The Circulatory System

1
The Circulatory System

• Cardiovascular and Lymphatic systems combined
• Incorporates lymphomas and leukaemias
• Both systems and diseases involve blood
  production sites
• Bone marrow, spleen, lymph nodes etc

2
(No Transcript)
3
BLOOD

• 45 formed elements
• Erythrocytes
• Leucocytes
• Thrombocytes

• 55 Plasma
• Water
• Proteins
• Electrolytes
• Gases
• Hormones
• Etc

4
Normal Blood Count

• RBC
• WBC
• PLATELETS

• 4.5-5.5 106/mm3
• 5-10 103/mm3
• 250-400 103/mm3

5
Diagrammatic Representation of acute and chronic
leukaemia pathways
6
Blood Cells

• Erythrocytes
• Carry oxygen to cells of body and CO2 away from
  cells

• Thrombocytes (platelets)
• Clotting factor

7
White Blood Cells
8
Hematopoietic Diseases

• Characterised by an overproduction of one
  (sometimes more than one) type of blood cell
  (usually WBC)

9
HaematopoieticDiseases

• Myeloid Disease
• Myelodysplastic disease
• Myeloproliferative disease (Chronic)
• Acute Myeloid Leukaemia (AML)

• Lymphoid disease
• Lymphocytic leukaemia
• Lymphomas
• B-cell
• Myeloma (plasma cell)
• T-cell

10
Diagrammatic Representation of acute and chronic
leukaemia pathways
11
LeukaemiaIncidence

• 3 of all cancers in UK

Source ONS
12
(No Transcript)
13
(No Transcript)
14
AETIOLOGY

• ACQUIRED
• Radiation
• viral
• chemical
• cytotoxic drugs

• GENETIC
• Down syndrome
• Siblings, twins
• PH ve (CML, AML)

15
PATHOLOGY

• ACUTE
• Immature blood cells
• Usually WBC
• causes crowding out of normal production of RBCs
  and platelets

• CHRONIC
• mature leucocytes - but live longer than
  normal
• enlargement of organs

16
Typical blood picture

• Normal
• Hb 10-14 g/dl
• WBC4-10 109/l
• Platelets 250 109/l

• Leukaemic (approx)
• 7-9 g/dl
• 10-200 109/l
• 30 109/l

17
LEUKAEMIASIGNS AND SYMPTOMS

• Tired, listless, pale
• Epistaxis, haematemesis, haematuria, melaena,
  bruising, petechiae
• Fever, infection, ulceration,
• bone pain, lymphadenopathy, hepatomegaly,
  splenomegaly

• ANAEMIA
• THROMBOCYTOPENIA
• NEUTROPENIA
• other

18
Myeloid Disease

• Myeloid neoplasms consist of diseases that are
  commonly considered together because of their
  origin from the same initial differentiation
  pathway

19
Myeloid Disease

• These diseases manifest themselves in over-
  production of any one of the resultant blood
  cells (red, platelets, monocytes, basophils,
  eosinophils or neutrophils) at the expense of
  other blood cells.

• Myelodysplastic disease
• Myeloproliferative disease
• Acute Myeloid Leukaemia (AML)

20
Myelodysplastic syndromes (MDS)

• True malignant haemopoetic disease is sometimes
  preceded by a group of disorders known as
  myelodysplastic syndromes (MDS), a group of
  diseases in which the production of blood cells
  is severely disrupted
• Myelodysplasia suggests a problem with the bone
  marrow, but in contrast to leukaemia, where
  usually one type of blood cell is over- produced,
  MDS manifests itself in the over production of
  more than one kind--and sometimes all kinds--of
  blood cells

21
(No Transcript)
22
Myelodysplastic syndromes (MDS)

• Poor quality blood cells often die before
  getting to circulation
• Leads to panocytopenia decrease in all types of
  blood cells, with associated symptoms
• No real cure, treatment supportive rather than
  curative. May attempt BMT in highly selected
  patients (younger)
• Often termed pre-leukaemia may progress to
  Myeloproliferative disorders

23
Myeloproliferative Disorders

• Chronic myelogenous leukaemia (Ph)
• Chronic neutrophilic leukaemia
• Chronic eosinophilic leukaemia
• Chronic idiopathic myelofibrosis
• Polycythemia vera
• Essential thrombocytothemia

