Prevalence of periodontal disease in patients with leukemia: a systematic review

Abstract

Background

Studies have shown that oral manifestations, such as gingival bleeding, gingival inflammation or overgrowth, and periodontitis, are the first symptoms of leukemia.

Many studies have also shown a linkage between chemotherapy and worsening oral conditions. This research study aims at conducting a systematic review of existing literature to investigate the prevalence of periodontal diseases in patients with leukemia, how leukemia can be a cause of them and how to determine these signs as a tool for an early diagnosis of the disease.

There are three objectives of this research paper: 1) to investigate the frequency of leukemia as a cause of gingival enlargement in the adult and children population, 2) to investigate the frequency of leukemia as a cause of gingival bleeding in the adults and children population, and 3) to determine periodontal clinical manifestation as an early sign of leukemia.

Methods

The studies included must have fulfilled the following inclusion criteria: Studies analyzing the periodontal tissues of the oral cavity, Periodontal signs and symptoms of leukemia as early signs of the cancer, No time limit in the publication of the

articles, Population age including pediatric and adults (+ and - 18 years old), Studies published in English, Spanish, Italian, or with English translation included in the article, Patients having a definitive diagnosis of leukemia and information about their age, type of leukemia and stage of illness treatment, Periodontal state of the patients and/or enough data to calculate gingivitis and/or periodontitis prevalence.

The studies that were excluded were based on the following exclusion criteria:

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Articles focused on genetics, Other types of cancer, Studies regarding other parts of the human body, Duplicate studies, Case reports and animal studies, Reviews and meta analysis, Patients with severe periodontal pathology previous to the cancer diagnosis. A literature search was performed in the Medline Complete and Scopus databases up to the day 15th of January 2022 with no time limit while collecting the literature. The study followed the Critical Appraisal Skills Programme español (CASPE) guide, through which the quality assessment was determined. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.

Results and discussion

The total articles included in our review were 24, with the year of publication spanning from 1958 to 2021. The following data was gathered from each included study and summarized in a table: author details, year of publication, country, language, type of study, sample information such as groups, age, sex and age, type of leukemia. Another table gathered outcome variables data from each article about each objective.

Systematic review showed mixed findings on the linkage between leukemia and gingival enlargement and the linkage between gingival bleeding and leukemia. In terms periodontitis being an early sign of leukemia, the systematic review showed that poor oral hygiene is a problem among patients with leukemia. Chemotherapy treatment creates gum leading in patients, which make them refuse cleaning teeth.

As a result, the strong gum bleeding associated with chemotherapy treatment combined with poor oral hygiene aggravate gingival manifestations, resulting in periodontitis. The mixed outcomes could be attributed to the small sample size of most of the studies and also because most of the studies did not take into consideration the confounding factors.

Keywords

Leukemia, Periodontal diseases, Gingival bleeding, Gingival hyperplasia, Gingivitis, Periodontitis, Oral manifestations.

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6

1. Introduction

4.1 LEUKEMIA DEFINITION

Leukemia is a malignancy of hematologic origins due to proliferating white blood cellular-forming tissues, resulting in a marked growth in circulating immature or peculiar white blood cells. Leukemia arises from hematopoietic stem cells characterized by using a disordered differentiation and proliferation of neoplastic cells. The etiology is both genetic and environmental, the evolution of this cancer is related to several risk factors: genetic syndromes, viral infections, exposure to ionizing radiation, exposure to benzene, history of exposure to chemotherapy or any previous hematological malignancy. [1]

4.2 CLASSIFICATION

Leukemia can be classified as lymphoid or myeloid, based on the originator cell and the cellular lineage, and as acute or chronic, depending on the rapidity of the proliferation.

The malignant cells found are abnormal, immature and not differentiated leukocytes, which are called blasts, these can be lymphoblasts or myeloblasts.

Blasts normally make for up to 5 % of bone marrow cells in a healthy patient; if we consider a patient with chronic leukemia this number increases up to maximum of 20%, while in acute leukemia the percentage rises to more than 20%, this explains why the onset of symptoms will be more rapid in the acute and more chronic in the other case. Chronic leukemia cells are partially mature , they proliferate rapidly and accumulate in peripheral blood or organs of the lymphoid causing anemia, leukopenia and thrombocytopenia . It is called a blast phase when the chronic turns into an acute type leading to a quick increase in the amount of blasts.

Acute lymphoblastic leukemia (ALL): is the type that appears the most in pediatric patients, making for 80% of the cases whereas adults make 20% of it.

Lymphoblasts precursors, lymphoid cells, show a blastic mutation caused by abnormal chromosomal numbers.

Acute Myelogenous leukemia (AML): the most aggressive type and most common

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in adults is acute myelogenous leukemia. It features more than 20% myeloid blasts. These abnormal and mutated myeloblasts are a result of re- arrangements, translocations,gains or losses of chromosomes .

