Module 2: Oral Manifestations of Hematological Disorders

anemia

-decreased volume of RBCs (hematocrit)

-decreased concentration of Hb and/or O2 binding capacity of Hb

-often a sign of an underlying disease (liver disease, chronic inflammatory conditions, malignancies, vitamin/mineral deficiencies)

anemia signs/symptoms

-mostly non-specific: weakness, fatigue, poor concentration, shortness of breath on exertion, skin and mucosal pallor

-less common: swelling of legs/arms, chronic heartburn, vague bruises, vomiting, increased sweating, blood in stool

-in severe anemia: body may compensate by increasing CO (symptoms may include palpitations)

anemia diagnosis

*Blood test:

  1. RBC count

  2. Hb concentration

  3. MCV (normo-, micro-, macro- cytic)

  4. Red cell distribution width (RDW)

→ calculate hemocrit, MCH, MCHC to compare values adjusted for age and sex

*Other tests: serum iron, serum B12, Hb electrophoresis

*Microscopic examination of a stained blood smear

*Can also do bone marrow biopsy if diagnosis still difficult

NORMAL RBCS:

*uniform in size and shape

*diameter ~ nucleus of a lymphocyte

*central pallor = 1/3 of rbc diameter

iron-deficiency anemia etiology

*Occurs in 4 different settings:

  1. Excessive blood loss

  2. Increased demand for rbcs (pregnancy)

  3. Decreased uptake of iron (dietary restriction)

  4. Decreased absorption of iron (Celiac Disease)

*Most common cause of anemia in the world

  - U.S: men → GI disease; women → excessive menstrual flow

  - Developing nations: parasite infection

iron-deficiency anemia clinical features

SYSTEMIC:

*Fatigue, lightheadedness, lack of energy

*Skin pallor

*Atrophy of gastric mucosa

*Alopecia

*Koilonychia (spoon-shaped nails)

*Restless Leg Syndrome

*Pica (consumption of non-food based items)

ORAL:

*Atrophic glossitis +/- burning sensation

*Generalized mucosal atrophy

*Gingival pallor

*Angular cheilitis (may predispose to candidiasis)

iron-deficiency anemia diagnosis

*Complete blood count: decreased MCV and MCHC

*Peripheral blood smear: hypochromic (paler) micocytic (smaller than nucleus of lymphocytes)

*Reduced blood iron levels

iron-deficiency anemia treatment

*Dietary iron supplements

*IV iron supplements

*Treatment of underlying cause

Plummer-Vinson Syndrome (Paterson-Kelly Syndrome)

*Rare

*F, 30-50 yrs, Scandanavian/N. European

*Significant increased risk for oral and esophageal carcinoma

Clinical Features:

*TRIAD:

  1. Dysphagia/Esophageal Webs (🡪dysphasia)
  2. Atrophic Glossitis

  3. Iron Deficiency (hypochromic/microcytic) Anemia

*Angular cheilitis, koilonychia, burning sensation, GERD, esophagitis

Treatment:

*Dietary iron supplementation

*+/- esophageal dilation

pernicious anemia- etiology

*Poor absorption of cobalamin (B12, extrinsic factor)

  1. Lack of intrinsic factor (necessary for B12 absorption) 

     - usually due to autoimmune destruction of parietal cells of stomach

     - absorption of cobalamin cannot occur without IF!

  2. Poor absorption of Cobalamin

     - GI bypass surgery

     - Strict vegetarian diet (food sources = eggs, meat, poultry, shellfish, milk, milk products)

pernicious anemia clinical features

*More common in elderly

*Fatigue, weakness, lightheadedness

*Paresthesia, tingling, numbness of extremities

*Atrophy of gastric mucosa

*Increased risk of gastric carcinoma (1-2%)

ORAL:

*Burning sensation of tongue, lips, buccal mucosa

*Oral mucosal atrophy and erythema

*Atrophic glossitis

*”Beefy red tongue”

*Yellow-tinged mucosa

pernicious anemia diagnosis

*CBC (Increased MCV)