24
Myeloproliferative Disorders

• Over production of mature(ish) cells from the
  myeloid series
• Typical symptoms include, enlarged spleen, fever,
  infection
• May progress to become acute myelogenous
  leukaemia

25
CHRONIC MYELOID LEUKAEMIA

• Onset slow, progressive tiredness
• gross splenomegaly
• skin infiltration - rare
• WBC 100 - 300 109/ l
• 30 myelocytes
• platelets normal or raised

• 50 -60 Yrs
• related to the Philadelphia Chromosome 95 of
  cases

26
PHASES OF CML

• CHRONIC PHASE few blast cells (lt10)
• Palliative treatment or no treatment if
  asymptomatic
• Chemo. if symptoms
• Interferon, Glivec (Imatinib) or Stem cell
  transplants
• ACCELERATED PHASE
• Results of treatment v.v.poor for myeloblastic
  type
• lymphoid type
• chemo
• cranial rt with intrathecal MTX
• BLASTIC PHASE
• Advanced stages of disease.
• Very difficult to cure.
• Patient usually dies within weeks due to
  infection, bleeding or organ failure

27
GLIVEC (Imatinib)

• Blocks the production of proteins which stimulate
  WBC production
• 98 in Chronic phase - complete or good response
• 20 in accelerated phase will regress to the
  chronic phase
• 2 out of 3 will have disease kept under control

28
GLIVEC (Imatinib)

• Does have some side effects which some people may
  not be able to tolerate and therefore stop
  treatment
• Nausea
• Water retention
• Puffy eyes
• Vomiting
• Rash
• Headaches

29
ACUTE LEUKAEMIA AML

• 80 of all adult cases, mainly middle aged and
  elderly
• associated risk with radiation exposure, workers
  who use benzene, people treated for ALL using
  alkylating agents. Smoking (?double the risk)
• Can be a progression from myeloproliferative
  disorders

30
ACUTE LEUKAEMIA AML

• Pathology
• diagnosed by bone marrow aspirate with lt20 blast
  cells
• various categories defined by the World Health
  Organisation
• Categories based on the type of myeloid cell
  proliferating (see handout)

31
Diagrammatic Representation of acute and chronic
leukaemia pathways
32
Acute Myelogenous Leukaemia

• Over production of one type of myeloid immature
  (blast) cell which do not function as normal
• Causes crowding out of red cells (anaemia),
  platelets (thrombocytopenia), and normal white
  cells (neutropenia)

33
Management

• Chemo. mainstay of treatment
• Daunorubicin
• Cytarabine
• Bone Marrow Transplant BMT with TBI

34
Lymphoid disease

• Two main groups
• B cell neoplasms
• T cell neoplasms
• Of these three subgroups can be identified by
  their individual characteristics

35
Lymphoid disease

• Lymphocytic leukemia a lymphoid neoplasm with
  bone marrow involvement, accompanied by tumour
  cells in the peripheral blood. Lymphocytic
  leukaemias may suppress haematopoiesis and may
  also spread and infiltrate into and enlarge the
  spleen and liver.
• Lymphoma a proliferating discrete mass that
  mainly affects the lymphatic system of the body.
  The subtypes are Hodgkin Lymphoma (HL) and
  non-Hodgkin lymphoma (NHL).  
• Plasma cell neoplasms mature B-cells that are
  made in the marrow attack bone or soft tissues
  also called myeloma.

36
Lymphocytic Leukaemia

• Neoplasms manifesting in the bone marrow
• Precursor (Acute) or Mature (chronic)
• B or T origin
• At different stages of the differentiation pathway

37
ACUTE LYMPHOBLASTIC LEUKAEMIA

• 3/4 OF ALL CHILDHOOD LEUKAEMIAS
• normally presents between 2-8 years of age
• PEAK AGE - 4YRS
• BG 21

• ? IONISING RADIATION
• ? GENETIC (20-30 fold increased incidence in
  those with Down Syndrome
• ? IDENTICAL TWIN WITH LEUKAEMIA

