Oral Manifestation as the Main Sign of an Advanced Stage Acute Promyelocytic Leukemia.

Acute myeloid leukemia is an aggressive malignant neoplasm occurring mainly in elderly, with the median age of 65 years. Oral manifestations, mainly spontaneous bleeding, are a common finding in acute myelocytic leukemia and may represent the initial evidence of the disease. This report describes a case of a 47-year-old man with a one-month history of spontaneous oral bleeding. The patient had already been consulted by two professionals but he remained undiagnosed. The physical examination revealed paleness, fever, epistaxis and ecchymoses in the oral mucosa. The complete blood count revealed anemia, severe thrombocytopenia and leukocytosis with blasts predominance, reinforcing the diagnosis hypothesis of an acute leukemia. The patient was immediately referred to the Hospital and despite having received a quick intervention, he died 3 days after the admission due to diffuse pulmonary alveolar hemorrhage. According to the peripheral blood immunophenotyping the diagnosis of hypogranular variant of acute promyelocytic leukemia was established. The delay in the diagnosis may have influenced the unfavorable outcome. Early diagnosis and management are indispensable for survival of leukemia patients. In this way, dentists may be responsible for an early detection of oral manifestations of leukemia and for a fast referral to an adequate professional.

Introduction

Leukemias represent a group of neoplastic diseases characterized by proliferation of immature white cells in the bone marrow and/or blood, often resulting in an impressive leukocytosis (-). The leukemias are classified according to the progenitor cell involved (lymphoid or myeloid lineage) and whether the disease follows an acute or chronic course (). It is the most common neoplastic disease of the white blood cells with an incidence of 9 cases per 100,000 people (). The exact etiology of leukemia is unknown and your development has been associated with several risk factors, such as genetic disorders, radiation exposure, chemotherapy, and physical and chemical exposures ().

Clinical manifestations of leukemia may result from suppression of hematopoietic cell lines, direct infiltration of leukemic cells into tissues or loss of normal leukocyte function (). Therefore, the main signs and symptoms may include bleeding, purpura, fatigue, anemia, lymphadenopathy and infection (, ). Oral manifestations occur frequently in leukemic patients and may present as initial evidence of the disease (). They include petechial hemorrhages of the tongue, lips, posterior hard and soft palate, gingival hyperplasia, spontaneous gingival bleeding, oral ulcerations and mucosal pallor (, ).

In view of the important role that dentists play in the early detection of oral manifestations of complex systemic diseases, this report describes a case of an advanced acute myeloid leukemia that was diagnosed through oral manifestations.

Case report

A 47-year-old man was referred to our clinic complaining of pain in the mouth. According to the patient, it was caused by the mandibular removable partial denture. He also reported a one-month history of spontaneous oral bleeding and fatigue. According to these signs and symptoms, the patient looked for a physician, who examined and referred him to a dentist. The dentist examined the patient and promptly referred him to our service. The time between the first medical appointment and our evaluation was about 30 days, leading to a delay in the diagnosis. Physical examination revealed that the patient was weak, pale, febrile and presenting ecchymoses in the left ventral surface of his tongue (Figure 1) and a hematoma in the gingiva around the mandibular left canine and first premolar (Figure 2). Besides, during the examination, the patient developed a spontaneous gingival bleeding and epistaxis (Figures 3 and 4), that were controlled by local pressure using a gauze. According to these findings, morphologic features were inconclusive and diagnosis of an acute leukemia was established and an urgent complete blood count was indicated. The result revealed anemia, severe thrombocytopenia and leukocytosis with blasts predominance (75%), reinforcing the diagnosis hypothesis of an acute leukemia (Table 1). On the same day, the patient was referred to the Hematology Department of the University Hospital of the State University of Londrina where he developed a frontal subarachnoid hemorrhage. Despite having received a quick intervention, the patient died 3 days after his admission to the Hospital due to a diffuse pulmonary alveolar hemorrhage. A bone marrow aspirate from the sternum revealed a hypercellular bone marrow infiltration of myeloblasts, and the peripheral blood immunophenotyping confirmed the diagnosis of hypogranular variant of acute promyelocytic leukemia.

Figure 1

Diffuse ecchymoses in the left ventral surface of the tongue.

Figure 2

The presence of a hematoma in the gingiva around the mandibular left canine and first premolar.

Figure 3

Spontaneous gingival bleeding in the right superior canine.

Figure 4

Epistaxis developed during the physical examination.

Table 1

A complete blood count. The result revealed anemia, leukocytosis and severe thrombocytopenia. The exam also revealed blasts predominance (75%) and anisocytosis.

