|Year : 2015 | Volume
| Issue : 1 | Page : 8-16
Kadalagere Lakshmana Girish Babu1, Geeta Maruti Doddamani2, Joe Mathew2, Kyatsandra Narasimhaiah Jagadeesh3, Lambani Ramanaik Kumaraswamy Naik4
1 Department of Pedodontics and Preventive Dentistry, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Bengaluru, Karnataka, India
2 Department of Orthodontics, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Bengaluru, Karnataka, India
3 Department of Prosthodontics, Krishnadevaraya Dental College, Bengaluru, Karnataka, India
4 Department of Oral Pathology, SJM Dental College and Hospital, Chitradurga, Karnataka, India
|Date of Web Publication||20-Feb-2015|
Dr. Kadalagere Lakshmana Girish Babu
Department of Pedodontics and Preventive Dentistry, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Bengaluru - 560 068, Karnataka
Source of Support: None, Conflict of Interest: None
Leukemia, although a rare disease, exceeds a cause of death from many of the acute communicable diseases because of its fatal character. It is characterized by widespread, rapid, and disorderly proliferation of leukocytes. In India, leukemia is the most common childhood cancer with a relative proportion varying between 25% and 40% and continues to be the largest contributor to cancer-related mortality in children. This paper reviews the etiology, risk factors, diagnosis, oral complications, and prognosis of pediatric leukemia.
Keywords: Acute lymphocytic leukemia, diagnosis, etiology, india, oral complications, pediatric leukemia, prognosis
|How to cite this article:|
Girish Babu KL, Doddamani GM, Mathew J, Jagadeesh KN, Kumaraswamy Naik LR. Pediatric leukemia. J Pediatr Dent 2015;3:8-16
| Introduction|| |
Leukemia is a malignancy with disseminated proliferation of immature or blast cells of the bone marrow, which replace the normal marrow elements and tend to accumulate in various tissues of the body.  Leukemia was first identified by researchers, Virchow and Bennet in the year 1845.  European physicians in the 19 th century were the earliest observers of patients who had markedly increased white cell counts. The term "Weisses Blut" or "white blood" emerged as a designation to this disorder. Later, the term leukemia, which is, derived from the Greek word "leukos," meaning "white," and "haima," meaning blood was used to indicate the disease. 
Leukemia, although a rare disease, exceeds a cause of death from many of the acute communicable diseases because of its fatal character.  It is characterized by widespread, rapid, and disorderly proliferation of leukocytes and their precursor and the presence of immature leukocytes in the blood often in very large numbers unexceptionally at some time during the course of the disease.  Leukemias are usually classified according to their clinical behavior (acute or chronic) or histogenesis (myeloid or lymphocytic/lymphoblastic). Hence, there are four main types of leukemia, namely chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and acute myelogenous leukemia (AML).
According to the Leukemia and Lymphoma Society, USA, there were approximately 13,410 new cases of AML, 5,200 new cases of ALL, 4570 cases of CML and 15,110 cases of CLL diagnosed in the year 2007-2008 in USA. Again, this society has reported in the year 2010-2011 that blood cancers would account for 9.0% of the 1,529,560 new cancer cases diagnosed in the US this year. Leukemia alone  comprises 27.5% of cancers affecting the children aged 0-19 years in United States. It further states that every 4 min, one person in the United States is diagnosed with a blood cancer. Even in Britain the second largest contributor to mortality from childhood cancer is leukemia. 
In India, leukemia is the most common childhood cancer with a relative proportion varying between 25% and 40% and continues to be the largest contributor to cancer-related mortality in children.  Sixty to 85% of all leukemias reported are acute lymphoblastic leukemia. Reported annual incidence of ALL is approximately 9-10 cases per 100,000 population in childhood.  Compared to the developed world, the biology of ALL appears different in India, with a higher proportion of T-cell ALL (20-50% as compared to 10-20% in the developed world), hypodiploidy and translocations t(1;19), t(9;22), and t(4;11), all of which contribute to a poorer prognosis of this leukemia. ,,,
The cause of ALL remains largely unknown, although many conditions may influence its development. Some of the risk factors which are important in the pathogenesis of leukemia are; ionizing radiation; chemicals; (e.g., benzene, heavy metals, pesticides, petroleum distillates), drugs (chemotherapeutic drugs agents, alkylating agents, and etoposide, especially when used with radiotherapy); viral infection and genetics. 
