B-cell lymphoma

Lymphoma is a cancer of the White Blood Cells namely lymphocytes & their precursor cells which constitute the lymphatic system. Lymphoma is the most common blood cancer & the 3^rd most common cancer of childhood¹⁷. Both B cells and T cells can develop in to lymphomas and B cell lymphomas are more common than T cell Lymphomas³.

Two main types of lymphoma are Hodgkin & non Hodgkin lymphoma. Hodgkin disease first described by Thomas Hodgkin in 1832 is characterised histologically by the presence of multi nucleated Reed Sternberg cells. While consensus was rapidly reached on the classification of Hodgkin's lymphoma, there remained a large group of very different diseases requiring further classification. The Rappaport classification, proposed by Henry Rappaport in 1956 and 1966, became the first widely accepted classification of lymphomas other than Hodgkin's. Following its publication in 1982, the Working Formulation became the standard classification for this group of diseases. Of the more than 35 types of lymphomas, 30 are classified as non Hodgkin lymphomas (NHL). Diffuse large B cell lymphoma is an aggressive lymphoma & the most common of the NHL accounting for up to 30% of nearly diagnosed cases.

Nearly all NHL cases occur in adults with the average age of 50 – 60 years^4,14. NHL can arise in lymph nodes or up to 24 – 45 % extra nodal sites^2,13. Eg: GI tract , salivary glands , skin , bones. Infra bony lymphomas were first described by Parker & Jackson as “primary reticulum cell sarcoma of bone” in 1939⁸.

2 -3 % of the extra nodal cases may arise primarily in the oral cavity and jaws. Most common site for the NHL in oro-facial region is Waldeyer’s ring¹¹. Other than that oral mucosa, salivary glands, Paranasal sinuses, laryngeal tissue, osseus structures have been reported⁵.

NHL of bone is rare, representing only 5% of extra nodal lymphomas¹⁴. They arise from the medullary cavity & manifests as localised, solitary lesions. Jaw involvement by NHL is rare, but when it occurs maxilla is more frequently involved than mandible with a male: female ratio of approximately 3:2 showing a male predilection^{4, 14}. Mandible accounts for 0.6% of isolated

malignant NHL. Primary mandibular involvement makes up about 5% of all NHL of bone & accounts for 8% of all mandibular tumours⁴. To be classified as primary NHL of bone there must be no evidence of visceral or lymphatic involvement, no distant metastasis for at least of 6 months following diagnosis¹⁰.

Clinical presentation of mandibular NHL usually involves localised bone swelling, often anaesthesia or paraesthesia along distribution of the inferior alveolar nerve, tooth resorption or mobility, with or without pain^4,5,6,7. Paraesthesia along distribution of inferior alveolar nerve is common in NHL of the mandible with reports ranging from 20 – 100%⁹.

Diagnosis of NHL of the mandible is frequently delayed or erroneously diagnosed as dental disease because the clinical presentation mimics that of an odontogenic pathology or localised osteomyelitis.

There are no pathognomonic radiographic findings. Features are usually that of non specific osteolysis. Panoramic radiographs can show loss of cortical definition or widening of the mandibular canal, widening of the mental foramen, loss of lamina dura or widening of periodontal ligament¹⁶. Buccal or lingual cortical destruction is often found.

Typically symptoms are continued to persist in the face of attempted pharmacologic or dental therapies. This lead the biopsy specimen to a histopathologic evaluation together with immunophenotypic & cytogenic studies to elucidate the pattern of involvement & histologic type.

When the diagnosis is confirmed as NHL of the mandible, determination is made regarding origination & spread of the tumour. This workup should assess the extent of the disease & staging. Staging helps the physician to select appropriate treatment options and helps him/her to arrive at a prognosis, or estimate of disease outlook and survival. Clinical information is reviewed, including findings from the physical examination, blood tests, and imaging studies. Although laboratory studies are typically non specific, elevated Lactate dehydrogenase (LDH) is observed as a poor prognostic factor¹. The imaging studies most often employed are chest X-ray and computed tomographic (CT) scan of the chest, abdomen, and pelvis. Skeletal survey can be carried out if any presence of bone pain.

If the patient has non-Hodgkin's lymphoma (NHL), the physician may order additional tests such as blood tests that reflect kidney and liver function which are important factors in the choice of chemotherapeutic drugs, bone marrow aspiration/biopsy, and lumbar puncture.

As with many other cancers, NHL is categorized on the basis of tumour burden. The Ann Arbor Staging System is the most popular system for classifying NHL¹⁸.

The Ann Arbor Staging groups are as follows:

Stage 1: NHL is limited to one lymph node group (e.g., neck, underarm, groin, etc.) above or below the diaphragm, or NHL is in an organ or extra nodal. But has not spread to other organs or lymph nodes.

Stage 2: NHL is limited to two lymph node groups on the same side of the diaphragm, or NHL is limited to one extra nodal organ and has spread to one or more lymph node groups on the same side of the diaphragm.

Stage 3: NHL is in two lymph node groups, with/without partial involvement of an extranodal organ or site above and below the diaphragm.

Stage 4: NHL is extensive (diffuse) in one organ or site, with/without NHL in distant lymph nodes.

Additional Designations (applicable to any of the stages of HD or NHL):

A - absent symptoms.

B - Presence of any of the following B symptoms: fever (greater than 101.5°), drenching night sweats, unexplained weight loss of 10% or more within the last 6 months, severe itching

E - Involvement of a single extra nodal site that directly adjoins or is next to the known nodal group.

