Lymphoma

Dr Tom Leach

8 years ago

Introduction

Lymphoma is a type of cancer that affects the lymphatic system – and occurs when lymphocytes proliferate abnormally.

Lymphoma be divided into two types; Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Hodgkin lymphoma is a single disease (albeit divided into two main types) and generally carries a better prognosis than non-Hodgkin’s lymphoma. Non-Hodgkin lymphoma is an umbrella term over 60 different types of lymphoma – with variable prognosis – although on average the prognosis is generally worse than for Hodgkin’s lymphoma.

Lymphoid leukaemias also exist, and the distinction between these and leukaemia – especially chronic lymphocytic leukaemia – can be difficult.

It may present with a firm, tender, swollen lymph node. Sites where lymph nodes can be easily examined include the beach, air pits and groin. Other symptoms can often be non-specific but can include:

Fever
Night sweats
Weight loss
Reduced appetite
Fatigue

Lymph node sites commonly affected by lymphoma

The causes are not well understood, but there is an increased risk of lymphoma in those with previous mononucleosis (glandular fever), a family history of lymphoma, or who are immunosuppressed.

Diagnosis is usually made with a combination of blood tests and biopsy of an affected lymph node. After he diagnosis is made, imaging such as CT, MRI or PET scanning may be performed for staging. The treatment depends on the exact type and stage of disease but might typically include radiotherapy +/- chemotherapy. In recent years immunotherapy treatments have also become more common. Occasionally stem cell transplants are used. Treatment may often be curative – especially in Hodgkin’s lymphoma and / or in earlier stage of the disease.

Hodgkin’s Lymphoma

Hodgkins lymphoma is a malignancy of lymphocytes – characterised by the presence of Reed-Sternberg cells on histology. There are two main types; classical Hodgkin lymphoma and Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). NHPHL is much more rare than the classical type and does not have Reed-Sternberg cells. It can transform into Non-Hodgkin lymphoma and is treated differently to the classical type. The rest of this section discusses classical Hodgkin lymphoma unless otherwise specified.

Epidemiology

Hodgkin’s lymphoma is rare; incidence is 2.5-4 per 100 000
Male: female is 1.5:1
Peak incidence is in the 3^rd decade, and there is a second peak between around the age of 70
The incidence is stable

Aetiology

There is some evidence linking this disease to mononucleosis infections. These are infections of the monocytes of the blood, and the term is an umbrella term, basically for EBV and CMV

Up to 40% of patients have increased EBV antibodies at the time of diagnosis, and for several years prior to the development of clinical HL.
50% of cases have EBV found in the Reed-Sternberg cells
In the case of HL, CMV is not thought to be involved
The risk is 3x greater if you have a previous mononucleosis infection
Hodgkin’s lymphoma is more common in people from small families and well-educated backgrounds

Pathology

The hallmark cell of HL is the Reed-sternberg cell (aka lacunar histiocytes). These are giant malignant cells seen on light microscopy. They have multi nuclei, and are often referred to being ‘owl like’. They are most commonly derived from germinal centre B cells, but can also come from peripheral T cells (rarely).
CD15 and CD30 antigens are almost always expressed on these cells in HL.
The Reed-Sternberg cells are only usually present in small numbers, but are then surrounded by large number of reactive, normal T cells, plasma cells (activated B cells) and eosinophils. – see below for different classifications of HL depending on which cell types are present

The appearance of Hodgkin’s lymphoma – note the Reed-Sternberg cells

WHO classifications of Hodgkin’s Lymphoma:

Nodular lymphocyte predominant HL

Accounts for 5% of all HL
Slow growing, localised, rarely fatal

Classical HL

There are 4 sub-types of classical HL – although the treatment is typically very similar.

