Oral manifestations as an early clinical sign of acute myeloid leukaemia: a case report
G Guan,* N Firth*
*Department of Oral Diagnostic and Surgical Sciences, School of Dentistry, The University of Otago, Dunedin, New Zealand.
ABSTRACT
Leukaemia is the most common malignancy in children and one of the most common malignancies in young adults.
Acute myeloid leukaemia is often associated with early oral manifestations. The purpose of this study is to report the case of a 49-year-old male with spontaneous gingival bleeding for over two years with undiagnosed leukaemia. Haema- tological investigation was instigated and on referral to the Haematology Department at Dunedin Public Hospital, the diagnosis of an acute myeloid leukaemia was confirmed. Since oral lesions can be one of the early events of acute mye- loid leukaemia, they may be considered as an important diagnostic indicator for oral health practitioners, and their roles in diagnosing and treating such patients.
Keywords: Acute myeloid leukaemia, leukaemia, oral manifestations, spontaneous bleeding.
Abbreviations and acronyms: AML = acute myeloid leukaemia; CBC = complete blood count.
(Accepted for publication 27 May 2014.)
INTRODUCTION
Oral manifestations are often potential indicators of systemic diseases, so recognizing them can lead the way to a prompt diagnosis and management. The oral cavity can act as a mirror that reflects many internal problems. Oral health practitioners should be familiar with the oral manifestations of systemic diseases as some are disease-specific. Leukaemia is a malignancy of haematopoietic cells characterized by the prolifera- tion of malignant leucocytes and destruction of the bone marrow. General manifestation of leukaemia may include fatigue, anaemia, lymphadenopathy, recurrent infection, bone and abdominal pain, bleed- ing and purpura.1 Oral manifestations of leukaemia may include petechial haemorrhages of the tongue, lips, posterior hard and soft palate, gingival hyperpla- sia and spontaneous gingival bleeding.1,2 Oral ulcer- ations are common. They may be due to either neutropenia or direct infiltration by the leukaemic cells.3 Patient may also suffer from severe viral, bacte- rial and fungal infections as a consequence of pancy- topenia.4 The relationship between leukaemia and a wide variety of oral lesions has been well documented in many studies.1,5–8 It has been suggested that oral manifestations of leukaemia could be considered as diagnostic indicators of the disease.9
CASE REPORT
In September 2013, a 49-year-old male was referred by the Urgent Care Unit to the Dental House Surgeon Clinic (Dental School, Dunedin, New Zealand) for evaluation and treatment of persistent bleeding gingi- vae palatal to his maxillary central incisors that the patient had first noticed two years previously. He had not been concerned until the previous evening when the bleeding would not stop. In addition to the bleed- ing gingivae, he had a history of exertional breathless- ness, which had worsened over several weeks. The gingivae were painless and showed no abnormal swelling during this period. He had no history of facial trauma. Medically, he had chronic muscular skeletal back and neck pain, congenital glaucoma with bilateral goniotomies and right buphthalmos. He was taking clindamycin due to tonsillitis. He had no regular medications and supplements. He was allergic to penicillin. He had no family history of any bleeding disorders. He worked as an information technology consultant and was married with two young children.
He did not smoke and rarely drank alcohol.
On extraoral examination, no regional lymphade- nopathy or salivary gland swelling was observed.
However, the patient appeared very fatigued, weak and pale. Spoon-shaped fingernails (koilonychia) were
Australian Dental Journal 2015; 60: 123–127 doi: 10.1111/adj.12272
Australian Dental Journal
The official journal of the Australian Dental Association
noted (Fig. 1). Intraoral examination revealed buccal mucosal pallor (Fig. 2) and severe gingival haemor- rhage around tooth 11 and 21 palatal gingival mar- gin. The gingivae bled spontaneously without any touching or probing. Both Tooth 11 and 21 were positive to sensibility testing. Periodontal pocket depths were less than 3 mm. No dental plaque or cal- culus deposits were detected clinically. Panoramic and periapical radiographs showed no abnormal dental or osseous finding. Haematological tests, including com- plete blood count (CBC), liver function test, kidney function test, clotting profile, C-reactive protein, rheu- matoid factors and anti-nuclear antibodies were ordered. He was given tranexamic acid 5% mouth- wash to arrest the bleeding. The patient’s CBC revealed a marked decrease in haemoglobin (63 g/L), haematocrit (0.19), platelet count (23*109/L) and leu- cocytes (0.5*109/L) (Table 1). Neutrophils are the body’s main defence against bacterial and fungal infection. When neutrophil counts fall to <500/lL, normal inflammatory response may be muted and endogenous microbial flora can cause infection. Acute, severe neutropenia (<500/lL) can lead to rapidly fatal infections. The CBC also showed pancytopenia with
rare circulating blast cells. Other haematologic and laboratory exams are shown in Tables 2 and 3. He was admitted to the Department of Haematology (Dunedin Public Hospital, New Zealand) immediately due to pancytopenia. A bone marrow biopsy con- firmed hypoplastic acute myeloid leukaemia (AML) without maturation. Cytogenetics studies showed deletion of chromosome 7q and an additional copy of one chromosome 8 in cell cultures. He received stan- dard dose daunorubicin/cytarabine induction chemo- therapy, achieving complete morphologic and cytogenetic remission. As this patient’s leukaemia had been determined high risk by the AML 17 risk score, he had been given consolidation therapy with a more intensive chemotherapy regimen known as FLAG/
Idarubicin. As his AML was unlikely to be cured with chemotherapy alone, an allogeneic stem cell transplant was planned.
