Lymphoma and disease of bone marrow

Chapter 29 Lymphoma and disease of bone marrow

Gillian D. Thomas, Matthew Ahearne, Martin J.S. Dyer

Chapter contents

Introduction

Malignant lymphomas

Aetiology and epidemiology

Pathological characteristics

Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma

Clinical features

Diagnosis and staging

Clinical prognostic factors

Initial management

Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma

Special situations

Multiple myeloma

Clinical features

Prognostic factors

Radiotherapy in myeloma

Acute leukaemia

Clinical features

Treatment of AML

Chronic myeloid leukaemia

Clinical features

Chronic lymphocytic leukaemia

Clinical features

Myeloproliferative disorders

Haemopoietic stem cell transplantation (HSCT)

Radiotherapy doses, techniques and toxicities

Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma

Diffuse large B cell lymphoma

Indolent lymphoma: follicular and marginal zone

Total body irradiation (TBI)

Splenic radiotherapy

Palliative treatment of multiple myeloma

Mycosis fungoides

Total body electron therapy (TBE)

Chemotherapy regimens and toxicities

Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma

Follicular grade 1 and 2 and marginal zone

Diffuse large B-cell, T-cell-rich, B cell, follicular grade 3 (and for T-cell lymphomas)

CNS prophylaxis

Burkitt type, lymphoblastic, (some DLBCL if 100% MIB-1 staining)

Acute myeloid leukaemia

Further reading

Introduction

Lymphomas present as solid masses arising in lymph nodes or at extranodal sites anywhere in the body, while the leukaemias and multiple myeloma are diseases primarily of the bone marrow. They are chemo- and radiosensitive and, in contrast to the common ‘solid’ tumours, many are curable despite being widespread. Treatments range from simple oral chemotherapy and low-dose radiotherapy to high dose chemotherapy, total body irradiation and haemopoietic stem cell transplantation (HSCT). Immunotherapy now has an important role.

Malignant lymphomas

The malignant cell is the lymphocyte, with 90% of B cell and 10% of T cell origin. Lymphomas are conventionally divided into Hodgkin’s (HL) and non-Hodgkin’s (NHL). The former, named after Thomas Hodgkin who described it in 1832, is highly curable, while NHL is a diverse group of conditions.

Aetiology and epidemiology

HL accounts for 0.7% of all cancers and 0.4% of cancer deaths. In the UK, the incidence is three per 100 000 population per year in men and 1.8 for women. There are two age peaks, from 15 to 35 and a smaller old-age peak. There is an association with the Epstein-Barr virus (EBV) and with higher social class.

NHL occurs in 11 per 100 000 and the median age is 55–60. Childhood incidence is very low but higher (particularly Burkitt’s lymphoma) in developing countries. Overall, the male:female ratio is 1.5:1, although this varies between subtypes.

The causes of most NHL are unknown, but the risk is increased in immunodeficiency syndromes, immunosuppression following organ transplantation, AIDS, autoimmune disorders, and coeliac disease, and following certain infections or exposure to ionizing radiation and carcinogenic chemicals. Characteristic acquired chromosomal defects include the following translocations, involving the immunoglobulin genes on chromosome 14q32:

• t(14;18)(q32;q21) in about 80% of follicular lymphoma, involving the BCL2 gene on chromosome 18q21

• t(11;14)(q13;q32) in all cases of mantle cell lymphoma, involving the Cyclin D1 gene on chromosome 11q13

• t(8:14)(q24;q32) in Burkitt’s lymphoma, involving the MYC gene on chromosome 8q24.

NHL can result from chronic antigenic stimulation of lymphocytes, as in marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) following Helicobacter pylori infection, usually in the stomach or, rarely, following Chlamydia psittici infection. Burkitt’s lymphoma, originally described in East African children and classically in the jaw, is associated with the Epstein-Barr virus (EBV). A rare but very aggressive type of T-cell NHL is caused by infection with the human T-cell leukaemia virus type. 1 (HTLV-1).