X - Presence of "bulky" disease, that is, a nodal mass whose greatest dimension is more than 10 centimetres in size, and/or a widening of the mediastinum by more than one-third.

CS - Clinical stage as obtained by doctor's examinations and tests.

PS - pathological stage as obtained by exploratory laparotomy with splenectomy.

The International Prognostic Index (IPI) was designed to further clarify lymphoma staging. The IPI predicts the risk of disease recurrence and overall survival by taking into account factors such as age, stage of disease, general health (also known as performance status), number of extranodal sites, and the presence or absence of an elevated serum enzyme named lactate dehydrogenase (LDH).

Table 1: International Prognostic Index Scoring¹⁸

Risk	IPI score	Complete response rate	Relapse – free 5yrs survival	Overall 5 yrs survival
Low	0 - 1	87%	70%	73%
Low- Intermediate	2	67%	50%	51%
High – Intermediate	3	55%	49%	43%
High	>4	44%	40%	26%

Table: 03

NHL can be treated with chemotherapy, radiotherapy & surgery in various combinations. NHL arising in the bone is best treated by chemotherapy & may not require radiotherapy. Survival is excellent in localised disease, whereas disseminated disease seems less favourable^3,12. Diffuse large B cell lymphoma advances very quickly, it requires immediate treatment. A combination of chemotherapy & monoclonal antibody therapy can lead to cure in large number of people with this form of lymphoma. If cure is not possible, treatment can often keep the disease away for several years.

The most commonly used chemotherapy is a mixture of drugs abbreviated CHOP (Cyclophosphamide, Doxorubicin, Vincristine & Prednisolone)¹⁷. Because of side effects of these drugs such as damaging healthy cells, neuro-sensory disturbances, loss of appetite, hair loss, mucositis medications to offset these effects are prescribed. These include Growth factors (G-CSF, GM-CSF) to protect against infection, Erythropoietin to prevent anaemia, anti emetic drugs.

Though Lymphomas of the mandible are rare, it must be considered in differential diagnosis of swellings arising in that region. Thus with the rising incidence of extra nodal lymphomas, it has become very important for present age dentists not to take any swellings of the orofacial region at “ face value “ but to properly investigate its pathology & treat it judiciously.

B-cell lymphoma

Lymphoma is a cancer of the White Blood Cells namely lymphocytes & their precursor cells which constitute the lymphatic system. Lymphoma is the most common blood cancer & the 3^rd most common cancer of childhood¹⁷. Both B cells and T cells can develop in to lymphomas and B cell lymphomas are more common than T cell Lymphomas³.

Two main types of lymphoma are Hodgkin & non Hodgkin lymphoma. Hodgkin disease first described by Thomas Hodgkin in 1832 is characterised histologically by the presence of multi nucleated Reed Sternberg cells. While consensus was rapidly reached on the classification of Hodgkin's lymphoma, there remained a large group of very different diseases requiring further classification. The Rappaport classification, proposed by Henry Rappaport in 1956 and 1966, became the first widely accepted classification of lymphomas other than Hodgkin's. Following its publication in 1982, the Working Formulation became the standard classification for this group of diseases. Of the more than 35 types of lymphomas, 30 are classified as non Hodgkin lymphomas (NHL). Diffuse large B cell lymphoma is an aggressive lymphoma & the most common of the NHL accounting for up to 30% of nearly diagnosed cases.

Nearly all NHL cases occur in adults with the average age of 50 – 60 years^4,14. NHL can arise in lymph nodes or up to 24 – 45 % extra nodal sites^2,13. Eg: GI tract , salivary glands , skin , bones. Infra bony lymphomas were first described by Parker & Jackson as “primary reticulum cell sarcoma of bone” in 1939⁸.

2 -3 % of the extra nodal cases may arise primarily in the oral cavity and jaws. Most common site for the NHL in oro-facial region is Waldeyer’s ring¹¹. Other than that oral mucosa, salivary glands, Paranasal sinuses, laryngeal tissue, osseus structures have been reported⁵.

NHL of bone is rare, representing only 5% of extra nodal lymphomas¹⁴. They arise from the medullary cavity & manifests as localised, solitary lesions. Jaw involvement by NHL is rare, but when it occurs maxilla is more frequently involved than mandible with a male: female ratio of approximately 3:2 showing a male predilection^{4, 14}. Mandible accounts for 0.6% of isolated

malignant NHL. Primary mandibular involvement makes up about 5% of all NHL of bone & accounts for 8% of all mandibular tumours⁴. To be classified as primary NHL of bone there must be no evidence of visceral or lymphatic involvement, no distant metastasis for at least of 6 months following diagnosis¹⁰.

Clinical presentation of mandibular NHL usually involves localised bone swelling, often anaesthesia or paraesthesia along distribution of the inferior alveolar nerve, tooth resorption or mobility, with or without pain^4,5,6,7. Paraesthesia along distribution of inferior alveolar nerve is common in NHL of the mandible with reports ranging from 20 – 100%⁹.

Diagnosis of NHL of the mandible is frequently delayed or erroneously diagnosed as dental disease because the clinical presentation mimics that of an odontogenic pathology or localised osteomyelitis.

There are no pathognomonic radiographic findings. Features are usually that of non specific osteolysis. Panoramic radiographs can show loss of cortical definition or widening of the mandibular canal, widening of the mental foramen, loss of lamina dura or widening of periodontal ligament¹⁶. Buccal or lingual cortical destruction is often found.

