majority (> 90%) are treated with intravenous combination chemotherapy, typically with the
CHOP regimen:
Cyclophosphamide
Hydroxydaunorubicin (adriamycin)
Oncovin (vincristine) and
Prednisolone
Radiotherapy
A few stage I patients without bulky disease may be suitable for radiotherapy.
Monoclonal antibody therapy.
When combined with CHOP chemotherapy, rituximab (R) increases the complete response rates
and improves overall survival.
R-CHOP is currently recommended as first line therapy.

Bone marrow transplantation.
Autologous BMT benefits patients with relapsed chemo-sensitive disease

BURKITT LYMPHOMA
Burkitt lymphoma is a high-grade malignant B-lymphocyte lymphoma.
Clinical features
• Prevalent in central Africa (the endemic form)
• Affects children 2–12 years of age.
• Observed in other countries (the non-endemic
form), and recently in patients with AIDS.
• The jaws are the most common site of lymphoma
(60–70%).
– Presents as a rapidly growing hard swelling that
causes bone destruction, tooth loss, and facial
deformity
– Pain,
– Paresthesia and
– Ulcerating or non-ulcerating masses may also be seen
Burkitt lymphoma, gingival mass
Laboratory tests
Histopathological examination, radiography
Differential diagnosis
• Central Giant-cell Granuloma,
• Ossifying Fibroma,
• Non-Hodgkin Lymphomas,
• Odontogenic tumors
Treatment
Chemotherapy
Cyclophosphamide
Vincristine
Cytarabine
Radiotherapy

Oral and Dental Considerations of
Lymphoma
• The dentist should play a significant role in
early detection by routine examination of the
neck
• More commonly, dental complications result
from radiotherapy or chemotherapy
administered to children with HD during tooth
development.
o These abnormalities include agenesis,
hypoplasia, and blunted or thin roots.
• The jaws and mouth, particularly the palate,
has been reported by several authors.
• Palatal lesions have been described as slow-growing, painless, bluish, soft masses, and they
have been confused with minor salivary gland tumors
• Oral NHL also mimics inflammatory diseases and may present as:
 A gingival mass,
 Tongue mass, or
 Intraosseous lesion.
• Isolated loose teeth, paresthesia of the face, and major salivary gland enlargement also may be
presenting signs of NHL.
• Oral lesions also have been described in patients with cutaneous T-cell lymphoma (mycosis
fungoides).

• These lesions are often described as either
indurated plaques with a red or white surface
or ulcerated tumors.
• The most common site of involvement is
the tongue and usually follows skin lesions.
MULTIPLE MYELOMA
Myeloma is a malignant disease of the plasma cells of bone marrow, accounting for 1% of all
malignant disease
Etiology
Unknown
Suggested predisposing factors include:
• Viral infection with Human Herpesvirus 8 (HHV-8).
• MGUS (monoclonal gammopathy of undetermined significance).
Epidemiology
• Myeloma is a disease of the elderly, the median age at presentation being over 60 years.
• It is rare under 40 years of age.
• The annual incidence is 4 per 100 000
• It is commoner in males and in black Africans but less common in Asians.
Clinical Features
• Clinically, it presents with bone swelling, tooth
mobility, pain, and paresthesia.
• A painless soft swelling, usually on the alveolar
mucosa and gingiva, may develop as part of the
overall disease spectrum
Investigations
Full blood count. Hb, WBC and platelet count are
normal or low,presence of highly polymorphic
plasma cells.
ESR. This is almost always high.
C-reactive protein is almost always raised.
Blood film. There may be rouleaux formation as a
consequence of the paraprotein.
Urea and electrolytes. There may be evidence of
renal failure.

Radiologic Findings
• In more than 60% of all cases,
• Osteolytic foci can be detected, typically in the proximal part of the femur, humerus, the
ribs, or the skull (characteristic hollow lesions)
A generalized osteoporosis occurs in about 20% of all patients, with signs of compression fractures
of the spine in some patients with compression of the spinal cord

Bone marrow aspirate shows characteristic infiltration by plasma cells. Amyloid may be found.
Diagnosis
Major criteria
• 30% Plasma cells in bone marrow aspirate
• Plasma cell tumor on biopsy result
• Monoclonal band on electrophoresis 35 g/L for IgG,
• 20 g/L for IgA, or 1 g of light chains excreted in urine per day
Minor criteria
• 10−30% Plasma cells in bone marrow aspirate
• Abnormal monoclonal band but levels less than for major criteria
• Lytic bone lesions
• Immunosuppression (IgG 6 g/L, IgA 1.0 g/L, IgM 0.5 g/L)
The diagnosis of multiple myeloma requires:
• one major criterion plus one minor criterion or
• three minor criteria (including at least the first two minorcriteria) and
• a symptomatic patient

