Oral health in children with leukemia
Correspondence Address: DOI: 10.4103/0973-1075.97343
Leukemia is one of the most common malignancies affecting children in India. These children usually suffer from various oral complications, which may be due to the leukemia or due to the chemotherapeutic agents and/or radiotherapy. The complications may include some of the opportunistic infections like candidiasis, herpes simplex; hemorrhage, mucositis, taste alterations and increased incidence of dental caries etc. These complications can cause significant morbidity and mortality in the patients. The aim of this review is to summarize the various oral complications in these children and the methods of prevention and management.
Keywords: Children, Complications, Leukemia, Management, Oral
Cancer is described as an uncontrolled proliferation of malignant cells and is generally regarded as a disease of adults. The types of cancer seen in children worldwide are very different from those found in adults: Leukemia, lymphoma, and brain tumors are relatively more common in children.  Leukemia is the most common childhood cancer in India with relative proportion varying between 25-40%.  It is classified clinically on the basis of the duration and character of the disease (acute or chronic), the type of cell involved (myeloid, lymphoid, or monocytic), and increase or non-increase in the number of abnormal cells in the blood.  Amongst various leukemias, acute lymphoblastic leukemia (ALL) accounts for 60-85% of all cases in children in India.
Initial signs and symptoms of leukemia can appear in the mouth or neck due to infiltration of leukemic cells or due to associated decrease in normal marrow elements. An acute leukemia is usually treated with chemotherapy, irradiation, or bone marrow transplantation. Chemotherapy and radiotherapy are generally cytotoxic for rapidly multiplying malignant cells, but also negatively impact the production of normal hemopoietic and secretary cells as these do not differentiate between normal and malignant cells. This side effect often results in immune-suppression and reduced secretions in the body. The systemic sequelae as a result of these medication or radiation can also induce a number of oral and dental complications. The patient with cancer faces an assault on oral health from both the disease and the treatment options. The direct and indirect ill effects to the oral cavity are associated with the development of ulcerative, hemorrhagic, or infectious complications.  Some of these complications include: Gingival bleeding, ulcerations, mucositis, taste alteration, skin desquamation, xerostomia, opportunistic infections. As a consequence, all these problems can potentially cause an increase in mortality and morbidity in children with leukemia.
Various factors increase the potential for developing oral complications. They may include the age of the patient, nutritional status, type of malignancy, pretreatment oral condition, oral care during treatment, and pretreatment neutrophil counts.  Patients in younger age group show a higher rate of radiotherapy and chemotherapy-induced oral complications. Akyol H, et al recently reviewed 50 patients receiving chemotherapy and radiotherapy in a hospital in Turkey and reported that 42% of the subjects developed oral complications. An early intervention reduces the frequency of problems, minimizing the risk for oral and associated systemic complications and must be based on the probable cause of the complication and associated factors. A proper understanding of the pathogenesis of oral complications in these patients is important for the treating oncologists and hematologists, and a multidisciplinary approach is essential to improve the quality of life of these patients. Since occurrence of oral complications is related to several factors, the multidisciplinary team including oncologist, hematologist, dental surgeon, and intensive care expert is required for management of these conditions.
There have been several approaches to classify the oral complications in leukemic children, however, most accepted and broad classification can be described as: 
Various common oral complications seen in children with leukemia and their management are enumerated below:
One of the most common oral problem occurring during antineoplatic treatment is mucositis or inflammation of the oral mucosa. The patient usually complains of mucosal burning, pain, dry mouth and discomfort as initial symptoms. Clinically, it manifests as generalized redness or sometimes a pale appearance with an interspersed erythema, scattered ulceration and/or some bleeding sites. Sometimes mucosal swelling is also seen. , Even a mild local irritant, such as sharp teeth or restoration, presence of calculus, and plaque may aggravate the mucosal inflammation. Younger patients appear to have a greater risk of chemotherapy-induced mucositis, which may be attributed to a more rapid epithelial mitotic rate or the presence of more epidermal growth factor receptors. Oral mucositis can appear as early as 4-7 days after the initiation of chemotherapy, but sometimes it can be seen later also. It involves the soft palate, oropharynx, buccal and labial mucosa, floor of the mouth and the ventral and lateral surfaces of the tongue. The pain associated with mucositis may cause difficulty in feeding, hydration and speech, which further may lead to weight loss, anorexia, cachexia and dehydration. , As a result, the quality of life of a patient may be affected. Complete resolution of mucositis occurs 7 to 14 days after its onset and discontinuation of the therapy. Sometimes, radiation-induced mucositis may remain for weeks to months and regress slowly.