Typically symptoms are continued to persist in the face of attempted pharmacologic or dental therapies. This lead the biopsy specimen to a histopathologic evaluation together with immunophenotypic & cytogenic studies to elucidate the pattern of involvement & histologic type.

When the diagnosis is confirmed as NHL of the mandible, determination is made regarding origination & spread of the tumour. This workup should assess the extent of the disease & staging. Staging helps the physician to select appropriate treatment options and helps him/her to arrive at a prognosis, or estimate of disease outlook and survival. Clinical information is reviewed, including findings from the physical examination, blood tests, and imaging studies. Although laboratory studies are typically non specific, elevated Lactate dehydrogenase (LDH) is observed as a poor prognostic factor¹. The imaging studies most often employed are chest X-ray and computed tomographic (CT) scan of the chest, abdomen, and pelvis. Skeletal survey can be carried out if any presence of bone pain.

If the patient has non-Hodgkin's lymphoma (NHL), the physician may order additional tests such as blood tests that reflect kidney and liver function which are important factors in the choice of chemotherapeutic drugs, bone marrow aspiration/biopsy, and lumbar puncture.

As with many other cancers, NHL is categorized on the basis of tumour burden. The Ann Arbor Staging System is the most popular system for classifying NHL¹⁸.

The Ann Arbor Staging groups are as follows:

Stage 1: NHL is limited to one lymph node group (e.g., neck, underarm, groin, etc.) above or below the diaphragm, or NHL is in an organ or extra nodal. But has not spread to other organs or lymph nodes.

Stage 2: NHL is limited to two lymph node groups on the same side of the diaphragm, or NHL is limited to one extra nodal organ and has spread to one or more lymph node groups on the same side of the diaphragm.

Stage 3: NHL is in two lymph node groups, with/without partial involvement of an extranodal organ or site above and below the diaphragm.

Stage 4: NHL is extensive (diffuse) in one organ or site, with/without NHL in distant lymph nodes.

Additional Designations (applicable to any of the stages of HD or NHL):

A - absent symptoms.

B - Presence of any of the following B symptoms: fever (greater than 101.5°), drenching night sweats, unexplained weight loss of 10% or more within the last 6 months, severe itching

E - Involvement of a single extra nodal site that directly adjoins or is next to the known nodal group.

X - Presence of "bulky" disease, that is, a nodal mass whose greatest dimension is more than 10 centimetres in size, and/or a widening of the mediastinum by more than one-third.

CS - Clinical stage as obtained by doctor's examinations and tests.

PS - pathological stage as obtained by exploratory laparotomy with splenectomy.

The International Prognostic Index (IPI) was designed to further clarify lymphoma staging. The IPI predicts the risk of disease recurrence and overall survival by taking into account factors such as age, stage of disease, general health (also known as performance status), number of extranodal sites, and the presence or absence of an elevated serum enzyme named lactate dehydrogenase (LDH).

Table 1: International Prognostic Index Scoring¹⁸

Risk	IPI score	Complete response rate	Relapse – free 5yrs survival	Overall 5 yrs survival
Low	0 - 1	87%	70%	73%
Low- Intermediate	2	67%	50%	51%
High – Intermediate	3	55%	49%	43%
High	>4	44%	40%	26%

Table: 03

NHL can be treated with chemotherapy, radiotherapy & surgery in various combinations. NHL arising in the bone is best treated by chemotherapy & may not require radiotherapy. Survival is excellent in localised disease, whereas disseminated disease seems less favourable^3,12. Diffuse large B cell lymphoma advances very quickly, it requires immediate treatment. A combination of chemotherapy & monoclonal antibody therapy can lead to cure in large number of people with this form of lymphoma. If cure is not possible, treatment can often keep the disease away for several years.

The most commonly used chemotherapy is a mixture of drugs abbreviated CHOP (Cyclophosphamide, Doxorubicin, Vincristine & Prednisolone)¹⁷. Because of side effects of these drugs such as damaging healthy cells, neuro-sensory disturbances, loss of appetite, hair loss, mucositis medications to offset these effects are prescribed. These include Growth factors (G-CSF, GM-CSF) to protect against infection, Erythropoietin to prevent anaemia, anti emetic drugs.

Though Lymphomas of the mandible are rare, it must be considered in differential diagnosis of swellings arising in that region. Thus with the rising incidence of extra nodal lymphomas, it has become very important for present age dentists not to take any swellings of the orofacial region at “ face value “ but to properly investigate its pathology & treat it judiciously.

Effects of Radiotherapy on oral tissues

Introduction

Radiation

Radiation is defined as the transmission of energy through space and matter. Matter is anything that occupies space and has inertia. It has mass and can exert force or be acted on by a force. Matter occurs in three states-solid, liquid, and gas-and may be divided into elements and compounds.

Radiation occur in two forms

1. Particulate Radiation-Particulate radiation consists of atomic nuclei or subatomic particles moving at high velocity. Alpha particles,beta particles and cathode rays are examples of particulate radiation.
2. Electromagnetic Radiation-Electromagnetic radiation is the propagation of energy through space accompanied by electric and magnetic force fields.Eg: X-rays,Gamma rays

Electromagnetic radiation is generated when velocity of electrically charged particle is altered.both ionizing and non ionizing radiation is present in the electromagnetic spectrum.