Chronic lymphocytic leukemia (CLL): CLL is a clinically heterogeneous pathology affecting mostly lymphocytes, especially the B type; it may range in activation, maturation status, or cellular subgroup. It is mostly seen in patients of 60 to 70 years of age. The level of white cells in the blood increases and is considered for diagnosis when the absolute lymphocyte count (ALC) it's more than 5.000.

Chronic myelogenous leukemia (CML): Monoclonal abnormal granulocytes, neutrophils,basophils and eosinophils are the result of this type of leukemia which is related to a dysregulation of the tyrosine kinase on chromosome 22. The most affected cells are granulocytes. [1]

4.3 GENERAL SIGNS AND SYMPTOMS

When the blast cells start to proliferate and interfere with the normal functioning of the blood it's when we start to notice clinical symptoms.

Acute leukemia mostly affects pediatric patients, most usual signs are fever, bleeding and lethargy. Adults will show more symptoms related to anemia or thrombocytopenia such as bruising, heavy menstrual cycles and short breath.

Chronic leukemia will affect mostly adult patients who most of the time will find out about the disease in an incidental way due to the asymptomatic nature of it in many cases. An increased size of the liver and lymphadenopathies are common signs . [1]

4.4 ORAL SIGNS AND SYMPTOMS

Blasts, or undifferentiated cells, can enter the circulation and spread to various organs and tissues throughout the body, including the buccal cavity.

Tissue infiltration, in combination with blood changes, can result in significant clinical oral changes such as gingival bleeding and edema, which can be early indications and symptoms of leukemia. Local symptoms and findings of leukemia within the oral cavity consist of paleness of the oral mucosa because

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8 of underlying anemia, with presence of petechiae, ecchymosis and gingival hemorrhage or gingival bleeding due to underlying thrombocytopenia, oral ulcers, bacterial and fungal infections, osteoblastic and osteolytic maxillary lesions.

Infiltration of the gingival tissue with leukemia cells causes gingival hyperplasia that is characterized by means of progressive growth of the interdental papillae in addition to the marginal and attached gingiva. Gingival hyperplasia is seen mostly in acute leukemia. Chronic lymphocytic leukemia is characterized by a dysregulated immune system. All patients have decreased immunoglobulin levels, even in early stages, and this is related to an elevated frequency and severity of infection. The clinical path in CLL is dominated via events related to immune dysfunction, manifested predominantly as an elevated susceptibility to infection and/or autoimmunity. There are both quantitative and qualitative defects in immune effector cells that result in unusual cellular and humoral- mediated immune responses.

Production of immunoglobulin from regular B cells and antibody reaction to different antigens are substantially decreased in CLL patients. All three classes (IgG, A and M) are affected, even though predominantly IgG3 and IgG4. The humoral immune reaction, specially IgG and IgA, is taken into consideration to have a protecting function within the pathogenesis of periodontal disorder, so it could be assumed that these patients would be much more prone to periodontitis.[1]

Gingival infiltration is the first symptom of AML in about 5% of cases, and it is more common in myelomonocytic (M4) and monocytic (M5) leukemia. The proposed explanation for gingival involvement is based on the microanatomy of the gingiva and the expression of endothelial adhesion molecules, which permits leukocyte infiltration, resulting in a soft overgrowth. Neutropenia or direct infiltration of immature (blasts) proliferating leukocytes, or thrombocytopenia and immunodeficiency, can cause gingival hypertrophy and ulcerations. Secondary inflammatory infiltration results from this infiltration, which causes an increase in gingival thickness and the creation of pseudo- pockets. The progress of myeloid cells from the circulation into the tissues at the sites of gingivitis or periodontitis is attributed to their continual trafficking in specialized post-capillary venules. Edentulous people do not have leukemic gingival infiltration, implying that local irritation and dental trauma are involved in

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the pathophysiology. The gingival findings have been demonstrated to be partially influenced by tissue inflammation. Gingival enlargement, despite being seldom documented in the literature], may be the initial sign of acute leukemia.

The presence of an increased number of cells and an accumulation of connective tissue describe gingival overgrowth. Gingival enlargement can be characterized as inflammatory, drug-induced, neoplastic, or false enlargement based on the etiologic factors and pathologic alterations, and is frequently associated with systemic disorders (in particular, granulomatous diseases and leukemia).

Because the former is deadly and has a poor clinical result, differentiating leukemic gingival enlargement from gingival enlargement owing to other etiologies is critical. [2]

In addition, people with leukemia usually get large doses of chemotherapy and radiation, which can affect the oral cavity and flora. Teeth are predicted to be more susceptible to periodontal inflammation as a result of these changes.