*Peripheral blood smear: megaloblastic (seen in marrow), macrocytic (seen in peripheral blood)

*Low serum cobalamin

*Schilling Test: measures radiolabeled Cobalamin absorption & excretion rates

pernicious anemia treatment

*Monthly intramuscular injections of Cobalamin

*High-dose oral cobalamin

*Periodic evaluation by GI doctor (increased risk of gastric carcinoma)

aplastic anemia etiology

*Failure of precursor cells in bone marrow to mature into all types of blood cells

  - environmental toxins (benzene)

  - drugs (chloramphenicol)

  - infection (non-A, non-B, non-C, non-G hepatitis)

  - genetic disorders (Fanconi’s anemia, dyskeratosis congenital)

  - idiopathic

*Risk of developing recurrent aplastic anemia and acute leukemia

aplastic anemia clinical features

SYSTEMIC:

1. Anemia → fatigue, lightheadedness, weakness

2. Neutropenia → bacterial & fungal infections

3. Thrombocytopenia → bleeding, bruising

ORAL:

1. Anemia → mucosal pallor

2. Neutropenia → oral ulcerations with minimal peripheral erythema

3. Thrombocytopenia → gingival hemorrhage, mucosal petechiae, purpura

*Also see ecchymoisis of eye and mouth

aplastic anemia diagnosis

*Pancytopenia (>2 of the following): 

  - <10,000 rbcs /mm3

  - < 500 wbcs/mm3

  - < 20,000 platelets/mm3

aplastic anemia treatment

*Discontinue inciting agent (if drug or toxin)

*Supportive therapy (Abx, blood transfusions)

*Androgenic steroids

*Bone marrow transplant

*Immunosuppressive therapy (Cyclosporine)

Prognosis is guarded – risk of recurrent aplastic anemia and acute leukemia

sickle cell anemia etiology

*AR genetic disorder of Hb synthesis

*Hb molecule prone to molecular aggregation in deoxygenated state → Hb forms long, inflexible chains → rbcs assume rigid, curved shape

*Reduced O2 carrying capacity of sickled rbcs

*Sickled rbcs aggregate and block capillaries

*One allele affected → 40-50% abnormal Hb, sickling only under certain conditions (low O2)

*Both alleles affected → most abnormal Hb

sickle cell anemia epidemiology

*Trait: 8% of AA

*Disease: 1:350-400 AA

*Geographic predilection – where malaria is endemic (Africa, Mediterranean, Asia)

  → sickle cell trait = resistance to malaria

clinical features of sickle cell anemia

SYSTEMIC:

*Chronic hemolytic anemia

*Ischemia, infarction, ulcers of distal extremities

*Infections (due to destruction of spleen)

*Impaired kidney function

*Ocular damage

*CNS damage/stroke

*Sickle Cell Crisis = severe sickling of rbcs

  - precipitated by hypoxia, infection, hypothermia, dehydration

  - extreme pain from ischemia and infarction of tissues

  - mostly affect long bones, lungs, and abdomen

  - pulmonary involvement = acute chest syndrome

ORAL:

*Reduced trabecular pattern

*Enlarged marrow spaces

*“Hair-on-end” on skull x-ray

*Increased prevalence of osteomyelitis

*Spontaneous, asymptomatic pulpal necrosis

sickle cell anemia treatment

*Avoid precipitating events

*Supportive care (fluids, rest, anelgesics)

*Hydroxyurea (inhibits polymerization of abnormal Hb, reduces adherence of RBCs to vessel walls)

*Bone marrow transplant

*Genetic counseling

hemoglobinopathies- thalassemia etiology

*AR genetic disorder characterized by reduced synthesis of alpha-globin or beta-globin chains of Hb molecule

*Hb structure:

  - tetramer of 2 alpha and 2 beta chains

  - 4 genes → alpha chain; 2 genes → beta chain

*Defective production of 1 chain → reduced amounts of Hb and abnormal rbcs

*Abnormal rbcs sequestered in spleen & destroyed → hemolytic anemia

thalassemia epidemiology

*Geographic predilection: Mediterranean, Africa, India, SE Asia

*Thalassemia trait = malaria resistance

beta-thalassemia genetics

*remember: 4 genes code for alpha, 2 for beta 

*Beta-Thalassemia Minor:

