Lymphoma

What is lymphoma?

Lymphoma is basically a proliferation (tumour) of lymphoid tissue. They primarily occur in lymph nodes, but not always (up to 20% of non-Hodgkin’s lymphoma occur outside of the lymph nodes, in other lymphoid tissues.)

They are divided into two types; Hodgkin’s and non-Hodgkin’s.

Lymphoid leukaemias also exist, and the distinction between these and lymphomas can be difficult.

Hodgkin’s Lymphoma (HL)

Epidemiology

-          This 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 the ages of 50-70.

-          The incidence is stable

Aetiology

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

o   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.

o   In the case of HL, CMV is not thought to be involved

o   The risk is 3x greater if you have a previous mononucleosis infection

-          It 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).

o   CD25 and CD30 antigens are almost always expressed on these cells in HL.

o   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:

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’

o   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

o   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.

o   Patients with nodular sclerosing disease may have asymptomatic enlarged mediastinal masses, although sometimes these can cause respiratory symptoms, such as cough and breathlessness

o   In about 10% of cases there are isolated subdiaphragmatic nodes

o   Spread occurs to adjacent nodes. Spread to other tissues, such as skin, brain and bone is rare.

o   Nodes are also often found in the axilla and inguinal regions

o   The size of the nodes can increase and decrease spontaneously

o    

-          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

-          Symptoms due to the involvement of other organs – e.g. if the lung 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

o   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 (IAE)
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 (IIIS), (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 and a bit of chemo), 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.

o   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 cessationpreventive 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. and regular

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 (from PBL)

-          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 (3rd decade)	Older age of onset (7th decade)

-          Infections can cause enlarged lymph nodes – but there can be tender, but in hodgkin’s, they aren’t.

-          What is a Hickman’s 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.

o   the line is inserted under local or general anaesthetic

o   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.

o   Haemorrhage and pneumothorax are possible at insertion

o   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)

These 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)

Epidemiology

-          The incidence increases with age – the median age of presentation is 55-75

-          The incidence is roughly 15 per 100 000, and is rising (over the last 20-30 years)

-          There is a slight male predominance

-          Incidence is much higher in developing countries, due to prevalence of human lymphotropic T cell virus. This tends to cause Burkitt’s lymphoma thus, this tends to be caused the T cell virus.

Aetiology

The cause is basically unknown. There is very wide geographical variation, which probably indicates environmental factors are involved.

-          Associated with the EBV virus – Burkitt’s lymphoma

-          Also associated with the T cell lymphotropic virus

-          Increased incidence in patients with AIDs – both HL and NHL are increased in AID’s, but more commonly NHL

-          H pylori increases the incidence of gastric MALT lymphoma

-          Compression syndromes can occur as a result of NHL, and can often be the initial presenting complaint. Examples include; gut obstruction, ascites, SVC obstruction, spinal chord compression

-          lymphomas also occur as a result of congenital immunodeficiencies and transplantation

Pathogenesis

Generally speaking, the lymphomas of non-dividing mature lymphocytes are low grade, and the one of lymphoblasts are much more aggressive.

-          In the aggressive tumours, the errors leading to malignancy usually occur during the ‘class switch’ when T cells are taking on their specific role. Often what happens is that proto-oncogenes that are next to Ig coding sequences are mistakenly activated, instead of the Ig gene.

-          Many of the types of NHL have had their specific mutations identified. Usually it is a translocation mutation, where a proto-oncogene is translocated next to a promoter sequence (instead of the proper gene; usually for Ig, being translocated to here).

Investigations

You should do all the investigations of HL as well as the following;

-          Bone marrow aspiration and trephine – these are routine in NHL, but in HL are rarely performed. A trephine is a surgical instrument with a cylindrical blade. It is basically used to bore into the bone. This is often done in the pelvis, or sometimes at the head of femur. It is extremely painful!

-          Immunophenotyping to distinguish B and T tumours – this can be done on blood, marrow or nodal material

-          Measurement of uric acid – some very aggressive NHL’s can cause very high uric acid levels, which can lead to renal failure

-          Immunoglobulin tests – check if it is IgG or IgM – as this can influence treatment options

-          HIV testing – may be appropriate if certain risk factors are present

Clinical features

-          Superficial lymphadenopathy – most patients (75%)will present with painless, superficial lymph node enlargement

-          Systemic symptoms – the ‘B’ symptoms – fever, sweats, anorexia, weight loss

-          Extranodal presentation (25%)– e.g. compression symptoms; GI tract, testes, brain, thyroid, skin. Hepatosplenomegaly. It could also present in the oropharynx and skin.

o   For example, there can be disease of the oropharynx lymphoid tissue (Waldeyer’s ring) which can cause a sore throat and obstructed breathing.

-          Pancytopaenia – can be due to bone marrow involvement. Pancytopaenia is basically ‘anaemia’ of white cells, red cells and platelets – so all of these are reduced! So there can be anaemia, neutropaenia (increased infections) and decreased platelets, leading to increased bleeding.

General prognosis

Low grade NHL – will follow a relapsing and remitting course; with an overall median survival of 10 years. They are generally not curable. Low grade NHL is capable of transforming to high grade NHL, in which case, survival is worse.

