Aetiology

There is epidemiological evidence linking previous infectious mononucleosis with HL; up to 40% of patients with HL have increased EBV antibody titres at the time of diagnosis and EBV DNA has been demonstrated in tissue from patients with HL. These data suggest a role for EBV in pathogenesis. Other viruses have not been detected. Other environmental and occupational exposures to pathogens have been postulated.

Diagnosis

Hodgkin’s lymphoma is subclassified according to the WHO classification (Table 9.23) into:

Table 9.23 Hodgkin’s lymphoma – pathological classification

From Harris NL, Jaffe ES, Diebold J et al. 1999 World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting – Airlie House, Virginia, November 1997. J Clin Oncol 17:3835–49, with permission.

Figure 9.17 Histological appearance of Hodgkin’s lymphoma. Scattered mononuclear Hodgkin’s cells and a classical malignant binucleate Reed–Sternberg cell (arrow) are seen to the right of centre on a background of benign small lymphocytes and histiocytes.

(Courtesy of Dr AJ Norton.)

Clinical features

The commonest presentation of HL is painless cervical lymphadenopathy, commonly described in examination as ‘rubbery’. Other causes of cervical lymphadenopathy are shown in Table 9.24. A smaller proportion present with disease localized to the mediastinum (often young women), with cough due to mediastinal lymphadenopathy (Fig. 9.18), others with ‘generalized disease’, including hepatosplenomegaly and constitutional ‘B’ symptoms. Other less common symptoms, undoubtedly associated with Hodgkin’s lymphoma, but not recognized in the staging classification, are pruritus and alcohol-related pain at the site of lymphadenopathy.

Table 9.24 Cervical lymph node enlargement–differential diagnosis

Figure 9.18 Chest X-ray of a mediastinal mass that is due to Hodgkin’s lymphoma.

Investigation

This is summarized in Table 9.22. Bone marrow biopsy is only indicated in patients with clinically advanced disease (stage III, IV), those with ‘B’ symptoms and those who are HIV-positive. The clinical utility of the PET scan is becoming established in the management of Hodgkin’s lymphoma (Fig. 9.19).

‘Stage’ is currently assigned according to the Cotswolds modification of the Ann Arbor Classification, although this is under review (Table 9.25). The Hasenclever score is used for prognostication (Box 9.8); however its relevance to treatment planning is limited because of the very small number of patients at high risk of standard treatment failure. On the basis of ‘stage’ and other prognostic factors, patients with HL are divided into three groups (Table 9.26).

Table 9.25 Cotswolds modification of Ann Arbor staging classification of Hodgkin’s lymphoma

From Diehl V, Thomas RK, Re D et al. Hodgkin’s lymphoma – diagnosis and treatment. Lancet Oncology 2004; 5:19–26 with permission from Elsevier.

Table 9.26 Hodgkin’s lymphoma prognostic groups

Initial management

Treatment is aimed towards a curative intent with expectation of success. However, in patients with NLPHL who usually present with stage I disease with longstanding lymphadenopathy, an expectant policy with close surveillance, is followed. Older patients, with or without co-morbidity, require considerable modification of therapy and there is an expectation of success. Patients with HIV infection should be managed, in conjunction with their HIV clinicians, in the same way as those who are seronegative.

Treatment

Management of failure of initial therapy

This has become a declining problem because of improvements in the outcome of first-line therapy. The median survival from first recurrence is more than 10 years, possibly being influenced by the duration of the first remission; it may not be so good if failure occurs after very intensive therapy. Second and third remissions may be achieved with ‘appropriate’ re-induction therapy, consolidated, if possible with an autograft. Registry data suggest this may be curative for up to 50%, but follow-up only extends to 15 years.

Experimental approaches

With such excellent results of first- and second-line conventional therapy, experimental treatment is seldom required. The antigen-targeted immunoconjugate, anti-CD-30-auristatin (SGN-35, brentuximab) has shown such efficacy in phase II trials and the histone deacetylase inhibitor (HDAC) panobinostat also has potential. Allogeneic haemopoietic stem cell transplantation (HSCT) following myeloablative conditioning has high treatment-related mortality and morbidity. Reduced intensity conditioning HSCT, followed if necessary by donor lymphocyte infusion, is being investigated.

Long-term follow-up

The risks of late effects of therapy, particularly second malignancy and cardiac and endocrine problems, require appropriate and indefinite surveillance of patients at ‘high risk’.

Aetiology

A family history is associated with a minor increase in risk of lymphoma and common genetic polymorphisms with only a small risk for an individual may be significant in population terms. Certain inherited syndromes, e.g. ataxia-telangiectasia and Wiskott–Aldrich syndrome, are associated with an increased risk of lymphoma. The human T-cell leukaemia virus type 1 (HTLV-1) is causally related to adult T-cell lymphoma/leukaemia. Helicobacter pylori is known to ‘cause’ extranodal marginal zone lymphoma in the stomach. There is a very strong epidemiological relationship between EBV and endemic Burkitt’s lymphoma and a lesser one with sporadic Burkitt’s lymphoma and Hodgkin’s lymphoma.

Immune suppression, immunosuppressant drugs, particularly as used for solid organ transplantation, and HIV infection are all associated with an increased incidence of lymphoma. Agricultural work is associated with lymphoma, but no other data show any convincing evidence of an association between occupation or lifestyle. In the majority of individual cases, the cause is unknown.

Pathogenesis

Malignant clonal expansion of lymphocytes occurs at different stages of lymphocyte development, leading to the different subtypes of lymphoma (Fig. 9.20). In general, neoplasms of non-dividing mature lymphocytes are ‘indolent’, whereas those of proliferating cells (e.g. lymphoblastic) are much more ‘aggressive’. Malignant transformation is usually due to errors in gene rearrangements which occur during the class switch, or gene recombinations for immunoglobulin and T-cell receptors. Thus, many of the errors occur within immunoglobulin loci or T- cell receptor loci. For example, an abnormal gene translocation may lead to the activation of a proto-oncogene, by moving it next to a promoter sequence for the immunoglobulin heavy chains (Ig-H).

Figure 9.20 Differentiation of T and B lymphocytes and their relationship to neoplasms. Top. T-cell differentiation. Progenitor T cells from the bone marrow enter the thymus and develop into different naive T cells. αβ T cells leave the thymus, are exposed to antigen (AG) and undergo blast transformation. They then develop into CD4+ and CD8+ effector and memory T cells. T regulatory cells are the major type of CD4+ effector cells. The other specific effector T cells are the follicular helper T cell (TFM) in the germinal centres (GC). Upon antigenic stimulation, T-cell responses to antigenic stimulation pathways of natural killer cells (NK) and γδ T cells is unknown. Bottom. B cell differentiation. Precursor B cells mature in the bone marrow and undergo apoptosis or mature to naive B cells. Following exposure to antigen and blast transformation, they develop into short-lived plasma cells or enter the germinal centre (GC). Somatic hypermutation and heavy chain class switching occur here (not shown). The transformed cells of the GC (centroblasts) undergo apoptosis or develop into centrocytes. Post-GC cells include long-lived plasma cells and memory/marginal cells. AG, antigen; DLBLC, diffuse large B-cell lymphoma; CLL/SLL, chronic lymphocytic leukaemia/small lymphocytic lymphoma.