Various methods have been proposed to prevent mucositis during treatment. Radiation induced mucosal injury can be reduced by use of midline radiation blocks and 3-dimensional radiation treatment to the oral cavity. Oral Cryotherapy (sucking ice chips), biological response modifiers such as Keratinocyte Growth Factor 1 (KGF-1), Keratinocyte Growth Factor 2 (KGF-2), Interleukin-11 and Transforming Growth Factor Beta-3 have been shown to be effective in preventing an oral mucositis. , Mucosal coating agents may be used to provide a temporary physical barrier. It is recommended to use water-soluble lubricating agents (e.g. artificial saliva) to moisten the mucosa if patient is experiencing dry mouth. Various other agents have been proposed by Keefe et al,  and Kostler et al,  to prevent oral mucositis such as Amifostine, Topical Vitamin E, Topical Beta-carotene, Prostaglandin E (PGE2) Lozenge, Glutamine, Granulocyte Colony Stimulating Factor (GCSF). However, these are still undergoing investigations.
Once mucositis has developed, its severity and the patient's hematologic status govern its appropriate management. Meticulous oral hygiene and palliation of symptoms are essential. General care of an oral mucosa is of utmost importance, which include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases. Atraumatic debridement of necrotic tissue is very important. Cleaning the oral hard and soft tissues may be done with a 4 × 4 inch gauze pad wrapped around a finger or with a disposable sponge moistened in a diluted solution of baking soda and water. Patients should be encouraged to use warm water with baking soda added to it for rinsing mouth several times a day in case of ulcerations and painful oral tissues. Topical analgesic (i.e. benzydamine) and topical anesthetics (e.g. lidocaine) are also used to reduce pain. Mouthwashes such as 0.12% chlorhexidine and sodium bicarbonate may provide symptomatic relief as they create an alkaline environment, interfering with the bacterial colonization. Costa et al,  conducted a study to assess the effectiveness of preventive protocol using 0.12% chlorhexidine mouth wash in children receiving treatment for acute lymphoblastic leukemia and found a significant decrease in the incidence of mucositis using 0.12% chlorhexidine. Only 1 (14.3%) out of 7 children who used 0.12% chlorhexidine experienced mucositis. Sometimes the patients may complain of burning sensation with the mouthwashes. In such cases, normal saline (0.9% NaCl) may also be advocated. Effective mechanical cleansing cannot be done with sponges, foam brushes, and supersoft brushes due to their softness; therefore, they should be used only when the patient cannot tolerate a regular brush in cases of severe mucositis (Best Practice Guidelines for the Management of Oral Complications from Cancer Therapy. Cancer Care Nova Scotia  ). Wright et al,  affirmed that the use of toothpaste with heavy flavoring agents should be avoided as they may irritate the oral tissues, and brushes should be air-dried between uses. The bioadhesive agents such as hydroxypropyl cellulose may be useful as a physical barrier over mucosal ulcerations, thus providing pain relief and improved healing.
Kostler et al,  has advocated the use of low-intensity laser as a newer approach for management of mucositis. It has been proven to be capable of alleviating pain significantly and may also reduce the severity and duration of mucositis. It has been found to eliminate the pain in the first application. The laser energy is believed to act on the nerve endings of the ulcer and cause the release of P-endorphin; promote tissue biostimulation, and facilitate a more rapid healing of ulceration.
Xerostomia or reduced salivation is one of the most frequent effects of radiotherapy in the head and neck region. A variety of drugs other than chemotherapeutics like sedatives, opiates, antidepressants, antihistamines, diuretics may also be responsible to induce xerostomia. 
Salivary glands are expected to be relatively radio-resistant due to slow turnover rates of their cells. Yet changes in saliva may be seen quantitatively and qualitatively shortly after antineoplastic therapy. Since there is an increase in viscosity and proportion of organic material, the color of saliva may change from transparent to opaque white or yellow. The pH and buffering capacity of saliva decreases, and there is alteration in electrolyte levels. The radiation therapy causes fibrosis, degeneration of salivary acinar cells, and necrosis of salivary glands leading to these changes. Due to low pH, the oral flora shows a shift from gram-positive to gram-negative bacteria.  Decreased flow and increased viscosity can also cause difficulty with chewing, swallowing, speech etc. There is a significant increase in the prevalence of infections such as candidiasis, periodontal disease, and caries due to alteration in pH and oral flora. Lack of adequate saliva also hampers the function of taste buds resulting in taste alteration, dislike for food, and subsequent appetite loss. This is further complicated by the episodes of nausea, vomiting, pain, and discomfort resulting in fall in general health of the patient.