DISCUSSION
AML is an aggressive myeloid neoplasm that results from clonal transformation of haematopoietic precur- sors through the acquisition of chromosomal rear- rangements and multiple gene mutations.10
In New Zealand, the Ministry of Health reported leukaemia was the seventh most commonly registered cancer and 591 patients were diagnosed with leukae- mia in 2010.11 Under the age of 24, leukaemia was the most common cancer for both males (44 registra- tion) and females (22 registrations).11 Although the incidence of acute leukaemia accounts for less than 3% of all cancers, it is still the leading cause of death due to cancer in children.12 AML is a relatively uncommon disease, accounting for approximately 25% of all leukaemias in adults in the western world.13 It comprises 1.2% of cancer deaths in the United States.14 In New Zealand of the 591 patients diagnosed with leukaemia, 185 patients were diag- nosed with AML in 2010.11 In addition, some of the risk factors for developing AML have been identified, as summarized in Table 4. However, these recognized risk factors account for only a small number of observed cases.15
AML is an aggressive disease that predominantly occurs in older adults, with a median age at diagnosis of over 65 years.16,17AML is rarely diagnosed before the age of 40 years and thereafter the incidence increases in parallel with age.
The incidence of AML varies with gender and eth- nicity. AML in adults has a slight male predominance in most countries. For example, in New Zealand the male registration rate was more common than the female (1.5:1), and the male mortality rate was nearly twice as high as the female in 2010.11 The population of New Zealand is approximately four million. New
Fig. 1 Spoon-shaped fingernails (koilonychia).
Fig. 2 Mucosal pallor.
Zealand has four main ethnic groups: Caucasians, Maori, Pacific Islanders and Asians. New Zealand Asians had the lowest rate for AML.18 Maori and Pacific Islanders had a higher incidence compared to Caucasians during 1993 to 2002.18
Clinical presentation
AML has a variable presentation and results from leukaemic infiltration in vital organs causing splenomegaly, hepatomegaly and lymphadenopathy.
Replacement of normal bone marrow haematopoietic stem cells results in neutropenia, thrombocytopenia and anaemia. Most of these clinical signs and symp- toms are related to the reduction of leucocytes and
erythrocytes. Therefore, AML patients commonly present with signs and symptoms of pancytopenia, such as fever, fatigue, pallor, bleeding and purpura, bone and abdominal pain and recurrent infections.12
Oral manifestations
Oral manifestations may occur in any of the leukae- mias, but they are more common in AML.19 Oral examination may show mucosal pallor due to anaemia, spontaneous bleeding and petechial haemorrhages of gingivae, palate, tongue or lip as a result of thrombocy- topenia, and gingival hyperplasia due to leukaemic infil- tration. Oral ulcerations are common and may result from either neutropenia or direct infiltration by the leu- Table 2. Biochemistry, liver function tests, C-reactive protein, urea and creatinine 18–24 September 2013
18th 20th 21st 22nd 23rd 24th Normal value range
Na 141 140 138 138 133 131 135–145 mmol
K 4.9 4 4 3.9 4.3 4.1 3.5–5.2 mmol
Urea 6.5 4.0 3.5 3.6 4.7 4.6 3.2–7.7 mmol
Creatinine 74 64 60 60 62 60 50–110 lmol
Albumin 38 35 29 35–50 g/L
Total protein 74 65 60 64–83 g/L
Total bilirubin 13 7 9 2–20 lmol/L
Alk phosphatase 86 85 71 30–150 U/L
ALT 19 15 10 0–40 U/L
GGT 13 12 19 10–50 U/L
CRP 95 94 97 131 143 162 <5 mg/L
Elevated level of CRP indicates inflammation.
Table 3. Blood clotting test 18–24 September 2013
18th 20th 21st 22nd 23rd 24th Normal value range
Prothrombin time 13.8 13.3 14.4 9.0–14.0 seconds
INR 1.2 1.1 1.3 0.8–1.2 seconds
APTT 35 31 34 22–34 seconds
Fibrinogen 6.7 6.3 6.0 1.8–4.0 g/L
Elevated fibrinogen level may suggest inflammation as it is an acute-phase protein.