Radiation Biology

Radiation biology is the study of the effects of ionizing radiation on the biological systems. The initial interaction between ionizing radiation and matter occurs at the level of the electron within the first 10^-13 second after exposure. These changes result in modification of biologic molecules within the ensuing seconds to hours. In turn, the molecular changes may lead to alterations in cells and organisms that persist for hours, decades, and possibly even generations. If enough cells are killed in an individual, it may cause injury or death. If cells are modified, such changes may lead to cancer or disorders in the descendents of the exposed individual.

Biologic effects of ionizing radiation may be divided into two broad categories:

1. Deterministic effects
2. Stochastic effects

Deterministic effects are those effects in which the severity of response is proportional to the dose. These effects, usually cell killing, occur in all people when the dose is large enough. Deterministic effects have a dose threshold below which the response is not seen. Examples of deterministic effects include oral changes after radiation therapy.

Stochastic effects are those for which the probability of the occurrence of change, rather than its severity, is dose dependent. Stochastic effects are all or none: either a person has or does not have the condition. For example radiation induced cancer is stochastic effect, because greater exposure of a person or population to radiaton increases the probability of cancer but not its severity. Stochastic effect are believed are not to have dose thresholds.

Radiotherapy

Radiation therapy, or radiotherapy also called radiation oncology, and sometimes abbreviated to XRT, is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis). Radiotherapy may be used for curative or adjuvant treatment. It is used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). Total body irradiation (TBI) is a radiotherapy technique used to prepare the body to receive a bone marrow transplant. Radiotherapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, prevention of keloid scar growth, and prevention of heterotopic ossification. The use of radiotherapy in non-malignant conditions is limited partly by worries about the risk of radiation-induced cancers.

Radiotherapy is used for the treatment of malignant cancer, and may used as a primary or adjuvant modality. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient.

Radiation therapy is commonly applied to the cancerous tumour. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumour, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumour to allow for uncertainties in daily set-up and internal tumour motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumour position.

To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumour), shaped radiation beams are aimed from several angles of exposure to intersect at the tumour, providing a much larger absorbed dose there than in the surrounding, healthy tissue.

Brachytherapy, in which a radiation source is placed inside or next to the area requiring treatment, is another form of radiation therapy that minimizes exposure to healthy tissue during procedures to treat cancers of the breast, prostate and other organs.

Mechanism of Action

Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly.

One of the major limitations of radiotherapy is that the cells of solid tumours become deficient in oxygen. Solid tumours can outgrow their blood supply, causing a low-oxygen state known as hypoxia. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumour cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Much research has been devoted to overcoming this problem including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine. There is also interest in the fact that high-LET (linear energy transfer) particles such as carbon or neon ions may have an antitumour effect which is less dependent of tumour oxygen because these particles act mostly via direct damage.

Dose

The amount of radiation used in radiation therapy is measured in gray (Gy), and varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy. Preventative (adjuvant) doses are typically around 45 - 60 Gy in 1.8 - 2 Gy fractions.

Fractionation

The total dose is fractionated (spread out over time) for several important reasons. Fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. Fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic (and therefore more radioresistant) may reoxygenate between fractions, improving the tumor cell kill. Fractionation regimes are individualised between different radiotherapy centres and even between individual doctors. In North America, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week. In some cancer types, prolongation of the fraction schedule over too long can allow for the tumor to begin repopulating, and for these tumor types, including head-and-neck and cervical squamous cell cancers, radiation treatment is preferably completed within a certain amount of time. For children, a typical fraction size may be 1.5 to 1.8 Gy per day, as smaller fraction sizes are associated with reduced incidence and severity of late-onset side effects in normal tissues.

Types of Radiotherapy

1. External beam radiotherapy

· Conventional external beam radiotherapy-Conventional external beam radiotherapy (2DXRT) is delivered via two-dimensional beams using linear accelerator machines. 2DXRT mainly consists of a single beam of radiation delivered to the patient from several directions: often front or back, and both sides.

· Stereotactic radiation-Stereotactic radiation is a specialized type of external beam radiation therapy. It uses focused radiation beams targeting a well-defined tumor using extremely detailed imaging scans. Radiation oncologists perform stereotactic treatments, often with the help of a neurosurgeon for tumors in the brain or spine.

· Virtual simulation, 3-dimensional conformal radiotherapy, and intensity-modulated radiotherapy-The planning of radiotherapy treatment has been revolutionized by the ability to delineate tumors and adjacent normal structures in three dimensions using specialized CT and/or MRI scanners and planning software.

· Particle therapy-In particle therapy (Proton therapy), energetic ionizing particles (protons or carbon ions) are directed at the target tumor.

2. Brachytherapy-Brachytherapy (internal radiotherapy) is delivered by placing radiation source(s) inside or next to the area requiring treatment. Brachytherapy is commonly used as an effective treatment for cervical,prostate,breast, and skin cancer and can also be used to treat tumours in many other body sites.

3. Radioisotope therapy-Systemic radioisotope therapy is a form of targeted therapy. Targeting can be due to the chemical properties of the isotope such as radioiodine which is specifically absorbed by the thyroid gland a thousandfold better than other bodily organs

Side effects of Radiotherapy

Radiation therapy is in itself painless. Many low-dose palliative treatments (for example, radiotherapy to bony metastases) cause minimal or no side effects, although short-term pain flare up can be experienced in the days following treatment due to oedema compressing nerves in the treated area. Treatment to higher doses causes varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and the patient.

Most side effects are predictable and expected. Side effects from radiation are usually limited to the area of the patient's body that is under treatment. One of the aims of modern radiotherapy is to reduce side effects to a minimum, and to help the patient to understand and to deal with those side effects which are unavoidable.