The child should rinse with cold sterile water or with cold normal saline as often as possible to keep the oral tissues clean and wet. This will ensure removal of thick saliva and debris, and decrease the risk of opportunistic infections. Xerostomia may be treated with the use of artificial saliva based on carboxymethylcellulose, stimulation of salivary flow etc. Apart from this, meticulous oral hygiene and topical fluoride application can also help in reducing the complications related to xerostomia. Pilocarpine is a cholinergic parasympathomimetic agent, which is also being used to stimulate salivary flow in patients with dry mouth.
Osteoradionecrosis (ORN) is considered as one of the most severe and serious oral complications of radiotherapy for head and neck region. The etiological factor responsible is radiation, which damages the endothelial linings of the vessels of the bones resulting in hypocellularity, vasculitis followed by obliterate endarteritis, ischemia, fistula, and sometimes pathological fracture of the bone. The mucosa also becomes thinner with telangectasia formation in the irradiated area. This makes it more susceptible to mechanical injury. There is decrease in collagen formation and the capacity for wound healing. There is decreased blood flow due to alterations in vessels, thus reducing nutrients and defense cells. This causes bone ischemia, especially if the bone is subjected to trauma e.g. tooth extraction. The most common site for ORN is the mandible due to its relatively poor vascularization and presence of teeth. Introduction of preventive oral hygiene and thorough dental assessment before and after an irradiation may result in a decreased incidence of osteo-radionecrosis. It is recommended that all children should be referred for an oral examination one month prior to initiation of the chemo- or radio- therapy and treatment of pre-existing or associated oral disease. It permits adequate healing from any required invasive oral procedures. It is possible to prevent, reduce and alleviate potential oral sequelae with pre evaluation and appropriate dental care. It is important to identify possible factors causing osteoradionecrosis before the start of radiation therapy. Even a carious-exposed tooth can have periapical infection leading to osteoradionecrosis. Hyperbaric oxygen therapy (HBO) is generally recommended for management of ORN because it increases oxygenation of irradiated tissue, promotes angiogenesis, and enhances osteoblast repopulation and fibroblast function. 20 to 30 dives of HBO at 100% oxygen is usually prescribed at 2 to 2.5 atmospheres of pressure. Wright et al,  recommended 10 dives of postsurgical HBO in case surgery is required. Recently, Grimaldi et al,  reported good results with the use of low intensity laser radiation for bone fracture and bone neoformation. It also works as a bio-stimulator in osteoblasts and as a bio-modulator of mesenchymal undifferentiated cells in osteoblasts and osteocytes.
Candidiasis is often referred to as disease of the diseased. It is one of the most common opportunistic infections seen in children with leukemia. Candida spp. adheres to the epithelial surface via extracellular polymeric materials and further penetrates by liberation of enzymes.  The presentation may vary from soft white adherent patches on the oral mucosa seen in pseudomembraous candidiasis to erythematous painful eroded areas of erythematous form. Acute pseudomembranous candidiasis, which has been referred to as "Thrush" traditionally, shows a classical "curdled milk appearance" clinically. On scraping, the lesions show pin point hemorrhagic areas.
Erythematous candidiasis, previously referred to as atrophic oral candidiasis, typically manifests as diffuse erythematous areas in the oral cavity. The appearance produced is not only due to atrophy of the oral mucosa but also due to an increased vascularization. It has been observed clinically that acute pseudomembraous candidiasis progresses to erythematous candidiasis. Often it may also be manifested as angular cheilitis. Children with leukemia show immunosuppression and hence, they are at an increased risk of dissemination of Candida infection, which may be life-threatening. 
Various topical and systemic antifungal agents are used for management of candidiasis. The most commonly used topical antifungal agents are nystanin, clotrimazole, and ketoconazole. In severe cases, systemic agents such as fluconazole, itraconazole, and ketoconazole are prescribed. It is seen that candidiasis regresses with an improvement in immune status.
Other opportunistic infections
Various opportunistic infections other than Candida are seen in children with leukemia due to immunosuppression caused by the disease as well as chemotherapeutic agents used for its management. The viral infections seen in children with leukemia are herpes simplex, varicella zoster, cytomegalovirus, adenovirus, and Epstein barr virus.
