The oral cavity is an accurate indicator of a patient’s systemic health and gives the healthcare practitioner valuable information about the health status of their patient [1]. Systemic disease can often manifest itself with early signs that can especially be seen in gingiva and surrounding tissue in the oral cavity. As a result, dentists have been trained to be keen observers in the hopes of identifying pathologic problems that can show early symptoms in the mouth. Current research shows encouraging evidence for the association between systemic diseases and periodontal diseases [2]. Thus, most healthcare practitioners are aware that the oral cavity is a useful tool to diagnose pathological diseases in their early stage of development. It is the responsibility of all dentists to properly examine and treat any possible symptom of a pathophysiological problem associated with the oral cavity. Systemic disease can show oral signs in the early stages of development, it is during this time period where a proper diagnosis and treatment plan should be implemented [3]. The systemic disease focused on in this report is the early symptomatic signs of leukemia in the oral cavity. This report will examine the different types of different types of leukemia and how the disease can manifest itself in the oral cavity. Leukemia is a type of cancer caused by malignant proliferation of white blood cell (WBC) precursors developing within the confines of the bone marrow [3]. Leukemia is commonly called a blood cancer, representing a group of neoplastic syndromes portrayed by proliferation of juvenile white cells in the bone marrow and/or blood, resulting in leukocytosis [4-6]. Leukemia is considered the most neoplastic disease of the leukocytes with an incidence of 9 cases per 100,000 people [7]. This type of malignancy can occur in the myeloid or lymphoid cell paths [4]. In most cases, abnormal cells are produced resulting in drastic hyperplastic changes in the cell’s structure. The production of dysfunctional cells leads to the gradual decline of the hematopoietic function. In addition, leukemia can affect peripheral blood and the bone marrow, which leads to eventual debilitation of a person’s cardiovascular function [3]. There are several risk factors for the etiology of leukemia including chemotherapy, radiation exposure, genetic mutations, and environmental and chemical exposures [8]. Certain geographical locations are more prone to cancer than others. Daily exposure to toxins in our environments (detergents, pesticides, chemicals) can increase malignancy in mitotically dividing cells. Cancer risks are significantly higher in urban residents versus rural residents on average [9]. Clinicians and diagnosticians categorize two types of leukemia: acute and chronic types. Acute leukemia is more sudden and can potentially be fatal if not hospitalized and properly treated [10]. Leukemia is further separated into myelocytic and lymphocytic forms. Acute lymphoid leukemia (ALL) is most prevalent in children, accounting for 80% of all leukemias and 50% of all neoplasms in childhood illness [11]. If patients are older than 30 years old, the prognosis of ALL is unfortunately poor [11]. Contrary to ALL, the chances of developing acute myeloid leukemia (AML) rises with increasing age, especially in the people older than 65 years old. Interestingly, the occurrence of AML has considerably risen in the last ten years [12]. In 2011, South Korea reported an incidence of leukemia with 5.7 per 100,000 people [13]. In 1976, the French-American-British (FAB) classification system was created, based on the principles of cytochemistry and cytomorphology. This system divides the different subtypes of AML: M0-M7 [14,15]. Below in Table 1 is a summary of the different subtypes of leukemia:

Table 1: The French American British Classification System [15].