Furthermore, during hospitalization for leukemia treatment, patients' systems are damaged, and regular oral hygiene is impossible to maintain, which can lead to the development of both caries and periodontal disorders. Given these findings, it's possible that leukemia affects the periodontium of patients both before and during therapy. [2]

4.5 PERIODONTAL DISEASES

Gingivitis and periodontitis are symptoms of periodontal disease, often known as gum disease. Gingivitis, or gum inflammation, leads to bleeding inflamed gums, is a type of periodontal disease that develops early and it is reversible. If untreated this can evolve into periodontitis. Periodontitis is a condition that develops over time as a result of the accumulation of dental plaque, bacterial dysbiosis, the formation of periodontal pockets, gum recession, tissue degradation, and alveolar bone loss, all of which can lead to tooth loss. These consequences such as bone loss and tissue degradation are irreversible therefore periodontal treatment, such as rooting and scaling, can help to halt the advancement of periodontal disease by eliminating plaque from the teeth's roots and lowering inflammation, but once tissue and bone loss has happened, it is irreversible. [3]

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10 4.6 PERIODONTAL DISEASE AS CAUSE OF CANCER

Several studies suggest that the risk of developing cancer increases by the presence of periodontal disease, especially for breast cancer in women and prostate, head and neck and hematological cancer in men, and the risk increases the more severe the periodontal condition. The motivation for these investigations stems largely from recent findings relating periodontitis and pathogenic microorganisms to a systemic impact on the body, notably on the immune response, suggesting that these pathways could play a role in the carcinogenesis of distant tumors [3]. The mechanisms related to this association are several. A number of underlying processes for the link between periodontal disease and cancer have been hypothesized.

• Systemic inflammation caused by periodontal disease, immunological disregulation, and changes in the oral flora are among them. The gingival tissue's extremely vascular and delicate design makes it a vulnerable entrance point for oral infections during regular activities such as eating and teeth cleaning.

• Alteration of the oral flora

• Confounding factors: smoking, socio economic status, diet, gender, age, ethnicity, genetics, diabetes.

It is suggested that periodontitis is linked to subclinical systemic inflammation.

This link is supported by a rise in systemic indicators of inflammation and tumor necrosis factor in periodontitis patients' plasma. Periodontitis has higher levels of myeloperoxidase and superoxide dismutase, two key regulators of inflammation. These findings lead to the hypothesis that treating periodontal disease early on could minimize inflammation and its long-term repercussions on other organs. [4]

4.7 LEUKEMIA AND CHILDREN

Children's leukemia is a prevalent malignant tumor disease, with acute lymphoblastic leukemia (ALL) being the most frequent kind in children aged 1 to

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4 years old. Leukemia treatments involve radiotherapy or chemotherapy which both have as effect oral complications, in children moreover, consequences are also seen on the oro facial growth and developing permanent or primary dentitions [5].

Chemotherapy is the most common treatment for ALL although it almost always results in microbiota-related oral problems. Methotrexate for example, is a common chemotherapeutic medication that is used to treat ALL patients. Its administration at a high dose (HDMTX) , followed by calcium folinate, is an important part of ALL therapy. Children, on the other hand, are susceptible to chemotherapy’s toxicity, with side effects including: the destruction of oral mucosal tissues, reduced immunological function, changes in eating habits and oral hygiene, mucositis, gingivitis, gum bleeding and xerostomia. In comparison to their healthy peers, these children's oral microbiota are less diverse and rich.

[6]. Gingival hyperplasia, oral mucositis, dental caries, delayed exfoliation, delayed eruption, and long term consequences such as hypodontia, micro dontia, and enamel hypoplasia are all common oral findings in Acute Lymphoblastic Leukemia. Leukemic infiltration in areas of moderate chronic irritation causes gingival edema. One of the most consistent symptoms of the condition is gingival hyperplasia, which is usually widespread and varies in severity. The teeth could be basically fully covered in severe situations. The gingiva is swollen, edematous, and bright red, and it bleeds easily. [7]

When compared to healthy children, children with ALL have a higher chance of developing gingival inflammation. In addition, patients with chemotherapy- induced thrombocytopenia may experience spontaneous muco gingival hemorrhage, trauma-related bleeding, petechiae, and ecchymosis.

Chemotherapy reduces saliva volume and flow rate, resulting in xerostomia. [6]

A lower salivary flow rate favors plaque buildup, which can lead to periodontal inflammation in immune compromised patients if left untreated [8]. In addition to periodontal and gingival inflammation, as a result of chemotherapy, leukemia children patients eat more high-energy foods and consume sugar-rich beverages to alleviate oral dryness. Children have a reduced food intake due to nausea and vomiting produced by chemotherapy medicines, thus the number of meals increases significantly. [6] Excessive sugar consumption and eating frequency lead to poor dental hygiene and the development of caries. Direct radiation damage to gustatory buds, as well as alterations in saliva viscosity and

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12 flow, cause taste abnormalities, the diffusion of chemotherapy medicines into the oral cavity can result in a metallic or chemical taste. Cisplatin, carboplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, and methotrexate are some of the drugs linked to taste changes. [5] Leukemia treatments of chemotherapy and radiotherapy have a significant negative impact on the oral health of children with leukemia and increases oral microbiota dysbiosis. [6]

4.8 THE ROLE OF THE DENTIST

Usually the first signs of leukemia manifest in the mouth, and patients often search for dental care thinking that diseases are of local origin. So, the dentist plays an essential role in the early diagnosis of the hematologic disorder.