The main side effects reported are fatigue and skin irritation, like a mild to moderate sun burn. The fatigue often sets in during the middle of a course of treatment and can last for weeks after treatment ends. The skin irritation will also go away, but it may not be as elastic as it was before. Patients should ask their radiation oncologist or radiation oncology nurse about possible products and medications that can help with side effects.

Acute and Subacute Complications of Radiation Therapy

Acute reactions are those which arise during or shortly after radiation therapy and resolve within ninety days post-therapy.

Mucositis

One of the first symptoms of radiation complications is mucositis ,which occurs 12- 17 days after the initiation of therapy. Mucosal inflammation varies with dosage, target size and duration of therapy. Oral mucositis can present as patchy mild erythema to frank confluent ulceration. Chemotherapeutic agents such as 5FU, procarbazine, methotrexate, etc., may increase the severity of these symptoms. Currently, there are no drugs available to prevent mucositis, and it is imperative to distinguish these lesions from those caused by infections. Cultures may be needed to differentiate between fungal, bacterial and viral lesions versus those secondary to radiation effects.

Prevention, on the part of the Radiation Oncologist is essential to minimizing excessive morbidity of the oral mucosa . This is accomplished by designing portals that limit the exposure to tissues not at risk for tumor reoccurrence. When interstitial implants are a part of a treatment protocol, soft tissues of the oropharynx are at greater risk for developing soft tissue ulcerations. Mucosa thickness, another important predictor of exaggerated tissue response, should be considered. The anterior commisures of the mouth and the medial surface of the angle of the mandible are sites which contain very thin mucosa and would benefit from field blocks if possible.

Lack of saliva and damaged taste buds may alter the sensation of taste during radiotherapy. Often, patients complain that many foods taste excessively salty which may reduce the motivation for adequate oral intake. In response to their altered taste sensation, patients tend to compensate by increasing their intake of sugar. Counseling should be provided to avoid this behavior due to the increased risk of dental caries. However, altered taste sensorium is a transient phenomenon since the taste buds recover in two to four months post therapy.

Mechanisms of damage to the Oral Mucosa

The mucosa joins the skin and the lining of the digestive tract to form a barrier against microorganisms that protects the deeper organs and tissues.The oropharyngeal mucosa, covered by nonstratified squamous epithelium, is composed of endothelium and connective tissue. Stem cells, which form the basement membrane of the endothelium in the oropharyngeal cavity, replicate and differentiate to form layers of mucosal cells that compose the lining.

The oropharyngeal mucosa has a very high cell turnover rate. These self-renewing cells live for approximately 3 to 5 days, resulting in replacement of the lining every 7 to 14 days.This rapid course of cellular proliferation and constant epithelial replacement renders the mucosa vulnerable to the cytotoxic effects of radiation. The atrophic changes in the epithelium of the oral membrane usually occur at a total dose level of 1600 to 2200 cGy when radiation is administered at a rate of 200 cGy per day.

Acute mucositis is the result of hypoplasia and destruction of the squamous epithelium, sterilization of mucosal stem cells, inhibited proliferation of transit cells, and absence of cell regeneration. Oral mucositis is compounded by high-dose radiation to tooth-bearing bone that results in hypoxia and reduces the vascular supply to the bone and soft tissues, causing vascular thromboses and fibrosis. Head and neck irradiation not only can cause ulcerative oral mucositis clinically similar to that caused by high-dose chemotherapy, but also can induce damage that results in permanent dysfunction of the vasculature, connective tissue, salivary glands, muscle, and bone.

Management

Many untested topical oral preparations can reduce symptoms of oral mucositis. Efficacy and safety of these agents has not been established. Currently accepted elixirs include a combination of Benadryl, Kaopectate, MOM, antacids, sucralfate, corticosteroids, dyclonine, and viscous lidocaine. If pain is severe enough to limit eating, systemic analgesia should be considered. Extremes in mucosal inflammation which demonstrate confluent lesions may warrant a treatment break to allow tissues to continue therapy. However, cessation in treatment can be dangerous by allowing rapid repopulation of tumor cells during breaks in therapy. Commercial mouth rinses should be avoided. The alcohol and phenols contained in these preparations may further dehydrate the mucosa causing further pain. Chlorhexidine should be continued during radiation therapy and may be diluted for tolerance.

Xerostomia

Local and total body irradiation may irreversibly affect the production and quality of saliva in the major and minor salivary glands. Doses as low as 20 Gy will result in clinically noticeable changes such as sparse thick ropy saliva. In particular, if the parotid glands are in a field which received 40Gy or over, permanent dysfunction of the salivary glands should be expected and discussed with the patient prior to treatment. Concomitant administration of medications which are known to induce xerostomia (i.e. psychotropics, antiemitics, antihistamines, and thousands of other commonly prescribed medications.) should be carefully considered.

The diagnosis of xerostomia is based on subjective impressions by the patient and the clinician. Dry mouth may affect speech, taste, nutrition and the patients ability to wear a prosthesis. Saliva also contains antimicrobial compounds (i.e. sIgA, and mucins) which reduce pathogenic bacteria and decrease the risk of infection in the oropharynx . However, saliva's most important role lies in its ability to mechanically cleanse the teeth and soft tissues. Therefore, with radiation induced xerostomia it is common for this to lead to an increased incidence of caries, especially in the cervical portion of the clinical crown at the cementoenamel junction. Similarly, the change in salivary content and quantity also leads to an increased incidence of candidiasis and periodontal disease.

