Flashcards in White Cell Disorders - Neoplastic proliferation of white cells Deck (59):
What are the broad categories of white cell malignancies?
1) Lymphoid neoplasms - a diverse group of B cell, T cell and NK cell tumours. In many instances they resemble they resemble the particular stage of normal lymphocyte maturation from which the tumour arose, which is helpful in categorisation and diagnosis.
2) Myeloid neoplasms - these arise from early haematopoietic progenitors. Within this there are 3 categories: a) acute myeloid leukaemia - immature progenitor cells accumulate in the bone marrow. b) myelodysplastic syndromes - associated with ineffective haematopoiesis and peripheral blood cytopenias. c) chronic myeloproliferative disorders - increased production of one or more terminally differentiated usually leads to elevated peripheral blood counts.
3) Histiocytoses - uncommon proliferative lesions of macrophages and dendritic cells. Immature dendritic cell (Langerhaans cell) gives rise to a spectrum of neoplastic disorders.
Discuss the etiologic and pathogenic factors in white cell neoplasia.
1) Chromasomal translocations and other acquired mutations are present in the vast majority of white cell neoplasms
- Mutated genes play roles in the development, growth and survival of the cell. Loss of function and gain of function mutations are common.
- Oncoproteins often block normal maturation, turn on pro-growth signaling pathways and protect the cell from apoptotic death
- Proto-oncogenes are often activated at the antigen receptor gene rearrangement and diversification stage.
2) Inherited genetic factors - certain genetic diseases that promote genetic instability make individuals more at risk of developing leukaemia. e.g. Bloom syndrome, Down syndrome.
3) Viruses - 3 viruses have been implicated in certain types of lymphoma. Human T-cell leukaemia virus-1 (HTLV-1), Epstein-Barr Virus (EBV), Human Herpes Virus 8 / Kaposi's sarcoma herpesvirus (HHV8/KSHV)
4) Chronic inflammation - neoplasia almost always arrises in the inflamed tissue and can include H. pylori infection and gastric B cell lymphomas, gluten-sensitive enteropathy and T-cell lymphomas. HIV increases risk of B-cel lymphoma in almost any organ.
5) Iatrogenic factors - radiotherapy and chemotherapy
What is the problem with classifying lymphoid neoplasms?
There is great overlap.
Leukaemia is used for neoplasms that present with widespread involvement of the bone marrow and usually the blood.
Lymphoma is used to describe proliferations that arise as discrete tissue masses.
These were originally thought to be discrete entities, though it is now appreciated that there can be considerable overlap.
Many lymphomas occasionally leukaemic presentation, and evolution from lymphoma to leukaemia is not unusual with incurable lymphomas.
Conversely, tumours identical to leukaemias sometimes arise as discrete soft tissue masses without and apparent bone marrow disease.
This means that the terms lymphoma and leukaemia merely reflect the usual tissue distribution of each disease at presentation.
What are the precursor B and T cell neoplasms called?
Acute Lympoblastic Leukaemia/Lymphoma
- Neoplasms composed of immature B and T cells, called lymphoblasts
- 85% B-ALLs, which typically manifest in childhood as "leukaemias"
- Less common T-ALLs tend to present in adolescent males as thymic "Lymphomas"
- there is considerable overlap in behaviour between the two
ALL is the most common cancer in children, most younger than 15, more common in whites than blacks, hispanics are most susceptible.
What are the clinical features of ALL?
Accumulation of blast cell in the bone marrow suppress normal haematopoieses by physical crowding, competition for growth factors etc.
Similar clinical features to AML
- Abrupt stormy onset: days to weeks of first symptoms
- Depression of marrow function causing fatigue due to anaemia, fever reflecting infections due to neutropenia, bleeding due to thrombocytopenia
- Mas effects caused by neoplastic infiltration: bone pain, generalised lymphadenopathy, splenomegaly and hepatomegaly, testicular enlargement, in T-ALL compression of vessels and airways in the mediastinum
- CNS manifestations: headache, vomiting, nerve palsies resulting from meningeal spread.
What is the prognosis of ALL?
Good. Up to 95% remission and 75-85% cured.
Success depends on factors such as age of presentation etc.
What are the peripheral B-cell neoplasms?
