Haematology: Pathology - Haematopoietic system Flashcards
Two broad causes of neutropenia
- Decreased or ineffective haematopoiesis
- Increased neutrophil removal/destruction
Four causes of decreased or ineffective haematopoiesis which may lead to agranulocytosis
- HSC suppression (e.g. in aplastic anaemia or infiltrative marrow disorders)
- Suppression of granulocytic precursors (commonly due to drugs e.g. chlorpromazine)
- Ineffective haematopoiesis (e.g. in megaloblastic anaemia or MDS)
- Congenital conditions
Three causes of increase neutrophil removal/destruction which may lead to agranulocytosis
- Immunologically mediated (e.g. SLE or due to drugs e.g. thiouracil or sulfonamides)
- Splenomegaly (increased neutrophil sequestration)
- Increased peripheral utilisation (due to infection)
How is agranulocytosis treated?
Broad-spectrum Abx if evidence of infection
May use G-CSF
At what neutrophil level is serious infection more likely?
<500 neutrophils per mm^3
What fungal organisms may cause deep infection in the neutropenic patient?
Candida
Aspergillus
What causes of neutropenia will result in bone marrow hyper- vs hypo-cellularity?
Hypercellularity: ineffective haematopoiesis, increased peripheral utilisation
Hypocellularity: suppression of granulocytic precursors
Four broad causes of leukocytosis
- Increased bone marrow production
- Increased release from marrow stores
- Decreased margination
- Decreased extravasation into tissues
Three causes of increased bone marrow production of leukocytes
- Chronic infection/inflammation
- Paraneoplastic (e.g. Hodgkin’s lymphoma)
- Myeloproliferative disorders (e.g. CML)*
*GF-independent (others are GF-dependent)
Three causes of increased release of leukocytes from marrow stores
- Endotoxaemia
- Infection
- Hypoxia
Two causes of decreased margination of leukocytes
- Exercise
- Catecholamines
Cause of decreased leukocyte extravasation into tissues
Glucocorticoids
Outline the typical causes of the various subtypes of leukocytosis (neutrophilia, eosinophilia, basophilia, monocytosis and lymphocytosis)
Neutrophilia: bacterial infection, sterile inflammation (e.g. in MI, burns)
Eosinophilia: allergic disorders, parasitic infection, drug reactions, some malignancies (e.g. lymphomas), collagen vascular disorders and some vasculitides
Basophilia: rare, often indicative of myeloproliferative disease (e.g. CML)
Monocytosis: chronic infection (e.g. TB), bacterial endocarditis, rickettsiosis, malaria, SLE, IBD
Lymphocytosis: accompanies monocytosis in chronic infection/inflammation, viral infection
What morphological changes are seen in neutrophils in severe inflammatory disorders (e.g. Kawasaki disease)?
Toxic granulations
Dohle bodies (dilated ER)
Cytoplasmic vacuoles
Microscopic changes seen in acute lymphadenitis
Large reactive germinal centres
Macrophages
May be central necrosis
Hyperplasia of endothelial cell lining
Three subtypes of microscopic patterns seen in chronic lymphangitis. What causes each?
- Follicular hyperplasia: humoral responses (e.g. RA, toxoplasmosis, early HIV)
- Paracortical hyperplasia: T-cell mediated responses (e.g. acute viral infection such as infectious mononucleosis)
- Sinus histiocytosis: in lymph nodes draining cancers
Microscopic pattern seen in follicular hyperplasia
Large oblong germinal centres (secondary follicles) surrounded by mantle zone of naive B cells
Germinal centres divided into dark zone (with centroblasts) and light zone (with centrocytes)
Interspersed antigen-presenting dendritic cells and “tingible-body” macrophages
Microscopic pattern seen in sinus histiocytosis (reticular hyperplasia)
Hyperplasia and hypertrophy of cells lining lymphatic sinusoids
Increased macrophages
Microscopic pattern seen in paracortical hyperplasia
Expanded T-cell zones, may efface B-cell follicles
Immunoblasts may be so numerous that special studies are needed to exclude lymphoid neoplasm
Hypertrophy of sinusoidal and vascular endothelial cells
What is the most common types of chromosomal abnormality seen in white cell neoplasms?