  - 1 beta globin gene defective

  - clinically insignificant disease

*Beta-Thalassemia Major (Cooley’s Anemia)

  - 2 beta globin genes defective

beta-thalassemia clinical features

Thalassemia Major

*Manifestations at ~1 yr

*Hemolytic anemia

*Increased hematopoiesis with bone marrow hyperplasia 

and enlarged marrow spaces

*”Hair-on-end” appearance on skull xray

*Enlargement of liver & spleen, lymphadenopathy

*Enlargement of maxilla and mandible (“chipmunk faces”)

*Altered trabecular pattern

beta-thalassemia treatment

*Blood transfusions every 2-3 weeks

  - complicated by iron overload

*Bone marrow transplant

*Surgical Recontouring for abnormal faces

beta-thalassemia prognosis

*Without therapy: tissue hypoxia, bacterial infections, cardiac failure by 1 yo

*With therapy: relatively normal lifespan

alpha-thalassemia genetics

*remember: 4 genes code for alpha, 2 for beta 

*No disease – 1 gene defective

*Alpha Thalassemia Trait – 2 genes defective

*HbH Disease – 3 genes defective

*Hydrops Fetalis – 4 genes defective  (fatal within a few hours of birth)

alpha-thalassemia clinical features

*Alpha Thalassemia Trait

  - mild anemia, may be clinically insignificant

*HbH Disease

  - more severe hemolytic anemia, splenomegaly

alpha-thalassemia treatment

*Iron and Folic Acid supplementation

  - caution: iron overload (hemochromatosis)

*General Supportive care

  - transfusions, may be needed periodically

*Splenectomy – risk of infection

*Severe cases: allogeneic hematopoetic stem cell transplant (curative)

polycythemia vera etiology

*Idiopathic disorder characterized by increased mass of rbcs 

and abnormal proliferation of marrow stem cells  

*Myeloproliferative Disease

*Increase in wbcs and platelets

*Cells function normally, just in excess (very crowded smear)

→ % of rbcs in blood may be so high 

→ blood ceases to flow in some smaller vessels and capillaries

polycythemia vera clinical features

*Older adults ~ 60 yrs

*Symptoms: nonspecific – HA, weakness, dizziness, visual disturbances, sweating, weight loss

*Ruddy complexion

*Pruritis – 40%

*Transient ischemic attacks, stroke, heart attacks – related to thrombosis

*Erythema and burning of hands and feet, gangrene and necrosis (related to thrombosis)

ORAL:

*Excessive hemorrhage – including gingiva

polycythemia vera treatment

*Phlebotomy – removal of blood (risk of thrombosis)

*Aspirin therapy – to reduce thrombotic events

*Myelosuppressive Therapy/Chemotherpeutic Drugs (risk of leukemia)

polycythemia vera prognosis

*Fair: average survival 10-12 years after diagnosis

*2-10% develop acute leukemia

leukemia etiology

*Malignant proliferation of hematopoetic stem cell derivatives (may be component of a syndrome – Down, Bloom, Klinefelter)

*Increased risk associated with exposure to certain environmental agents (pesticides, benzene, ionizing radiation)

*Generally bone marrow involvement

Classification:

1. Acute Myeloid – broad age range

2. Chronic Myeloid – primarily affects adults

                 - Philadelphia Chromosome – translocation of long arms of chromosomes

3. Acute Lymphoblastic – primarily affects children

Chronic Lymphoblastic – primarily affects adults

clinical features of leukemia

*Due to reduction of rbcs and wbcs caused by crowding out of normal marrow cells by malignant leukemic cells → myelophthisic anemia

SYSTEMIC:

*Anemia → fatigue

*Neutropenia → ulcerations, bacterial, fungal, viral infections

*Thrombocytopenia → bleeding, bruising

ORAL:

