Myeloma and Lymphoma

Question 1

Describe the origins of blood cells

Answer 1

Question 2

What is multple myeloma?

Answer 2

A disease of plasma cells; consists of clonal proliferation of malignant plasma cells, although the cell in which the malignant event initially occurs is thought to be more immature

Question 3

Describe the physiological differentiation of immature B cells

Answer 3

As immature B cells migrate from the bone marrow, Ag exposure yields either memory B cells or plasmablasts

Plasma cells return to the marrow and secrete low levels of Ab

Question 4

Describe the sequence of biological events related to progression from precursor disease to multiple myeloma

Answer 4

Transition from normal plasma cells to precursor disease (MGUS) and ultimately MM reflects a progression of oncogenic events, with acquisition of mutations and cytogenetic abnormalities en route (“karyotypic instability”)

Almost all cases of MM are cytogenetically abnormal

Question 5

What changes are seen in the bone marrow of patients with MM?

Answer 5

Normal marrow normally has <5% non-malignant plasma cells

In MM there is infiltration of excess plasma cells, often with bizarre morphology e.g. binucleate forms

Question 6

How does the bone marrow microenvironment aid the progression of myeloma?

Answer 6

Interactions of plasma cells and the bone marrow microenvironment provides a sanctuary for MM by both promoting proliferation and blocking apoptosis:

1) MM cells adhere to ECM proteins and bone marrow stromal cells through a series of adhesion molecules e.g. VLA-4, VCAM-1, ICAM-1
2) Bone marrow homing of plasma cells is further facilitated through other adhesion molecules expressed by myeloma cells e.g. CD138, CD38, CD44, CD106
3) The binding of MM cells to the bone marrow microenvironment induces transcription and secretion of cytokines (TNF-a, IL-6, IGF, VEGF), triggering signalling pathways which promote cell proliferation and prevent apoptosis

Question 7

What are the main future therapeutic targets for MM?

Answer 7

Pathways within the malignant plasma cells

Interactions between malignant plasma cells and their marrow microenvironment

Question 8

What does polyclonal mean?

Answer 8

Normal plasma cells secrete immunoglobulins, composed of heavy chains and light chains, and these are different for each plasma cell (i.e. polyclonal)

Question 9

What is the M protein in MM?

Answer 9

In myeloma, the Ig made is clonal and can be detected and quantitated as an intact paraprotein called the M protein, and/or just the light chain component of Ig (i.e. some myeloma is “light chain only”)

Question 10

How can the abnormal proteins in myeloma be detected on testing?

Answer 10

Light chains can be detected in serum or urine as Bence Jones protein; the type and quantity of these abnormal proteins can be measured by protein electrophoresis and immunofixation in serum and urine

Question 11

What are the characteristics of MGUS?

Answer 11

Monoclonal gammopathy of unknown significance:

Serum M-protein <30g/L

Marrow clonal plasma cells <10%

No CRAB

No evidence of B-cell lymphoma or other disease known to produce M protein

Precedes myeloma

Question 12

What are the characteristics of asymptomatic (smouldering) myeloma?

Answer 12

M-protein in serum at myeloma levels (>30g/L)

AND/OR 10% or more clonal plasma cells in bone marrow

BUT no CRAB

Question 13

What are the diagnostic criteria for myeloma?

Answer 13

M-protein in serum or urine: in most cases >30g/L of IgG or >25g/L of IgA, or high level of light chain in urine or serum in light chain only myeloma (occasionally patients with symptomatic myeloma have levels lower than these)

Bone marrow clonal plasma cells or plasmacytoma: plasma cells usually >10% of nucleated cells in the marrow, there may be a plasmacytoma (mass of clonal plasma cells outside the BM)

Most important criteria for symptomatic myeloma are manifestations of end-organ damage i.e. CRAB

Question 14

CRAB symptoms

Answer 14

Hypercalcaemia

Renal insufficiency

Anaemia

Lytic Bone lesions

Can add: hyperviscosity, amyloidosis, recurrent infection

Question 15

Describe how myeloma causes its symptoms

Answer 15

Question 16

Describe 5 clinical scenarios in which myeloma should be part of the DDx

Answer 16

Patient presenting with # or bone pain (often in neck or back) without any precipitating event and XR shows lytic lesions, severe OP or crush fractures