Chronic Lymphocytic Leukaemia (CLL) and Small Lymphocytic Leukaemia (SLL)
CLL is the most common leukaemia of adults in the western world. Median age 60yr.
What is the pathogenesis and morphology of CLL?
Lymph nodes are infiltrated by predominantly small lymphocytes, with variable numbers of larger activated lymphocytes that clump together in aggregates called proliferation centres, which are mitotically active.
Growth is largely confined to proliferation centres.
When present, these are pathognomonic for CLL (/SLL).
The bone marrow is almost always involved by interstitial infiltrates or aggregates of tumour cells.
Aggregates are almost always seen in the spleen and hepatic portal tracts.
What are the clinical features of CLL?
- Patients are often asymptomatic at diagnosis
- Symptoms are often non-specific, easy fatiguability, weight loss and anorexia
- There is generalised lymphadenopathy and hepatosplenomegaly is present in 50-60% of symptomatic patients.
- leukocyte count is variable
- disruption of immune function - mechanisms largely uncertain, though hypogammaglobulinaemia is common so increased succeptibilty to infection. 10-15% of patients may develep a haemolytic anaemia or thrombocytopenia due to autoantibodies.
- prognosis is variable, median survival 4-6 years
- a major complication is the conversion to a more aggressive diffuse large B-cell lymphoma (Richter syndrome)
What is the aetiology of Follicular Lymphoma?
Most common form of indolent lymphoma in the US, middle age presentation.
Where do follicular lymphomas arise? What is the pathogenesis?
Germinal centre B cells, strongly associated with chromasomal translocations involving BCL2.
While normal germinal centres contain numerous B cells undergoing apoptosis, follicular lymphoma is characteristically devoid of apoptotic cells.
Early in the disease, follicular lymphoma cells growing in lymph nodes are surrounded yb a network of follicular dendritis cells mixed with macrophages and T-cells.
Primarily a lymph node disease with bone involvement in 85% of cases, but also involvement of spleen and hepatic portal triads.
How does follicular lympoma typically present?
Painless, generalised lymphadenopathy.
Involvement of extranodal sites (GI, CNS, Testis) not common.
Incurable, folloews a waxing and waning course, median survival 7-9 years. Survival not improved by aggressive therapy.
Like normal germinal centre B cells, follicular lymphomas have ongoing somatic hypermutation, which can promote transformation. Survival after transformation usually 1 year.
Transformaiton occurs in 30-50%, mostly to a diffuse large B cell or Burkitt's lymphoma.
What is the aetiology of Diffuse large B-cell Lymphoma?
DLBCL id the most common non-hodgkins lymphoma. Median age 60.
What is the pathogenesis and morphology of DLBCL?
There a multiple genetic causes.
Diffuse pattern of growth of large cells. Sometimes multinucleated like Reed-Sternberg cells in hodgkins.
There are several subtypes of DLBCL including immunodeficiency related (in the setting of T-cell depletion caused by HIV or bone marrow transplantation, tumour cells normally infected with HBV) and primary effusion lymphoma (causing malignant pleural and ascitic effusions, tumour cells infected with HHV8).
How does DLBCL present clinically?
- Rapidly enlarging mass at nodal and extrnodal sites
- can arise virtually anwhere in the body (waldeyer ring - oropharyngeal lymph tissue - commonly involved)
- Primary and secondary involvement of the liver and spleen may take the form of large destructive masses
- Extranodla sites include GI tract, brain, skin, bone
- Bone marrow involvement NOT common (if it does then usually late in course)
- Tumors are aggressive and rapidly fatal if untreated
- With aggressive treatment 60-80% remission, 40-50% cured
- 5% show considerable overlap with burkitt's so should essentially be treated as such
What 3 types does Burkitt's lymphoma cosist of?
1) African (endemic)
2) Sporadic (nonendemic)
3) HIV infections
They are all histologically identical, but differ in some clincial, genotypic and virological characteristics.
What is the pahtogenic change common to all Burkitt's lymphomas?
They are all associated translocations of the MYC gene on chromosome 8 that leads to an increase in MYC proteins.