*Mucosal pallor

*Mucosal petechiae, purpura

*Ulcerations

*Fungal infections (eg candidiasis)

*Viral Infections (eg herpetic lesions)

*Gingival Leukemic Infiltrate = tumor-like collection of leukemic cells (granulocytic sarcoma or extramedullary myeloid leukemia, old term = chloroma), usually myeloid, type, spontaneous bleeding (no spontaneous bleeding in benign hyperplasia)

treatment of leukemia

*Chemotherapy + radiation

*Bone marrow transplant

*Supportive care (blood transfusions, Abx)

*Encourage optimal oral hygiene

leukemia prognosis

*Depend on type, age, other factors

*5 year survival rates:

  - older patients with AML = 10-20%

  - children with ALL = 70%

lymphoma etiology

*Group of malignant solid tumors involving cells of the lymphoreticular or immune system (T/B Cells)

*Most arise within lymph node (vs leukemias which begin in bone marrow and are characterized by malignant cells circulating in peripheral blood)

*Unknown etiology – viruses?

*2 major categories:

  - Hodgkin’s Disease

  - Non-Hodgkin’s Lymphoma

Non-Hodgkin’s lymphoma epidemiology

*Lymphoma of oral cavity is rare (more often Non-Hodgkin’s type: 3-5%) 

  - oral lesions rarely initial presentation

*Primarily affects adults (66 yrs)

*Male 

*Increased incidence in AIDS

Non-Hodgkin’s Lymphoma clinical features

*Most common presentation: painless, persistent enlargement of lymph nodes

*Extra nodal disease can occur → mainly presents in soft tissue

*Usually in patients >40 y/o

*Increased incidence in AIDS patients

ORAL:

*Enlarged tonsil, painless palatal swelling, or gingival mass (may mimic inflammatory disease)

*Tumor isnontender, diffuse, boggy, discolored swelling (+/- ulcerated)

*Rarely can occur in jaw bones

Non-Hodgkin’s Lymphoma pathology

-diffuse sheet of inflammatory cells

Non-Hodgkin’s Lymphoma treatment

-radiation and/or chemotherapy

Non-Hodgkin’s Lymphoma prognosis

-5 year survival ~50%

Burkitt’s lymphoma epidemiology

*Unique high grade non-Hodgkin’s Lymphoma, very rapid growth

*t(8:14)

*2 types: 

  - African – 6 years, 2x M, EBV found in 90%

  - American – 11 years, no gender predeliction, EBV found in 10% of American

Burkitt’s lymphoma clinical features

African Type:

*Primarily involves jaw bones (most often maxilla) with secondary visceral involvement

American Type:

*Primarily presents as abdominal swelling  - only 15% jaw involvement → Jaw involvement in both types = rapidly growing mass, teeth become mobile and can exfoliate

Radiograph:

*Destructive, ragged, “moth-eaten” radiolucency

*Teeth “floating in air”

Histology:

*Diffuse small lymphocytes with “starry sky”

  - sky = lymphocytes

  - stars – macrophages

Burkitt’s lymphoma treatment

-chemotherapy

Burkitt’s lymphoma prognosis

-depends on volume of tumor at initiation of chemo → tumor often surgically debulked first

-survival rate ~70%

extranodal NK/T-cell lymphoma (angiocentric T cell lymphoma, midline lethal granuloma) clinical features

*Rare, affects mainly adults

*Most frequent in Asian, Guatemalan, & Peruvian 

*Destruction of midline structures of palate and nasal fossa

*Pain, nasal stuffiness, epistaxis, swelling of palate, 

ulceration, oral-antral communication

extranodal NK/T-cell lymphoma treatment and prognosis

*Tumor responds well to radiation

*Good prognosis with early treatment

*Untreated → secondary infection, hemorrhage, involvement of vital structures → death

neutropenia etiology

*Decreased number of circulating neutrophils (<1500/mm3)