Unexplained anaemia with rouleaux on blood film and high ESR

High total protein despite normal or low albumin level

Unexplained hypercalcaemia

Unexplained renal failure

Question 17

Myeloma Ix

Answer 17

FBE: anaemia

UEC: renal function

CMP: hypercalcaemia

Serum and urine protein electrophoresis and measurement of free light chains

B2 microglobulin

Serum albumin

LDH

Bone marrow examination: morphology of BMAT (quantify plasma cells usuing a CD138 stain), cytogenetics and FISH for chromosomal abnormalities (prognostic information)

Imaging: skeletal survey of skull, spine and long bones (often may show many lytic lesions, hence the term MULTIPLE myeloma), spinal MRI in some instances (e.g. for severe back pain where there is suspected cord compression due to crush fractures of spine and plasmacytomas)

Question 18

Outline a chromosomal abnormality which confers a poor prognosis in myeloma

Answer 18

t(4;14)

Question 19

55 year old man presents to GP with progressive mid-thoracic pain without any precipitating factors; more recently has developed mild leg weakness

GP arranges FBE/biochemistry and a plain XR; radiologist calls urgently to inform her of multiple lytic lesions in the pelvis and crush fractures in thoraco-lumbar vertebrae

FBE: normochromic anaemia

CMP: high Ca2+

GP is concerned RE spinal cord compression and transfers patient by ambulance to nearest ED

What features would be expected on XR in a patient with MM and what is the pathogenesis of these signs?

Answer 19

Destructive lytic lesions, osteopaenia and crush fractures of vertebrae

Due to tumour growth and activation of osteoclasts via IL-6 signalling

Question 20

What treatment may be indicated in a patient with lytic lesions in weight-bearing bones?

Answer 20

May require surgical intervention (e.g. can get destruction of neck of femur)

Question 21

55 year old man presents to GP with progressive mid-thoracic pain

Examination shows signs consistent with early cord compression

Blood tests suggest the possibility of myeloma

Patient is referred to the haematology unit and an urgent MRI is arranged

He is scheduled to have a skeletal survey and a bone marrow biopsy the following day

What abnormalities on FBE, blood film, plasma biochem and LFTs would be consistent with MM?

Answer 21

FBE: low Hb, low platelets, normal MCV, elevated ESR

Film: severe anaemia with rouleaux and mild background protein staining

Biochem: may be signs of renal impairment (elevated urea/creatinine), hypercalcaemia

LFTs: low albumin, high total protein

Question 22

What are rouleaux?

Answer 22

Rouleaux are stacks or aggregations of RBCs which form because of the unique discoid shape of the cells in vertebrates; the flat surface of the discoid RBCs gives them a large surface area to make contact with and stick to each other; thus forming a rouleau

They occur when the plasma protein concentration is high, and because of them the ESR (erythrocyte sedimentation rate) is also increased; this is a non-specific indicator of the presence of disease

Question 23

Mx of MM with cord compression

Answer 23

High dose steroids

Urgent referral for immediate radiotherapy to control imminent cord compression

Medical management of hypercalcaemia (rehydration and IV bisphosphonate)

Ongoing radiotherapy and systemic chemotherapy after confirmation of Dx on PEP, marrow and XR

Question 24

What results would be expected on EPG in MM?

Answer 24

Increased total protein

Low albumin

Increased kappa LC

Low lambda LC

High K/L ratio

High B2 microglobulin

Serum EPG results: monoclonal band 36 g/L in gamma region, residual gamma globulins markedly reduced

Question 25

What results would be expected on bone marrow biopsy (and cytogenetic analysis of the aspirate) in a patient with MM?

Answer 25

Extensive infiltration with plasma cells CD138+ by immunohistochemistry

Cytogenetic analysis of the aspirate: hyperdiploidy

Question 26

What does hyperdiploidy on cytogenetic analysis of BMAT indicate about the prognosis of a MM?

Answer 26

Poor prognostic sign

Question 27

Mx of MM (underlying disease and chemotherapy)

Answer 27

Underlying disease: chemotherapy, judicious transfusions if severely anaemia, bisphosphonates +/- radiotherapy for bone disease

Chemotherapy: thalidomide-based induction in combination with alkylator and steroids (e.g. cyclo/thal/dexa = CTD), lenalidomide or bortezomib for relapse, autologous transplants, clinical trials now using new monoclonal Abs

Question 28

List 5 medical emergencies seen in MM

Answer 28

Hypercalcaemia

Spinal cord compression

Renal failure

Hyperviscosity (uncommon)

Infections

Question 29

75 year old lady presents to her GP with a fractured radius after a fall; plain XRs suggest OP