Mechanism of Salivary Glands damage

Ionizing radiation to the regions of the oral mucosa causes not only specific histologic and physiologic changes, but also structural and functional alterations in the underlying supportive tissues including the salivary glands and bones. Saliva and mucus produced by the salivary glands protect the mucous membranes and teeth, lubricate the food bolus, and facilitate eating and speaking. Saliva has additional protective roles in the regulation of acidity and in antimicrobial defense through the action of immunoglobulin and nonimmunoglobulin glycoproteins.

Salivary secretions decrease dramatically in the irradiated field, especially when that field includes the parotid and submandibular glands.Acinar and ductal cells in the salivary glands degenerate, and the normal cellular arrangement is replaced by ductal remnants and loose fibrous connective tissue that is infiltrated moderately with lymphocytes and plasma cells.

Generally, there is a direct relation between the changes in saliva and the extent of glandular changes. The decline in saliva reflects radiation-provoked inflammatory and degenerative changes in the acinar cells of the salivary glands. A decrease in free-flowing saliva is followed by the accumulation of sticky mucus because the acini of the serous glands are affected more than the acini of the mucus glands.

The severity of xerostomia is related directly to the dosage of radiation. At a total dose of approximately 3000 cGy, damage to the salivary glands occurs and causes viscous saliva. Radiation-induced xerostomia is rapid in onset, with a decrease in saliva greater than 50% after 1 week of RT at an approximate total dose of 2000 cGy, and a decline in saliva greater than 75% after 6 weeks of RT at a total dose of 6000 cGy. With a dose less than 6000 cGy, changes in the salivary glands, including edema and inflammation, are reversible. When the dose exceeds 6000 cGy, changes may be permanent, with fibrosis and glandular degeneration. Xerostomia is progressive, persistent, and irreversible, producing a reduction in saliva output greater than 95% 3 years after RT.

The sensitivity of the various salivary glands located in different areas of the mouth is related to this initial shift in saliva quality. For example, the change initially affects the parotid glands more than the mucous glands. The result is an abundance of thick mucus. In addition, if the irradiated portals are located over the parotid and submandibular glands, xerostomia eventually becomes severe. Because of the diminished lubricating ability of the saliva, patients often lose all desire for food, which intensifies the vicious cycle of nutritional deficiency. Bäckström et al reported that patients with a low saliva secretion rate produced by RT had a significant decrease in daily caloric intake.

Changes in Saliva Quality

The changes in saliva quality associated with RT include a decline in the production of glycoproteins and a decrease in salivary pH. Radiation therapy-induced damage to the salivary glands decreases the production of antibodies and antibacterial agents and limits the binding ability of large salivary glycoproteins (eg, immunoglobulin A) to the surface of the oral mucosa. Glycoproteins reduce the adhesion of microorganisms to the oral mucosa and serve as a protective barrier for the superficial cells in the oral cavity. The absence of the glycoproteins' protective properties renders the epithelial cells more vulnerable to irritation and trauma.

Normally, the saliva maintains the homeostasis of the acid-base balance that inhibits some opportunistic infections. The pH of saliva, which normally is between 6.8 and 7.0, may fall below 5.5 during RT. Alterations in the various components of saliva and decreased salivary flow inhibit the protective effects of saliva. Therefore, mucositis often is aggravated by infectious ulceration.

Management

Management for xerostomia is directed at several levels. First, addressing the patients chief complaint of chronic dry mouth, treatment is generally palliative--utilizing artificial saliva, carrying water bottles for periodic mouth moistening. Salivary substitutes are available in two types. All contain electrolytes commonly found in saliva including those normally used for remineralization and should be used in dentate patients. The other solutions contain dextrans which should be reserved for edentulous patients so as not to raise the caries index. Sialogogues (pilocarpine) may also be used to stimulate saliva formation if residual salivary tissue remains. These drugs alleviate many of the problems encountered during therapy.

However, the critical aspect in managing head and neck irradiated patients with xerostomia is controlling the risks for oral diseases. Therefore, initiation of meticulous oral hygiene regimens including topical fluoride trays , chlorhexidine rinses, and regular dental hygiene therapy sessions are required. In addition, dietary advice is recommended to reduce the intake of carogenic foods.

Candidiasis

Another acute effect commonly associated with mucositis is oral candidiasis. Colonization of the yeast on damaged tissue can intensify the symptomatic effects of radiation on the mucosa.

The practitioner should be aware of the multiple presentation of candida including pseudomembranous (removable white plaques with an erythematous base), chronic hyperplastic (leukoplakia like plaques that do not wipe away), and chronic cheilitis. These infections should be eliminated to decrease mucositis and the chance of distant gastrointestinal infections.

Management

Management of patients with oral pharyngeal candidasis include both topical and systemic approaches. Historically, nystatin topical solution have been used with mixed efficacy. Patients involved in this therapy should be advised that the solution must be refrigerated at all times or the solution will become inactivated. Other topical solutions include clotrimazole troche which is recommended for edentulous patients and angular cheilitis. However, this medication should be avoided by the dentulous patient for caries control, due to its high sugar content. Currently, the best medication for oral or systemic candidiasis is Diflucan. The treatment regimen includes a 200mg loading dose the first day, followed by a 100mg /day dose for the remaining thirteen days. However, it is imperative that the physician obtain liver function tests prior to initiation of treatment because of the potential toxic side effects on the liver.

