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.