These account for 45% of cases. Often widely disseminated at presentation, due to them being asymptomatic.

-          Types include: MALT, follicular lymphoma, lymphocytic lymphoma

High grade NHL

-          Much more aggressive, but also more likely to be cured

-          80% of patients will initially respond to treatment

-          35% will be disease free at 5-years

-          Quite deadly without treatment

-          Types include; Burkitt’s lymphoma, lymphoblastic lymphoma, diffuse, large B-cell lymphoma

Examples

MALT – mucosa associated lymphoid(/lymphatic) tissue

Most commonly occurs in the stomach, but not always. In MALT tissue there is an abnormally large collection of lymphocytes, and macrophages. These have positioned themselves to be in a good position to intercept any antigens they come into contact with.

-          In intestinal MALT, there are also M cells, which sample antigens from the lumen and deliver them to the lymphoid cells

-          In the case of gastric MALT, it is associated with H-pylori infection, and eradication of the infection will often cure the condition.

Burkitt’s lymphoma

-          Commonly seen in West Africa, it is usually a childhood disease

-          Associated with jaw lymphadenopathy

-          It is the most common malignancy of childhood in West Africa

-          Often associated with malaria infection – which is thought to reduce resistance to EBV – thus allowing the virus to take hold

 

Staging

The same as Hodgkin’s

Treatment

Low grade

Basically it depends on the sub-type present. There are loads of sub-types, and each disease would need discussing by an MDT meeting to decide on the best course of action.

-          If it is symptomless, then it is likely no treatment will be given and it will just be monitored.

-          Radiotherapy may often be curative in localised disease

-          Chlorambucil is a chemotherapeutic agent, and may be successful in some cases.

-          once in remission (which I presume must sometimes spontaneously occur), the remission can be maintained with α-interferon or rituximab

High grade

A chemotherapy regimen called CHOP, (4 chemotherapuetic agents) + rituximab may be used.

Monoclonal antibodies can be useful for B cell lymphomas, and have greatly improved prognosis – being the only major advance in treatment in the last 30 years.

Survival

The histology is important in determining survival. Prognosis is worse if, at presentation:

-          age >60

-          bulky disease (abdominal mass >10cm)

-          raised lactate dehydrogenase

-          disseminated disease (widespread disease)

-          5 year survival is roughly about 30% for high grade disease and 50% for low grade disease, but this is very variable.

Chronic Lymphocytic leukaemia (CLL)

This is basically a massive over-production of B cells, such that the mutated, non-functioning (in terms of being able to fight infection) B cells crowd out any normal B cells that are left, and prevent the normal ones from doing their job properly.

-          The B cells tend to accumulate in the blood and bone marrow

-          It is often now considered to be a type of Non-Hodgkin’s lymphoma – The WHO classifies CLL as the same disease as SLL (small lymphocytic lymphoma), but just at a different stage.

-          CLL is an adult disease; 75% of new diagnosis are over the age of 50, and there is a male bias.

Presentation

-          Often discovered incidentally on a blood count, as a raised white cell count

-          If allowed to progress it can cause:

o   Swollen lymph nodes

o   Splenomegaly

o   Hepatomegaly

o   Polycythaemia

o   B symptoms

Management

Basically, in the lack of B symptoms it is not treated. In the presence of B symptoms, then treatment usually involves chemotherapy, and monoclonal antibodies – this appears to be the same as for a high-grade NHL – thus I presume this is because CLL is actually classed as a type of NHL.

Differentials of cervical lymph node enlargement

Infection

-          Acute

o   Infective mononucleosis

o   Toxoplasmosis – a parasitic disease caused by the organism toxoplasma gondii. Most commonly found in cats, but can affect any mammal – its the one from the QI book! C behaviour changes in rats to make them attracted to cats. It is only able to replicate in cats

o   Infected eczema

o   Cat scratch fever – an infectious condition caused by the bacterium bartonella. Most commonly found in children, about 1-2 weeks after suffering a cat scratch. It is a gram-negative rod. Kittens are carriersmore than cats, and thus more likely to cause infection.

§    Tics also have the disease, and thus it often trasmited at the same time as Lyme disease.

o   Acute childhood exanthema – a widespread rash, most often affecting children. Has a very wide range of causes, including toxins, drugs, microorganisms and autoimmune disease. Measles, rubella and scarlet fever are all types of exanthema (there are 6 types in total)

-          Chronic

o   TB

o   HIV

o   Syphilis

o   Sarcoidosis

Malignancies

-          Primary

o   Hodgkin’s lymphoma

o   Non-Hodgkin’s lymphoma

o   Chronic lymphocytic leukaemia

o   Acute lymphoblastic leukaemia

-          Secondary

o   Naropharyngeal

o   Thyroid

o   Pharyngeal

o   Lung

o   Breast

o   Stomach

Others

-          Rheumatoid arthirits

-          Reaction to phenytoin  - a commonly used anti-epileptic drug

-          Kawasaki’s syndrome – an inflammation of middle sized arteries. Will cause death in 1% of cases within 6 weeks of onset. Thought to be triggered off by viral infection. Causes enlargement of the cervical lymph nodes as well as oedema of the hands and feet. May also cause aneurysms of the coronary arteries.