(Redrawn from information in Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Geneva: WHO; 2008.)

Cytogenetic features

Burkitt’s lymphoma was the first tumour in which a cytogenetic change was shown to involve the translocation of a specific gene (Table 9.28). The most frequent change is a translocation between chromosomes 8 and 14 in which the MYC oncogene is translocated from chromosome 8 to a position near the constant region of the immunoglobulin heavy chain gene on chromosome 14, resulting in upregulation of myc. Similar rearrangements involving the light chain loci are seen in the alternative Burkitt’s lymphoma translocations between chromosome 8 and either chromosome 2 or 22. Other somatic cytogenetic abnormalities associated with human lymphoma are the t(14;18) in follicular lymphoma, involving upregulation of BCL2 or the upregulation of the cell cycle regulator cyclin D1, as a result of t(11;14) in mantle cell lymphoma. Gene expression profiling and other molecular techniques are identifying new molecular subclasses of lymphoma with prognostic significance.

Table 9.28 Chromosome translocations in non-Hodgkin’s lymphoma

Diagnosis

The non-Hodgkin’s lymphomas are subclassified according to the cell of origin (T or B lineage) and the stage of lymphocytic maturation at which they develop (precursor or mature) (see above).

Clinical presentation

The commonest presentation overall is with painless lymphadenopathy or with symptoms caused by a lymph node mass. Primary extranodal lymphomas present with soft tissue masses and related symptoms at the relevant site.

Clinical presentation and course

Follicular lymphoma occurs in middle to late life, being rare in childhood. The majority of patients will present with painless lymphadenopathy at more than one site, although a small proportion will be ill, some with ‘B’ symptoms. In the latter, there should be suspicion that the diagnostic biopsy was not representative. This may be the case when the presenting symptom relates to an abdominal mass, but a peripheral node is biopsied. Percutaneous needle biopsy of the abdominal mass may reveal transformation to diffuse large B-cell lymphoma, with potentially different management. Bone marrow infiltration is common in certain subtypes.

There have been dramatic improvements in the outcome of therapy since the introduction of antibody therapy (rituximab), targeting the CD20 antigen expressed on almost all B-cell lymphomas, leading to the development of chemoimmunotherapy, but to date, however, the proportion of patients cured has been small. The illness has been shown to regress spontaneously in some cases which has led to an expectant policy of treatment for many patients. The clinical course following initiation of treatment to date has been that of a remitting recurring disease, often with several biopsy-proven episodes of lymphadenopathy which are, albeit usually transiently, responsive to therapy. Transformation to diffuse large B-cell lymphoma occurs in up to 25% of patients over 15 years and usually heralds a grave prognosis, although this may be improving. Death occurs because of resistant disease, transformed or not, the complications of therapy, or unrelated causes. The median survival now exceeds 10 years. Prognostic factor are shown in Box 9.9.

Management

Introduction

This is the commonest lymphoma worldwide in the adult population (increasing in incidence with age) and the second commonest in childhood, accounting for approximately 30% of all cases. There is a slight male preponderance.

Clinical presentation

The majority of patients present with painless lymphadenopathy, clinically at one or several sites. Intra-abdominal disease presents with bowel symptoms due to compression or infiltration of the gastrointestinal tract. In a small proportion there is a primary mediastinal presentation, most often in men, with symptoms and signs akin to those of Hodgkin’s lymphoma. There may be ‘B symptoms’, which should not be confused with symptoms related to the site of involvement. Investigation will lead to the demonstration of either locally or systematically advanced disease in the majority of cases. The illness is itself rapidly progressive, without intervention, death occurring within months rather than years. Approximately 30% present at an extranodal site as opposed to having nodal disease with extranodal spread.

Initial treatment

Treatment should be initiated immediately after the diagnosis is confirmed and in younger patients without co-morbidity there is a high expectation of cure. Treatment is assigned on the basis of the International Prognostic Index (Box 9.9, Fig. 9.22).

Figure 9.22 A predictive model for aggressive non-Hodgkin’s lymphoma. Survival among the 1274 younger patients (≤60 years) according to risk group defined by the age-adjusted international index. L, low risk; LI, low–intermediate risk; HI, high–intermediate risk; H, high risk.

(Reproduced with permission from: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. New England Journal of Medicine 1993; 329(14):987–994.)

Although this was constructed in the pre-rituximab era, it remains broadly applicable. Further refinement using gene expression profiling has identified at least two distinct subtypes of DLBCL (Fig. 9.23). Allopurinol is given routinely and also in some cases with different prognoses – germinal centre cell (GC) and activated B-cell (AB). A high proliferative index, aggressive prophylaxis against tumour lysis is indicated.

Figure 9.23 Kaplan–Meier plot of overall survival of DLBCL patients grouped on the basis of gene expression profiling.

(Reproduced with permission from Alizadeh AA. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403(6769):503–511.)

Low-risk (IPI score 0–1) with anatomically localized disease

At present, ‘R-CHOP’ followed by involved field irradiation, or ‘more R-CHOP’, are both used. Interim PET scanning may be used to inform individualization of therapy.

Two studies conducted in France suggest that the prognosis is better with chemotherapy alone provided ‘enough’ is given, with more than 80% of younger patients being alive 10 years after therapy. A trial comparing ‘R-chemo’ with ‘chemo’ in all patients with low-risk disease showed a marked advantage for those receiving chemoimmunotherapy. Further studies are awaited (Fig. 9.24).

Figure 9.24 Overall survival in patients treated with CHOP and R-CHOP. Median overall survival (OS) was 3.5 years (95% CI: 2.2–5.5) in the CHOP arm and 8.4 years (95% CI: 5.4–not reached) in the R-CHOP arm (p<0.0001). DLBCL, diffuse large B-cell lymphoma.

(Reproduced with permission from Coiffier B, Thieblemont C, Van Den Neste et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010; 116(12):2040–2045.)

Second (and subsequent) therapy

Although there may be responsiveness initially to alternative chemotherapy, after failure of initial therapy or subsequent progression, the prognosis is very poor. Patients entering a partial remission do better than those who recur after entering an initial complete remission.

The major issues to be addressed are whether treatment is to be undertaken with palliative or curative intent and if the latter, the expectations of success. The palliative approach involves both chemotherapy and irradiation. The curative approach involves complete re-evaluation followed by second-line chemotherapy, with a proven response rate of approximately 50%. If at least a further partial remission is achieved, in the younger, fitter patient, peripheral blood stem cell harvest is undertaken, followed, if successful, by an autograft. Overwhelmingly, the best results are achieved in those entering an unequivocal second complete remission. Even so, the proportion of patients in a prolonged second remission does not exceed 25%.