Bacterial Infections

Local infections can lead to sialadenitis, periodonditis, abscesses, pericoronitis, or other causes of ulceration. Emperic treatment with antibiotics are usually adequate; however, periodontal lesions usually need additional debridement. The oral cavity may be the portal of entry for systemic infections. Therefore, chlorhexadine rinses should be considered for these patients.

Bleeding

Gingival bleeding may be the first sign of thrombocytopenia. The patients' ability to accomplish adequate oral hygiene may be limited. In these instances flossing may have to be discontinued . Again chlorhexadine rinses may be required to reduce pathogens found in plaque.

Chronic Complications of Radiation Therapy

Osteoradionecrosis

Certainly one of the most devastating complication of radiation therapy to the head and neck is the development of osteonecrosis of the mandible. Long term effects of radiation therapy on osseous and soft tissues is soft tissue fibrosis and ischemia, which may never resolve. The main mechanism of osseous involvement is injury which occurs to the small vasculature of the Haversian canals and the periosteal tissue. Fortunately, osteonecrosis is a relatively uncommon complication, with an incidence ranging from less than two percent to as high as 10%. This range in incidence varies with total dose administered to the mandible. (i.e. greater than 70 Gy yielding the larger number) Another compounding factor is location of the primary tumor. If the lesion is large and is situated at the floor of mouth the rate of osteonecrosis more than doubles to 25%. Due to the decrease in healing capacity of the tissues from decreases in blood supply, infections to the jaw are devastating. The major etiologies are extraction of failed dentition after radiation therapy. Therefore, posterior mandibular teeth may be planned for extraction if more than 6,000 rads are expected in that field.

Great importance should be placed on pretreatment evaluation of all remaining dentition. Any questionable teeth that cannot be adequately maintained for years should be extracted. A period of two weeks prior to radiation therapy is advised for adequate healing of extraction sites. All preprosthetic surgery required, should be performed prior to the initiation of radiation therapy.

Management

Occasionally systemic antibiotics will be required if osteoradionecrosis develops. Technically it is not an infection of bone but rather a nonhealing hypoxic wound. Systemic antibiotics are of limited value to the mandible itself due to the decreased vasculature and subsequent poor drug delivery to the site. However, in secondary infections they may have a role in preventing the spread of infection. No attempt should be made initially to obtain primary soft tissue closure of bone, since most wounds less than 1 cm or less will heal in weeks to months without surgical intervention other than removing sequestrum. For large defects in the jaw, surgery will be required with osseous and soft tissue reconstruction with the aide of preoperative and postoperative hyperbaric oxygen.

The role of hyperbaric oxygen has greatly enhanced the ability to reconstruct patients with osteoradionecrosis with large boney and soft tissue defects. However, the cost is tremendous and access to treatment is limited. Additionally it is felt that patients with active malignancies should not be exposed to HBO for fear that it can accelerate the repopulation process. The mechanism of action appears to be supporting neovascularization within tissues ,increasing the oxygen tension . The protocol is 20 pre- surgical hyperbaric oxygen (HBO) sessions, each consisting of 90 minutes of 2.4 atm of absolute pressure/day x five days /week. After the reconstructive surgery, an additional ten treatments is prescribed to ensure adequate vascularization of the grafted bone and soft tissue.

Soft Tissue Necrosis

The primary etiologies for this type of chronic complication are due to excessive doses delivered to the tissues via interstitial implants or secondary to soft tissue irritation from an inadequate fitting prosthesis. If the patient can tolerate being edentulous, it is recommended for the first six months post-therapy to allow for adequate healing and remodeling of bone. Occasionally it is required to administer HBO and antibiotics to alleviate the necrotic tissue.

Trismus

This condition is secondary to fibrosis which occurs in the muscles of mastication after being within the field of radiation. Best management is to encourage physical therapy during and after the radiation is administered. This feature can also be an important factor for adequate oral hygiene if the patient is unable to open the mouth for proper dental care.

Suggestions for the Edentulous Patients

Proper fitting of prostheses is essential, discrepancies can result in ulcers which may lead to osteoradionecrosis. New dentures should be constructed only after adequate healing time; in the interim, soft tissue liners may be used. Chlorhexidine two times a day until salivary function returns can be used to keep the mouth clean. Salivary analogues may also be used to increase retention of the dentures.

Candida is often a problem and antifungals should be used. These drugs may be added into tissue conditioners or placed where needed. Dentures should be removed and cleaned every night. At first sign of discomfort, the denture should be removed, adjusted or relined. It is extremely important not to have soft tissue ulcerations, because the risk of osteoradionecrosis is a life-long threat.

Other effects of radiotherapy to Head and Neck region

Radiation induced dental caries

As mentioned earlier, radiation may permanently alter the quality and quantity of salivary flow. Saliva plays an integral role in the prevention of dental caries. Without its protective action, the cariogenic oral bacteria are permitted to colonize the teeth unchecked. In the absence of a strict and meticulous preventive hygiene regimen, rampant caries typically results. Carious lesions may begin to appear within three months of radiation therapy and proceed rapidly to devastate the dentition. The key to managing this problem is prevention. As will be discussed later, a regimen of strict oral hygiene, daily fluoride application, carbohydrate restriction and frequent dental follow up are essential.