| Etiology|| |
In ALL, chromosomal translocations occur regularly. It is thought that most translocations occur during prenatal development. These translocations cause a rearrangement of genes, which in turn to transformation of proto-oncogene into an oncogene. The oncogene causes leukemia either by stimulating cell division or by inhibiting the programmed cell death called apoptosis. A translocation can activate a proto-oncogene by two different mechanisms. A more frequent event is a merger of two genes to form a fusion gene that produces abnormal chimeric protein inducing leukemia. As an example, translocation t(1; 19) in ALL creates the fusion of E2A (immunoglobulin enhancer-binding factors E12/E47) and PBX1 (pre-B-cell leukemia transcription factor 1) genes. In the E2A-PBX1 fusion, protein transactivating domains of E2A are joined to the DNA-binding domain of PBX1, which alters the transcriptional properties of the PBX1 transcription factor. ,
Inactivation of a tumor suppressor gene is another event that may initiate leukemia. Tumor suppressor genes are essential for normal cell development, and they prevent carcinogenesis. Very few tumor suppressor genes have been reported in acute leukemias. Screening for chromosomal regions with loss of heterozygosity is one way to track novel tumor suppressor genes. In childhood ALL, short arms of chromosomes 9 and 12 (in about 30-40% and 25-30% of the patients, respectively) are the regions that most frequently show loss of heterozygosity. ,
The other mechanism by which a translocation causes leukemia is transfer of a normally quiet transcription factor gene to the neighborhood of active promoter or enhancer elements, which accelerate the function of the gene. For example, in translocations t(8;14), t(2;8), and t(8;22) in Burkitt leukemia, the gene encoding the MYC transcription factor is exposed to the enhancer elements of an immunoglobulin gene. These enhancer elements cause overexpression of the MYC gene, which is important in the regulation of cell division and cell death.  Further characterization of these genes revealed that they are often involved directly or indirectly in the development and homeostasis of normal blood cells, and that abnormal protein products of fusion genes created by specific translocations and inversions can deregulate proliferation, differentiation or programmed cell death (apoptosis) of blood cell precursors. ,
Evidence in support of prenatal origin of ALL in children comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth. Similarly, studies have observed that children with ALL characterized by specific chromosomal abnormalities had blood cells carrying the abnormalities at the time of birth. ,, Further, genetic studies of identical twins with concordant leukemia also support the prenatal origin of some leukemia.  As an association between certain dermatoglyphic patterns and specific chromosomal aberrations has been observed, dermatoglyphic traits can be used as a diagnostic tool in medicine.  In pediatric leukemia, studies have indicated that most chromosome translocations and preleukemic clones arise during fetal hematopoiesis with secondary genetic events that occur postnatally.  However, there is little evidence that ALL is heritable.
| Risk Factors|| |
Indian population being multicultural and multiethnic have conserved their gene pool because of the caste system and intra caste marriage requirement. Hindus (including Sikhs, Buddhists, Jains) constitute 85% of the population, and 15% religious minorities are comprised of Muslims and Christians. The records of leukemia comprise 86.5% of Hindus and rest for other religions which are in accordance with their population. 
The significant presence of AML has been observed in all types of blood groups but not with other types of leukemias. Data have shown a significant association of ABO blood groups and different cancers like duodenal ulcer,  gastric cancers  etc. Macmohan et al. have shown a tendency of leukemia to occur less frequently in persons of group O than in persons of group B and AB.  However, Modak et al. nullifies the concept of tendency of any particular blood group toward leukemia. 
Males show a higher risk for all forms of leukemia with the overall ratio of 1:8.1. There is no explanation for females to be protected against leukemia.  In a study from Haryana by Kumar et al., there were 70.2% children and 29.8% adult patients of ALL in which male to female ratio was 2.03:1. 
It has been proposed that T-cell ALL predominates in economically disadvantaged areas, but with urbanization, industrialization, and increasing affluence incidence of ALL have increased.  ALL is reported to be the most frequent in the south  and intermediate in the East, West,  and central India.  Interestingly, the incidence of ALL is lesser in east India  as well as Northern areas.  However, this has be determined if this is a true difference or a registration artifact (cancer registration in the North East started in 2003).
The age distribution of children of ALL in developed countries shows a very marked early peak between 2 and 5 years, followed by a small peak between 11 and 15 years and the median age of 4 years. ,, There has been a gradual increase in the incidence of ALL in the past 25 years. 
Ionizing radiation is considered as a known cause of ALL. The risk is also higher for those exposed at an earlier age  and secondary leukemias in the individuals treated by radiotherapy.  Radiation from nuclear power plants  and X-ray examinations of pregnant women may be associated with increased risk of childhood ALL.  Postnatal exposure of infants for diagnostic X-ray increased the risk by 60%.  and was associated with of ALL, specifically B-cell ALL but no AML or T-cell ALL. 