Herpes simplex is clinically manifested as multiple ulcers at corners of mouth, lips, palate, and gingiva. An erythema may also be seen around the ulcerative lesions. Anti-viral drugs like acyclovir and valacyclovir are used for its treatment. In strains resistant to these drugs, foscarnet is the drug of choice.
Varicella zoster is seen as multiple blisters, which show a protracted course. It may involve lungs, CNS, and liver and is associated with high morbidity. The management is palliative mainly, aimed at pain control, supportive care, and maintaining hydration.
Infections may be caused by both gram positive and gram negative bacteria. Drug resistant bacterial infections, specifically by staphylococcus, are seen with increased frequency. Other infections seen in these patients include tuberculosis and pneumonia.
The patients on chemotherapy and radiation often show signs of bleeding or hemorrhage from oral cavity. It may range from minor bleed from inflamed gingiva to ecchymosis, hematoma, or hemorrhage depending upon the severity of thrombocytopenia, oral hygiene, and contributing factors like sharp tooth of denture etc. Gingiva, buccal mucosa, tongue, floor of the mouth, and hard and soft palate are the most common sites of petechiae. Ecchymosis is commonly found in the tongue and floor of the mouth. Trauma associated with an oral function can also induce hemorrhage. Spontaneous mucosal petechiae and gingival bleeding can occur when the platelet level drops below 20,000 cells per mm 3 . Intra-oral bleeding can be alarming to patients and caregivers for future complication. Eliminating potential areas of trauma (sharp restorations, fractured teeth) and preexisting intraoral disease before chemotherapy minimizes the chances of hemorrhage. Patients should be advised to use a soft brush and eat soft or semi-solid food in severe thrombocytopenia. The most efficient means to reduce the risk of significant bleeding and infection in the gingiva is use of regular soft toothbrush or an electric brush at least twice daily.  Local therapy for arresting bleeding is directed toward establishing an adequate clot. Direct pressure can be used to control minor bleeding, but major oral bleeding may need platelet transfusions.
Spontaneous bleeding or bleeding from traumatic brushing may be seen commonly from gingiva in patients receiving chemotherapy. It occurs mainly due to poor oral hygiene but can be exacerbated by reduced platelet counts. The patients reporting with gingival bleed must be explained that oral hygiene maintenance is of utmost importance for them. Gentle massage of the gums with wet finger after brushing twice-daily can also help in reducing bleeding episodes. Sometimes topical styptics and antiseptic mouthwashes like povidone iodine solution (betadine) are also used in gingival bleeding.
Direct radiation to the oral cavity may result in damage to the gustatory buds. Due to highly viscous and minimal saliva, the eatables do not reach to the taste buds situated in the posterior part of the tongue and may also cause taste alteration. It causes 50% reduction in the perception of bitter and sour tastes. Chemotherapy drugs also causes bad taste, termed as Venous taste phenomenon that results from the diffusion of the drug into the oral cavity. Taste loss is often transitional as affected buds usually regenerate. Partial or total recovery may occur between 2-12 months after myelosuppresive therapy.  Zinc supplementation in the form of zinc sulfate at a dosage of 220 mg twice a day may be used for treatment of dysgeusia. 
Limited mouth opening or trismus is often seen as an oral complication induced by antineoplastic therapy. It is mainly a consequence of edema, cellular destruction, and muscular fibrosis caused by chemotherapeutic agents. Sometimes the muscles coming in direct path of radiation can also develop fibrosis or degeneration. Limited mouth opening may also lead to an inadequate oral hygiene, further hampering the health of the oral cavity. Patient should follow regular exercises to stimulate mouth opening and closing. Symptomatic relief may be achieved by an administration of anti-inflammatory medication, and muscle relaxants.
An increase in dental caries has been observed in patients with leukemia. However, dental caries does not occur due to the effect of either the disease process or radiotherapy or chemotherapy on the tooth structure. It is due to the alterations in salivary gland, tendency to eat soft diet, changes in oral microflora, and inability to maintain an oral hygiene. Dens et al,  conducted a study to examine the caries prevalence, gingival health, and oral hygiene of 52 children receiving chemotherapy and found a significantly higher caries prevalence. There were no significant differences in gingival/plaque index for cancer patients. The treating team should encourage the patient to maintain an oral hygiene by brushing twice-daily along with gum massage. These patients should also be advised on restriction of sticky food and dietary sucrose and have regular dental check-up. Various pediatric drug formulations contain sugar. It is important that caretakers and the medical team are aware of this and use medications in a manner so that caries risk is minimized. Children should not be allowed to fall asleep immediately after taking a sugar-containing medication or rinsing with nystatin or a clotrimazole troche that is not sugar-free. Use of topical fluorides in the form of mouth wash and fluoride-containing toothpaste gives an added protection to the teeth against dental caries. The dental surgeon can also apply concentrated topical fluorides and various remineralizing agents periodically to further prevent dental caries. Currently, there are some products available in the market in the form of dental cream for direct application on teeth for 5-10 minutes and have claimed to be having remineralizing potential or reversal for dental caries.