*Decreased production or increased destructed of neutrophils

*Congenital or acquired

*Benign Ethnic Neutropenia: several ethnic groups (African, Middle eastern) will consistently have neutrophil counts that would qualify as neutropenia, yet are otherwise healthy

causes of acquired neutropenia

*Destruction of bone marrow by malignancy or metabolic disease

*Drugs (chemotherapy, penicillins, sulfonamides, diuretics, tranquilizers, phenothiazines)

*Nutritional deficiencies (B12, folate)

*Viral Infections (hepatitis, rubella, measles, HIV)

*Bacterial Infections (TB)

*Autoimmune Diseases (SLE)

neutropenia clinical features

*Bacterial > Viral/Fungal infections

  - may demonstrate reduced suppuration/abscess formation

  - Common infection site = middle ear, oral cavity, perirectal area

ORAL:

*Infection of oral mucosa may be initial sign!

*Ulcerations (minimal peripheral erythema, usually gingiva, 

biopsies show neutrophilic infiltrate)

*Premature periodontal disease

neutropenia treatment

*Abx (for infections)

*Encourage optimal oral hygiene

*G-CSF – promotes growth and differentiation of neutrophils

cyclic neutropenia etiology

*Idiopathic periodic reductions in neutrophil counts

*May be related to defect in bone marrow stem cells

*Most sporadic, some inherited (AD)

*Neutrophil count lowest (nadir) for 3-5 days in ~21 day cycles

*Incidence 1/1,000,000

*Diagnosed in childhood

  - diagnosed with sequential complete blood counts (2-3x/week for 8 weeks)

  - neutrophil count <500/mm3 for 3-5 days for at least 3 successive 21 day cycles

cyclic neutropenia clinical features

*Related to neutrophil count at nadir

  - recurrent fever, cervical lymphadenopathy, pharyngitis, malaise, ulcerations of GI tract

ORAL:

*Ulceration of mucosa with minor trauma 

   - gingiva, lips, tongue, buccal mucosa

   - with reduced neutrophilic infiltrate

*Severe periodontal bone loss

*Tooth mobility

*Marked gingival recession

cyclic neutropenia treatment

*ABx (for infections)

*Encourage optimal oral hygiene

*G-CSF several times weekly → reduced duration of nadir and severity of infections/ulcerations

agranulocytosis etiology

*Absence of cells of granulocytic series – especially neutrophils

*Decreased production or increased destruction

*Most drug-induced, some idiopathic

agranulocytosis clinical features

*Bacterial infections, malaise, sore throat, fever (a few days after drug is taken)

ORAL:

*Necrotizing, punched-out, deep mucosal ulcerations 

  - buccal mucosa, tongue, palate

  - sparse inflammation and abundant bacterial colonies

*Gingivitis resembling necrotizing ulcerative gingivitis (NUG)

agranulocytosis treatment

*Discontinue offending drug (count returns to normal in 10-14 days, longer for chemotherapeutic drugs)

*Abx (for infections)

*Encourage optimal oral hygiene

*Chlorhexidine mouth rinses

*G-CSF when counts don’t return to normal

multiple myeloma etiology

*Malignant neoplasm of plasma cells 

*Involves many bones in the body: vertebrae, ribs, skull, jaw (5-30%)

*40+ years

multiple myeloma clinical features

SYSTEMIC:

*Most common: skeletal pain – due to bone lysis by accumulation of tumor cells → multiple punched out radiolucencies with ill-defined margins/lack sclerotic border → pathological fractures

*Renal failure

*Severe bacterial infections

*Clotting defects → dental management considerations (bisphosphonate exposure?)

*Histology: sheets of plasma cells in various degrees of differentiation

ORAL:

*Jaw lesions → pain, swelling, numbness, tooth mobility

*Amyloid deposits throughout body: tongue, vestibule

multiple myeloma histology

*sheets of plasma cells in various degrees of differentiation

*plasma cells have eccentric nucleus, perinuclear halo, clockface nucleus

multiple myeloma treatment

*Chemotherapy

*Radiation for local symptomatic lesions

*Stem cell transplant

multiple myeloma prognosis

*Poor prognosis

*Average survival: 2-3 yrs with chemo/radiation

*Younger patients have better prognosis

*Better with stem cell transplant (~25% remission)

Note: dental management considerations – increased risk of hemorrhage nad increased susceptibility to infection, bisphosphonate exposure?