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Periodontal recalls should be arranged more frequently to keep illness and inflammation to a minimum while emphasizing the significance of regular dental appointments and good oral cleanliness. Patients should also be urged to collaborate with their other medical providers in order to adhere to all proper screening examination regimens for early identification of malignancy, including periodic oral cancer screenings in the dental health environment. Finally, these patients should be encouraged and supported to make positive lifestyle changes that may lower their cancer risk, such as quitting smoking, eating a healthy diet, and exercising regularly, as well as eliminating environmental risk.

Dentists have a unique opportunity and responsibility to aid in preventative medicine by assisting their patients in achieving the best possible oral health.(9) Patients should be directed to the Oral Health Program clinic, which offers imaging, precision periodontal equipment, and other auxiliary methods for evaluating oral tissue.

The following stages are used to examine the oral mucosa: vermillion lip border, labial mucosa, buccal mucosa, tongue, hard and soft palate, and oropharynx on both sides of the mouth. Oral conditions discovered during examinations are divided into two categories: those related to the underlying disease or its treatment (dry lips or mucosa, mucositis, bleeding disorders, fungal or viral infections, and aggravation of odontogenic infections) and those unrelated to the underlying disease or its treatment (keratosis, traumatic ulcer, reacting fibrous hyperplasia, leukoplakia, aphthous ulcer, coated tongue, mucocele). Pre-

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existing constitutional or syndromic dental abnormalities are documented, and treatment is halted or postponed until the remission/recovery is complete.

Oral health-care professionals should be aware of the oral manifestations of leukemia, as well as the necessity of diagnosing the indicators of this systemic disease, which frequently prompt patients to seek dental care first. To create an early diagnosis and treatment plan, the dentist must be able to notice these changes, investigate them with additional testing, and refer the patient to a specialized clinic. Patients might develop a variety of oral problems, the most of which are caused by the harsh treatment. Oral hygiene is a critical step in preventing infections that could lead to an abscess or sepsis. [2]

4.9 KNOWLEDGE GAP, THE IMPORTANCE OF COLLABORATION BETWEEN SPECIALTIES

Leukemia is a complex disease requiring vast and elaborated diagnosis and treatments, therefore an interdisciplinary team is needed with members from different disciplines and specialties including hematologists, oncologist, pediatrics, nurses, nutritionist, dentists, physical therapists to name some. The dentist's position in a multidisciplinary team is also critical for the prevention, diagnosis, and treatment of previous disorders such tooth decay, periodontal disease, and other oral and perioral tissue changes. [2] Successful outcomes for the patient can be guaranteed only through the effective management, communication and mutual decision making of everyone.

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2. Justification, Hypothesis and Objectives

5.1 Justification

Estimating periodontal disorders among leukemia patients can offer a clear picture of a patient's oral health, early signs such as gum bleeding and inflammation could be easily mistaken as just gingivitis whereas it is essential to keep in mind these signs as possible early symptoms of a leukemia cancer and don't underestimate them when seen in patients. This can be used to promote dental care and prevention strategies, as well as future study in this area. In this setting, this study conducts a comprehensive evaluation of the information on the periodontal health of leukemia patients in both the children and adult population and promotes further research on the topic.

5.2 Hypothesis

Adults and children with leukemia who have periodontitis symptoms will have a considerable improvement in their health and life expectancy if they undertake early prevention and diagnosis.

5.3 Research question

The research question is: “ What is the prevalence of periodontal diseases in individuals with leukemia?”.

5.4 General objective

The aim of this study is to investigate the literature about the prevalence of periodontal diseases in patients with leukemia, how leukemia can be a cause of them and how to determine these signs as a tool for an early diagnosis of the disease.

5.5 Specific objectives

1. To investigate the frequency of leukemia as a cause of gingival enlargement in the adult and children population

2. To investigate the frequency of leukemia as a cause of gingival bleeding in the adult and children population

3. Determine periodontal clinical manifestation as an early sign of leukemia

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3. Materials and Methods

The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.

6.1 Eligibility criteria

PICO question:

The PICO (Population, Intervention, Comparison, and Outcomes) model was used to select the study population. The population included were both adults and pediatric of the age below and above 18 years old, therefore without any age or gender differentiation. The incidence of all our patients was for them to be affected by cancer, specifically leukemia; any subtype of the cancer was accepted. The comparison population were the patients not affected by leukemia and with a healthy periodontal state. The outcome of our research was the presence of periodontal lesions in these patients, with a specific focus on gingival enlargement and gingival bleeding as a result of leukemia.