Prognosis

The outlook for patients with diffuse large B-cell lymphoma has improved by at least 15% in terms of cure, with the incorporation of rituximab into the initial therapy, the expectation of cure now being between 40% and 80% depending on the presenting features. The challenge of progressive disease following initial treatment is great, with overall less than 20% of patients alive long term.

Introduction

This is the most rapidly proliferating lymphoma with a doubling time approaching 100% and a very rapid evolution. The commonest childhood malignancy worldwide, it has a male : female preponderance of approximately 3 : 1 and occurs in all ages. There are three types:

The commonest presenting feature in the endemic type is a rapidly growing jaw tumour in a young child (Fig. 9.25). Otherwise, the next commonest is an abdominal mass often associated with bone marrow involvement. Other common sites are the central nervous system, the kidney and the testis. Investigation is along conventional lines for lymphoma, at least in the Western world, but must be conducted as a matter of urgency. A different staging classification is applied to children.

Figure 9.25 A child with Burkitt’s lymphoma.

Management

Burkitt’s lymphoma should be treated with curative intent whenever feasible, regardless of HIV status. Investigation having been completed, it is essential that the patient is haemodynamically and metabolically stable prior to the initiation of specific therapy. Particular attention must be paid to the risk of the tumour lysis syndrome. Whenever possible, rasburicase prophylaxis should be given. If this is not available, other standard measures based on fluids and allopurinol to minimize the risk of tumour lysis syndrome should be pursued. Very frequent monitoring of electrolyte balance is essential for at least 72 hours after treatment is commenced, with particular attention to potassium and phosphate levels.

Standard treatment comprises if possible, intensive, cyclical combination chemotherapy, including cyclophosphamide, methotrexate and cytosine arabinoside in high doses. Rituximab is now included, although the evidence base for this is minimal. The details and number of cycles administered will be determined by the perceived level of ‘risk’. Prophylactic central nervous system therapy is essential, intrathecal methotrexate or cytosine arabinoside often being given in addition to high-dose systemic administration. The chances of cure are very high for ‘low-risk’ patients and exceed 50% for ‘poor-risk’ patients as well, provided all treatment can be administered.

Failure to achieve complete remission is a very poor prognostic factor as is recurrence, which does so within the first year after completion of initial therapy if it is to happen. Although there may be further chemo-responsiveness, it is rare for second-line therapy to be more than transiently beneficial, regardless of whether it is followed by consolidation, with either myeloablative chemotherapy or allogeneic haematopoeitic stem cell transplantation.

Summary

In the Western world, the prognosis of Burkitt’s lymphoma has improved markedly over the past 10 years, with cure being the probability for the large majority at low risk and being substantial for those at high risk, including the HIV-positive cases.

Treatment

In the majority of patients, therapy is started after investigation has been completed. It is usual for there to be regression of disease with chemotherapy, although it is not often that complete remission is achieved. A prognostic index is used to help determine whether more or less ‘aggressive’ treatment is best employed. In reality, the major determining factors are the age of the patient and the presence or absence of co-morbidities. The outcome is likely to be best when ‘more’ treatment is given. Hence, younger, fitter patients are now treated with relatively intensive chemoimmunotherapy, incorporating rituximab, followed by, depending on its efficacy, myeloablative chemotherapy, with autologous stem cell rescue. Older, less fit patients are treated with less intensive therapy. In general, the strategy is to stop treatment after the planned initial course of treatment, provided the patient is well and at least a partial remission has been achieved. Almost inevitable progression for both older and younger patients occurs; palliation being the expectation for most. Experimental approaches include reduced intensity allogeneic haematopoietic stem cell transplantation and novel drugs targeting both the NFκB and mTOR pathways.

Summary

Mantle cell lymphoma is a lymphoma with a natural history untreated which lies between that of diffuse large B-cell lymphoma and follicular lymphoma. The prognosis has improved in recent years with the introduction of treatment strategies which have prolonged the period of remission without curing the patient and with the discovery of new ‘effective’ agents, making the overall median survival nearer 5 years.

Management

Following completion of investigation, the critical decision is whether to initiate specific therapy or not. A prognostic score is assigned, the critical decision being whether to initiate specific therapy or not. In an emergency, with severe symptoms of hyperviscosity, it is most appropriate to lower the paraprotein by plasmapheresis. In some circumstances, particularly in the otherwise less fit, it may be best to use maintenance pheresis and blood transfusion as the primary therapy. ‘Responses’ occur in about 50% of cases, with a fall in the paraprotein to 50% of the baseline level with single agent therapy and higher with combination chemotherapy and rituximab. The general strategy is to treat when it is clinically indicated and to stop after a conventional course of treatment. Treatment, either repeating the initial therapy or changing, is re-instated only when progression is clearly documented, most often by fall in the haemoglobin or significant rise in the M-band and the illness is a threat to quality and quantity of life. In the very small proportion of younger patients for whom complete remission is achieved, consolidation with a bone marrow transplant is used. Similarly, in the same group of patients who have recurrent disease, which is again responsive, allogeneic haematopoietic stem cell transplantation is also used.

Prognosis

Lymphoplasmacytic lymphoma is a relatively rare chemotherapy- and immunotherapy-sensitive disease, which may have an indolent course for some years without therapy. Although the median survival is only 5 years, as it presents in later life, 10–20% of patients die of unrelated causes.

Primary central nervous system lymphoma

This diffuse large B-cell lymphoma occurs in both the immunocompetent (predominantly the elderly) and the immunosuppressed, in the context of post-solid organ transplant or HIV infection. It presents with symptoms relating to single or multiple parenchymal mass lesions. The diagnosis needs to be made on the basis of a biopsy, particularly in the immunocompromised, in whom an infectious aetiology of the symptoms is possible, e.g. toxoplasmosis. MRI scan is the first choice investigation; cerebrospinal fluid is usually normal. Further investigation is necessary to exclude the cerebral lesion being a manifestation of generalized disease.

Primary gastric lymphoma

This B-cell lymphoma, either extranodal marginal zone lymphoma of mucosa-associated tissue (MALT), or diffuse large B-cell lymphoma arising on a background of MALT lymphoma, is closely related to Helicobacter infection. It presents with symptoms of gastric ulceration or a mass, indigestion or bleeding and the diagnosis is made by endoscopic biopsy to include both the confirmation of lymphoma and H. pylori status. This is followed by investigation as for nodal lymphoma, which reveals local nodal involvement in a proportion of patients and distant spread in only a small number. Treatment is entirely dependent on whether or not there is any evidence of diffuse large B-cell lymphoma. If only ‘low-grade’ gastric ‘MALT’ lymphoma is present, Helicobacter eradication therapy is the treatment of choice (p. 249). This almost invariably alleviates the symptoms. Re-evaluation after 3 months with endoscopy, repeat biopsy and in some circumstances, endoscopic ultrasound is carried out. In general, a conservative approach is followed, as responses may take many months to achieve and rapid progression is very unlikely. Regular endoscopy 6-monthly should be continued for at least 2 years. Failure is not common and if it occurs, it is rarely rapid. If it occurs, the biopsy should be repeated. If the histology is unchanged after further Helicobacter eradication therapy (if necessary) either irradiation to the gastric bed or chemoimmunotherapy is likely to be effective or possibly curative. Overall, the prognosis is very good, the very large proportion of patients being alive 10 years after diagnosis.