MYC is a master transcription regulator, incresing the expression of genes that are responsible for aerobic glycolysis (Warburg effect) - when nutrients are available it allows the cells to grow and divide.
For this reason Burkitt's lymphoma is thought to be the fastest growing human tumor.
What is common to all endemic burkitt's lympomas?
They are latently infected with HBV, present also in sporadic and HIV but only 15-25%.
Infection preceded transformation.
What are the clinical features of a Burkitt's lymphoma?
- Endemic and sporadic found mainly in children
- Most tumours ar extranodal
- Endemic commonly presents as a mass involving the mandible and also the abdominal viscera esp. kidneys, ovaries, adrenals
- Sporadic common presents in ileocaecum and peritoneum
- Inovolvement of bone and peripheral blood is NOT common.
- Aggressive but responds well to intensive chemotherapy. Most children and young adults are cured.
What is characteristic of plasma cell neoplasms?
Neoplastic plasma cells nearly always secrete monoclonal Ig or Ig fragment, which serve as tumour markers and often have pathological consequences.
What is the significance of the Ig in plasma cell neoplasms?
A monoclonal Ig frangment found in the blood is referred to as an M component.
Normal complete M components are large and so confined to the blood and extracellular fluid. Neoplastic plasma cells often secrete incomplete or 'Light chain' components.
Light chain levels are often elevated, specifically the 'kappa' chain, asa opposed to 'lambda'.
These free light chains are small and so are excreted ni the urine, where they are known as 'Bence-Jones' proteins.
Abnormal Igs associated with plasma cell neoplasms are referred to as monoclonal gammopathy, dysproteinemia and paraproteinemia.
What are the key types of plasma cell neoplasms with paraproteinemia?
1) Multiple myeloma
2) Waldenstrom macroglobulinemia
3) Heavy chain disease
4) Primary or immunocyte-associated amyloidosis
5) Monoclonal gammopathy of undetermined significance MGUS
What is the aetiology of multiple myeloma?
Chiefly a disease of older adults 65-75, more prevalent in african descent, primarily bone disease with lesions, late involvement of lymph nodes + extranodal.
What is the pathogenesis of multiple myeloma?
Proliferatoin and survival of myeloma cells is dependent on IL-6 which is an important growth factor for plasma cells. It is produced by tumor cells themselvs and by resident marrow stromal cells.
Factors produced by neoplastic plasma cells mediate bone destruction, and is the major pathologic feature of multiple myeloma.
Particular importance - myeloma derived MIP1-alpha up-regulated the expression of RANKL by bone marrow stromal cells, which in turn activates osteoclasts.
Other factors are modulators of the Wnt pathway, cause potent inhibition of osteoblasts. Net effect - bone resorption, hypercalcaemia, pathological fractures.
What are the morphological changes in multiple myeloma?
- Usually presents as destructive plasma cell tumours, plasmacytomas, involving the axial skeleton
- Bones most commonly affected: vertebral column, ribs, skull, pelvis, femur, clavicle, scapula
- Lesions begin in medullary cavity, progress though cancellous bone to erode the cortex, causing pathological fractures, most comonly vertebral column
- Radiographically - bone lesions appear as 1-4cm punched out lesions and consist of soft gellatinous red tumor mass (rarely there is a diffuse osteopenia)
- kidney involvement is known as 'myeloma kidney', caused by excreted Igs (Bence-Jones) which are toxic to renal tubular epithelial cells
What are the clinical features of Multiple Myeloma and what causes them?
Clinical features stem from 1) the effects of plasma cell growth in tissues particularly bone, 2) the production of excessive Igs which have abnormal physiochemical properties, 3) the suppression of normal humoral immunity ( the aspect of immunity that is mediated by macromolecules)
- Pathologic fractures and bone pain from bone resorption
- Neurological manifestations from hypercalcaemia, e.g. confusion, weakness, lethargy, constipation, polyuria and contributes to renal dysfunction
- Cellular immunity is relatively unaffected
- Renal inssuficiency is key cause of death
How is the diagnosis of multiple myeloma made?
Clinicopathological diagnosis rests of radiographic and laboratory findings.
Radiographic findings are strongly suggesting but must be backed up by lookig at bone marrow.
What is the prognisis of multiple myeloma?