P: Adults and pediatric patients (+ - 18 yo) I: Leukemia

C: Patients not affected by leukemia

O: Periodontal lesions (gum enlargement and gum bleeding) Inclusion and exclusion criteria:

Studies were considered if they had the following elements

The studies included must have fulfilled the following inclusion criteria:

· Studies analyzing the periodontal tissues of the oral cavity

· Periodontal signs and symptoms of leukemia as early signs of the cancer

· No time limit in the publication of the articles

· Population age including pediatric and adults (+ and - 18 years old)

· Studies published in English, Spanish, Italian, or with English translation included in the article

· Patients having a definitive diagnosis of leukemia and information about their age, type of leukemia, and stage of illness treatment

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· Periodontal state of the patients and/or enough data to calculate gingivitis and/or periodontitis prevalence.

The studies that were excluded were based on the following exclusion criteria:

· Articles focused on genetics

· Other types of cancer

· Studies regarding other parts of the human body

· Duplicate studies

· Case reports and animal studies

· Reviews and meta analysis

· Patients with severe periodontal pathology previous to the cancer diagnosis

6.2 Search strategy

A literature search was performed in several databases up to the day 15^th of January 2022. The search was conducted in the Medline Complete and Scopus databases. Only terms related to or defining the study topic were included in the search strategy:” leukemia”, “periodontal disease”,

“periodontitis”,” gingivitis”, “gingival bleeding”, “gingival hyperplasia, “gingival enlargement” in combination with Boolean operators “OR” and “AND”. Search keywords were customized for each database and used alone or in combination: ( TITLE ( leukemia ) OR TITLE ( leukaemia ) AND TITLE ( periodontal AND disease ) OR TITLE ( periodontitis ) OR TITLE ( gingivitis ) OR TITLE ( gingival AND bleeding ) OR TITLE ( gingival AND enlargement ) OR TITLE ( gingival AND hyperplasia ) OR TITLE ( gum AND bleeding ) OR TITLE ( gum AND overgrowth ) OR TITLE ( gingival AND overgrowth ) OR TITLE ( gum AND enlargement ) OR TITLE ( gum AND hyperplasia ) ).

In addition, the reference list of included research was hand-searched to find any potentially suitable publications that were missed by the computerized search.

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Database Search Filters Date

SCOPUS

“Leukemia” OR

“Leukaemia” AND “gum bleeding” OR “gingival bleeding” OR “gum enlargement” OR

“gingival hyperplasia”

OR “gingival

overgrowth” OR “gum overgrowth” OR

“periodontitis” OR

“periodontal disease”

OR “gingivitis”

Publication year: No time limit

Language: English, Spanish, Italian Document type: Article

January 15^th 2022

Medline Complete

“Leukemia” OR

“Leukaemia” AND “gum bleeding” OR “gingival bleeding” OR “gum enlargement” OR

“gingival hyperplasia”

OR “gingival

overgrowth” OR “gum overgrowth” OR

“periodontitis” OR

“periodontal disease”

OR “gingivitis”

Publication year: No time limit

Language: English, Spanish, Italian Type of publication:

observational study, randomized controlled trial, evaluation study, controlled clinical trial, pragmatic clinical trial, equivalence trial, clinical trial, comparative study.

January 15^th 2022

6.3 Study selection

One independent reviewer assessed the titles and abstracts of the publications and chose the studies that would be included in the full text analysis. Only studies that used cross-sectional, case-control, or longitudinal observational designs were eligible. Previous meta-analysis, Reviews or case reports were excluded. The outcomes of the studies have to be reported based on clinical evaluations of leukemia patients. Oral manifestations that were self- reported were not included in the studies. Duplicate studies were removed.

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18 6.4 Data extraction

The following data was gathered from each included study and summarized in a table: author details, year of publication, country, language, type of study, sample information such as groups, age, sex and age, type of leukemia.

6.5 Quality assessment

The study followed the Critical Appraisal Skills Programme espanol (CASPE ) guide, through which the quality assessment was determined.

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4. RESULTS

7.1 Study selection and Flow chart

As has been described in the material and methodology section that the researcher searched through the databases of Medline Complete and Scopus databases to find journals that could be included for the systematic review. The researcher filtered the articles based on the abstracts that matched with the basic inclusion and exclusion criteria. The researcher initially came up with 190 journals but eliminated 112 journals to remove duplicate copies and based on the exclusion criteria. The researcher then performed further screening based on the inclusion and exclusion criteria on the remaining journals (n=78) and excluded all the non-medical papers (n=30). Upon the removal of non-medical papers, the researcher ended with 48 journals and then the researcher had the selected journals reviewed by an independent reviewer who evaluated the titles and abstracts of the journals and shortlisted only those publications that could be included for the full text analysis (n=18). The researcher then scanned through the reference lists of the selected journals and included 25 additional journals for review but after applying inclusion and exclusion criteria on the 25 additional journals, 19 journals were eliminated.