Pathological characteristics

Prognosis and therapy depend on the maturity and subtype of the cell of origin. This is defined by:

1. morphology – appearance and arrangement of cells

2. immunophenotyping – cellular differentiation (CD) cell surface antigens identified by a panel of antibodies

3. cytogenetics – chromosome translocations

4. molecular biology – gene expression.

The WHO classification includes HL and NHL (Table 29.1). A specialist haematopathologist is essential for accurate categorization. Morphologically, aggressive NHL can resemble poorly differentiated carcinoma and indolent NHL may be confused with benign lymphadenopathy.

Table 29.1 Simplified WHO classification of tumours of haematopoietic and lymphoid tissues

Chronic myeloproliferative diseases

CML

PRV

Myelofibrosis

Thrombocythemia

Myelodysplastic/myeloproliferative diseases and syndromes

Acute myeloid leukaemias

AML with cytogenetic abnormalities or with prior dysplasia/therapy

Precursor B-cell neoplasm

Precursor B lymphoblastic leukaemia/lymphoma (ALL)

Mature B-cell neoplasms

CLL/small lymphocytic lymphoma

Marginal zone lymphoma: splenic/nodal/MALT

Myeloma and plasmacytoma

Follicular lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Mediastinal large B-cell lymphoma

Burkitt’s lymphoma

B-cell proliferations of uncertain malignant potential

Post-transplant lymphoproliferative disorder

Precursor T-cell neoplasms

Precursor T-lymphoblastic leukaemia/lymphoma (ALL)

Mature T-cell and NK-cell neoplasms

T-cell and NK-cell leukaemias

NK/T-cell lymphoma

Peripheral T-cell lymphoma

Anaplastic large cell lymphoma and cutaneous ALCL

Mycosis fungoides and Sézary syndrome

Angioimmunoblastic T-cell lymphoma

Enteropathy-type T-cell lymphoma

Hodgkin’s lymphoma

Nodular lymphocyte predominant HL

Classical HL

Nodular sclerosis

Lymphocyte-rich

Mixed cellularity

Lymphocyte-depleted

Hodgkin’s lymphoma

Hodgkin’s lymphoma is characterized by RS (Reed-Sternberg) cells, although these are only 2–4% of the cells present: the bulk of the tumour consists of normal, reactive lymphocytes, histiocytes, plasma cells, granulocytes and fibroblasts. RS cells are large and multinucleate with prominent eosinophilic nucleoli and express CD30 and CD15. Overall survival is excellent, around 80% at 5 years.

There are four histological subtypes termed classical HL (cHL), lymphocyte rich, nodular sclerosing grade 1 and 2, mixed cellularity and lymphocyte depleted, which is very rare but carries a poor 5-year survival of 20%. The most common is nodular sclerosing, with ‘nodules’ of cells within ‘sclerosing’ fibrous bands which often persist as a residual inactive mass after treatment. The fifth category of HL, lymphocyte predominant, differs histologically and clinically. It has an extremely long natural history with distant relapses, more like indolent NHL.

Non-Hodgkin’s lymphoma

Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) together make up 80% of all NHL seen in the West. They may be described as indolent and aggressive respectively, and grouped with other NHL subtypes though each is quite distinct.

Aggressive NHL

DLBCL behaves aggressively but is curable in about 50%. Bone marrow is involved in 10–15%. It forms sheets of large cells, often multinucleate with prominent nucleoli. Adverse prognostic markers include expression of p53 and BCL2 proteins and MIB-1 (Ki67). High proliferation rates (100% MIB-1 staining) are associated with programmed cell death (apoptosis) as in Burkitt’s lymphoma. Pale apoptotic cells in a uniform background of dark blue malignant lymphocytes appear as a ‘starry sky’. Thus, at the aggressive end of the spectrum of DLBCL, it may appear and behave like Burkitt’s or lymphoblastic lymphoma, which are the truly ‘high grade’ types which grow and spread most rapidly but are curable with aggressive treatment. Over the last decade, gene expression profiling of DLBCL cases have identified two major subtypes based on unique gene ‘signatures’: germinal centre B-cell like (GCB-DLBCL) and activated B-cell like (ABC-DLBCL). The latter is associated with greater resistance to conventional chemotherapy and worse clinical outcomes.