Variable, median survival 4-7 years, no cure.
What are the treatment options at the moment and coming for multiple myeloma?
- Proteasome inhibitor (proteasomes degrade unwanted misfolded proteins, accumulation of misfolded proteins leads to apoptosis, so prevent the breakdown of misfolded proteins will cause the cell to apoptose)
- Thalidomide and similar drugs - may also be due to protein degradation mechanisms
- Bisphosphonates - inhibit bone resorption, reduce incidence of pathological fractures and hypercalcaemia
- Haematopoietic stemm cell transplantation - prolongs life, not yet shown to be curative
What are the progresisvely less pathologically active sypes of myeloma?
1) Solitary myeloma (plasmacytoma)
2) Smouldering myeloma
3) Monoclonal Gammopathy of Uncertain Significance
What is the Lympoplasmacytic lymphoma?
- B-cell neoplasm of older adults
- It bears a resemblance to CLL/SLL, though differs in that a substantial fraction of tumour cells undergo terminal differentiation to become plasma cells
- Neoplastic plasma cells often secrete monoclonal IgM, leading to a Waldenstrom's macroglobulinemia type hyperviscosity
- unlike multiple myeloma, complications from free light chains are rare
What are the peripheral T-cell and NK-cell neoplasms?
- Periperal T-cell lymphoma, unspecified
- Anaplastic large-cell lymphoma, ALK positive
- Adult T-cell leukaemia/lymphoma - exclusively associated with Human T-cell Leukemia Retrovirus Type-1 which infects CD4+ T-cells
- Mycosis Fungoides / Sezary Syndrome - different manifestation of a CD4+ tumour that home to the skin
- Large granular lymphocytic leukaemia
- Extranodal NK/T-cell lymphoma - highly associated with EBV
What are theless common Lymphoid neoplasms?
- Mantle cell lymphoma
- Marginal cell lymphoma
- Hairy cell lymphoma
What are the characteristic features of Hodgkin Lymphoma?
- Hodgkin Lymphoma arises in a single node or chain and spreads first to anatomically contiguous lymphoid tissues
- Characteristic histology - Reed-Sternberg cells. These Reed cells are what release factors that induce the accumulation of the other cells making up the tumour, such as reactive lymphocytes, granulocytes and macrophages. Reed cells are normally derived from germinal centre of postgerminal centre B cells.
What is the aeitology of Hodgkin Lymphoma?
One of the most common cancers of young adults and adolescents.
Average age of diagnosis is 32
Curable in most cases
What are the 5 subtypes of HL?
1) Nodular sclerosis
2) Mixed cellularity
4) Lymphocyte depletion
5) Lymphocyte predominance
First 4 are 'classic' HL because Reed-Sternberg cells are similar.
Which virus is associated with classic HL?
What is the morphology of HL?
Presence of Reed-Sternberg cells - these are large with multiple nuclei, or single nuclei with multiple lobes, each with the a large inclusion-like nucleolus. Abundant cytoplasm.
What are the clinical features of HL?
- Painless lymphadenopathy
- Some will have more systemic symptoms than others:
nodular sclerosis and lymphocyte predominant tend not to have systemic symptoms, mixed cellularity and lymphocyte depletion are more likely to have systemic symptoms.
- Follows clear clinical course: Nodal disease, splenic disease, hepatic disease, marrow and other tissues.
Staging involves clinical exam, radiography of the chest, abdo, pelvis and bone marrow biopsy
What is the Ann Arbor classification of Lymphomas (HL and NHL)?
Stage 1 - Involvemnent of a single limphnode region (I) or a single extralymphatic organ or site (IE)
Stage 2 - Involvement of two or more lymphnode regions on the same side of the disphragm alone (II) or localised involvement of an extralymphatic organ or site (IIE)
Stage 3 - Involvement of lymph node regions on both sides of the diaphragm without (III) or with (IIIE) localised involvemnet of an extralymphatic organ or site
Stage 4 - Diffuse involvement of one or more extralymphatic organs or sites with or without lymphatic involvement
What is the common factor in all Myeloid Neoplasms?
They have an origin in a haematopoietic progenitos cell.
They are usually disease of the marrow and to a lesser degree the secondary haematopoietc organs of liver, spleen and lymph nodes.