Home use of different multiple pesticides put the children into risk of developing ALL. Exposure of expecting mothers to solvents, paints, or thinners increased the risk of ALL in children. The father's exposure to plastics before conception was also associated with greater risk. Furthermore, time of exposure is an important factor. 
Children living near high voltage power installations were more likely to be found to have leukemia than other children.  One recent study found that risk of leukemia was elevated when exposure to electromagnetic field was consistent over the term of the pregnancy and in cases where the design of the water system in the home led to "ground currents" from connections between plumbing pipes and the grounding for the electricity. 
Association with genetic diseases
Children with trisomy 21 (i.e., Down syndrome) are up to 15 times more likely to develop leukemia than normal children. Other less common preexisting chromosomal abnormalities have been linked to leukemia, included are Klinefelter's syndrome, Bloom syndrome, Neurofibromatosis type I, Schwachman syndrome, ataxia telangiectasia syndrome, Wiskott-Aldrich syndrome, and Fanconi's anemia. Lymphoid malignancies, with a predominance of T-ALL, have been reported in patients with ataxia-telangiectasia, an autosomal recessive disorder characterized by increased chromosomal fragility. ,,,
Evidence supports the hypothesis that an infection is involved in the etiology of ALL in children, particularly those cases seen in children between 2 and 5 years of age. ,, However, some studies show a protective effect  and others suggest the opposite.  Association of human T-cell lymphotrophic virus type 1 with adult T-cell leukemia, epstein-Barr virus with mature B-cell ALL, and human immunodeficiency virus (HIV) with lymphoproliferative disorders has also been described. ,
| Diagnosis|| |
ALL is diagnosed with medical history, physical examination, peripheral blood smears, bone marrow biopsy, cytogenetics, and immunophenotyping. The higher the white blood cell (WBC) counts, the worse the prognosis.  Pathological examination, cytogenetics (in particular for the presence of Philadelphia chromosome), and immunophenotyping establish whether leukemia is myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes) and identify the cell surface antigens expressed by the tumor cells. RNA testing can establish how aggressive the disease is; different mutations have been associated with shorter or longer survival. Medical imaging can find metastasis to other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs. ,
Peripheral blood smear
Microscopic examination of leukemia affected tissue shows diffuse infiltration and destruction of the normal host tissue by sheets of poorly differentiated cells with either myelomoncytic characteristics or lymphoid features. Blast cells are seen on the blood smear in majority of cases. 
Bone marrow biopsy
Bone marrow biopsy is normally performed in conjunction with the peripheral blood smear because some patients may undergo through an aleukemic phase in which atypical cells are absent from the circulation. 
The stages of ALL include early pre-B ALL, common ALL, Pre-B-cell ALL, mature B-cell ALL (Burkitt leukemia), pre-T-cell ALL, and mature T-cell ALL.  B-and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface along, with nuclear terminal deoxynucleotide transferase (TdT), while precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.  In a study by Bayram et al. the most frequently detected five antigens were I2, CD10, CD41, CD2, and CD7/CD19 at the time of diagnosis and CD41, I2, CD10, CD19, and CD2 at the time of relapse. Flow cytometric investigations revealed that antigen levels determined at the time of diagnosis increased or decreased by 10% at the time of relapse.  CD19 is also expressed on the earliest B-precursor lymphocytes that are malignantly transformed in ALL.
Many technical difficulties make it difficult to gain information for chromosomal findings in ALL. Chromosome studies in ALL exhibit poor morphology; chromosomes tend to spread poorly, and appear blurred and fuzzy with indistinct margins, making banding studies challenging or even impossible. , Williams identified clonal karyotypic abnormalities in 94% to 98% of cases of ALL.  The majority of cases of ALL demonstrate an abnormal karyotype, either in chromosome number (ploidy) or as structural changes such as translocations, inversions or deletions. These changes were detected in only half of ALL patients in the first banding studies.  Improvements in spreading and banding techniques have resulted in higher rates of detection, and most studies now report chromosomal changes in 60-85% of ALL cases. ,,, The Third International Workshop on Chromosomes in Leukemia found the majority of cytogenetic changes in cases of B precursor ALL, with only 39% occurring in T-cell ALL. ,
Most studies on karyotypic abnormalities and their clinical significance have been performed in childhood ALL. Adult ALL showed nonrandom chromosomal abnormalities similar to those found in childhood ALL, but their distribution and their biological significance were different. However, in adult ALL the role of cytogenetics in patient management has largely been centered on the presence of the Philadelphia (Ph) chromosome which usually arises from t(9;22)(q34;q11.2) and results in BCR-ABL fusion.  Among the several changes, ploidy distribution and recurrent translocation associated with specific morphology and immunophenotype are well-recognized in ALL. Numerical chromosomal abnormalities alone are less common in adult ALL, possibly reflecting a fundamental difference in the pathogenesis between childhood and adult ALL.  Among adults, patients with normal karyotype and those with isolated 9p/CDKN2A-CDKN2B deletions had a relatively favorable (standard) prognosis, whereas those with 6q deletions, miscellaneous, and hyperdiploid karyotype had an intermediate prognosis, and patients with t(9;22)/BCR/ABL1, t(4;11)/MLL/AF4, t(1;19)/TCF3/PBX1 constituted the unfavorable prognosis group. 