Any evidence of diffuse large B-cell lymphoma is an indication for chemoimmunotherapy. Helicobacter eradication therapy should also be given, but should not be considered definitive treatment. The potential risk of gastric perforation or haemorrhage because of therapy is not a contraindication to treatment. Surgery is rarely needed, but irradiation is used for persistent disease. The prognosis is approximately the same as for nodal DLBCL of equivalent extent.

Introduction

These are much less common than their B-cell counterparts, although they are relatively more frequent in the East than the West. The commonest presentations are nodal or cutaneous (p. 1226) and specific subtypes involve the liver and subcutaneous tissue. Peripheral T-cell lymphomas with nodal presentation have a poor prognosis. They are treated as for DLBCL without rituximab.

Figure 9.27 Relative frequencies of T-cell lymphoma subtypes in adults. NOS, not otherwise specified.

(Reproduced with permission from WHO. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Geneva: WHO; 2008: Fig 8.07.)

The two ‘commonest subtypes’ of ‘nodal’ T-cell lymphoma are peripheral T-cell lymphoma, ‘not otherwise specified’ (NOS) and angioimmunoblastic T-cell lymphoma, which together account for about 50% of T-cell lymphomas. Both occur in the middle-aged to elderly population, the primary presentation being lymphadenopathy. In contrast to the B-cell lymphomas, ‘B symptoms’ are common. Patients with angioimmunoblastic T-cell lymphoma also present with features akin to inflammatory disease, with fevers, rashes and electrolyte abnormalities, which in the first instance may be rapidly responsive to corticosteroids or low doses of alkylating agents.

Management

Following standard investigation, which usually reveals widespread disease, patients are treated with cyclical combination chemotherapy as used for diffuse large B-cell lymphoma. CD20 is not expressed on T cells so rituximab is not used and, as yet, there is no equivalent drug for T-cell lymphoma. Resolution of symptoms almost invariably occurs, although they may recur between cycles. Overall, the outcome of treatment is worse than for DLBCL, in terms of quality of response, duration of response and overall survival. Second-line therapy is rarely satisfactory, although a small proportion of patients may benefit from myeloablative therapy to consolidate a second response.

Clinicopathological features

Myeloma is a disease of the elderly, the median age at presentation being over 60 years. It is rare under 40 years of age. The annual incidence is 4 per 100 000 and it is commoner in males and in black Africans but less common in Asians. The clinical features include:

Kidney biopsy of a patient with myeloma and acute kidney injury due to light chain cast nephropathy.

(Courtesy of Professor Michael Sheaff, Barts and The London NHS Trust.)

In addition, there is a reduction in the normal immunoglobulin levels (immune paresis), contributing to the tendency for patients with myeloma to have recurrent infections, particularly of the respiratory tract. The WHO classification (2008) of plasma cell neoplasms is shown in Table 9.29.

Table 9.29 WHO (2008) classification of plasma cell neoplasms

Symptoms

Patients can be asymptomatic, the diagnosis being suspected by ‘routine’ abnormal blood tests. Life-threatening complications are shown in Box 9.11.

Investigations

Immunological

Total protein is normal or raised.

Serum protein electrophoresis and immunofixation characteristically shows a monoclonal band and immune paresis (Fig. 9.28). The serum free light chain assay, more sensitive than urine electrophoresis, may show an abnormal ratio and an increased total amount of free kappa or lambda chains and is often abnormal earlier than routine electrophoresis.

24-hour urine electrophoresis and immunofixation is used for assessment of light-chain excretion.

Figure 9.28 Immunofixation and electrophoresis. (a) Immunofixation IgG kappa monoclonal paraprotein. (b) Quantitation and serum electrophoresis IgG paraprotein. Serum electrophoresis and immunofixation of a patient with an IgG K paraprotein (left). The column on the far left is the total serum electrophoresis stained with anti-protein reagents. Albumin is at the top with the increased immunoglobulins at the bottom. These are shown to stain with anti-IgG and anti-kappa light chain reagents. The paraprotein is quantified (right) by calculating the area under the paraprotein spike and comparing it with the albumin concentration.

Radiological

Skeletal survey. This may show characteristic lytic lesions, most easily seen in the skull (Fig. 9.29). CT, MRI and PET are used in plasmacytomas (bone or soft tissue deposits). MRI spine is useful if there is back pain – may show imminent compression/collapse.

Figure 9.29 Myeloma affecting the skull. Note the rounded lytic translucencies produced by infiltration of the skull with myeloma cells.

Other

Bone marrow aspirate or trephine shows characteristic infiltration by plasma cells (Fig. 9.30). Amyloid may be found (see p. 1043).

Figure 9.30 Multiple myeloma. Histology shows replacement of the medullary cavity by abnormal plasma cells with some binucleate forms (arrow). A residual bony trabeculum is present towards the right.

(Courtesy of Dr AJ Norton.)

Prognostic factors

Reduced serum albumin, increased serum β2-microglobulin and increased serum lactate dehydrogenase (LDH).

Diagnosis

Symptomatic myeloma (SMM) can be diagnosed if either of the following are present:

with evidence of end organ failure, i.e. hypercalcaemia, renal impairment, anaemia, lytic bone lesions (CRAB).

An international prognostic index based on serum albumin + β2 microglobulin (β2M) at diagnosis is used for prognostic information (Box 9.12).

Asymptomatic myeloma (AMM) (10% cases) has a significant paraprotein (IgG or IgA >30 g/dL or urinary light chain excretion >1 g/day) and/or a marrow plasmacytosis >10% but no end organ damage. The median time to progression for these patients is 2–3 years. The risk is highest for those with IgA isotype and light chains in the urine

Monoclonal gammopathy of unknown significance (MGUS). MGUS describes an isolated finding of a monoclonal paraprotein in the serum, usually in the elderly, that does not fulfil the diagnostic criteria for SMM or AMM. 20–30% go on to develop multiple myeloma over a 25-year period. Low-risk MGUS is characterized by those with an IgG subtype, a paraprotein <15 g/dL and a normal serum free light chain ratio.

Plasmacytoma. Patients may present with an isolated tumour of neoplastic plasma cells called a plasmacytoma and no evidence of multiple myeloma. This may be a ‘solitary plasmacytoma of bone’ within the skeleton or an ‘extramedullary plasmacytoma’ outside the marrow cavity typically in the upper aerodigestive tract.

For paraprotein associated neuropathy and POEMS, see page 1079.

Treatment

With good supportive care and chemotherapy, median survival is now 5 years with some patients surviving to 10 years. Young patients receiving more intensive therapy may live longer.