There are several physical manifestations within the oral cavity that are often affiliated with systemic disease. The recognition of these signs is vital for an early diagnosis and treatment [5,29]. Oral manifestations are most often seen in patients with acute myeloid leukemia, rather than patient with one of the chronic and lymphoid leukemias [19]. AML is notoriously known as an aggressive form of cancer that preferably appears in patients older than 65 years of age with a slight preference for males over females [31,32]. A unique subgroup of acute myeloid leukemia called acute promyelocytic leukemia (APL) accounts for 6.5% of all cases of AML [33]. This pathology has a hypogranular variant accounting for an estimated 17.5% of all adult APL cases presenting specific biological characteristics like elevated white blood cells count in the CBC report [34]. The main symptoms associated with leukemia are lymphadenopathy, bone and abdominal pain, bleeding, fatigue, purpura, recurrent infection, and fever [33]. Leukemia patients are susceptible to petechial hemorrhages of the gingiva, lip, palate, or tongue tissue and spontaneous bleeding episodes as a consequence of thrombocytopenia, hyperplasia of the gingiva triggered by leukemic infiltration, and mucosal pallor due to the anemia [34]. In addition, ulcerations seen around the teeth may result from direct infiltration by malignant cells or neutropenia [7,19,29]. The most prevalent type of symptoms in patients diagnosed with AML were episodes of bleeding, ecchymoses, petechiae, and gingival oozing [28,33]. AML causes complications within the bloodstream. AML, in some scenarios, can cause capillary ruptures to form beneath the skin. These tiny red, black, and blue clots (petechiae) form during the proliferation of abnormal cell types which skews the normal production of platelets in the peripheral blood. Consequently, the shortage of platelets allows blood leakage throughout the surrounding tissues giving a blue-black appearance to the skin [34]. Acute leukemia can have detrimental effects to the patient if left untreated or improperly diagnosed. Life threatening possibilities of acute leukemia may be severe infection, pulmonary hemorrhage, or gastrointestinal bleeding [35]. Nevertheless, it is important to examine the primary cause of gingival hyperplasia because early detection of possible malignancies exponentially increases the patient’s chances of survival. Most notably, gingival bleeding is considered to be the first initial oral sign of acute and chronic leukemia [36]. Lower thrombocyte levels ranging from 25 000 mm−3 to 60 000 mm−3 are generally noted to cause spontaneous gingival bleeding. It is important to note that the frequency of thrombocytopenia is lower in patients with chronic leukemia and higher in those with acute leukemia [33]. Chronic leukemia is a slow growing cancer that can vary in its stage of development. Most patients with chronic leukemia do not present any symptoms for several months. Although it is slow growing, it could still have devastating effects on the body’s homeostatic balance. Spontaneous bleeding episodes occur because of the decreased thrombocyte levels within the peripheral blood circulation. Most patients with leukemia develop compromised immune systems over time due to both chemotherapy and radiation. Immunosuppressed leukemic patients are at greater risk of acquiring bacterial, fungal (candidiasis), and viral (herpes) infections [7,19]. Most notably, fungal infections, once manifested in the body, are more difficult to treat than bacterial infections. Immunosuppressed individuals are especially prone to acquiring opportunistic pathogens in the surrounding environment. Immunocompromised patients tend to be older than 65 years of age. Patients with AML habitually present symptoms of fatigue, pallor, bone and abdominal pain, and signs of pancytopenia [37]. Clinically, it is difficult to correlate pancytopenia to leukemia because there are other possible causes of pancytopenia including viral infections, immune conditions, and adverse drug reactions [38]. In one rare case, a patient with an uncommon maxillary with osteolytic and osteoblastic lesions is shown as a preliminary indicator of AML has also been shown [36]. AML can impact patients in different ways with variable prognoses. Patients who have meager risk cytogenetics and health status are most commonly used to forecast clinical outcomes [39]. Older people cope with leukemia in worse ways, compared to younger patients diagnosed. Evidences shows roughly half of patients less than 40 years old are cured, while only 12.5% of patients 60 years of age or older will survive one year after their initial cancer diagnosis [40]. Interestingly, a high peripheral blood leucocyte count is correlated with worse prognosis outcome in patients who are younger than 60 years of age [39]. Effective early recognition of oral signs of leukemia is indispensable for survival [30]. Dentists, being trained observers and clinicians, must be able to detect oral manifestations of cancer for an emergency referral to a hematologist [3]. A CBC report gives the dentist valuable information about the health status of their patient. However, to positively identify leukemia, immunophenotyping of peripheral blood and a bone marrow biopsy of the iliac crest region of the pelvis are needed for a definitive diagnosis. Especially prevalent in developing countries is the arduous amount of time it takes clinicians to diagnose malignancies in their patients. Thus, most patients present to clinic with advanced and more severe stages of the ailment, which could have been treated if detected early in development [41]. There are several reasons why there are delays of diagnosis. The most common causes are level of suspicion by healthcare practitioner accessible by local population, tumor site, clinical features of the disease, and patient age [42]. Many people who develop leukemia in developing countries struggle to survive. Most common cause of premature death in acute leukemic patients are disseminated intravascular coagulation, infection, leukostasis, and tumor lysis syndrome [43]. As stated above, effective management, early detection, and early diagnosis are vital to minimize gradual deterioration of normal physiological function within the hematological tissue, which alleviates the above symptoms [44]. Early detection and diagnosis of acute promyelocytic leukemia is required for patient survival. Oral indicators of leukemic conditions, chiefly gingival hyperplasia and spontaneous bleeding episodes are highly prevalent in patients diagnosed with acute leukemia [33]. These symptoms may indicate initial presence of a disease, which reinforces early detection by practicing dentists. There are two cases discussed below. Both of these patients had shown leukemic signs in each of the patient’s mouths. Moreover, both patients were diagnosed with forms of acute leukemia. In the first case, the male patient presented to the clinic with complaints of fatigue, oral pain, and a one-month period of spontaneous oral bleeding. The patient explained that this was caused by his prosthetic removable denture. A physical exam with the patient revealed physical symptoms of weakness, paleness, and ecchymoses on the left ventral side of the patient’s tongue. This is shown below in Figure 1.