Mantle cell lymphoma, characterized by cyclin-D1 and CD5 expression, progresses slowly but has a poor prognosis (median survival 3–4 years) due to chemoresistance. Peripheral T-cell lymphoma also falls in this relatively poor prognostic category.

Indolent NHL

In follicular lymphoma, cells arise from lymph node germinal centres and form structures resembling normal follicles. Grade 3 behaves as DLBCL and grades 1 and 2 behave in a ‘low grade’ indolent way (median survival 7–9 years). It inevitably recurs, unless truly localized at diagnosis (15%). It can transform into DLBCL with a poor prognosis. Bone marrow involvement is common (>60%). Marginal zone lymphomas, presumed to arise from the small B cells of nodal or splenic marginal zones, also behave indolently.

Extranodal NHL

DLBCL is the usual type of NHL presenting in the head and neck (Waldeyer’s ring, nasal sinuses, thyroid), bone, testis, breast and brain. In the stomach, orbit, salivary glands, lung and spleen, the marginal zone lymphoma predominates, while intestinal lymphoma is commonly of T-cell origin and associated with coeliac disease. NHL may arise in the skin from either B or T cells. Histological diagnosis is often difficult and clonality studies using IG or TCR rearrangements are needed to distinguish reactive conditions. Mycosis fungoides is a very slowly progressive epidermal tumour of T-cell origin which may develop a leukemic form (Sézary syndrome). Anaplastic large cell lymphoma (ALCL) is also of T-cell origin, may arise in skin or elsewhere, and has a good prognosis if CD30 and ALK antigens are expressed. Cutaneous B-cell NHL includes follicular, marginal zone, and DLBCL.

Clinical features

All lymphomatous nodes may spontaneously wax and wane. They have a rubbery consistency and tend to be smooth, multiple, discrete, mobile and painless. They can enlarge to 10 cm or more without fixation or skin involvement, in contrast to carcinomatous nodes which invade surrounding structures early. However, patients with aggressive lymphoma can deteriorate rapidly with dehydration, hypercalcemia, anaemia, infection and damage to critical organs.

HL usually presents with enlarged nodes in the neck (60%), axilla (20%) or groin (15%). The spleen (10%) or, rarely, liver may be enlarged. Mesenteric nodes, bone marrow and extranodal sites are rarely involved in HL but commonly in NHL. Spread of HL is contiguous, from one lymph node group to the next: in NHL it may not be, and only 10% are localized at presentation.

Three characteristic ‘B’ symptoms are associated with lymphoma and a worse prognosis: drenching night sweats, weight loss (>10% of body weight in previous 6 months) and fever (>38°C) which may be of a specific periodicity (Pel–Ebstein fever). The disease is staged as A (none of these) or B (any of these). Itching (pruritus) occurs in 12%, but is not classed as a B symptom. Pain felt in involved lymph nodes after drinking alcohol is a symptom peculiar to cHL.

In NHL, 20% have involvement of extranodal sites. In the head and neck there is swelling, proptosis or nasal blockage. Thyroid lymphoma presents as a mass with stridor from tracheal compression, and sometimes a history of Hashimoto’s thyroiditis. Primary NHL of bone mainly affects proximal long bones, with pain, swelling and pathological fracture. Testicular NHL presents at age 60–80 with a painless smooth swelling. Bilateral involvement occurs in 20%. NHL of the breast presents with a mass often indistinguishable from carcinoma. Gastrointestinal lymphoma can present with pain, anaemia or bowel obstruction. Primary cerebral lymphoma presents with raised intracranial pressure or focal neurological deficits including siezures. In the skin, mycosis fungoides starts as erythematous, flat, slightly scaly itchy lesions on the buttocks, upper thighs or breasts. These develop into thicker plaques, and then to fungating tumours with nodal and visceral involvement. The whole skin may become involved resulting in generalized erythroderma or ‘l’homme rouge’. B cell cutaneous lymphoma is more likely to present as a discrete fleshy nodular lump with a tendency to ulcerate. Cutaneous ALCL occasionally undergoes spontaneous remission.

