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Non-Hodgkin’s lymphoma: symptoms and treatment

Non-Hodgkin’s lymphoma

Lymphomas arise from malignant clones of lymphocytes. Lymphocytes are a normal part of the peripheral blood population of circulating white cells and normally serve the functions of immune protection and inflammatory responses to foreign (or self) antigens. They are derived from progenitor cells in the bone marrow and the lymph nodes.


Lymphocytes are classified into B and T cells. Originally this classification was because the T cells derived from a Thymic origin, whereas the B cells came from an origin in the gut mesentery, which in the chicken was termed the Bursa of Fabricious.

The two groups of lymphocytes normally sub-serve different lymphocyte functions.


Lymphomas are classified into those arising from B or T lymphocytes but this is only part of a very complex classification system.


Nowadays the origins of the cells and the identification of different subsets of lymphoma has become much more complicated and the consequence is  that the term non-Hodgkin lymphoma encompasses a  very large and heterogenous spectrum of diseases, many of which are not described here in detail.


Incidence of Non-Hodgkin's lymphoma

The incidence of non-Hodgkin lymphoma across the world is approximately one case per 10,000 of the adult population. However, there are higher incidences in certain societies and amongst those who are predisposed. 


Symptoms of Non-Hodgkin’s lymphoma

Presenting clinical features/ what brings the patient to the doctor. The majority of patients present with an enlargement of lymph node groups, for example the enlargement of nodes in the neck. Such presentations are usually as the painless development of the lumps, which the patient soon realises are abnormal.


In low grade NHL the development of these nodal lumps is slow and insidious but in high grade tumours the growth may be fast and very worrying to the patient. Occasionally, the lymph nodes develop deep inside the patient; for example, a lymph node mass in the chest may remain silent (i.e. un-noticed by the patient) until it presses on the wind-pipe and then the patient comes urgently to the doctor because he has difficulty in breathing.


Sometimes, the nodal mass may be in the abdomen and disturbance of bowel function may cause the presenting symptom.


 Sometimes the NHL occurs outside the lymph nodes and the thyroid has already been cited above and is a good example. Others include primary stomach NHL, conjunctival or even intra-ocular NHL and primary brain NHL is a rare form (although commoner in kidney transplant recipients). In the preceding section, there is a photo of a lymphoma arising on the skin of the eyelid.


In patients with a large bulk of lymphoma in their bodies, there may be significant weight loss or sweating (the so-called 'B' symptoms).


Treatment of Non-Hodgkin’s lymphoma

For localised (stage 1) disease and for low grade histology disease, then regional radiotherapy to the affected lymph node region may be recommended, followed by a careful watch policy. Perhaps 50% of stage 1 low grade cases can be cured by such therapy; for the rest, there is no prejudice to their long term survival by adopting a watch policy rather than an ‘up front’ chemotherapy policy, so long as they are carefully followed such that any relapse is picked up early and appropriate chemotherapy introduced then.


The situation is different in the higher grade histology, stage 1, NHL patients; here, there is a higher overall cure rate if several cycles of chemotherapy are delivered before radiotherapy to the site of origin of the NHL. The difference is that short course (multi-agent) chemotherapy used first is this situation for high grade NHL lowers the late relapse rate and thereby increases the overall cure rate. Even though radiotherapy alone may cure up to 60% of cases without any chemotherapy at all, a short course of primary chemotherapy is recommended to all patients fit enough to undergo this.


This difference between the policy for stage 1, low grade and high grade NHL is worth stressing: take low grade follicular lymphoma, for example; here, any up front chemotherapy seems to delay relapse but not stop it and therefore primary chemotherapy in this low grade NHL does not increase overall survival. This is in contrast to that for stage 1 high grade NHL.


For higher stage disease (either high or low grade disease) the emphasis moves heavily towards chemotherapy. In low grade disease, there is the difficulty already mentioned that it is very difficult to eradicate the disease completely. In such low grade NHL, it is customary to start therapy with simple chemotherapy (e.g. chlorambucil in tablet form and as a single cytotoxic drug). If chlorambucil causes the disease to go into remission then there is no better therapy and the patient certainly has least side effects from this well tolerated therapy. If the disease does not remit on this simple drug, then the doctor uses a combination of intravenously administered drugs (of drug regimens by the acronyms: COP and even CHOP) are used. A newer single agent intravenopusly administered drug that is certainly active in many non-responders to chlorambucil is fludarabine.