Abnormal Development of the Dentition

Tooth development begins at four months in utero and continues until early adolescence when the permanent teeth complete their formation. As with many other tissues, radiation has the potential to interfere with normal growth and maturation of the developing dentition. The severity of malformation is dependent on the stage of development at which the teeth are irradiated and the total dose received. Abnormal development in humans has been observed with a total dose as low as 400 cGy.1 Dental abnormalities include crown and root dwarfism, root shortening, incomplete calcification, abnormal curvature of the roots, delayed or arrested eruption, and ankylosis of primary teeth. Shortened roots may lead to inadequate anchorage of the teeth in the supporting bone with subsequent loosening , increased susceptibility and involvement with periodontal disease, and early tooth loss. Ankylosis of primary teeth as well as delayed or abnormal eruption of permanent teeth may lead to significant malocclusion. These problems may require substantial efforts by the general dentist in conjunction with other specialists to restore adequate form and function to the dentition.

Abnormal Facial Development

In the same vein as disturbed dental development, the structures of the facial complex, which are also actively developing in the child, may also be adversely affected by radiation therapy. These changes are secondary to radiation effects on cartilagenous growth centers. These areas are located, for the mandible, in the condyles, and for the maxilla, in the sutural growth centers. Higher radiation doses on the order of 6000-7000 cGy are associated with disturbances of facial growth and associated malformations. The child with these growth disturbances may develop micrognathia, maxillary deficiency, retrognathia, skeletal and dental malocclusion as well as other abnormalities in the facial complex. The management of those long term survivors who manifest these complications involves a team approach involving the dentist, orthodontist, oral and maxillofacial surgeon as part of rehabilitation.

Oral changes following Radiotherapy to paediatric patient

The advent of chemotherapy and radiotherapy as treatment modalities for pediatric malignancies has produced a significant increase in cure rates for many of these cancers. However, along with the increased success of treatment with these modalities comes a potential for multiple organ system morbidity that may last the lifetime of the patient. These modalities have found their niche in the treatment of head and neck cancers, and as such, many of these pediatric patients will survive into adulthood. With this increased survival there is an increased potential to develop significant long term complications within the treatment fields. It is therefore imperative that the health care team be familiar with not only the potential complications of therapy, but also their prevention, recognition and management.

Oral complications of radiotherapy are usually the result of the direct effects of radiation on the oral tissues. The tissues most frequently affected are the mucosa, salivary glands and mineralized tissues.

Possible Changes That You May See In Your Child's Mouth During Radiation Therapy

Early changes

Mucositis: This is a reaction of the skin inside the mouth to radiation. It typically occurs within the first two weeks of treatment. Your child's mouth will become reddened and quite sore. There may even develop ulcerations throughout the mouth with severe discomfort. This reaction usually resolves completely 2-3 weeks after the cessation of therapy. The soreness of the mouth may make it difficult for your child to speak, swallow or eat. However, it is very important that your child continue to take fluid and food to maintain hydration and nutrition for proper healing. Your doctor or dentist may be able to prescribe anesthetic mouth rinses to soothe the soreness and make eating and drinking easier.

Dry Mouth: If the glands that produce saliva have been included in the area to be treated, your child may develop a dry mouth. Depending on the degree of involvement of the glands, the dry mouth may be mild to severe, and may partially return or be permanent. This too may be uncomfortable for your child and make eating difficult. It may be necessary to take frequent sips of fluids (such as water or milk) with each bite of food, as well as take smaller bites, in order to properly moisten and allow easier swallowing. There are man made saliva substitutes available that may ease the discomfort of a dry mouth and make eating and speech easier.

Late changes

Tooth Decay: Saliva is an important part of the body's mechanism for preventing tooth decay. As mentioned above, radiation therapy can cause a permanent decrease in the amount of saliva produced. This, in turn, can lead to an increased rate of tooth decay in your child's mouth. It is therefore very important to follow your dentist's recommendations on oral hygiene during radiation therapy. Brushing and flossing of the teeth to remove plaque and tartar is crucial to minimizing the risk of severe tooth decay and early tooth loss. Fluoride tooth paste should be used with a soft tooth brush. In addition, fluoride gels in custom trays supplied by your dentist should be used daily according to your dentist's recommendations. Any cavities or tooth aches should be brought to the attention of your dentist right away to avoid unnecessary loss of teeth due to decay. Finally, it is very important to keep your regularly scheduled check up appointments with your dentist so that any problems or concerns may be addressed.

Abnormal Eruption of Adult Teeth:Radiation therapy that involves the head and neck has affects on the developing adult teeth that lie within the jawbone. These affects include delayed eruption (the teeth will come into the mouth later than normal), eruption of teeth in an abnormal alignment (teeth may be crooked), or fusion of the baby teeth in the jaw bone preventing the adult teeth from erupting. These abnormalities can also be corrected, most times, with orthodontics and/or oral surgery.

Abnormal Facial Development:Radiation can also effect the areas of active growth, called growth centers, in the jaws and facial region. If these areas are in the area being treated by radiation, it is possible that future growth of the jaws and/or face may be delayed or disturbed. This altered growth may result in a small jaw with a poor bite, or an altered facial appearance later in life. However, many of the resultant deformities can be adequately corrected through a combination of orthodontic and/or oral surgical procedures.

Difficulty Opening the Mouth:The muscles that open and close the mouth may lie within the area to be treated with radiation. If so, they may be affected and undergo changes which make it difficult to open the mouth, called trismus. This may require a substantial amount of time to occur, even after treatment has stopped, and may develop gradually, making it difficult to notice. This is another reason to make sure you keep your follow up visits with your radiation oncologist and dentist even though treatment may be completed.