Her GP refers her to the OP clinic where as part of a series of Ix she is noted to have a paraprotein IgG 5g/L

She is then referred to the haematology unit for an opinion on whether she may have myeloma; Ix include a normal FBE, Ca2+, renal function, serum free light chains, skeletal survey

It is decided not to perform a bone marrow biopsy as there are no clinical features to support a Dx of MM

Diagnosed with MGUS

She is counselled about the low risk of progression to myeloma and advised regarding annual assessment of her M protein and potential concerning symptoms

She elects to be followed by her GP and is discharged from the specialist clinic, with the understanding to be seen again promptly should there be concern

Given annual zoledronic acid infusion for osteoporotic #

Mx for MGUS?

Answer 29

No treatment

Generally monitored annually due to 1-2% annual risk of progression to myeloma

NB Interestingly, studies have suggested that virtually all patients with myeloma have a preceding MGUS phase

Question 30

Is a finding of low paraproteins (usually <10-15g/L) cause for concern?

Answer 30

Not if there are no clinical features of MM; low level paraproteins are quite common, esp in the elderly, and may be found incidentally in the Ix of other clinical presentations such as OP or renal impariment

Question 31

What are the most common ways true MM presents?

Answer 31

Can present in a number of different ways but problems related to bony disease and renal impairment are the commonest

Question 32

What is the current prognosis for multiple myeloma?

Answer 32

Have been major therapeutic advances in myeloma which have substantially improved the outcome in what traditionally was a poor prognosis disease

Question 33

How is non-Hodgkin lymphoma classified?

Answer 33

According to cell lineage (e.g. B vs T cell)

Functionally into clinically distinct disease groups based on aggressiveness

Question 34

Give a common example of a low, intermediate and highly aggressive B cell NHL

Answer 34

Question 35

What are the clinical features of lymphoma?

Answer 35

Palpable pathological lymphadenopathy (firm, rubbery, non-tender; rate of growth depends on biological aggressiveness of subtype)

Dyspnoea and cough with subsequent demonstration of a mediastinal mass

Abdominal swelling and/or progressive discomfort (although non-specific)

PUO and night sweats)

Question 36

A 28 year old woman presents to her GP with progressively enlarging lower neck lump and worsening dyspnoea over the last few weeks

FBE and CXR are arranged

FBE: low Hb, elevated platelets, elevated WCC with elevated neutrophils and eosinophils and low lymphocytes

ESR: 65mm/hr

CXR: enlarged superior mediastinum

GP discusses her case by phone with the empathic and committed haematology registrar at the local hospital, who arranges to see the patient the next day in clinic and notes that the palpable supraclavicular lymphadenopathy is pathological

Suspecting lymphoma (clinical scenario, typical FBE findings), an urgent biopsy of the LN is arranged with further blood studies and a PET scan

What features would be expected on LN biopsy in classical HL at high and low power? What findings on immunohistochemistry would confirm the Dx?

Answer 36

Low: nodularity and sclerosis

High: abundant Reed-Sternberg cells and occasional eosinophils

Immunohistochemistry with CD30+ and CD15+ cells confirm the Dx

Question 38

How is lymphoma diagnosed?

Answer 38

On the basis of Hx (e.g. B symptoms) and examination, relevant blood tests (FBE, chemistry, LDH), and histopathology examination and Dx of LN or other biopsied lesion

Question 39

What Ix are used in staging lymphoma?

Answer 39

Radiological (most commonly CT or PET/CT)

Bone marrow assessment: morphology, immunohistochemistry +/- flow cytometry

Question 40

Describe the Ann Arbor staging classification

Answer 40

Stage I: lymphoma is located in a single region, usually one LN and the surrounding area

Stage II: lymphoma is located in two separate regions, confined to one side of the diaphragm

Stage III: lymphoma involves nodes or organs on both sides of the diaphragm

Stage IV: indicates diffuse or disseminated involvement of one or more extra lymphatic organs, including any involvement of the liver, bone marrow or nodular involvement of the lungs

A or B: absence of constitutional (B-type; weight loss +/- fever +/- night sweats) symptoms is denoted by adding an “A” to the stage, the presence is denoted by adding a “B” to the stage

Question 41

28 year old woman presents to her GP with progressively enlarging lower neck lump and worsening dyspnoea over the last few weeks

PET scan: multiple foci of intense FDG uptake corresponding to lymphadenopathy are demonstrated in the posterior triangle cervical nodes bilaterally, both supraclavicular nodes, the superior and anterior mediastinum, upper and lower paratracheal nodes, and in the anterior chest wall deep to the pectoralis muscles

Case is discussed at the lymphoma MDM which includes representatives from haematology, radiology, pathology and cancer support staff

Dx of stage IIB Hodgkin lymphoma is confirmed

MDM consider the treatment options including chemotherapy or combined chemo-radiotherapy; treatment recommendation is individualised to maximise the chances of cure with the least short and long-term toxicity

What considerations should be made when considering treatment regimens for this patient?