Prognostic factors

Lung cancer histology is divided into two main types: small-cell (neuroendocrine) lung cancers (SCLC), which tend to disseminate early in their development, and non-small-cell lung cancers (NSCLC), which are more likely to be diagnosed in a localized form. Tumour stage and patient performance status are used in selecting treatment and predicting response and prognosis. While overall 5-year survival has remained approximately 15%, treatment is beginning to have an impact in selected groups and the multidisciplinary team can greatly aid in the appropriate application of treatment and the avoidance of nihilism.

Treatment

Surgery can be curative in non-small-cell lung cancer (T1, N0, M0) but only 5–10% of all cases are suitable for resection; about 70% of these survive for 5 years. Surgery is rarely appropriate in patients over 65 years, as the operative mortality rate exceeds the 5-year survival rate. Trial data suggest that neoadjuvant chemotherapy may downstage tumours to render them operable and may also improve 5-year survival in patients whose tumours are operable at presentation.

Preoperative assessment: lung function tests, including walking oximetry, are used to predict postoperative potential. An active life after pneumonectomy is unlikely if the gas transfer is reduced below 50%.

In operable disease stages T1N0 to T3N2 (stage I to IIIa), adjuvant radiotherapy and chemotherapy following surgery can improve prognosis in patients of good performance status as shown by the international adjuvant lung cancer trial and a meta-analysis of 12 randomized controlled trials. Cisplatin-based combination chemotherapy induced a response in 60% and produced a relative risk reduction of 11% with an absolute improvement in 5-year survival for stage II and IIIa disease of 4% from 40.4% to 44.5%.

A practical molecular assay to predict survival in resected non-squamous lung cancer is becoming available.

Prognostic factors

The staging of small-cell lung cancer is divided into limited and extensive disease according to whether or not it is confined to a single anatomical area or radiation field. Systemic therapy is the primary therapeutic modality because of the usually disseminated nature of the disease.

Treatment

Limited disease is present in approximately 30% of patients and is best treated with concurrent chemo- and radiotherapy using a co-mbination of cisplatin and etoposide or irinotecan, which increases the survival at 5 years from 15% to 25%, compared with radiotherapy alone. A similar degree of improvement can also be achieved with hyperfractionated radiotherapy. Prophylactic whole-brain radiation to prevent cerebral metastases can reduce symptomatic CNS disease and improve overall survival by 5%.

Extensive disease can be palliated with the combination of carboplatin and etoposide or irinotecan, which when compared with best supportive care, can increase median survival from 6 months to 9–13 months and the 2-year survival to 20%.

Symptomatic care for lung cancer patients

The prognosis for the majority of patients remains poor because the disease is diagnosed in an advanced stage and the co-morbidity from other smoking-related disease compromises treatment. Therefore, much of the treatment whether symptomatic or anticancer is delivered with palliative intent. (General palliative care is discussed in Chapter 10.) Specific issues for lung cancer are the relief of bronchial obstruction and breathlessness and the relief of local pain for which radiotherapy is often employed alongside appropriate opiate analgesia. Laser therapy, endobronchial irradiation and tracheobronchial stents are used (see p. 862).

Metastases in the lung

Metastases are very common and usually present as round shadows (1.5–3.0 cm diameter). They are usually detected on chest X-ray in patients already diagnosed as having carcinoma, but may be the first presentation. Typical sites for the primary tumour include the kidney, prostate, breast, bone, gastrointestinal tract, cervix or ovary.

Metastases develop in the parenchyma or pleura usually and are often relatively asymptomatic even when the chest X-ray shows extensive disease. Rarely, metastases may develop within the bronchi and present with haemoptysis.

Carcinoma, particularly of the stomach, pancreas and breast, can involve mediastinal glands and spread along the lymphatics of both lungs (lymphangitis carcinomatosa), leading to progressive and severe breathlessness. Chest X-ray signs of hilar lymphadenopathy and basal shadowing are unreliable compared with the characteristic signs on CT scan of irregular thickening of the interlobular septa in a polygonal pattern around a thick-walled central vessel.

Occasionally, a pulmonary metastasis may be detected as a solitary round shadow on chest X-ray in an asymptomatic patient. The most common primary tumour to do this is a renal cell carcinoma.

The differential diagnosis includes:

Single pulmonary metastases can be removed surgically but, as CT scans usually show the presence of small metastases undetected on chest X-ray, detailed imaging including PET scanning and assessment is essential before undertaking surgery

Aetiology and pathology

The majority of breast cancers arise from the epithelial cells of the milk ducts and reproduce their histological features in a variety of patterns (Table 9.30), of which the most common is an infiltrating ductal carcinoma. The molecular biology of breast cancer has revealed that further subdivision based on resemblance to basal, luminal A, or luminal B type ductal cells is associated with differing behaviour. For example the oestrogen receptor(ER), negative, progesterone receptor (PR) negative, mutated EGFR (Her2) negative, triple negative phenotype corresponds to a portion of the basal cell population and is associated with a worse prognosis than the luminal types. Some triple negative cancers also resemble the BRCA1 mutated cancers with an associated DNA repair deficiency which has been targeted with new drugs such as PARP inhibitors. For many cancers it is thought that there is an identifiable precursor in situ stage which is confined within the basement membrane and is still truly localized and detectable by its trademark microcalcification on a screening mammogram. For others, this stage may be so brief or non-existent as to not be detectable and invasive disease is present from very early in development with a consequently worse prognosis. Approximately 10% of women have familial breast cancer (Table 9.31) and 3% have detectable mutations in the BRCA1 and 2 genes and TP53. The hormonal environment exerts a major effect on the expression of the breast cancer potential and is related to reproductive behaviour, diet, exercise, weight and exogenous hormones from oral contraception and postmenopausal hormone replacement therapy.

Table 9.30 Breast cancer histology

Table 9.31 Familial patterns of breast and ovarian cancer with increased risk of inherited BRCA mutations

Symptoms and signs

Most women with symptomatic rather than screen-detected breast cancer present with a painless increasing mass which may also be associated with nipple discharge, skin tethering, ulceration and, in inflammatory cancers, oedema and erythema. In developing countries, 80% are likely to present with advanced disease and metastases.

Investigations

The triple assessment of any symptomatic breast mass by palpation, radiology (mammography, ultrasound and MRI scan) and fine-needle aspiration cytology is the most reliable way to differentiate breast cancer from the 15 times more common benign breast masses. Large bore core needle biopsy should follow to provide histological confirmation and predictive factors such as grade, Ki-67 proliferation index and oestrogen, progesterone and Her2 receptor status to inform the subsequent decision-making process. Assessment should be carried out in a dedicated one-stop clinic able to provide the appropriate support and referral. Staging is both surgical with respect to tumour size and axillary lymph node status and, in advanced disease, by investigation of common sites of metastasis by chest X-ray and CT scan of lungs and liver and bone scan. At present, only 20% of patients are diagnosed with no evidence of microscopic nodal metastases.

Prognostic factors

The following are all significant independent predictors of risk of recurrence: size of the primary tumour; the histological subtype (most are infiltrating ductal carcinoma); histological grade/differentiation; oestrogen and progesterone receptor (ER, PR) status; patient age and menopausal status. Expression of Her2 is an adverse factor for small otherwise good prognosis tumours and like ER and PR is a predictor of treatment response.