Nodular sclerosing

Accounts for 70% of all HL
Most common in young women
In particularly involves the lymphnodes of the mediastinum and neck
There are many ‘fibrotic bands’ present

Lymphocyte rich HL

Accounts for 5% of all HL
Typically has an infiltrate of lots of small lymphocytes, and Reed-Sternberg cells
Most common in men

Mixed cellularity

Accounts for about 25% of all HL
There is a mixed infiltrate’ of lymphocytes, eosinophils, neutrophils, and histocytes
Reed-Sternberg cells are present, but there are no fibrotic bands
More common in the elderly (the second peak of the disease described in epidemiology)
No fibrotic bands
Associated with ‘B symptoms’
These are seen in both hodgkin’s and non-hodgkins lymphoma. They are associated with a worse prognosis.They include:
- Drenching sweats
- Fever
- Weight loss
Stage B disease often requires chemotherapy (as opposed to stage ‘A’ disease – where you just monitor the condition).

Lymphocyte depleted

There is a lack of infiltrate, but again, Reed-Sternberg cells are present; however, in this case, the cells are slightly different, and called ‘popcorn cells’.these cells tend not to express CD30, and express other CD antigens (20, 45 and 79a)
This has very poor prognosis
This is associated with HIV

Pathogenesis

It is not totally clear how this occurs, however there are several factors involved:

B cells – somewhere along the process of these becoming Reed –Sternberg and Hodgkin cells, these stop expressing surface immunoglobulin (antibodies).This is possibly due to destructional mutations of the Ig genes, and/or errors in transcription
Resistance to apoptosis – normally defects like this would result in apoptosis. There have been defects found in the Fas-gene
Development of self-regulation – again, somewhere along the pathway, the cells develop a self-regulatory growth mechanism, possibly producing their own growth factors. Again, defects have been found in relevant genes (IКβα gene)
Environmental factors – it is possible that Reed-Sternberg cells are the result of a late exposure to common pathogens (e.g. EBV), and that the late exposure causes these unusual changes
Genetic factors – monozygotic twins have 100x increased risk if the other twin is affected. There is no difference in dizygotic twins (thus this hints the genetic factor is not inherited, but perhaps random in the foetal process?)

The main points are that B cells no longer express Ig, and they no longer undergo apoptosis –so they become massive large cells, that no longer perform their original function.

Clinical features

Enlarged lymph nodes – these are usually rubbery, and most commonly found in the cervical region (70%) (usually supraclavicular region and neck). The nodes can fluctuate in size.

Patients with nodular sclerosing disease may have asymptomatic enlarged mediastinal masses, although sometimes these can cause respiratory symptoms, such as cough and breathlessness
In about 10% of cases there are isolated subdiaphragmatic nodes
Spread occurs to adjacent nodes. Spread to other tissues, such as skin, brain and bone is rare.
Nodes are also often found in the axilla and inguinal regions
The size of the nodes can increase and decrease spontaneously

Enlarged spleen/liver – this can be present, but remember it may not be indicative of the lymphoma!
B symptoms – fever (25%), drenching night sweats, weight loss of >10% body weight
Other vague symptoms – pruritis (itch), fatigue, anorexia, alcohol induced pain at the site of the lymph nodes (10% of cases but very specific!)

Symptoms due to the involvement of other organs – e.g. if the lungs become involved there may be breathlessness and cough.

Investigations

Blood count – can be normal, or there can be normocytic, normochromic anaemia. There may also be lymphocytopaenia (abnormally low lymphocytes) or eosinophilia (abnormally high eosinophils)
ESR – may be raised
Liver biochemistry – will usually be normal, even if there is liver involvement (although gamma GT and ALP may be raised)
Serum lactate dehydrogenase (LDH)– a raised level is a bad prognostic indicator
Uric acid – may be normal or raised
CXR – may show mediastinal widening, even when there is no lung involvement
CT scan – will show the involvement of intrathoracic nodes in 70% of cases. Abnormal abdominal and pelvic lymph nodes are also often found
Bone marrow aspirateand trephinine – very rarely done, but will show involvement in advanced disease
Lymph node biopsy – required for definitive diagnosis – looking at the histology for RS cells
- You can’t do a fine needle aspiration because this just give you cells (cytology style), where as lymph node biopsy gives you full histology.