Thus, the ultimate number of studies that were included in the final systematic review were 24 journals. Below is presented the flowchart of the journal selection:

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Table 1 PRISMA Flow diagram for new systematic reviews which included searches of databases and registers only

7.2 Analysis of the characteristics of the reviewed studies

General characteristics of the studies that were not outcome variables have been presented in the table below:

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Author and reference

Year Country language Type of Study

Sample Information Type of Leuke mia Hou GL,

Huang JS, Tsai CC [10]

1997 Taiwan English Retrospective study

Sample size = 230, consisting of 138 males and 92 females aged between 0-61+ years.

The classif ication of leuke mia was based on histolo gical scree ning of bone marro w biopsy into AML, ALL, CML, CLL Kapoor G,

Goswami M, Sharma S, Mehta A, Kaur J [11]

2019 India English Cross- sectional study

Sample size = 220, consisting of both males and females aged between 3-14 years.

ALL

Nasim VS, Shetty YR, Hegde AM [12]

Sample size = 104, consisting of both males and females aged between 2-14 years.

The sample was divided into two groups Group I (68 ALL patients) and Group II (36 ALL patients)

ALL

Ashok L, Sujatha GP, Hema G. [13]

2010 India English Controlled- clinical trial

Sample size = 30, consisting of 20 males and 10 females aged between 5-80 years.

Control Group = 25

participants, consisting of 12 males and 13 females aged between 5-65 years

ALL,A ML CLL,C ML

Rinčić N, Božić D, Rinčić G, Gaćina P, Plančak D.

[14]

2016 Croatia English Controlled- clinical trial

Sample size = 30, consisting of 17 males and 13 females aged between 67.9 years and above.

Control Group = 30

participants, consisting of 10 males and 20 females aged

CLL

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22

67.9 years and above.

Angst PDM, Dutra DAM, Moreira CHC, Kantorski, KZ [15]

2011 Brazil English Cross- sectional study

AML, ALL, CML, CLL

Parra, J.J.

et al [16]

2019 Ecuador English Longitudinal study

Sample size = 32, consisting of 15 males and 17 females aged less than 14 years.

ALL

Ponce- Torres, E.

et al [17]

2010 Mexico English Cross- sectional study

ALL

Kaskova, L.F. et al.

[18]

2019 Ukraine English Cross- sectional study

Sample size = 373, consisting of males and females aged between 7-15 years.

The test group consisted of 160 children (83 males and 77 females) while the control group consisted of 213 healthy individuals.

The test group children was divided into three groups, with L1 consisting of 50 children examined before the initiation phase, L2 consisting of 50 children examined a month after the chemotherapy

treatment, and L3 consisting of 60 children examined in permanent hematologic remission.

ALL

Angst et al [19]

2012 Brazil English Cross- sectional study

AML, ALL, CLL,C ML

Busjan R, et al [20]

2017 Germany English Cross- sectional study

Sample size = 39, consisting of males and females aged over 18 years.

The control group consisted of 38 healthy individuals of both genders.

AML, ALL

Dholam KP, Gurav S, Dugad J, Banavli S. [21]

AML, ALL

Dens F, 1995 Belgium English Cross- Sample size = 52, consisting of ALL

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Boute P, Otten J, Vinckier F, Declerck D. [22]

sectional study

males and females aged between 2-17 years.

Duffy JH, Mass F, Driscoll EJ. [23]

1958 USA English

Observational study

Sample size = 38, consisting of males and females with an average of 3 years

AML, ALL

Hegde AM, Joshi S, Rai K, Shetty S [24]

2011 India English Controlled- clinical trial

Sample size = 90, consisting of males and females aged between 4-10 years

The control group consisted of 30 healthy children of the same age group

ALL

Ninawe N, Bhaje P, Doifode D, Dolas A, Bahadure R, Bahetwar S [25]

ALL

Maciel JCC, Castrojr CGD, Brunetto AL, Leone LPD, Silveira HEDD [26]

2009 Brazil Englishh Controlled- clinical trial

Sample size = 56, consisting of males and females aged less than 13 years.

The control group consisted of 56 healthy individuals of both genders of the same age group.

ALL

Wang et al [27]

2021 China English Controlled- clinical trial

Sample size = 39, consisting of 23 males and 16 females aged over 18 years.

