The Non-Leukaemic Lymphoproliferative Disorders

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The Non-Leukaemic Lymphoproliferative Disorders

• Ahmad Sh. Silmi
• Msc Hematology, FIBMS
• IUG

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The Non-Leukaemic Lymphoproliferative Disorders

• These are malignant clonal disorders of the
  lymphopoietic system and include
• Multiple Myeloma and Related Plasma Cell
  Disorders
• HD
• NHL

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Multiple Myeloma and Related Plasma Cell Disorders

• Multiple Myeloma (MM) is a B lymphoid malignancy
  which, is characterized by the proliferation of a
  malignant clone of plasma cells which synthesize
  and secrete excessive amounts of monoclonal
  immunoglobulin. In many respects, MM behaves as a
  solid tumour with a prior involvement for bone
  marrow.

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Incidence

• Disease of elderly.
• The median age at diagnosis is about 62 years.
• The disease is more common in blacks than in
  whites.
• The disease shows slight excess incidence in male
  than female.

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Pathophysiology
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Clinical symptoms

• bone pains, pathologic fractures
• weakness and fatigue
• serious infection
• renal failure
• bleeding diathesis

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Laboratory tests

• ESR gt 100
• anaemia, thrombocytopenia
• rouleaux in peripheral blood smears
• marrow plasmacytosis gt 10 -15
• hyperproteinemia
• hypercalcemia
• proteinuria
• azotemia

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Diagnostic Criteria for Multiple Myeloma

• Major criteria
• I. Plasmacytoma on tissue biopsy
• II. Bone marrow plasma cell gt 30
• III. Monoclonal M spike on electrophoresis IgG gt
  3,5g/dl,
• IgA gt 2g/dl, light chain gt 1g/dl in 24h urine
  sample
• Minor criteria
• a. Bone marrow plasma cells 10-30
• b. M spike but less than above
• c. Lytic bone lesions
• d. Normal IgM lt 50mg, IgA lt 100mg, IgG lt 600mg/dl

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Diagnostic Criteria for Multiple Myeloma

• Diagnosis
• I b, I c, I d
• II b, II c, II d
• III a, III c, I II d
• a b c, a b d

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Staging of Multiple Myeloma

• Clinical staging
• is based on level of haemoglobin, serum calcium,
  immunoglobulins and presence or not of lytic bone
  lesions
• correlates with myeloma burden and prognosis
• I. Low tumor mass
• II. Intermediate tumor mass
• III. High tumor mass
• subclassification
• A - creatinine lt 2mg/dl
• B - creatinine gt 2mg/dl

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Poor prognosis factors

• cytogenetical abnormalities of 11 and 13
  chromosomes
• beta-2 microglobulines gt 2,5 ug/ml

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Treatment

• At present, there is no curative therapy, but
  symptomatic treatment may be as
• Blood transfusion if anaemia present.
• Antibiotic to treat infection.
• Local radiotherapy for osteolytic bone.
• Dialysis in case of renal failure.
• Alkalating agents may provide pain relief, but
  the response to these drugs is slow.

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Waldenstrom's Macroglobulinaemia
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Waldenstrom's Macroglobulinaemia

• Waldenstrom's Macroglobulinaemia (WM) is an
  uncommon B lymphoid disorder, which is
  characterized by hyperviscosity secondary to the
  excessive secretion of a monoclonal IgM
  immunoglobulin by the malignant clone.

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Causes

• It is caused by the loss of regulation of a clone
  of cells, which appear to be in an intermediate
  stage of development between the mature
  lymphocytes and the early plasma cells.
  Morphologically, the malignant cells of WM are
  rather more immature than those in MM and
  frequently are described as being
  "lymphoplasmacytoid".

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Incidence

• WM is a disease of elderly, with a peak incidence
  occurring in the seventh decade of life with no
  sex predilection.
• Life expectancy ranges from 8 months to 8 years

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Symptoms

• Weight loss.
• Hepatosplenomegaly.
• Lymphadenopathy.
• bruising or bleeding tendency.
• A long history of vague weakness, fatigue and
  weight loss.
• Hyperviscosity syndrome due to malignant
  infiltration or accumulation of monoclonal
  immunoglobulin.