| Treatment|| |
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 this 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. 
| Oral Complications|| |
Various factors increase the potential for developing oral problems in these children. They may include the age of the patient, nutritional status, type of malignancy, pretreatment oral condition, oral care during treatment, and pretreatment neutrophil counts.  The oral complications seen in leukemic children can be broadly classified as: 
- Primary complications - Mainly occurring due to the disease itself, that is, resulting from leukemic infiltration in the oral structures such as gingiva and bone. E.g., leukemic gingival enlargement.
- Secondary complications - These are usually associated with a direct effect of the radiation or chemotherapy, like the ones associated with thrombocytopenia, anemia, and granulocytopenia. These include a tendency to bleeding, susceptibility to infections, and ulcers, etc.
- Tertiary complications - The tertiary complications are usually due to the complex interplay of therapy itself, its side effect, and a systemic condition arising out of the therapy. They may be ulcerations, mucositis, taste alteration, skin desquamation, candidiasis, gingival bleeding, xerostomia, dysphasia, opportunistic infections, trismus, etc. Sometimes latent and late effects like some of the vascular lesions, tissue atrophy, permanent taste loss or change, fibrosis, edema, soft tissue necrosis, loss of teeth, salivary flow decrease, carious lesions, osteoradionecrosis, and chondronecrosis are also attributed to tertiary effects.
Mucositis is one of the most common oral problems seen during antileukemic treatment. 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. Rarely mucosal swelling is can be seen. , Even a mild local irritant (like sharp teeth or restoration, calculus, and plaque) may aggravate the mucosal inflammation. Younger patients are more prone to chemotherapy-induced mucositis; may be due to a more rapid epithelial mitotic rate or the presence of more epidermal growth factor receptors. 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 due to mucositis may lead to difficulty in feeding, hydration and speech, which further may lead to weight loss, anorexia, cachexia, and dehydration. ,
Quantitative and qualitative changes in saliva may be seen soon after anticancer therapy. The radiation therapy causes fibrosis, degeneration of salivary acinar cells, and necrosis of salivary glands. Xerostomia is seen due to radiotherapy as well as various chemotherapeutic drugs used during treatment , leading to increase the incidence of dental caries. There is an increase in viscosity, and organic material of the saliva leading to change is the color from transparent to opaque white or yellow. Decrease in pH and buffering capacity is seen due to alteration in electrolyte levels. The oral flora shows a shift from Gram-positive to Gram-negative bacteria due to low pH. These changes in saliva cause difficulty in chewing, swallowing, speech, taste alteration, dislike for food, and subsequent appetite loss. 
Osteoradionecrosis is the most severe and serious oral complications of radiotherapy. Radiation 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 telangiectasia formation in the irradiated area making the bone more susceptible to mechanical injury. There is a decrease in collagen formation and the capacity for wound healing if the bone is subjected to trauma, e.g., tooth extraction. 
Candidiasis is the most common opportunistic infections seen in children with leukemia. Candida species adhere to the epithelial surface via extracellular polymeric materials and further penetrates by liberation of enzymes.  The presentation of candidiasis may vary from soft white adherent patches (pseudomembraous candidiasis) to erythematous painful eroded areas(erythematous form) on the oral mucosa. It has been observed clinically that acute pseudomembraous candidiasis progresses to erythematous candidiasis. Children suffer from increased risk of dissemination of Candida infection, which may be life-threatening. 
Herpes simplex is clinically manifested as multiple ulcers at corners of the mouth, lips, palate, and gingiva. An erythema may also be seen around the ulcerative lesions. Varicella zoster is seen as multiple blisters, which show a protracted course. Other infections seen in these patients include tuberculosis and pneumonia. 