Langerhans Cell Histiocytosis (LCH)

*Clonal proliferation of Langerhans Cells = type of APC usually seen in suprabasal layer of epidermis/mucosa

*Pulmonary Langerhans Cell Histiocytosis: unique form that occurs almost exclusively in cigarette smokers

  - now considered a form of smoking-related interstitial lung disease

  - some recover after quitting

  - other develop pulmonary fibrosis, pulmonary HTN

LCH diagnosis

*Biopsy: diffuse infiltration of lymphocytes, plasma cells, eosinophils, 

  - large pale staining “histiocytes”/Langerhans Cells indented kidney bean shaped nuclei

*Immunostaining to identify 

Langerhans Cells: S-100+, CD1-a+

*Electron Microscopy: former gold standard 

  - Birbeck Granules (rod shaped structures in cytoplasm)

Letter-Siwe disease (multifocal multisystem) clinical features

*Occurs before age 3

*Most acute form

*Skin rash, enlarged spleen, liver, lymph nodes

Letter-Siwe disease oral manifestations

*Ulcerated gingival lesions 

*Diffuse bone destruction with loss of teeth

*Significant oral involvement may not occur due to rapid course → death

Hand-Schuller-Christian disease (multifocal unisystem) clinical features

*Children: 5yrs – adolescence

*Chronic

*50% spontaneous remission

*Skeletal and Extraskeletal lesions

*Classic Triad (25%)

  1. Single/multiple punched out lesions of skull and/or jaws

  2. Uni or Bilateral exopthalmus

  3. Diabetes Incipitus

ORAL:

*Lesions: sore mouth, gingival ulcers, halitosis, gingivitis, loose teeth and premature loss, loss of alveolar bone  - Mimics advanced periodontal disease

Hand-Schuller-Christian disease treatment

*Curettage, Excision, chemo, radiation

eosinophilic granuloma (unifocal) clinical features

*Older children & Young adults

*Some cases of spontaneous regression

*Solitary or multiple lesions in bone   

  - skull & mandible most common sites

*Radiograph: irregular radiolucent areas

  - can mimic periodontal disease or periapical cysts/granulomas

*Some cases with skin involvement but NO visceral involvement

*Looks like periodontal disease but unresponsive to scaling

eosinophilic granuloma treatment

*Curettage, steroid injections

*Very good prognosis

thrombocytopenia etiology

*Deficiency of circulating platelets (<100,000/mm3)

*Platelets: necessary for normal hemostasis & clot formation

*Decreased production of platelets

  - infiltration of bone marrow by malignant cells (leukemia)

  - chemotherapeutic drugs

*Increased destruction of platelets

  - immunologic drug reaction

  - viral infection, vaccination → autoantibodies against plt

*Sequestration of platelets in spleen

  - some conditions that cause splenomegaly can cause platelets to be sequestered in spleen (portal HTN)

thrombotic thrombocytopenia purpura (TTP) and idiopathic (immune) thrombocytopenic purpura (ITP)

A. Thrombotic Thrombocytopenia Purpura (TTP)

  - Increased destruction of platelets

  - Consumption of platelets by abnormal clot formation

B. Idiopathic (Immune) Thrombocytopenic Purpura (ITP)

  - Usually occurs after non-specific viral infection

  - Most cases resolve spontaneously in 4-6 weeks

clinical features of thrombocytopenia

*Increased bleeding, even with minor trauma

*Platelets <10,000/mm3 → risk of GI, GU, pulmonary, intracranial hemorrhage

ORAL:

*Bleeding of oral mucosa, even with minor trauma

*Spontaneous gingival hemorrhage

thrombocytopenia treatment

*Discontinue offending drug if drug-related

*Platelet transfusions