Gene expression profiles have identified sets of between 20 and 70 genes, the expression pattern of which can identify low-and high-risk subsets independent of the clinical risk factors. Clinical trials are in progress to test whether this leads to better decision-making and outcome than the traditional clinical factors.

Local treatment

Surgery may vary from wide local excision or segmental mastectomy and breast conservation for masses <3 cm in diameter, to simple mastectomy with or without reconstruction. The choice is dictated by the location and extent of the breast mass in relation to the breast size and patient preferences. In the absence of clinical or radiological (usually ultrasound) evidence of lymphadenopathy, surgery of the axilla can be minimized by sentinel lymph node guided sampling (after dye or radioactive tracer injection); otherwise dissection to level 3 is required if there are clinically involved nodes in order to gain local control and provide prognostic information to guide adjuvant treatment. The greater the amount of axillary surgery, the greater the risk of postoperative lymphoedema.

Radiotherapy is given to the conserved breast after wide local excision to reduce local recurrence and to the chest wall after mastectomy if there are risk factors for local recurrence to complete the local control measures. The indications for breast cancer adjuvant radiotherapy are:

Radiotherapy to the axilla can be added after sampling but not after full dissection of the axilla because the combination raises the risk of severe lymphoedema to 30%. Adjuvant radiotherapy reduces the risk of local recurrence by 25% and improves 10-year survival by 3%.

Recent data suggest that women over 70 years with oestrogen receptor positive cancers up to 2 cm diameter may be offered surgery and tamoxifen alone without radiotherapy, without compromising outcome.

Adjuvant systemic treatment

Endocrine therapy

Women who have high levels of oestrogen receptors (ER) and progesterone receptors (PR) in their tumour have a greater chance of responding to endocrine treatments (i.e. 60% versus 10% for ER negative disease). Endocrine responsive disease characteristics are:

Endocrine therapy is usually tried first in those patients who have characteristics suggesting they are likely to respond and who do not have immediately life-threatening organ failure. Remission lasts on average 2 years and is consistent with an excellent quality of life. When relapse occurs, further treatment with different agents may produce another remission.

Chemotherapy

Chemotherapy is used for patients who lack the above features of hormone responsive disease or who fail to respond to endocrine therapy or who require a rapid response if at risk of, e.g. liver or respiratory failure. Chemotherapy can provide good-quality palliation and prolongation of life. The drugs listed below are all able to induce objective responses in metastatic disease and patients in whom the disease responds are likely to experience further serial responses to subsequent treatment at relapse. There is no advantage in combining more than two drugs at a time and considerable uncertainty over the advantages of combinations with higher response rates but only rarely better survival compared with single agent regimens which have the advantage of preserving more options for future use. There is very little difference in efficacy between the different regimens for metastatic disease, with response rates varying from 40% to 60% for median duration of 8–10 months. The most common regimens with either single agents or doublet combinations include:

The multiple regimens provide the possibility of avoiding drug resistance over several episodes of treatment interspersed with treatment-free periods so that the disease can be palliated, often for several years.

The addition of trastuzumab and more recently lapatinib to the cytotoxic drugs (except the anthracyclines, see above) has significantly improved survival for those women whose tumour overexpresses the c-erbB2/Her2 oncogene. Inhibition of VEGFR by bevacizumab may be effective in a small proportion of patients but it is without as yet a predictive biomarker. Markers of DNA repair deficiency such as BRCA1 mutations render the breast cancer especially sensitive to the PARP inhibitor olaparib.

Bisphosphonate therapy

Bone metastases are a common problem in the management of breast cancer and the bisphosphonates have a major role in reducing the incidence of osteolytic deposits, bone pain and fracture when used preventatively and in treating pain and hypercalcaemia from established metastases. Second generation bisphosphonates pamidronate and oral clodronate are often sufficient. The more potent third generation drugs such as zoledronate and oral ibandronate may require less frequent administration but can be associated with impaired bone healing and osteonecrosis of the jaw (see Chapter 11). Denosumab is a MAb to the RANK ligand that inhibits osteolysis and is equally effective as bisphosphonates.

Oesophageal cancer

Early diagnosis as pioneered in Japan, where there is a particularly high incidence, has shown that it is possible to improve the prognosis of a disease otherwise typically only diagnosed when local metastases have already occurred.

Gastric cancer

Presentation and diagnosis of gastric cancer are described in Chapter 6.

Gastrointestinal stromal tumours (GIST)

These rare slow growing tumours may arise in the stomach, small or large intestine and carry a mutation of the cKit oncogene, which renders them sensitive to the receptor tyrosine kinase inhibitor imatinib (see Ch. 6). Surgery is potentially curative for localized disease and Imatinib can induce remissions in 50–80% by PET-CT criteria for a median of 2 years with further responses to dasatinib.

Small intestine cancer

Predisposing factors of small intestine presentation and treatment are described in Chapter 6.

Colorectal cancer

Presentation and diagnosis of colorectal cancer are described in Chapter 6.

Screening

See page 436.

Treatment

Treatment should be undertaken by multidisciplinary teams working in specialist units. About 80% of patients with colorectal cancer undergo surgery, though fewer than half of these survive more than 5 years. The operative procedure depends on the cancer site. Long-term survival is determined by the stage of the primary tumour, the achievement of clear surgical margins and the presence of metastatic disease (Table 9.33). There has been a gradual move from using Dukes’ classification to using the TNM classification system.

Table 9.33 Staging and survival of colorectal cancers

Metastatic colorectal cancer

Advanced colorectal cancer is successfully palliated with little toxicity by 5-fluorouracil and folinic acid regimens or oral capecitabine in approximately 30% of patients for a median of 12–14 months. The addition of irinotecan or oxaliplatin increases the proportion who benefit to 55% and extended median survival to 18 months but with increased toxicity. The anti-VEGFR monoclonal antibody bevacizumab and anti-EGFR cetuximab or panitumumab (for those with wild type KRAS and BRAF genes) increase the response rate with chemotherapy to 68% and the median survival from 14 to 24 months.

Liver and lung metastases are a common problem with colorectal cancers. With appropriate selection of patients with a good performance status and in whom MRI and PET-CT scans do not demonstrate extrahepatic disease, local treatment can prolong good quality survival. This can be accomplished with a variety of methods from surgical resection to gamma knife irradiation, radiofrequency, or cryo-ablation, or hepatic artery embolization. Small lesions can be ablated, larger lesions are best managed by partial hepatectomy or a combination approach so that embolization is followed by hepatic regeneration before final resection. Long-term survival without recurrence is reported in up to 20% of patients at 5 years with a single <4 cm lesion amenable to resection presenting more than a year from initial diagnosis and may be further extended by perioperative chemotherapy.

Anal cancer

Treatment is, where possible, with surgery or if locally advanced by downstaging with chemoradiotherapy with mitomycin-C (MMC) and 5FU followed by surgery.