Figure 1: Physical signs of ecchymoses along the left ventral side of the patient’s tongue [31].

In addition, the patient presented with signs of hematoma along the gum line around the first premolar and mandibular left canine [30]. This is shown below in Table Figure 2.

Figure 2: Patients shows signs of hematoma along the gum line around the first premolar and mandibular left canine [31].

Ecchymoses is a physical discoloration of the tissue, which results from internal bleeding within the blood capillaries under the surface of the pithelial skin. This characteristic can be used as a possible sign of a pathological problem. The ecchymoses shows how the patient’s circulatory system is clearly dysfunctional. Below is the patient’s hematoma along the gum line. A hematoma is when the blood seeps outside of the circulatory system through the interstitial fluid within tissues. The blood often begins to coagulate and harden before it is reabsorbed back into the circulatory system. Hematomas have the potential to impact normal physiological function within the body. In some cases, hematomas have been known to accumulate large stores of circulating blood. As a consequence of this blood shortage, shock and low blood pressure can occur. Hypoxia may occur if a prolonged hematoma has developed. Significantly large hematomas can impact organ functionality and may require surgery [45]. Thus, the early recognition is imperative for the patient’s health and well-being. During the initial dental exam, the patient experienced an epistaxis and spontaneous gingival bleeding. These are shown in Figures 1 and 2. The diagnosis of this patient is most likely acute leukemia because of the symptoms of hematoma, spontaneous bleeding, ecchymoses, and general weakness. These symptoms are considered early precursor signs to underlying systemic disease, in this case, acute leukemia. These suspicious signs lead the dentist to order a Complete Blood Count (CBC). The CBC report is shown below in Table 2. The urgent CBC report revealed leukocytosis, thrombocytopenia, and anemia with high majority blast presence (75%) [30].

Table 2: The complete blood count (CBC). RESULTS: anisocytosis, leukocytosis, anemia, & thrombocytopenia: 75% blast-cell majority [30].

The most prevalent oral manifestation for acute leukemia is spontaneous gingival bleeding and gingival hyperplasia, which presents the initial evidence for the existence of the disease. The first signs of leukemia are often manifested in the mouth. To the average person, this is not common knowledge. This report stresses the importance of biannual check-ups at the dentist office. The dentist is commonly the first healthcare practitioner to witness early leukemic symptoms in the mouth. Specifically, dentists initiate the diagnosis in almost one-third of patients with acute myelomonocytic leukemia [49]. Thus, dentists play a paradigm role in the early detection and diagnosis of hematological diseases. It is the responsibility of all dentists to ensure they can recognize oral manifestations when they rarely present themselves in the dental office. With the collaboration of dentists, physicians, and other clinicians, symptomatic signs of disease can be recognized early so that early prognosis and treatment can be implemented.

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