38
CLINICAL PRESENTATION

• Malaise
• Anaemia
• Pallor
• Fever
• Purpura
• Lymphadenopathy

• Splenomegaly
• Hepatomegaly
• Bone, joint pain
• Thrombocytopenia

39
INVESTIGATION

• Blood test
• Bone marrow biopsy
• Chest radiograph
• Lumbar puncture
• CT scan

40
ACUTE LYMPHOBLASTIC LEUKAEMIA

• Pathology
• B or T cell lineage
• B cell leukaemia
• Precursor B
• Earlier in lineage tends to be younger patient
  and better prognosis
• T cell leukaemia
• Precursor T
• Male and older
• Often present with enlarged thymus and
  lymphadenopathy

41
MANAGEMENT

• Four main phases to treatment (2-3 years to
  complete)
• 1ST PHASE
• INDUCE REMISSION WITH SUPPORTIVE THERAPY
• PREDNISONE, VINCRISTINE,L-ASPARGINASE
• 2ND PHASE
• CNS TREATMENT cranial irradiation and
  intrathecal methotrexate
• 3RD PHASE
• Consolidation/intensification
• Methotrexate
• 4th PHASE
• Maintenance
• Oral methotrexate for 2yrs, or oral
  6-mercaptopurine
• Chance of relapse in testes for boys, confirm at
  biopsy and remove affected testis (or irradiate)

42
CHRONIC LYMPHOCYTIC LEUKAEMIA

• ? Leukaemia or low grade non-hodgkin lymphoma
• MF 21
• 40-50 yrs

• slow progression to disease
• 25 present incidentally
• tiredness
• enlarged lymph nodes
• enlarged spleen
• raised WBC usually small lymphocytes

43
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)

• The WHO classification recognises that here are
  many different types of CLL and referred to as
  MATURE neoplasms
• And that it may occur principally in the bone
  marrow (lymphocytic leukaemia) or the lymphatic
  system (lymphoma cell leukaemia)
• Cross over here between leukaemia and
  non-hodgkins lymphoma

44
TREATMENT

• Only indicated if patient has symptoms or if
  critical organ involved
• Chemotherapy
• Local RT to bulky tumor

• 50 survive 5yrs
• Less than 1yr if disease is advanced

45
PROGNOSIS5 yr survival rates
Source Cancer Research UK
46
(No Transcript)
47
LYMPHOMAS

• A group of diseases originating in the
  Lymphatic system,
• May also affect diffuse lymphatic tissue around
  the body
• spleen, liver, intestines, thymus and tonsils

48
LYMPHOMAS

• HODGKIN Lymphoma
• NON-HODGKIN Lymphoma

49
HODGKIN LYMPHOMA EPIDEMIOLOGY

• PROGNOSIS IMPROVING OVER LAST 25 YRS
• better understanding of RT and Chemo.
• better localisation and staging methods
• better understanding of patterns of spread

Reproduced with permission from the Office of
National Statistics,
50
HODGKIN LYMPHOMA EPIDEMIOLOGY

• Bipolar age of incidence inc.
• MF 32 (West)
• more common in higher social class

51
HODGKIN LYMPHOMA Aetiology

• Unclear as to what causes HL
• Some ideas include
• genetic susceptibility
• siblings at greater risk if member of family has
  HL
• Twins are at 100x risk
• infection
• EBV
• reduced immunity
• HIV
• transplants

52
HODGKIN LYMPHOMA Pathology

• normal lymphoid tissue replaced by (amongst
  others)
• atypical mononuclear cells
• multinucleate Reed-Sternberg cells

This is a diagrammatic representation of a high
power view of a Reed-Sternberg cell seen with
Hodgkin's disease. Note the large, prominent
nucleoli.
53
HODGKIN LYMPHOMA WHO -Histiological
Classification

• Nodular lymphocytic-predominant
• Classical Hodgkins Lymphomas
• LYMPHOCYTE - RICH
• NODULAR SCLEROSING
• MIXED CELLULARITY
• LYMPHOCYTE DEPLETED