Damage to developing orofacial structures
If chemotherapy or radiation is exposed to the developing tooth germ during the formative years (before the age of 9 years), it can damage ameloblasts and odontoblasts during mitotic stage. This can result in hypomineralization or hypomaturation of enamel or formation of short, thin, tapered root. Clinically, the defective enamel and dentin will be seen as deformed and discolored crowns of the teeth. Direct radiation of the head and neck region can lead to an incomplete development of the jaws, smaller-sized teeth due to arrested tooth development, atrophy of the overlying soft tissue, malformation of hard tissues of teeth, such as enamel and incomplete calcification of teeth. The younger the child, the greater is the risk for craniofacial and developmental abnormalities. 
There are certain other important points to keep in mind while treating children with leukemia. These include the emphasis on obtaining dental clearance prior to therapy and points to remember for an emergency dental management.
Pre-therapy dental clearance in leukemic children
The oral cavity harbors many bacteria including the viridians streptococci. Leukemia, by itself, or chemotherapy and bone marrow transplantation suppress the host immune response, thus making it possible for these bacteria to cause septicemia. It is recommended that all children should be referred for an oral examination before initiation of the chemo- or radiotherapy and treatment of pre-existing or associated oral disease. Such a step will be very essential in minimizing oral cavity related complications during the treatment. With pre evaluation of oral health and appropriate dental management, potential oral sequelae may be prevented, reduced and alleviated.
Team approach is necessary to maximize outcomes. The oncology team should clearly advise the dentist as to the patient's medical status and oncology treatment plan. In turn, the dental team should communicate the oral health care plan before, during, and after cancer therapy. The dental surgeon must obtain information about the type, stage, and prognosis of the leukemia, current treatment plan, latest hematologic reports, and their implications etc. from the treating oncologist. Further, he/she should also communicate to the oncologist team about oral health status, possibilities of its link with existing condition, proposed treatment plan, and time required before starting the treatment.
Emergency dental care during leukemic treatment
The oncologist and hematologist should consult with the dental surgeon in case of any dental emergency. Neutrophil count drops drastically after 7 to 10 days following induction therapy; therefore, the risk of infection is greatest during this time, hence it is critical to appropriately time the dental procedures. Da Fonseca MA  has suggested that minor procedures should be performed at a platelet count of 40,000/mm 3 -50,000/mm 3 , whereas for major surgeries, it is desirable that the platelet count is at a minimum level of 100,000/mm 3 . Platelet transfusion may be advised in case of an emergency situation. Only if the absolute neutrophils count exceeds 1000 per cubic mm, and platelet counts are appreciable, any dental treatment is performed. A prophylactic antibiotic coverage should be provided according to the norms of the American Heart Association. 
Oral management after completion of leukemia treatment
After bone marrow transplantation, there is profound impairment of the immune function; therefore, children may not be able to undergo any dental procedures for up to 1 year, except non-invasive preventive treatment like topical fluoride application, preventive resin restoration or pit and fissure sealant etc.  Latest blood pictures are required on every visit. The hematologist must be aware of the possible long term side effects of chemotherapy on the teeth, oral mucosa, and craniofacial complex and should monitor the child for the same. Periodic visits to the dentist should be encouraged.
Proper oral care in children with leukemia is critical. A thorough understanding of the nature of the disease and its treatment are an important part of total patient care. A combined effort of hematologist or oncologist with the dental clinician is very important to alleviate the oral complications before, during, or after the antineoplastic therapy in children. An effective team approach is required to minimize pain and discomfort and maximize the chances for a successful treatment outcome. Thus, it is believed that the presence of a dentist as a member of oncology team can reduce the morbidity and mortality related to complications of antineoplastic treatment.
The authors would like to thank Drs. Sonal, Chakshu, Vartika, Ambika and Pramod Jain for their help in arranging the reference material and proof reading.