Diagnosis and staging

A formal excision biopsy is essential and should be sent fresh to the laboratory. Fine needle aspiration is inadequate for accurate diagnosis of lymphoma. There is usually no need to debulk tumour surgically.

Staging establishes the extent of the disease, using the Ann Arbor classification (Table 29.2), clinical assessment and essential investigations:

1. blood tests – full blood count, plasma viscosity, serum urea and electrolytes, calcium, liver function tests, lactate dehydrogenase (LDH) and β2-microglobulin

2. chest x-ray as baseline for reference

3. computed tomography (CT) scan of chest, abdomen and pelvis with intravenous and oral contrast

4. a bone marrow aspirate and a small core of bone (trephine) are taken from the posterior iliac crest

5. lumbar puncture for high-risk groups (see below). At the time of the procedure, it is usual to inject methotrexate 12.5 mg

6. positron emission tomography (PET) shows uptake of fluorodeoxyglucose (FDG) into areas actively metabolizing glucose and representing viable tumour in most cases. FDG-PET can assess response where there is a residual mass on CT, which may be fibrous tissue or lymphoma. Ideally, a pretreatment scan would be available for comparison.

Table 29.2 Ann Arbor staging classification of lymphoma

I. Involvement of a single lymph node region (I) or of single extralymphatic organ or site (IE)

II. Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)

III. Involvement of lymph node regions on both sides of the diaphragm (III) which may be accompanied by localized involvement of an extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE)

IV. Disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement

Clinical prognostic factors

Early HL is ‘very favorable’ if stage 1A, NS or LP type, age <40 and female, and ‘unfavorable’ if age over 50, four or more sites involved, raised ESR and a large mediastinal mass.

Advanced HL is ‘unfavorable’ if stage 4, age over 50, low lymphocyte count, eosinophilia, low hemoglobin, low serum albumin and male.

In NHL, the international prognostic index (IPI) is a widely accepted prognostic score from 0 to 5, with one point for each of the following features:

2. more than one extranodal site

3. stage III or IV disease

5. WHO performance status 2–4.

There is an increased risk of CNS relapse in DLBCL of the testis, paranasal sinuses, breast, and orbit, and in patients with heavy bone marrow involvement or with a high IPI score, and in Burkitt’s and lymphoblastic lymphomas.

Treatment

Initial management

It is important to avoid treatment before any biopsy. If awaiting results then steroids may be given (e.g. prednisolone 60 mg daily) to arrest clinical deterioration. In an emergency, such as airway obstruction, treatment may have to be given with radiotherapy. Urgent chemotherapy can rescue very ill patients despite toxicity. Rapid tumour breakdown can cause a ‘tumour lysis’ syndrome due to release of cytokines and intracellular products causing raised serum urate, phosphate and potassium, reduced calcium and impaired renal and, rarely, lung function. To prevent this, patients should start allopurinol (300 mg daily), ideally, at least 24 hours before chemotherapy, and be very well hydrated. Individuals deemed at very high risk of tumour lysis (very high tumour burden as in Burkitt’s lymphoma) may receive Rasburicase, a synthetic enzyme that breaks down the damaging urate.

Men should be offered sperm storage, but there are problems in the storage of ova. Eggs which have been individually frozen cannot be successfully fertilized. It is currently necessary to store embryos, which might be attempted for instance between a first line and a consolidation therapy. Preservation of ovarian tissue is under study.

Hodgkin’s lymphoma

Radiotherapy (RT) was the first curative treatment for stage I–III HL. Staging originally involved laparotomy with multiple biopsies and splenectomy, and then total nodal irradiation (TNI) was given using ‘extended fields’ – a ‘mantle’ field covered all supradiaphragmatic nodes and an ‘inverted Y’ field the infradiaphragmatic nodes and spleen or splenic pedicle. This exploited the tendency for HL to spread along node chains.