Treatment
Standard Chemotherapy
VAD (vincristine, adriamycin, dexamethasone)
High Dose Chemotherapy
Bone marrow transplant
Peripheral stem cell transplant
Other Modalities
• Pulse dexamethasone
• Interferon
• Local radiotherapy to bony lesions
• Thalidomide
Oral Manifestations
 Approximately 5 to 30% of myeloma patients have jaw lesions, and accidental discovery of
lesions in the jaws may be the first evidence of this disease.
 The patient may experience pain, swelling, and numbness of the jaws, epulis formation, or
unexplained mobility of the teeth.
 Skull lesions are more common than jaw lesions.
 Multiple radiolucent lesions of varying size, with ill-defined margins and a lack of
circumferential osteosclerotic activity, should suggest this diagnosis.
 The mandible is more frequently involved in MM because of its greater content of marrow.
 Lesions are most common in the region of the angle of the jaw, where red marrow generally is
present.
 In most instances, the lesions appear unassociated with the apices of the teeth.
 Extraosseous lesions also occur in a significant number of patients although a majority of the
lesions are asymptomatic.

Intraoral radiographic series showing multiple involvement of the maxilla and the mandible
in multiple myeloma
• Several authors have called attention to the development of oral amyloidosis as a complication
of this disease.
• Tongue biopsy is an excellent method of diagnosis.
• Clinically, the tongue may be enlarged and studded with small garnet-colored enlargements,
including nodes on the cheeks and lips.
• Amyloidosis occurs in 6 to 15% of patients with MM and may be detected in tissue specimens
with use of a Congo red stain or electron microscopy.
• When a dentist is requested to take a biopsy specimen to detect amyloidosis, the specimen must
include muscle tissue from the muco-buccal fold or tongue.
Dental Management
• Hemorrhage and infection are the dentist’s major concerns when treating a patient with MM.
• Bleeding may result from several causes, including thrombocytopenia, abnormal platelet
function, abnormal coagulation, or hyperviscosity.

• If surgery is necessary, recent results of platelet count, bleeding time, prothrombin time, and
partial thromboplastin time should be obtained.
• If hyperviscosity is present, excess bleeding may occur even if these tests are normal, a
hematology consultation should be considered.
• The dentist also should determine whether the patient has an increased susceptibility to
bacterial infection due to hyper-gammaglobulinemia, bone marrow failure, or complications of
cancer chemotherapy.
CONCLUSIONS
• Wbc disorders
• Qualitative
• Chediak- higashi syndrome
• Non neoplastic
• Leukocytosis
• Leukopenia
• Neoplastic
• Leukemia
• Lymphoma
• Multiple myeloma
Leukemia
Lymphocytic leukemia (lymphoblastic) Myelogenous leukemia (myeloid or non
lymphocytiv)
Type Acute
lymphocytic
Chronic
lymphocytic
Acute myelogenous Chronic
myelogenous
Age
mainly
affected
Most common
childhood
leukemis
Adults >55 Adult males Adult
Treatment Chemotherapy
and radiation
Chemotherap
y and
Steroids
Chemotherapy Imatinib
%5 year
survival
85 in children
50 in adult
75 40 90
Lymphoma and Multiple Myeloma
– Malignancies of B cells.
– Sometimes preventable.
– Highly treatable and often curable.
– Study of these diseases have led to important advances in the understanding of the biology
of lymphoid cells.

REFERENCES
• Differential Diagnosis in Internal Medicine From Symptom to Diagnosis, Walter
Siegenthaler, Thieme Publishing Group)
• Kumar and Clark’s Clinical Medicine Seventh Edition, Elsevier’s
• Davidson’s Principles and Practice of Medicine, 21st Edition Elsevier Limited
• Pocket Atlas of Oral Diseases,George Laskaris Thieme Publishing Group
• Mayo Clinic Internal Medicine Review EIGHTH EDITION, MAYO CLINIC SCIENTIFIC PRESS
• Burket’s Oral Medicine Diagnosis & Treatment Tenth Edition
• National cancer institute, www.cancer.go

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