ALL

Shankarap illai et al [31]

Sample size = 73, consisting of 40 males and 33 females with an age range between 18 and 27 years

AML

Ptasiewicz M et al [32]

2022 Poland English Cross- sectional study

Sample size = 102, consisting of 51 males and 51 females with an age range between 22 and 72 years

CLL, CML, CHL, AML, ALL, APL López-

Valverde et al [33]

2019 Spain English Retrospective study

Sample size = 16,364, consisting of both males and females aged over 18 years

AML

Ali and Nurelhuda [34]

2019 Africa English Cross- sectional study

Sample size = 87, consisting of 53 males and 34 females aged between 0 and 6 years

ALL, AML

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24

Dodan et al. [35]

2001 Turkey English Cross- sectional study

Sample size = 85, consisting of 47 males and 38 females with a mean age of 7.8 years

ALL Lymp homa Mazaheri

et al [36]

2017 Iran English Case control Cross- sectional study

The control group consists of 32 healthy children

ALL

Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL).

As the characteristics table above shows that most of the studies that included pediatric cancer patients focused on only acute lymphoblastic leukemia (ALL) which is frequently found in most pediatric cancer patients. On the other hand, studies that included a combination of pediatric and adult population focused on all the four types of leukemia, including ALL, AML, CLL, and CML. Most of the studies were cross-sectional studies with a few being controlled-clinical trials and observational studies. Since there was no time limit followed while collecting the literature for the systematic review, the year of publication spanned from 1958 to 2021.

7.3 Evaluation of the quality methods and risk of bias

As mentioned in the material and methodology section, the Critical Appraisal Skills Program Espanol (CASPe) was followed for the assessment of the publication quality. Based on the CASPe methodology, the questions that were reviewed for evaluating the quality of the publications included the following:

1. What was the objective of the study?

2. What methodology and statistical tools were used for the study?

3. Were the participants “blind” to the intervention that was given?

4. Were the researchers evaluating or analyzing the outcomes “blinded”?

5. Were the investigators “blind” to the intervention that was given to the participants?

6. Did the authors consider the potential confounding factors in the analysis?

7. Did the researchers follow ethical approval procedures?

8. What were the findings of the studies?

9. What is the conclusion that researchers made out of the study outcomes?

10. What were the limitations of the study?

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The table below highlights detailed data addressing the questions 1,2,8,9,10 of CASPe.

Authors Study objectives

Methodology and statistical tools used

Study findings Conclusion Study limitations Hou GL,

et al [10]

Evaluate the oral

complications of leukemia at initial presentation.

A retrospective study design was followed with information related to age, gender, white blood cell and platelet counts at diagnosis, leukemia type, what are manifestations and symptoms at initial physical examination collected from the participants.

The study findings revealed that the incidence of leukemia is higher in male population than females.

The most common manifestations of leukemia at initial presentation are lymphadenopathy (71.4%

in ALL; 45% in AML), laryngeal pain (52.7% in ALL; 37.3% in AML), gingival bleeding (43.2% in AML; 28.6% in ALL), oral ulceration, and gingival enlargement..

Age prediliction and

prevalence of oral

manifestation have close connections with the leukemia type.

The researchers did not try to minimize the risk of bias and hence, selection bias and confirmation bias can remain within the study.

Kapoor G, et al [11]

Evaluate the oral hygiene status, gingival health status, and prevalence of dental caries, oral mucositis and xerostomia among children with leukemia and compare it with healthy children.

Evaluation of caries status using dmft/DMFT indices, oral hygiene status using OHI-S and plaque index by Sillness and Loe, gingival health status using modified gingival index, oral mucositis as per WHO oral toxicity scale, xerostomia as per common terminology criteria for adverse events for dry mouth, and salivary pH using pH paper strips was done.

The researchers used the Statistical Package for the Social Science-21 (SPSS Inc.,Chicago, IL), Descriptive statistics, including mean, standard deviation, and percentages for each of the variables, and Chi-square test and Student t-test. They determined the significance for all statistical tests at a probability value of .05 or less.

Findings showed a lower rate of dental caries, good oral hygiene and mild gingivitis in children with ALL compared to healthy children. Children with ALL were the only ones to suffer from oral mucositis, a reduced salivary flow rate and reduced salivary pH compared to healthy children.

The researchers concluded that children with ALL who underwent treatment and followed an oral care protocol experienced improvement in Oral Health Status when compared with healthy children.

The researchers did not try to minimize the risk of bias and hence, selection bias and confirmation bias can remain within the study.

Nasim VS, et al [12]

To evaluate the dental health status among children with ALL.

The researchers assessed the dental health status using a sterile mouth mirror. Based on WHO Oral Toxicity Scale, oral cavity was examined for enamel hypoplasia, dental caries, and oral mucositis. Gingival Status was recorded using Modified Gingival Index (MGI)7. Chi-square (c2) test and Kruskal-Wallis Test for statistical analysis.