PARAMETER	PATIENT VALUE	NORMAL VALUE RANGE
ERYTHROCYTES	3.35 million/mm3	4.3 a 6,1 million/mm3
HEMOGLOBIN	10.40 g/dl	12.8 a 17,8 g/dl
HEMATOCRIT	30.10%	38.8 a 54,0%
M.C.V	89.9 fL	77.0 a 100,0 fL
M.C.H.	31.0 pg	26.0 a 34,0 pg
M.C.H.C.	34.6 g/dL	29.0 a 36,0 g/dL
RDW	18.5%	9.0 a 15,0%
LEUKOCYTES	67.200/mm3	3.500 a 11.000/mm3
NEUTROPHILS	4.032/mm3	1.500 a 8.500/mm3
LYMPHOCYTES	9.408/mm3	900 a 3.900/mm3
MONOCYTES	3.360/mm3	100 a 1.100/mm3
EOSINOPHILS	0/mm3	100 a 700/mm3
BASOPHILS	0/mm3	0 a 200/mm3
PLATELETS	22.000/mm3	150.000 a 450.000/mm3
M.P.V.	9.70 fL	8.3 a 11.3 fL

Discussion

Oral manifestations are often associated with a variety of serious systemic diseases, hence recognizing them is crucial for a prompt diagnosis and management (, ). These manifestations may occur in any type of leukemia, but they are more prevalent in acute (vs chronic) and myeloid (vs lymphoid) leukemias (). Acute myeloid leukemia (AML) is an aggressive disease that mainly occurs in elderly people, with a median age of over 65 years at diagnosis and with a slight male predominance (, ). Acute promyelocytic leukemia is a distinct subtype of acute myeloid leukemia with characteristic clinical and molecular features, and accounts for 5-8% of all cases of AML (). The hypogranular variant accounts for approximately 10-25% of adult APL cases and has unique biological characteristics such as a higher white blood cell count at presentation ().

General manifestation of leukemia may include fever, fatigue, anemia, lymphadenopathy, recurrent infection, bone and abdominal pain, bleeding and purpura (). Oral manifestations of patients with leukemia reported in the literature are spontaneous bleeding and petechial hemorrhages of gingivae, palate, tongue or lip as a result of thrombocytopenia; mucosal pallor due to anemia; gingival hyperplasia caused by leukemic infiltration. Oral ulcerations may result from either neutropenia or direct infiltration by malignant cells (, , ). The most common oral manifestations reported in patients with AML were associated with bleeding and were manifested as gingival oozing, petechiae, hematomas, or ecchymoses (, ). Gingival bleeding is reported to be the most common initial oral sign in both acute and chronic leukemia (). Low-levels of platelet counts, generally from 25 000 mm−3 to 60 000 mm−3 are sufficient to result in spontaneous bleeding. Besides, the prevalence of thrombocytopenia was higher in patients with acute leukemia than those with chronic leukemia (). The presence of oral manifestation at initial presentation of leukemia is more common in AML than in other subtypes ().

Patients with leukemia may also develop recurrent viral, bacterial and fungal infections, like herpes or candidiasis, as a consequence of immunosuppression (, ). Therefore, AML patients frequently present with symptoms and signs of pancytopenia, such as fever, fatigue, pallor, bleeding and purpura, bone and abdominal pain (). Oral manifestations of pancytopenia due to leukemia are indistinguishable from other causes of pancytopenia, such as adverse drug reactions, immune conditions, and viral infections (). Recently, a rare case of unusual maxillary mixed, osteoblastic and osteolytic, lesions as an initial manifestation of AML has also been presented (). In routine dental practice, it may be rare to find leukemic patients who have oral symptoms as an early indicator of leukemia. Therefore, dentists may miss the correct timing for referral to a hematologist, which can be fatal (). Our patient developed almost all classical signs and symptoms of a malignant acute hematological disease, such as fever, fatigue, pallor, oral bleeding and epistaxis. Nevertheless, the delay in the diagnosis may have influenced the unfavorable outcome.

The prognosis of patients with AML is variable, and older age, poor risk cytogenetics, and performance status are most commonly used to predict clinical outcomes (). Younger patients tend to cope with it in a better way, and some series would suggest that about 50% of patients less than 40 years of age are cured, whereas in those who are over 60 years old, only 10–15% of patients will survive 1 year after the diagnosis (). A high peripheral blood leucocyte count at diagnosis is associated with worse prognosis in patients younger than 60 years (). Effective early diagnosis is indispensable for survival. Therefore, dentists are responsible for early detection of oral manifestations of leukemia and for a fast referral to a hematologist (). A complete blood count (CBC) can be helpful for dentists in cases suggestive of leukemia, but a bone marrow biopsy and immunophenotyping of peripheral blood are necessary for a final diagnosis.

The time for diagnosis of malignancies has been historically long in developing countries. Therefore, the diagnosis of cancer may occur in advanced stages of the disease (). Main causes for delays in diagnosis may include clinical features of the disease, patient age, tumor site, level of suspicion by a primary care physician and health care system available to the local population (). The main causes of early death in patients with acute leukemia include infection, tumor lysis syndrome, leukostasis, and disseminated intravascular coagulation (). Early diagnosis and effective management are very important to minimize these complications ().

The acute promyelocytic leukemia is an aggressive malignant neoplasm that requires an early diagnosis and management. Oral manifestations, mainly the spontaneous bleeding, are very common in patients with acute leukemia and may present as the initial evidence of the disease, reinforcing the importance of dentists in the early diagnosis of this disease.