Many of these low grade NHL cases have demonstrated CD 20 positivity (see section on immunophenotyping above) on their original biopsy specimen and this has allowed the clinically useful development of a humanised monoclonal antibody directed at this antigenic (immunoglobulin light chain) determinant and this drug (trastuzumab/rituximab) is now combined with chemotherapy in poor responding low grade NHL disease where the original biopsy histology demonstrated CD 20 positivity.


It is in the nature of uncured, low grade NHL to have a relapsing and remitting course; at first, it is relatively easy to put the disease into remission and then there follows a period of observation, which may be into years. Then the second time around it may be slightly more difficult to achieve as long a remission and so on and so forth until it eventually becomes impossible to achieve a further remission using conventional therapy.


Everything happens quicker in high grade lymphomas and it is essential to use multiple cytotoxic drugs, in combinations, in high stage disease to have any chance of cure. The drug regimens are often called by the acronym of the first letters of the constituent drugs, thus CHOP (Cyclophosphamide, Hydroxydaunorubicin- also called adriamycin or doxorubicin, Oncovin – also called vincristine and Prednisolone).


The drug courses are delivered by intravenous injection as close together as possible; this implies that as soon as the blood count has recovered from one course of chemotherapy the next is delivered; by this way, a progressively cumulative cell kill is affected on the lymphoma but the normal bone marrow is allowed to recover between courses. Using most of these chemotherapy regimens, the normal bone marrow has recovered the damage of one chemotherapy course by day 18 to 21 after drug delivery and therefore it is often found that chemotherapy is delivered at 21 day intervals.


For high stage and high grade NHL, it is customary to deliver three course of such chemotherapy and then re-asses the state of the disease; thus, if there was bone marrow disease at presentation and evidence of lymph nodal enlargement in the neck and chest (on CT scanning at presentation) then these sites would be restaged by repeating the initial staging tests after the third course of chemotherapy. Where the response is good (the majority of cases) then the same chemotherapy regimen is continued for a further three course or so. The aforementioned CHOP regimen is still the favoured regime for most high grade lymphoma patients, although some young patients with T cell lymphoblastic lymphoma are treated with an acute lymphoblastic leukaemia regimen. Approximately 60% of all patients will go into remission with CHOP type chemotherapy and two thirds of these are cured, giving an overall 40% cure rate in rough and ready statistics.


Where the response after three courses of first line chemotherapy is inadequate, then the chemotherapy is changed to an alternative drug regimen. If there was an initial very large bulk of NHL at one site or one such site was slow to go into remission, then the doctor may recommend radiotherapy to this region. However, the place of radiotherapy in higher stage patients is very limited.


Following completion of the chemotherapy course and in patients who remit ‘completely’, the patients are carefully observed with particular regard to the sites of initial disease (i.e. at presentation). Most high grade NHL patients who relapse will do so in the first two years off therapy and so follow up is concentrated on these first two years and thereafter the intervals between out-patient attendances will increase.


In high risk patients who remit with difficulty or are perceived to be at high risk of relapse despite achieving first time complete remission (i.e. a high IPI - International Prognostic Index) high dose therapy (or even a regimen that includes a high dose of total body irradiation) and some form of bone marrow rescue or transplant (i.e. a peripheral blood stem cell [PBSC] auto-transplant or an allogeneic - that is from another individual with similar tissue typing antigen profile - bone marrow transplant). In fact, the evidence of allogeneic transplant in first remission is very weak to non-existent for NHL patients (and carries considerable risks) and the evidence in favour of high dose chemotherapy and an autologous procedure in these patients should still be considered a research procedure, although some data do look persuasive for very high risk patients at presentation (e.g. T cell lymphoblastic lymphoma) who get into first time remission.


It is worth stressing that there is no place for an attempt at high dose chemotherapy and rescue/transplant in patients who have failed to get into remission or are in overt relapse and show no signs of remitting on conventional therapy; the use of this higher risk therapy in this situation is fraught with risk and is not attended by a cure rate that justifies these risks. High dose therapy with rescue/transplant is only useful for patients who are still chemosensitive and have been ‘debulked’ maximally by conventional chemotherapy (i.e. have minimal residual tumour burden).



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