The results showed moderate gingival inflammation in most of the children despite oral treatment. Children receiving cancer treatement suffered from tenderness on temporo mandibular joint, oral mucositis, and high DMFT values.

Cancer treatment deteriorated the oral health status of leukemic children who showed the symptoms of a moderate gingival inflammation despite receiving oral treatment.

Small sample size. The researchers did not try to minimize the risk of bias and hence, selection bias and confirmation bias can remain within the study.

Ashok L, et al [13]

To examine the existence of any correlation between the oral

manifestations

The researchers recorded the oral manifestations and radiographic changes (OPG).

They used ERBA ChemPro, semiautomated analyzer, and two reagents to estimate

A statistically significant difference for amylase levels (P<.05) was observed between the test and control groups. The test group showed a

Leukemic patients experienced a rise in salivary amylase and total protein

Small sample size. The researchers did not try to minimize the risk of bias and

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severity and the bony changes observed on orthopantomogr aph (OPG) with the salivary amylase and total protein in leukemia patients.

salivary total protein. The researchers used descriptive statistics and one-way ANOVA for statistical analysis.

number of oral problems, including showed pallor, gingivitis, gingival enlargement, petechiae, and ecchymosis.

levels, which deteriorated their oral health status.

hence, selection bias and confirmation bias can remain within the study.

Rinčić N, et al [14]

To evaluate periodontal conditions in patients with early stage CLL and to compare it with the periodontal status of age matched healthy controls, and to assess the correlation between periodontal and hematological parameters in CLL patients.

IBM SPSS Statistics version 17.0. was used for data analysis. Descriptive analysis was done by estimating arithmetic mean (M), standard deviation (SD) and range on continuous variables, while frequencies (f) and percentages (%) were estimated for categorical variables. Student’s t-test for continuous variables was used for estimating the significance of differences between CLL and control group, while Chi-Square test was used for categorical variables.

Results revealed that CLL patients had worse periodontal status than control healthy participants, even after eliminating the impact of age. The researchers found no statistically significant correlation between periodontal and

hematological parameters in CLL patients.

Patients with CLL had worse periodontal status than healthy control group.

Small sample size. The researchers did not try to minimize the risk of bias and hence, selection bias and confirmation bias can remain within the study.

Angst PDM, et al[15]

To evaluate the correlation between the Gingival Index and Bleeding on Probing with the platelet count in patients with leukemia.

Periodontal parameters, including PLI, GI, BOP, PPD and CAL, were evaluated at six sites per tooth

(mesiobuccal, midbuccal, distobuccal, distolingual, midlingual and mesiolingual), excluding third molars. All the oral tests were conducted in a dental office with the help of millimetric periodontal probe and a flat mirror.

Descriptive statistics was used to estimate the means and standard deviations of the respective variables.

Pearson’s correlation coefficient and SPSS software were used for data analysis.

The results showed no correlation between periodontal parameters, such as GI and BOP, and low platelet counts.

There exists no correlation between the low platelet count and the higher prevalence of gingival and periodontal bleeding in leukemic patients.

Small sample size could be a reason for the researchers to not find a correlation between the desired variables.

Parra, J.J. et al [16]

To assess the changes in the oral health status of children aged less than 14 years with ALL attending a cancer centre before and after chemotherapy treatment.

Silness and Löe plaque index (SLPI) were used for assessing bacterial plaque and gingival Löe and Silness index (GLSI) was used for assessing gingiva status. The severity of oral mucositis was evaluated by using WHO toxicity oral scale. The data analysis was done by using the McNemar’s test, t test, and Wilcoxon test.

Statistically signifcant diferences were observed in patients for palpable lymph nodes, paleness of oral mucosa, and ecchymoseis, with the symptoms manifestations of these oral problems decreasing substantially after treatment. Incipient gingivitis and salivary flow increased signifcantly after chemotherapy treatment.

Changes in the oral conditions were observed in all the patients after chemotherapy treatment.

Some symptoms decreased whereas some increased after treatment.

Small sample size. The researchers did not try to minimize the risk of bias and hence, selection bias and confirmation bias can remain within the study

Ponce- Torres, E. et al [17]

To determine the prevalence of oral manifestations in children with ALL receiving chemotherapy treatment, and

The OHI-S index was used to describe the oral health status and the IMPA index was used to describe periodontal conditions and to differentiate gingivitis from periodontitis.

Statistical analysis was

The results showed the prevalence of oral manifestations of gingivitis at 91.84%; caries at 81.63%; mucositis at 38.77%; periodontitis at 16.32%; cheilitis at 18.36%; recurrent herpes,

The leukemia type, gender, poor oral hygiene, and chemotherapy phase were risk factors for candidiasis,

Small sample size. The researchers did not try to minimize the risk of bias and hence, selection bias and

Prevalence of periodontal disease in patients with leukemia: a systematic review

Degree of DENTISTRY End of Degree Thesis

Year 2021-22