Translocation
What are the three categories of white cell neoplasms?
Myeloid
Lymphoid
Histiocytoses
Six aetiological factors for white cell neoplasms
- Chromosomal translocations and other acquired mutations
- Inherited genetic factors
- Viruses
- Chronic immune stimulation
- Iatrogenic factors
- Smoking
Three examples of a chromosomal translocation in the pathogenesis of white cell neoplasms
- Roles in growth and development: e.g. translocations involving MALT1 or BCL10 cause MALTomas (B-cell lymphomas in extranodal sites)
- Oncoproteins created which block normal maturation: e.g. mutations up-regulating BCL6 (which under normal conditions is needed for the formation of germinal centre B cells but also blocks their maturation)
- Proto-oncogenes activated during Ag receptor gene rearrangement and diversification: in lymphoid cells most commonly occurs in B cells during attempted Ab diversification (e.g. c-MYC)
Four examples of genetic diseases conferring increased risk of leukaemia
Fanconi anaemia
Ataxia telangiectasia
Trisomy 21
Type I neurofibromatosis
Three examples of viruses contributing to the pathogenesis of white cell neoplasms (and the specific neoplasms they are linked to)
- Human T-cell leukaemia virus 1 (HTLV-1): adult T-cell lymphoma/leukaemia
- Epstein-Barr virus (EBV): subset of Burkitt lymphoma, Hodgkin lymphoma, many B-cell lymphomas, rare NK-cell lymphomas
- Kaposi sarcoma herpesvirus (KSHV; aka human herpesvirus-8, HHV-8): Kaposi sarcoma, rare B-cell lymphoma that presents as malignant (often pleural) effusion
Three examples of chronic immune stimulation leading to increased risk of certain white cell neoplasms
- H. pylori infection: increased risk gastric B-cell lymphomas
- Gluten-sensitive enteropathy: increased risk intestinal T-cell lymphomas
- HIV: initially increased risk of germinal centre B-cell lymphomas, late-stage (in setting of AIDS) increased risk of B-cell lymphomas particularly those associated with EBV and KSHV
Smoking increases risk of developing which white cell neoplasm?
AML
Five categories of lymphoid neoplasms according to cell of origin (and give an example of each)
- Precursor B-cell neoplasms (immature B-cells): e.g. B-ALL
- Peripheral B-cells neoplasms (mature B-cells): e.g. DLBCL, follicular lymphoma
- Precursor T-cell neoplasms (immature T cells): e.g. T-ALL
- Peripheral T-cell and NK-cell neoplasms (mature T cells and NK cells): e.g. adult T-cell leukaemia/lymphoma
- Hodgkin lymphoma (Reed-Sternberg cells and variants)
What is the most common form of indolent NHL?
Follicular lymphoma
What kind of neoplasm is multiple myeloma?
Plasma cell neoplasm
Which growth factor is important in the proliferation and survival of myeloma cells?
IL-6
Describe the histological findings in multiple myeloma. What feature is seen on a peripheral smear? What proteins are excreted in the urine and what is the pathological significance of this?
Plasmacytomas (destructive plasma cell tumours) involving axial skeleton
May see relatively normal-appearing plasmablasts, or flame (with red cytoplasm) or Mott cells, bizarre multinucleated cells with cytoplasmic droplets containing Ig (Russell bodies; if nuclear they are called Dutcher bodies)
Roleaux formation on peripheral smear (high M proteins causes red cells to stick to one another)
Bence Jones protein (light chains) excreted in urine and contributes to myeloma kidney (renal disease)
Most common site of pathological fracture in multiple myeloma
Vertebral column
Clinical features of multiple myeloma
CRAB:
HyperCalcaemia
Renal disease
Anaemia
Bony involvement (lesions, pathological fractures)
How is risk of transition to multiple myeloma from MGUS measured/monitored?