What are the 3 broad categories of myeloid neoplasms?
1) Acute myeloid leukaemias
2) Myelodysplastic syndromes
What is the essence behind myeloid neoplasms?
The normal mechanisms that govern haematopoiesis have been evaded by cells, which then suppress the function of normal marrow cells.
What is Acute Myeloid Leukaemia?
A tumour of haematopoietic progenitors caused by acquiring oncogenic mutations that impede differentiation, leading to the accumulation of immature myeloid blasts in the marrow
Is AML one disease?
No it is quite hetergenous with 4 classifications.
How is the diagnosis of AML made?
Presence of at least 20% blast cells in bone marrow. £ different types: 1) Myeloblasts, 2) Auer rods, 3) monoblasts
How does AML present?
Most patients present withing a few weeks or months of onset complaining of effects of neutropenia, anaemia and thrombocytopenia.
Fatigue, fever, spontaneous mucosal and cutaneous bleeding. Bleeding diathesis due to thrombocytopenia, petechiae and ecchymoses, serosal haemorrhages, mucosal haemorrhages. Infections are frequent, often caused by opportunistic organisms such as funghi pseudomonas and commensals.
Findings similar to ALL, though involvement of tissues other than bone marrow is less common.
Rarely AML presents with a soft tissue mass known as a myeloblastoma.
What is the prognosis of AML?
Not great, 60% achieve complete remission with chemotherapy, though only 15-30% are free of disease at 5 years.
Outcome varies drastically among different mutational groups.
What are the myelodysplastic syndromes?
A group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective haematopoiesis and a high risk of transformation to AML
What are the characteristics of MDS?
The bone marrow is partly or completely replaced by the clonal progeny of a neoplastic multipotent stem cell that retains the capacity to differentiate, but does so in an ineffective and disordered manner.
What are the clinical features of MDS?
Usually presents in elderly patients 70+
Often an incidental discovery
When symptomatic it presents with weakness, infections and haemorrhages, all due to pancytopenia.
What are the Myeloproliferative disorders and what is their cause?
They commonly share a mutated but constitutively actived tyrosine kinases, or other abberations in signalling pathways, that lead to growth factor independence.
1) CML - White blood cells
2) Polycythaemia Rubra Vera - Red blood cells
3) Essential thrombocytosis - Platelets
4) Primary myelofibrosis - fibroblasts
Outline CML and it's clinical features
Characterised by uncontrolled clonal proliferation of myeloid cells.
Accounts for 15% of leukaemias
Peak age 40-60
Philadelphia chromosome is present in >80% cases (fusion of 9+22) which has tyrosine kinase activity
Most symptoms are chronic and insidious: decreased weight, tiredness, fever, sweats. Gout, bleeding and abdominal discomfort.
Often massive splenomegaly + hepatomegaly anaemia and bruising
What is the common cause of PRV?
JAK2 mutation in more than 90%
How does PRV manifest?
Most commonly asymptomatic.
If present symptoms are related to abnormal blood flow, particularly on the low pressure side.
Patients may be plethoric and cyanotic due to stagnation of blood in peripheral vessels.
May present with dizziness, headache, HTN, GI symptoms.
What is the treatment of PRV?
Try to reduce HCT to reduce risk of thrombosis.
Young low risk patients this is often done by venesection.
If older then hydroxycarbemide
Low dose aspirin 75mg give
What is essential thrombocythaemia?
Clonal proliferation of megakaryocytes leading to high platelets with abnormal function.
Causes bleeding and arterial and venous thrombosis
Microvascular occlusion is common, causing headache, atypical-chest pain, light-headedness, erythromyalgia
Treat with low dose aspirin 75mg + hydroxycarbemide if old or previous thrombosis
What is primary myelofibrosis?
Hyperplasia of megakaryocytes which produce platelet derived growth factor, leading to intense marrow fibrosis and myeloid metaplasia - haemopoiesis in the spleen and liver, massive hepatosplenomegaly.
Typically present with hypermetabolic symptoms: night sweats, fever, weight loss, abdominal discomfort.
Treatment involves bonemarrow support, allogenic stem cell transplant may be curative in young patients but carries a high risk of mortality