Table 1. Complete blood count 18–24 September 2013
18th 20th 21st 22nd 23rd 24th Normal value range
Haemoglobin 63 90 81 74 98 85 130–175 g/L
HCT 0.19 0.27 0.24 0.22 0.29 0.25 0.4–0.52
MCV 103 96 97 96 94 93 80–99 fL
MCH 34.8 32.6 32.5 33 31.3 32.1 27–33 pg
Platelets 23 21 53 35 31 21 150–400 *109/L
WBC 0.5 0.5 0.7 0.3 0.4 0.2 4–11 *109/L
Neutrophils 0.0 0.0 0.0 0.0 0.1 0.0 1.9–7.5 *109/L
Lymphocytes 0.4 0.4 0.6 0.2 0.3 0.2 1–4 *109/L
Monocytes 0.1 0.1 0.1 0.0 0.0 0.0 0.2–1.0 *109/L
Eosinophils 0.0 0.0 0.0 0.0 0.0 0.0 <0.6 *109/L
Basophils 0.0 0.0 0.0 0.0 0.0 0.0 <0.3 *109/L
Markedly decreased circulating haemoglobin level, and increased MCV and MCH suggests macrocytic hyperchromic anaemia. Neutrophils count was zero from 18th to 22nd September. This patient with neutrophil counts (<500/lL) is at greatest risk of rapidly fatal infection. Abnor- mal low platelets count (thrombocytopenia) results in spontaneous bleeding or causes delay in the normal process of clotting.
kaemic cells. Patients may also have severe recurrent viral, bacterial and fungal oral infection as a result of immunosuppression.7,8,19 Oral signs and symptoms of laryngeal pain, gingival bleeding, oral ulceration and gingival hyperplasia were the most prevalent com- plaints.7,19Fever was the most common reported symp- tom at the initial physical examination. It may be associated with neutropenia and bone marrow apla- sia.20,21 Laryngeal pain and oral ulceration were the second common complaints.19Therefore, all oral health practitioners should be aware of the significance of these oral manifestations in relation to AML.
There are many situations in which a patient pre- sents with gingival bleeding, including poor oral hygiene, malpositional teeth, trauma to the gingivae, Vitamin K, Vitamin C deficiency, hormonal changes in female, bleeding disorders, medications, liver dis- ease and cancers. The most common gingival bleeding is caused by a chronic inflammatory process produced by dental plaque in gingivitis and is not spontaneous.
In this case, gingivitis by dental plaque was ruled out because of the severity of spontaneous gingival bleed- ing related to relatively good dental hygiene. Oral signs of thrombocytopenia are the most common patient complaint and are often found at the initial clinical examination.7 It has been suggested that thrombocytopenia is due to infiltration of the leukae- mic cells in the bone marrow.22 In addition, as a result of inadequate synthesis, excessive consumption, or excessive destruction of coagulation factors, high levels of fibrinolytic activity and hypofibrinogenemia may contribute to increased gingival bleeding.23,24
Gingival swelling is commonly observed in patients with AML. The enlargement of the gingival swelling may be due to infiltration of gingival tissue by leukae- mic cells particularly since it develops in patients with the highest leucocyte count.19,25,26
Gingival infiltration of leukaemic cells as one of the oral manifestations of AML has been reported in sev- eral studies.27–30 Gingival hyperplasia is characterized by progressive proliferation of fibrous connective tis- sue causing enlargement of the interdental papillae, the marginal and attached gingiva, slowly covering the crowns of the teeth.6 Pre-existing periodontal dis- ease can exaggerate the leukaemic infiltration and worsen the gingival enlargement.31 Biopsy and fine needle aspiration cytology can be used to confirm leu- kaemic cells infiltration.32,33 Another oral sign, such as mucosal pallor is difficult to evaluate objectively.
Diffused chronic mucocutaneous candidiasis, recurrent herpetic gingivostomatitis and bacterial infection sug- gest immunosuppression.1
Leukaemic patients often fall sick and deteriorate fast. Neutropenia is usually asymptomatic until infection develops. The main concerns in the orofacial region are infection and bleeding. Oral health practitioners should always take non-specific spontaneous bleeding seriously, and simple haemato- logic laboratory tests such as CBC, liver function tests and clotting profile should be ordered. In addi- tion, infection of the orofacial region may be associ- ated with neutropenia or caused by dental treatment. Because the inflammatory response is lim- ited, neutropenic patients are particularly predis- posed to viral, bacterial and fungal infections.
Therefore, oral health practitioners should be alert to septicaemia. Antibiotic prophylaxis must be given for invasive operative procedures during the neu- tropenic period.34
CONCLUSIONS
Systemic diseases may present with abnormalities in the oral cavity. Oral lesions are one of the initial man- ifestations of acute myeloid leukaemia. This case emphasizes that oral health practitioners should be familiar with the systemic manifestations and oral complications of blood diseases and leukaemia in par- ticular, since they are frequently consulted by the leu- kaemia patient because of accompanying oral complications, thereby providing an opportunity for timely diagnosis and early referral to physicians.
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Table 4. Risk factors associated with AML
Genetics Down syndrome
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Chemical exposure Benzene
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Radiation Radiation exposure
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Chemotherapy Alkylating agents
Topoisomerase-II inhibitors Anthracyclines
Taxanes
Preleukaemia Myelodysplastic syndrome
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Address for correspondence:
Mr Norman Firth Department of Oral Diagnostic and Surgical Sciences School of Dentistry The University of Otago 310 Great King Street Dunedin New Zealand Email: norman.firth@otago.ac.nz