Chemotherapy was first used in HL for disease incurable with radiotherapy. Although side effects were severe with MOPP (mustine, vincristine, procarbazine and prednisolone), additional cures were achieved and six to eight cycles of chemotherapy plus extended field radiotherapy became routine. After 3–8 years up to 10% developed secondary acute myeloid leukaemia (AML) and from 8 to 20 years, other secondary malignancies particularly in irradiated areas. Heart disease was also increased. After 10–15 years, the risk of death from these causes was greater than from relapse of HL, with many patients rendered infertile. The most common second tumour is lung cancer, with an enhanced risk in smokers. In young women treated with mantle fields, the risk of breast cancer increases with age from 8 years after treatment up to as high as 50% in middle age for those treated in their early teens, or up to 25% if treated aged 20–29, and early screening is now offered. Thyroid cancer, colon cancer and sarcomas are also seen.

Cure rates have been maintained using less toxic chemotherapy to reduce leukaemia and infertility, and smaller radiation fields with lower doses to minimize second malignancies and cardiotoxicity. Chemotherapy is used in young patients for all stages except very favorable stage 1A, where it would be acceptable to use radiotherapy alone. ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) has become standard, although it causes acute myelotoxicity, a small risk of cardiomyopathy and a 1% risk of fatal bleomycin lung toxicity. Two to four cycles plus ‘involved field’ radiotherapy is used in stage 1A and 2A and six to eight cycles ± RT for others. PET scanning helps to define complete response and the need for RT. Current trials are focusing on the use of early PET imaging during treatment to stratify patients into good and poor risk. Good-risk patients may go on to receive less demanding chemotherapy while poor-risk patients are escalated to more intensive regimens, such as BEACOPP (bleomycin, etoposide, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).

Extended field radiotherapy is used after a partial response to chemotherapy with disease at several sites, or where chemotherapy has had to be curtailed, especially in patients who would be unsuitable for HSCT. For elderly and unfit patients with early disease, radiotherapy alone may be the treatment of choice.

The overall 5-year survival is 70–80%.

Relapsed cHL may be cured with HSCT or sometimes further conventional chemotherapy or radiotherapy. Anti-CD30 antibodies are a promising new treatment for relapsed/refractory disease. Brentuximab vedotin, a novel antibody-drug conjugate has shown promising results in early studies.

Non-Hodgkin’s lymphoma

Aggressive NHL

For more than 20 years, six to eight cycles of CHOP-21 (cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine) and prednisolone once every 3 weeks) was the best treatment for DLBCL despite many trials of more intensive regimens. The recent addition of an anti-CD20 human/mouse monoclonal antibody (rituximab) to each cycle (R-CHOP) has increased complete response rates from 63 to 76% and overall survival at 3 years from 51 to 62% with minimal toxicity, so is the new gold standard. R-CHOP-14 fortnightly treatment is under investigation, using granulocyte colony stimulating factor (GCSF) to avoid neutropenic sepsis. Newer generation anti-CD20 monoclonal antibodies are available (Ofatumumab and GA-101) and currently under investigation.

In high-risk groups, prophylactic CNS treatment is given concurrently as intrathecal or high-dose intravenous methotrexate. Radiotherapy to sites of bulk is conventional.

For stage IA or IIA DLBCL, including extranodal sites, radiotherapy alone is curative in about 50%, but adding three cycles of chemotherapy increases the cure rate to 80% in chemosensitive patients. Eight cycles of CHOP seemed as effective as CHOP × 3 plus RT in one pre-rituximab trial but others show an advantage for RT and the combination is preferred. Full-course chemotherapy should be given if there is bulky disease or B symptoms or a high IPI score, usually with RT afterwards. Only 40% of DLBCL are truly localized. In testicular DLBCL, the contralateral testis should be irradiated to reduce the risk of recurrence.

At relapse after full-course chemotherapy, HSCT can be curative if chemosensitivity can be shown with salvage regimens (IVE, ICE, ESHAP, DHAP). Time to relapse is the most important predictive factor with rituximab refractory disease showing the worst outcome. Alternatives are oral etoposide and palliative radiotherapy. Radiolabeled anti-CD20 antibody is under investigation for DLBCL.

Burkitt’s lymphomas are treated with mores intensive regimens, such as the CODOX-M/IVAC regimen, now combined with rituximab, and can cure around 50% of patients.