Treatment and prognosis

HCC arises in a cirrhotic liver in 95% of cases and can be screened and detected by cross-sectional imaging and a rise in serum α-fetoprotein. Surgical resection of isolated lesions <5 cm diameter or up to three lesions <3 cm diameter is associated with a median survival of 5 years although the remaining liver remains at risk of further recurrence. Liver transplantation offers the only opportunity for cure for patients with a small primary but is limited often by the underlying cause of the hepatitis and cirrhosis. Conventional chemotherapy and radiotherapy are unsuccessful, but transarterial embolization or radiofrequency ablation in patients with small primaries as above and adequate liver function prolongs survival though less successfully than surgery. Antiangiogenic compounds are being evaluated: sorafenib prolongs survival in patients with non-resectable tumours to 10 months.

Prognosis

The 5-year survival rate for carcinoma of the pancreas is approximately 2–5%, with surgical intervention representing the only chance of long-term survival. Approximately 20% of all cases have a localized tumour suitable for resection and a median survival of 2 years but in an elderly population, many of these have co-morbid factors that preclude such major surgery.

Treatment

There is no proven adjuvant therapy for pancreatic cancer following surgery. To optimize the percentage of patients undergoing possible surgical resection it is necessary to review each case in a multidisciplinary meeting. This approach also allows formulation of treatment strategies for those considered unsuitable for surgery.

In the majority of cases, the management is palliative. Obstruction of the biliary tree and jaundice is a debilitating complication, often associated with severe pruritus but also the cause of nonspecific malaise, lethargy and anorexia. Endoscopic placement of endoprostheses (stents) offers excellent palliation.

Palliative surgery has a role in duodenal obstruction (a complication seen in 10% of cases) but in advanced disease self-expanding metal stents can be placed across the duodenal obstruction with excellent short-term results.

Chemoradiotherapy with gemcitabine for small locally advanced disease can achieve response in 30% and a median survival of 17 months. Palliative chemotherapy for advanced disease with gemcitabine and cisplatin can achieve a response in approximately 20% of patients with advanced disease with an improvement in median survival from 6 to 12 months.

With disease progression, abdominal pain is a frequent complicating factor which may prove extremely difficult to treat but can be helped sometimes by radiotherapy.

Aetiology and pathology

There is uncertainty over the tissue of origin that gives rise to the 80% of all ovarian cancers that are epithelial (Table 9.34). The ovarian surface epithelium of the serosal peritoneum or the epithelial lining of the fallopian tubes are most likely. There is a consistent relationship between the risk of epithelial ovarian cancer (EOC) and the frequency and duration of ovulation. While not mechanistically explained this has provided a successful rationale for reducing risk of EOC by up to one-third through early pregnancy and the use of the oral contraceptive pill. The non-epithelial cancers are of germ cell or stromal origin although molecular biological markers have shown that the category of mixed Müllerian sarcoma is an entirely epithelial tumour with metaplastic stromal elements.

Table 9.34 Ovarian cancer pathology

Symptoms and signs

Ovarian cancer typically causes few specific symptoms, often leading to late diagnosis. However, the following are most often associated and need investigation:

Sometimes, there is a sensation of a pelvic mass, which may become (acutely) painful, often there is only vague abdominal distension and epigastric discomfort. Symptoms of irritable bowel syndrome can be confused with those of ovarian cancer but rarely present for the first time over the age of 50 when they should stimulate investigation for ovarian cancer.

On examination, the majority of patients present with a pelvic mass and advanced stage III (spread within the peritoneal cavity) or IV (extraperitoneal) disease. Screening (see p. 436) by serum CA125 tumour marker and transvaginal ultrasound scan does detect some early cancers with improved survival but is being further refined with serial tests to avoid too many negative laparotomies and is thus still considered a research tool.

Investigation

Pelvic examination should be complemented by a serum CA125 tumour marker in primary care and transvaginal ultrasound. MRI is the definitive imaging technique for the pelvis while CT-PET scans assist in staging the patient.

An RMI >250 (risk of malignancy index, Table 9.35) should trigger investigation by a specialist gynaecological cancer team.

Table 9.35 Risk of ovarian malignancy index (RMI)

Prognostic factors

Histological subtype (clear cell and mucinous are worse), grade/differentiation, stage, extent of residual disease following surgery (macroscopic versus microscopic or none) and performance status are all significant independent prognostic factors for survival (Table 9.36).

Table 9.36 Invasive epithelial ovarian cancer

From Heintz APM, et al 2006 Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gyneacol Obstet 95(Suppl 1):S161–192, with permission.

Treatment

Surgery (with total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy) has a major role in the treatment of ovarian cancer. For patients in whom the disease is confined to the ovary, i.e. stage I, the surgery can be curative in 80–90% if the histology is well to moderately differentiated. For patients with poorly differentiated or more advanced disease, with spread throughout the peritoneal cavity, surgery still has a major role in staging the patient and improving survival when it is possible to debulk optimally to no visible residual disease. Primary chemotherapy and delayed surgery is an alternative approach when the disease is too advanced to permit primary debulking surgery and is able to render approximately one-third of inoperable patients fit for optimal debulking surgery. Survival of patients with such advanced disease is equal whether chemotherapy is given before or after surgery but preoperative downstaging can avoid much surgical morbidity.

Carboplatin, which is associated with fewer side-effects than cisplatin, has become the mainstay of epithelial ovarian cancer chemotherapy. Response is achieved in approximately two-thirds of patients. Paclitaxel has been shown to increase the response rate and improve the survival of many patients when added to a platinum-based treatment.

Adjuvant treatment with carboplatin and paclitaxel for stage I high-risk disease increases the absolute 5-year survival by 9%, from 70% to 79% and for combined stages I–III completely debulked disease by 19%, from 60% to 79%, a relative risk reduction of 29%.

In more advanced disease, 75% of patients will respond to combination chemotherapy and the median survival is approximately 3 years. Treatment at recurrence can be delayed until the disease is symptomatic. Further palliative responses can be achieved with carboplatin and paclitaxel if the treatment-free interval is >6 months, or liposomal doxorubicin, etoposide, gemcitabine and trabectedin are all active drugs for the palliation of recurrent disease. Up to 30% of those with metastatic disease may be alive after 5 years, although this falls to 5–10% if the cancer is not able to be debulked at operation or has spread outside the peritoneal cavity. It has proven difficult to develop more tageted biological agents for ovarian cancer. Bevacizumab when added to chemotherapy has increased disease-free survival by a few months and BRCA-positive tumours are sensitive to PARP inhibitors such as olaparib.

Epithelial ovarian cancer tends to remain within the peritoneal cavity often exclusively which has led to new intraperitoneal routes of administration of treatment with potentially improved survival. However, at recurrence bulk disease in the peritoneum commonly causes progressive bowel obstruction which may require palliative operation or expert palliative care support to manage the terminal phases of the illness.

Investigation and treatment

At diagnosis, renal cancers are staged using CT and/or MRI scans to assess operability and the presence of distant metastases. Prognosis depends upon the TNM stage, histological subtype and grade, performance status and serum LDH, calcium and haemoglobin levels.