Management

HL is usually classified using the Ann Arbor classification:

Stage	Definition
I	Involvement of a single lymph node(I), or an extralymphatic site (IA_E)
II	Involvement of two or more lymph nodes (II), or a lymph node and an extralymphatic site, on the same side of the diaphragm (II_E)
III	Involvement of lymph node regions on both sides of the diaphragm, with (III_E) or without (III) extralymphatic involvement, and with involvement of the spleen (III_S), (III_SE)
IV	Diffuse involvement of one or more extralymphatic tissues (e.g. bone or liver)
A	No systemic symptoms
B	Weight loss, drenching sweats
X	Bulky disease – this means a widening of the mediastinum by more than 1/3 due to the presence of a nodal mass

Curative treatment is almost always recommended, and often successful.

Early stage treatment – stages I_A and II_A

The treatment of choice is irradiation with/without chemotherapy (often with a small dose of chemo). Usually women’s fertility is preserved due to short, targeted bursts of radiation (‘ extended megavoltage field radiation’)

70% of patients are cured in this way (with mainly radiation +/- chemotherapy), and of those who aren’t, half can be cured with further combination chemotherapy, thus 85% of these patients are cured
However – there is increased incidence of breast cancer (in young women), lung cancer (in smokers) and cardiac disease, following irradiation. The radiation can also affect fertility. Also don’t forget lung fibrosis as a complication of radiotherapy.
- Thus, radiation is usually highly targeted ; ‘involved field radiation’
There are currently trials to see if PET scanning would allow for PET negative patients to avoid irradiation altogether.

The type of chemotherapy used is ABVD. This stands for the drugs used: (typical regimen);

Adriamycin 25 mg/m² IV on days 1 and 15
Bleomycin 10 units/m² IV on days 1 and 15
Vinblastine 6 mg/m² IV on days 1 and 15
Dacarbazine375 mg/m² IV on days 1 and 15

The chemotherapy is typically given in 4 week cycles, with the drugs being given IV on days 1 and 15. It is usually an outpatient procedure to give the therapy.

ABVD is a relatively non-toxic chemotherapy compared to that used for other cancers.

Acute side effects

Hair loss, or alopecia, is a fairly common but not universal side effect of ABVD. Hair that is lost returns in the months after completion of chemotherapy.
Nausea and vomiting can occur with ABVD, although treatments for chemotherapy-induced nausea and vomiting have improved substantially (see Supportive care below).
Low blood counts, or myelosuppression, occur about 50% of the time with ABVD. Blood cell growth factors are sometimes used to prevent this (see Supportive care below). Blood counts are checked frequently while receiving chemotherapy. Any fever or sign of infection that develops needs to be promptly evaluated; severe infections can develop rapidly in a person with a low white blood cell count due to chemotherapy.
Allergic reactions to bleomycin can occur. A small test dose of bleomycin is often given prior to the first round of ABVD to screen for patients who may be allergic.
Neuropathy Numbness in tips of fingers and toes, this can be temporary or permanent.

Delayed side effects

Infertility is probably infrequent with ABVD. Several studies have suggested that, while sperm counts in men decrease during chemotherapy, they return to normal after completion of ABVD In women, follicle-stimulating hormone levels remained normal while receiving ABVD, suggesting preserved ovarian function. Regardless of these data, fertility options (eg sperm banking) should be discussed with an oncologist before beginning ABVD therapy.
Pulmonary toxicity, or lung damage, can occur with the use of bleomycin in ABVD, especially when radiation therapy to the chest is also given as part of the treatment for Hodgkin’s lymphoma. This toxicity develops months to years after completing chemotherapy, and usually manifests as cough and shortness of breath. High concentrations of oxygen, such as those often used in surgery, can trigger lung damage in patients who have received bleomycin, even years later. Pulmonary function tests are often used to assess for bleomycin-related damage to the lungs. One study found bleomycin lung damage in 18% of patients receiving ABVD for Hodgkin disease. Retrospective analyses have questioned whether bleomycin is necessary at all; however, at this point it remains a standard part of ABVD.
Cardiac toxicity, or cardiomyopathy, can be a late side effect of adriamycin. The occurrence of adriamycin-related cardiac toxicity is related to the total lifetime dose of adriamycin, and increases sharply in people who receive a cumulative dose of more than 400 mg/m². Almost all patients treated with ABVD receive less than this dose (for 6 cycles of ABVD, the cumulative adriamycin dose is 300 mg/m²); therefore, adriamycin-related cardiac toxicity is very uncommon with ABVD.
Secondary malignancies. Patients cured of Hodgkin lymphoma remain at increased risk of developing other (secondary) cancers. Treatment-related leukemias are uncommon with ABVD, especially as compared with MOPP. However, one study found a risk of second cancers as high as 28% at 25 years after treatment for Hodgkin lymphoma, although most of the patients in this study were treated with MOPP chemotherapy rather than ABVD. Many of these second cancers were lung cancers or, in women, breast cancers, emphasizing the importance of smoking cessation and regular preventive care after completion of treatment. Radiation and chemotherapy probably both play a role in the development of these secondary malignancies; the exact contribution of chemotherapy such as ABVD can be difficult to tease out.