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Clinical symptoms

• Accumulation of the IgM can lead to a variety of
  clinical symptoms include
• Neurological symptoms such as headache, vertigo,
  and in severe cases coma.
• Visual disturbances secondary to retinal
  haemorrhage and oedema, which may cause permanent
  blindness.
• Cardiac failure which is severe by the increased
  plasma viscosity.
• Platelet dysfunction secondary to coating of the
  platelets by the monoclonal IgM.
• Haemostatic disturbances secondary to the
  inhibition of fibrin polymerization and factor
  VIII activity by the monoclonal IgM.

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Laboratory Findings

• Normocytic normochromic anaemia secondary to
  suppression of erythropoiesis by the malignant
  clone.
• Rouleaux formation secondary to hyperviscosity.
• Chronic bleeding and dilution by the increased
  plasma volume.
• The WBC may be normal or depressed but a relative
  lymphocytosis commonly is present.
• The platelet count is normal at presentation.
  However, neutropenia and thrombocytopenia become
  more severe as the disease progress.
• Hypercellular and extremely hyperviscous bone
  marrow, which makes attempts to aspirate the bone
  marrow frequently difficult.
• The malignant cells are pleomorphic some
  resembles lymphocytes whereas others clearly
  resemble plasma cells most, however, have an
  intermediate appearance and are described as
  being lymphoplasmacytoid.

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Prognosis

• Depends on the pattern of infiltration of the
  malignant clone in the bone marrow
• Diffuse infiltration is associated with poor
  prognosis, with a median survival of 17 months.
• Nodular infiltration is associated with a much
  better prognosis, with a median survival of 72
  months.
• The intermediate form of infiltration, which
  shows features of both nodular and diffuse
  infiltration, is associated with a median
  survival of 52 months.

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Treatment

• Symptomatic relief from hyperviscosity syndrome
  is achieved mostly by repeated plasmapheresis.
  Progressive disease is treated with chemotherapy.

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Hodgkin's Disease
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Hodgkin's Disease

• Hodgkin's disease (HD) is a neoplastic disorder
  with development of specific infiltrate
  containing pathologic Reed-Sternberg cells. It
  usually arises in lymph nodes and spreads to
  contiguous groups. Extranodal presentation are
  rare. Disease is associated with defective
  cellular immunity.

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Incidence

• 2-4 cases per 100000 population / year
• bimodal age distribution
• 15-35 years and above 50 years
• male predominance MF 1,71

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Pathophysiology

• The most common presenting feature in HD is the
  presence of painless, a symmetrical enlargement
  of cervical or supraclavicular lymph nodes.
  Axillary, inguinal or femoral lymphadenopathy
  also is seen occasionally.
• The lymphadenopathy may be accompanied by severe,
  generalized itching in the absence of skin rash.
• In contrast to non-Hodgkin's lymphomas, which
  frequently are disseminated at presentation, most
  cases of HD are restricted to a single anatomical
  site at presentation.
• The presence of pyrexia and night sweats usually
  are associated with more advanced disease.

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Clinical Presentation

• Nontender lymph nodes enlargement ( localised )
• neck and supraclavicular area 60-80
• mediastinal adenopathy 50
• other ( abdominal, extranodal disease )
• systemic symptoms (B symptoms) 30
• fever
• night sweats
• unexplained weight loss (10 per 6 months)
• other symptoms
• fatigue, weakness, pruritus
• cough , chest pain, shortness of breath, vena
  cava syndrome
• abdominal pain, bowel disturbances, ascites
• bone pain

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Recognition

• The peripheral blood is entirely normal at
  presentation.
• Occasionally, mild non-specific changes such as
  a mild thrombocytosis, neutropenia or relative
  eosinophilia is present.
• The presence of anaemia, lymphocytopenia or
  leucoerythroblastosis all suggest the presence of
  advanced disease with bone marrow involvement,
  but this is uncommon at presentation.
• The disease is recognized by histological
  examination of an affected lymph node biopsy,
  which reveals the presence of a diffuse
  infiltrate of lymphocytes, histiocytes, and
  eosinophil, plasma cells and neutrophils, which
  are of normal appearance. Scattered among this
  infiltrate are variable numbers of Reed-Sternberg
  (RS) cells, the characteristic feature of HD.
• The presence of RS cells is not specific for HD,
  they also are present in some cases of infectious
  mononucleosis, NHL, and CLL but their
  demonstration is required for a diagnosis of HD.
  