A nephrectomy is performed unless bilateral tumours are present or the contralateral kidney functions poorly, in which case conservative surgery such as partial nephrectomy may be indicated. If metastases are present, nephrectomy may still be warranted when the primary tumour constitutes the main bulk of disease since regression of metastases has been reported after removal of the main tumour mass. Adjuvant treatments are unproven and being investigated. The 5-year survival rate is 60–70% with tumours confined to the renal parenchyma, 15–35% with lymph node involvement and only approximately 5% in those who have distant metastases.

Metastatic disease

Metastases are present in 20–30% of patients at diagnosis and are likely to develop in 40% of patients following surgery for apparently localized disease. Prognosis without treatment depends upon the extent of the disease as measured by the Memorial Sloan-Kettering Cancer Center (MSKCC) index comprising: performance status, high LDH, low haemoglobin, high calcium and primary in situ. Patients with no metastases and a score of 0 have a median survival of 20 months, those with a score of 1–2 have median survival 10 months and those with a score of >2 have median survival of 4 months.

Immunotherapy for renal cancer has been pursued since the observation of the occasional regression of metastases either spontaneously or following nephrectomy. In good performance status patients interferon-α produces a response in 16% with a median survival of 15 months. Interleukin-2 and interferon with 5FU is associated with a higher response rate (23%) but no longer survival. Other approaches such as tumour cell vaccines and stem cell transplants continue to be investigated.

Agents that target the VEGF (and other) receptors have been investigated because the inactivation of the VHL pathway in renal cancers leads to an increase in VEGF and PDGF production which is inversely associated with prognosis. The tyrosine kinase inhibitors sunitinib and sorafenib, the monoclonal antibody bevacizumab and the mTOR inhibitor temsirolimus have all demonstrated an ability to delay progression of disease and temsirolimus an improvement in survival. However, the incidence of cardiovascular and cerebrovascular toxicity may limit their use.

Presentation and diagnosis

Prognosis depends upon the performance status of the patient, the TNM stage of the tumour (in particular in the bladder whether it has penetrated the bladder muscle) and its degree of differentiation. After surgery, the surgical margins, lymphovascular invasion and nodal involvement are further prognostic factors.

Treatment

Prognostic factors

Diagnosis is usually made on a raised serum PSA (prostate-specific antigen) followed by a transrectal ultrasound-guided needle biopsy. The histological appearances are graded and accorded a Gleason Score, which together with the height of the serum PSA plus accurate staging of the local extent of disease with pelvic MRI and transrectal ultrasound can identify prognostic groups (Table 9.37). Treatment decisions must balance the age and performance status of the patient with the predicted behaviour of the cancer, which is becoming more objectively identifiable with advances in gene profiling. This allows the selection of patients with good prognosis for no active treatment who may reasonably choose to be kept under surveillance and, like 75% of men over the age of 80, die with, but not because of, their prostate cancer.

Table 9.37 Prostate cancer prognostic factors

Treatment (Chapter 12)

Patients with disease localized to the prostate requiring treatment can be managed by curative surgery (radical prostatectomy), or external beam radiotherapy, or brachytherapy implants which can achieve equivalent survival rates but differ in the spectrum of unwanted side-effects with respect to incontinence and sexual dysfunction. Radiotherapy tends to be more used in older patients who wish to avoid surgery. In appropriately selected series of patients a 5-year survival of 85% can be achieved. Adjuvant radiotherapy after radical prostatectomy can reduce PSA relapse but has not increased overall survival. Discussion between patient and clinician is vital to enable a treatment choice that is most appropriate to the patient’s circumstances; many of the patients are elderly and the side-effects of treatment are significant with often no improvement in mortality.

Symptoms and signs

Most men present with a testicular mass which is often painful, some with symptoms of metastases to the para-aortic lymph nodes with back pain and gynaecomastia if hCG secreting. In women, the mass presents with vague pelvic symptoms but at a younger age than the more common epithelial ovarian cancers.

Gynaecomastia in a man with β-hCG secreting testicular cancer.

Investigations and surgery

A urinary pregnancy test for hCG in A&E has saved the lives of young men with metastatic germ cell cancer.

Treatment

Diagnosis

Diagnosis requires histology first and foremost, as it will lead to the identification of several distinct groups.

Tissue tumour markers can be helpful (Table 9.39) and increasingly, gene profiles can identify the primary site of origin by gene expression microarray and RT-PCR.

Table 9.39 Adenocarcinoma of unknown primary (ACUP): immunohistochemistry markers of most probable but not exclusive tissue of origin

Investigations should therefore always start with a review of the histology, a chest X-ray and CT scan of chest, abdomen and pelvis, with, in men, serum PSA and rectal ultrasound to identify prostate cancers and in women, mammography and breast MRI to identify occult breast cancer and pelvic MRI to identify ovarian cancer.

For good prognosis patients wishing to have palliative chemotherapy, investigations such as endoscopy to identify lung, colon or stomach primaries are indicated to guide the choice of chemotherapy agents, although the diagnostic yield of 4–5% must be set against the discomfort and risks. Serum tumour markers for other solid cancers, although highly sensitive, are too nonspecific and unreliable to be useful as diagnostic aids in this situation.

Further investigation may require PET-CT for head and neck, lung and possibly other primaries and radioisotope scans for thyroid and carcinoid tumours. PET-CT may also be used to seek other metastatic sites if considering surgery for unifocal disease.

Prognosis

The histological type and extent of the disease and performance status of the patient are the key factors. Most large series report an overall median survival of 12 weeks but considerably better survival amongst the special subgroups such as patients presenting with isolated nodal metastases who have a significantly better prognosis than the majority with visceral and/or bone metastases and may warrant more extensive investigation.

Treatment

If investigations have not identified a primary site, surgery may be considered for unifocal ACUP metastases in lymph nodes, lung, liver and brain especially if due to melanoma with potential for long-term survival.

In women, an isolated axillary lymph node metastasis should be treated as for lymph-node-positive breast cancer with a similar prospect for long-term cure though without the need for breast surgery. Malignant ascites in women should have a trial of chemotherapy as for primary peritoneal, fallopian tube or epithelial ovarian cancer. The prognosis for those responding to the therapeutic trial is similar to the disease of known primary origin. Primary chemotherapy that achieves an excellent response by imaging and CA125 criteria should be followed by debulking surgery with, if successful, a median survival in excess of 4 years.

For men, the occasional occult prostatic cancer found from a raised serum PSA offers some palliative treatment prospects (Box 9.14).

For the patient presenting with hepatic metastases most commonly associated with an occult gastrointestinal primary there is an increasing choice and efficacy of chemotherapy agents for gastrointestinal cancers that have the potential to improve their palliation.

If there is an excellent response, suitable patients may even be considered for hepatic ablation or resection. If after all efforts no primary has been identified, palliative chemotherapy treatment can achieve responses in 20–40% in highly selected series, with median survivals of 9–10 months and 5–10% surviving to 5 years.