Advanced disease

This is curable in the majority of patients, and the median survival is longer than 5 years.

Treatment of choice – combinant chemotherapy with radiation to bulky areas.
Again, the type of chemotherapy used is ABVD, although it may take up to 6-8 cycles, providing blood count results are adequate
All patients with bulk will receive irradiation, even it appears they have a normal CT after ABVD. Again, PET scanning may reduce the number of patients requiring this.
This will cure approximately 50-60% of those with advanced disease. – the 15-year survival is approximately 65%
The major short term complication is myelosupression which has a mortality of 1%
About 25% of patient will fail to achieve some sort of remission after ABVD. For these patients, intensification of treatment may be beneficial. This involves increasing the number of drugs, and altering the combination. One particularly successful regimen has been to give 12-weeks of continuous chemotherapy with adjuvant irradiation at the same time.
Recurrence of the disease does occur (after an initial ‘successful’ treatment with ABVD) , and is not a good sign. The median survival after the first recurrence is 10 years. Remissions can be obtained, but further recurrences are likely.

Women who receive any sort of chest irradiation during treatment for any stage of the disease should be put on a screening program for breast cancer.

Survival rates

Obviously these vary depending on the stage, but:

Ia – 95% at 5 years
IVb – 40% at 5 years

Other bits

This disease is ‘contiguous’ – this means it only spreads to adjacent nodes/strcutres – due to the flow of lymph– this opposed to multicentric – where the disease can arise in several unlinked structures.

Hodgkin’s	Non-Hodgkin’s
Contiguous	Non-contiguous (multi-centric)
Reed-Sternberg Cells	No RS cells
Younger age of onset (3^rd decade)	Older age of onset (7^th decade)

Infections can cause enlarged lymph nodes – but there can be tender, but in hodgkin’s, they aren’t.
What is a Hickman line? – it is an IV catheter, mainly used in chemotherapy. They are also sometimes used in dialysis. They can remain in place for weeks or even months. This is because there is a relatively high risk of damaging the veins when inserting the line, and thus the risk of infection has to be balanced against the risk of damaging a vein.
- the line is inserted under local or general anaesthetic
- there are two incisions made, one at the jugular vein, and another on the chest wall. Ultimately, the line opens at into the SVC, near the atrium. Two inscisions are needed to be able to pull the line through into the right place.
- Haemorrhage and pneumothorax are possible at insertion
- Thrombosis and infection are possible whilst the line is in place
You are more likely to have infections of various kinds during leukaemia due to the fact your lymphocytes aren’t working properly, despite the fact you have increased eosinophils and neutrophils

Non-Hodgkin’s lymphoma (NHL)

Non-Hodgkin lymphomas are malignant tumours of lymphoid tissue, that do not contain Reed-Sternberg cells

70% are B cell in origin
30% are T cell in origin

The name ‘NHL’ encompasses a very wide range of conditions.

Not all conditions involve the lymph nodes (e.g. MALT – see later). There are at least 60 different types.

They can be broadly categories into low-grade tumours and high grade tumours. Low-grade have a relatively good prognosis but are not usually curable. High-grade tumours carry an overall worse prognosis but a significant number of patients may be curable with combination chemotherapy regimens.

NHL is more likely to disseminate (spread) to other tissues from the lymphatic system than HL.