54
ANN ARBOR STAGING

• STAGE I
• Involvement of a single lymph region (I) or a
  single extralymphatic organ (IE)
• STAGE II
• Involvement of two or more lymph node regions on
  the same side of the diaphragm (II) or localised
  involvement of an extralymphatic organ or site
  and of one or more lymph node regions on the same
  side of the diaphragm (IIE)
• STAGE III
• Involvement of lymph node regions on both sides
  of the diaphragm (III) which may also be
  accompanied by localised involvement of an
  extralymphatic organ or site (IIIE) or by
  involvement of the spleen (IIIS) or both (IIIES)
• STAGE IV
• Diffuse or disseminated involvement of one or
  more extralymphatic
• organs or issues with or without associated
  lymph node enlargement.
• B symptoms should also be noted

55
HODGKIN LYMPHOMA CLINICAL FEATURES

• Most people present with a lump in neck, chest,
  armpit, abdomen or groin
• B Symptoms
• unexplained weight loss (more than 10 of body
  weight)
• unexplained fever for more than 3 days
• drenching night sweats

56
HODGKIN LYMPHOMA INVESTIGATIONS AND DIAGNOSIS

• Clinical Examination
• Biopsy
• Full Blood Count and ESR (Erythrocyte
  Sedimentation Rate, Liver function tests
• CT Scan/MRI
• Chest X-ray
• Positron Emission Tomography (PET)

57
HODGKIN LYMPHOMA MANAGEMENT

• RADIOTHERAPY
• RT CHEMO.
• CHEMOTHERAPY

• Ia, IIa
• IIa (Bulky mediastinum)
• Ib, IIb, IIIa, IIIb, IVa, IVb

58
Radiotherapy for Hodgkin Lymphoma
59
Chemotherapy for Hodgkin Lymphoma

• Adriamycin (doxorubicin)
• Bleomycin
• Vincristine
• Dacarbazine (DTIC)
• Clinical trial ongoing comparing ABVD with
  Stanford V (Mustine (also called chlormethine),
  doxorubicin, Vinblastine, Vincristine, Bleomycin,
  etoposide and steroids).

60
Management

• Chemotherapy is overtaking radiotherapy as the
  treatment of choice
• Understand mechanisms of drug regimes far better
  than before
• Understand disease better and patterns of spread
• Radiotherapy (mantle) has been associated with
  increased risk of breast cancer in young females

61
HODGKIN LYMPHOMA PROGNOSIS
Reproduced with permission from the Office of
National Statistics, Cancer Trends, 2001
62
NON-HODGKIN LYMPHOMA

• 7th most common cancer in men, and the 6th most
  common cancer in women in the UK. Each year,
  there are over 4,700 new cases in men, and over
  4,300 cases in women.
• Immunosuppressed patients
• EBV

63
NON-HODGKIN LYMPHOMA
64
NHL

• Type
• Thirty or more sub-types, but low or high grade
  influence management
• Cell type/arrangement
• T, B or NK
• Follicular (grouped together), diffuse (spread
  out)
• Large or small
• Extranodal involvement
• Age
• B symptoms
• Stage
• Ann Arbor staging
• Grade low or high

65
NON-HL CLINICAL FEATURES

• MAYBE SIMILAR TO HD
• USUALLY MORE GENERALISED IN NATURE
• EXTRALYMPHATIC INVOLVEMENT COMMON
• BONE MARROW INFILTRATION

66
NON-HLINVESTIGATION AND DIAGNOSIS

• SIMILAR TO HD
• SURFACE CELL MARKERS
• For use with Monoclonal antibodies
• CT SCAN
• BONE MARROW
• Lumbar Puncture

67
NON-HLPRINCIPLES TO MANAGEMENT
68
Chemotherapy

• CHOP
• Cyclophosphamide
• Doxorubicin
• Oncovin
• Prednisolone

• Clinical trials are looking at Monoclonal
  antibodies as a treatment for NHL
• Rituximab (Mabthera) proving effective for low
  grade Follicular NHL
• If follicular NHL is resistant to CHOP
• or patient relapsed after chemotherapy

69
NON-HLEXTRANODAL SITES

• DEPENDS ENTIRELY ON SITE OF PRIMARY TUMOUR

70
NON-HLPROGNOSIS

• Low grade
• Difficult sometimes to get rid of but people can
  be in remission for many years
• High grade
• Although more aggressive tend to respond better
  to treatments
• 60 response rate