Hemorrhage seen in the leukemic patient 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. Petechiae and ecchymosis are commonly found on gingiva, buccal mucosa, tongue, floor of the mouth, and hard and soft palate. Spontaneous mucosal petechiae and gingival bleeding can occur when the platelet level drops below 20,000 cells/mm 3 . Spontaneous bleeding or bleeding from traumatic brushing may be seen commonly from gingiva in patients receiving chemotherapy. ,
Salivary changes and damage to the gustatory buds due to radiation leads to taste alteration. There is 50% reduction in the perception of bitter and sour tastes. Venous taste phenomenon caused due to diffusion of chemotherapeutic drugs into the oral cavity adds on to bad taste. Taste loss is often transitional and partial or total recovery is seen between 2 and 112 months postmyelosuppressive therapy. 
Trismus is a consequence of edema, cellular destruction, and muscular fibrosis or degeneration caused by chemotherapeutic agents and radiation. Limited mouth opening may also lead to an inadequate oral hygiene, further hampering the health of the oral cavity. 
Alterations in salivary gland, tendency to eat a soft diet, changes in the oral microflora, and inability to maintain an oral hygiene causes an increase in dental caries experience in the leukemic patient. Dens et al.,  observed a significantly higher caries experience in children receiving chemotherapy.
Damage to developing orofacial structures
Exposure of developing tooth germ during the formative years (before the age of 9 years) to chemotherapeutic agents or radiotherapy can damage the ameloblasts and odontoblasts, causing arrested tooth formation or hypomineralization or hypomaturation of enamel, or short, thin, tapered roots. Incomplete development of the jaws can also be seen. The younger the child, the greater is the risk for craniofacial and developmental abnormalities. 
| Prognosis|| |
Dramatic medical advancements in the treatment of ALL over the past three decades have changed it from a universally fatal to an almost curable disease in 85% of cases. Pediatric oncologists have become more successful in treating ALL as much of the clinical research efforts have focused on categorizing the patients into lower risk group (needing less intense therapy with much less side effects and toxicities) and patient with higher risk of treatment failure (targeted for more aggressive therapies)  based on known prognostic features. In the risk classification of ALL, not only cytogenetic alterations, but also many other factors are taken into account. These include, for example, WBC count at diagnosis, age, response to primary therapy, and the phenotype of the blasts (precursor-B cell/immature B cell/T cell).  The groups of patients formed according to the existing criteria, however, quite heterogeneous as regards the outcome of the patients, leading to excessive treatment of some patients and failure of treatment in others.
The cytogenetic abnormalities confer important prognostic information in ALL was first reported by Secker-Walker et al. in 1982 in a series of childhood ALL.  Complete remission rates, remission durations, as well as disease-free-survivals, were significantly affected by the karyotypic abnormalities.  Cytogenetic studies in childhood ALL have associated a better prognosis with the hyperdiploid karyotype and a worse prognosis with a balanced translocation. , The correlation of the karyotype in ALL with other recognized prognostic factor is an independent prognostic in childhood  as well as in adult patients.  The clinical outcome of patients with hyperdiploidy varies in different series, being more favorable in children than in adults, where a poor outcome has been repeatedly reported. ,
The survival rate for children younger than 15 years of age reaches about 75%, but, despite the significant improvement of outcome, still roughly 25% of patients suffer from a relapse.  Even if the management of relapse remains largely controversial, an increasing use of high-dose chemotherapy and stem cell transplantation is adopted in most cases. With the need to stratify patients in risk groups and to provide risk-adapted therapy, treatment requires high levels of organization, expertise, and knowledge.
Multiple inter-related factors are responsible for the poorer outlook of childhood cancer in India. Limited financial resources, lack of awareness of the meaning of symptoms, and difficulty in accessing healthcare contribute to advanced stage presentation.  Such a delay in presentation, along with unfavorable biology (e.g., as seen in ALL), leads to a need for more intense treatment, resulting in higher treatment-related morbidity and mortality. , Treatment refusal or abandonment, besides treatment-related death, is a frequent unwanted outcome.  A higher 5-year survival seen in those treated at specialist cancer centers and among those who complete their treatment reinforces the importance of centralization of treatment and compliance.  Recently, twinning programs, which foster interactions between public hospitals in developing countries and established cancer treatment centers elsewhere, have been seen to reduce abandonment and improve survival elsewhere in the world. ,,,, Similar strategies could be applied here. Clinical trials started by the Indian Cooperative Oncology Network (ICON, www.oncologyindia.org) and adoption of the MCP841 protocol for ALL in major Indian centers have been steps in the right direction for improving childhood cancer outcome. 
| Conclusion|| |
In India, child health is a priority health issue, and we are progressing toward reducing infection related childhood deaths. But childhood cancer is not yet a major area of focus, and it is not acceptable to ignore these children as they have an increasing likelihood of cure with appropriate treatment.
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