Answer 41

Using prognostic models based on clinical features (stage, Hb, ESR, bulk, etc) to determine the intensity of the chemo regimen (some acronyms include ABVD and BEACOPP) and the number of cycles

In young women, the potential impact on fertility by chemotherapy (and strategies to prevent infertility)

Radiotherapy: consider risk of breast malignancy in women and, in both sexes, the risk of later coronary arery disease by radiation exposure

Question 42

65 year old man presents to GP with progressive, nagging but not severe, vague abdominal pain

Observed for 3/52 but pain worsens

An anterior abdominal mass is palpated

The GP arranges blood tests and a CT abdomen/pelvis

FBE: low Hb, low WCCs, low platelets

Film: occasional circulating abnormal lymphoid cell

CT: diffuse peritoneal thickening (black arrows), diffuse nodular infiltration of omentum (white arrows), bowel wall thickening (black arrowhead) and ascites (asterisk)

Patient is referred to the same friendly, competent and decisive haematology registrar as the previous case

The following Ix are promptly arranged: additional blood tests and a biopsy of the abdominal lesion

What findings would you expect on biochem?

Answer 42

Elevated LDH

Elevated uric acid

Elevated urea and creatinine

Low Ca2+

Low albumin

Elevated ALP and AST

Question 43

What findings are expected on histopathology in diffuse large B cell lymphoma?

Answer 43

Large centroblast-like cells on H+E which are diffusely CD20 positive on immunohistochemistry

Question 44

Bone marrow biopsy for a patient with diffuse B cell lymphoma demonstrates extensive involvement (relatively uncommon)

PET/CT: no disease outside the abdomen

Classified as stage 4 disease with high LDH and uric acid indicating a DLBCL which is more aggressive than most (note there is substantial heterogeneity in clinical behaviour)

What degree of risk would this lymphoma be classified as, and on what basis?

Answer 44

High risk

Prognostic model includes age, stage, LDH, extranodal sites (such as BM) and performance status

Question 45

Woman diagnosed with stage 4 DLBCL with high LDH and uric acid, indicating a DLBCL which is more aggressive than most (note there is substantial heterogeneity in clinical behaviour)

MDM consensus is that the patient requires urgent multi-agent chemotherapy and prophylaxis against a) tumour lysis which can occur in treatment of rapidly growing lymphomas and b) CNS disease

Outline the specifics for her Mx

Answer 45

Urgent multi-agent chemotherapy with R-CHOP (R = rituximab, a monoclonal Ab against CD20 which is expressed on the surface of all B cell NHL, the use of which has increased survival rates by 10-15%)

Prophylaxis against tumour lysis which can occur in treatment of rapidly growing lymphomas: hydration, monitoring electrolytes, drugs to lower uric acid

BM involvement and high LDH indicate high CNS disease: extra chemotherapy via LPs

Question 46

How does follicular NHL (low grade) usually present?

Answer 46

Painless, slowly growing (may often wax and wane) lymphadenopathy

Question 47

When is follicular NHL usually diagnosed?

Answer 47

At stage 4 (often with BM involvement)

Question 48

Mx of follicular NHL

Answer 48

May only require therapy if symptomatic

Question 49

Histopathological appearance of follicular lymphoma

Answer 49

Question 50

What are the clinical features of Burkitt lymphoma?

Answer 50

Not common

Rapidly growing

Ix: high LDH, histology shows cells with vacuolated cytoplasm

Mx: requires urgent and aggressive chemotherapy

Question 51

What emerging treatments are available for treatment of lymphoma?

Answer 51

New monoclonal Abs: more potent anti-CD20 Abs (e.g. GA101), Abs against different targets on B cells (e.g. CD22, target of ofatumumab)

MoAbs conjugated with other bits: anti-CD19 (a B cell Ag) combined with a receptor which attract T cells, causing T cell mediated tumour cell kill (blinatumumab), or anti-CD30 combined with a microtubular toxin in HL (brentuximab)

Emerging role of allografting in selected patients