In primary cerebral lymphoma, standard chemotherapy can cross the blood–brain barrier initially while there is oedema around the tumour. CNS-penetrating drugs (high-dose methotrexate, cytarabine) are also used. Steroids are effective. Radiotherapy may prolong remission but causes lethargy and also significant cognitive impairment. Optimal chemotherapy, and the role of radiotherapy, are under investigation; prognosis is poor.

The optimal treatment of mantle cell lymphoma remains controversial and unsatisfactory. The benefit of maintenance Rituximab is currently under investigation. High-risk younger patients may be considered for consolidation with HSCT. Rare patients with localized disease may be considered for radical radiotherapy. Newer agents currently being tested alone and in combination with chemotherapy include lenalidomide, bortezemib, and temsirolimus.

Peripheral T-cell NHL is treated as DLBCL without rituximab as T cells lack CD20. Etoposide may be added to the CHOP regimen (CHOEP).

Indolent NHL

Truly localized (15%) follicular NHL may be cured with radiotherapy alone. For palliation, low doses can achieve lasting control.

In widespread disease, a ‘watch and wait’ approach is acceptable for asymptomatic patients. Immediate treatment with rituximab is under study. On symptomatic progression, for elderly patients, oral chlorambucil (e.g. 10 mg daily for 2 weeks every 4 weeks for six cycles) is appropriate. Younger patients should avoid alkylating agents and anthracyclines as first-line therapy. Currently, R-COP (=R-CHOP without Adriamycin; also called R-CVP) is often used; rituximab prolongs remission, although there is no known survival benefit as yet. R-CHOP is appropriate for follicular grade 3 or very bulky disease.

There is now increasing evidence that following induction and second-line chemotherapy, maintenance rituximab (375 mg/m² every 2–3 months for up to 2 years) significantly improves progression-free survival. However, to date, survival benefits have not been shown.

At relapse, re-biopsy is advisable to detect high-grade transformation. Selection and timing of treatment depends on the disease-free interval, extent of relapse, age and general condition, and includes HSCT. Rituximab alone (375 mg/m² weekly for 4 weeks) gives a 50% response rate with 13–17 months median time to progression in heavily pretreated patients and can be repeated with equal effect. Fludarabine is an effective oral agent.

Anti-CD20 monoclonal antibodies radiolabeled with yttrium-90 (a pure beta-emitter) or iodine-131 (beta and energetic gamma) are very promising new agents for refractory and transformed indolent NHL, with response rates of around 80% and remissions of several years in some patients. Zevalin (90Y-ibritumomab tiuxetan) is the murine parent of rituximab attached by the chelating agent tiuxetan to the radiolabel. It is given over 10 minutes with no need for hospital admission. Bexxar (131I tositumomab) is also a mouse antibody and seems equally effective but with more radiation protection issues; further research will establish the relative roles and optimal timing of these. Side effects include hypersensitivity reactions, delayed immunosuppression and secondary AML/MDS in 6%, partly due to previous chemotherapy.

Marginal zone NHL are described as three types: splenic, nodal, and those of MALT (mucosa-associated lymphoid tissue) origin. Splenectomy is appropriate for the first, and the others respond to the same agents and general approach as follicular NHL. Although the pattern of disease is different with more extranodal sites, radiotherapy can still be curative for disease truly localized to e.g. the stomach or parotid. Anti-helicobacter therapy is potentially curative in gastric MALT NHL. Gastric MALT can be monitored by regular endoscopies.

Mycosis fungoides has a median survival of 10 years. In the early stages, topical steroids can be used, then often photochemotherapy using long-wave ultraviolet light with oral psoralens (PUVA). Radiotherapy can be local or to the whole skin surface using low-energy electrons. Systemic treatments include CAMPATH (anti-CD52 antibody) which targets T cells. Combination chemotherapy with a CHOP-type regimen is used in visceral disease but complete response rates are low (20–25%).

Tags: T, Walter and Millers Textbook of Radiotherapy Radiation Physics

Mar 7, 2016 | Posted by admin in GENERAL RADIOLOGY | Comments Off

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