• RS cells typically are large, with two or more
  large, oval nuclei, each of which contains a huge
  nucleolus, which is separated from the thickened
  nuclear membrane by a clear zone.

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Classification

• On the basis of the pattern of the lymph node
  infiltration, four subtypes of HD are recognized

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Lymphocyte predominant HD (LPHD)

• is characterized by
• A heavy infiltrate of small lymphocytes and
  histiocytes which have a normal morphology.
• The infiltrate is diffuse but may form loose
  nodules.
• RS cells usually are sparse.
• This subtype of HD is common in young men.
• It's associated with a rapid response to
  treatment and good prognosis.

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Nodular sclerosing HD (NSHD)

• Involves
• Nodular sclerosis and the presence of classical
  RS cells, as well as a distinctive RS cell
  variant called Lacunar cell in which the cell
  cytoplasm has contracted as an artifact of
  fixation, leaving an unstained zone between it
  and the surrounding tissue.
• Sclerosis is found in the form of well-organized
  bands of collagen that subdivides the tissue into
  distinct nodules.
• NSHD is the most common subtype, accounting for
  more than 40 of cases.
• It appears to be commonly associated with a
  thymic origin and offers a fairly good prognosis.

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Mixed cellularity HD (MCHD)

• is characterized by
• The presence of large numbers of typical and
  mononuclear RS cells, scattered among
  morphologically normal lymphocytes, histiocytes,
  neutrophils, eosinophils, plasma cells and
  fibroblasts.
• This subtype of HD is associated with a less
  favorable prognosis than either of the above
  subtypes.

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Lymphocyte depleted HD (LDHD)

• Large numbers of RS cells and atypical
  histiocytes, scanty lymphocytes and variable
  fibrosis.
• This subtype is the least common form of HD, and
  is associated with elderly subjects, who often
  present with advanced disease and have a poor
  prognosis.

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Immunophenotyping

• The consistent antigenic markers on RS cells
  include
• CD25, the IL-2 receptor, CD15 and CD30.
• The NSHD and MCHD are more commonly associated
  with B lymphoid markers while LPHD is associated
  with T lymphoid markers.

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Staging of Hodgkin's Disease
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Treatment

• According to the stage of disease, early stage
  requires localized radiotherapy to the involved
  lymph nodes, while advanced stage involve the use
  of combination chemotherapy with or without
  radiotherapy.

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Prognosis

• With modern treatment, more than 80 of cases of
  stage I HD and more than 50 of stage IV HD
  survive for more than 10 years after
  presentation. Most of these can be considered to
  be cured.

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Non-Hodgkin Lymphoma
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Aetiology

• Possible infectious aetiology secondary to EBV.
  This virus induces chronic suppression of the
  immune system, such as occurs in AIDS. Recent
  evidence has suggested that reactivation of EBV
  is associated with an increase incidence of NHL.
• Epidemiological studies have shown a small excess
  of NHL among agricultural workers and rubber
  industry workers but the significance of this
  observation remains in doubt.
• Cytogenetic abnormalities are present in almost
  all cases of NHL. The most common chromosomal
  rearrangement often involves chromosome2, 3, 7,
  12, 14 and 18.

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Pathophysiology

• Lymphomas with a follicular pattern of growth are
  less aggressive than those with a diffuse pattern
  of growth.
• Small lymphocytic lymphomas are less aggressive
  than large cell lymphomas.
• In common with acute leukaemias, some forms of
  high-grade lymphoma are more amenable to
  treatment than the chronic types.
• In contrast to HD, most NHL is disseminated to a
  greater or lesser extent at presentation.

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Classification

• Low Grade Lymphoma
• Intermediate Grade Lymphoma
• High Grade Lymphoma

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Treatment

• Lymphomas with a follicular pattern of growth are
  less aggressive than those with a diffuse pattern
  of growth.
• Small lymphocytic lymphomas are less aggressive
  than large cell lymphomas.
• In common with acute leukaemias, some forms of
  high-grade lymphoma are more amenable to
  treatment than the chronic types.
• In contrast to HD, most NHL is disseminated to a
  greater or lesser extent at presentation.