Serum M proteins
Urine Bence Jones protein
Compare and contrast features of Hodgkin vs non-Hodgkin lymphoma in terms of typical distribution and progression, extra-nodal involvements, and specific histological features
Hodgkin lymphoma:
Distribution: localised to single axial group of lymph nodes (e.g. cervical, mediastinal, para-aortic), mesenteric nodes and Waldeyer ring rarely involved
Progression: orderly spread by contiguity
Extra-nodal involvement: rare
Histological features: Reed-Sternberg cells
Non-Hodgkin lymphoma:
Distribution: involvement of multiple peripheral nodes, mesenteric nodes and Waldeyer ring commonly involved
Progression: noncontiguous spread
Extra-nodal involvement: common
Histological features: dependent on subtype
What are Reed-Sternberg cells?
Large cells (>45um) with multiple nuclei or single nucleus with multiple lobes, each with a large inclusion-like nucleolus about the size of a small lymphocyte (5-7um)
What is the most common form of Hodgkin lymphoma?
Nodular sclerosis
Describe the Ann Arbor system of lymphoma staging
I: single lymph node region involvement (I) or single extra-lymphatic organ/site (IE)
II: >/= 2 lymph node regions on same side of diaphragm (II), or localised involvement of extra-lymphatic organ/site (IIE)
III: lymph node region involvement on both sides of diaphragm without (III) or with (IIIE) localised involvement of extra-lymphatic organ/site
IV: diffuse involvement of >/= 1 extra-lymphatic organs/sites with or without lymphatic disease
Further divided based on absence (A) or presence (B) of B symptoms
Histological features seen in AML
> 20% myeloid blasts (diagnostic criteria)
Auer rods (needle-like azurophilic granules)
Clinical features of AML
Related to marrow failure leading to anaemia, thrombocytopaenia and neutropenia
Two classifications of MDS based on aetiology
Primary: idiopathic
Secondary (t-MDS): due to genotoxic drug or radiation therapy
What are myelodysplastic syndromes?
Group of clonal stem cell disorders characterised by maturation defects associated with ineffective haematopoiesis and high risk of transformation to AML
Typically cause pancytopaenia (abnormal cells remain sequestered in bone marrow)
What are myeloproliferative disorders? Give four examples
Group of disorders caused by mutations in and constitutive activation of tyrosine kinases involved in haematopoiesis
Causes growth factor-independent proliferation and survival of marrow progenitors
Most commonly affects multipotent myeloid progenitors, others may arise in pluripotent stem cells (and so give rise to both lymphoid and myeloid cells)
E.g. CML, PV, essential thrombocytopaenia, primary myelofibrosis
What gene mutation is seen in CML?
BCR-ABL (100%)
What gene mutation is seen in PV?
Point mutation in JAK2
Which blood cells are increased in PV?
RBCs (responsible for most symptoms)
Platelets
Granulocytes
What is primary myelofibrosis?
Myeloproliferative disorder characterised by obliterative marrow fibrosis
Obliterative marrow fibrosis causes suppression of bone marrow haematopoiesis, leading to cytopenias and extensive neoplastic extramedullary haematopoiesis (e.g. spleen, liver, lymph nodes)
What mutations are seen in primary myelofibrosis?
JAK2 (50-60% of cases)
MPL (1-5% of cases)
Histological features of primary myelofibrosis
Fibrotic obliteration of marrow space
Hepatosplenomegaly due to increased extramedullary haematopoiesis
Leukoerythroblastosis
Dacrocrytes (teardrop-shaped RBCs damaged in fibrotic marrow)
Characteristic histological findings in Langerhans histiocytosis
Birbeck granules in cytoplasm
Five clinical features of primary myelofibrosis
- Normocytic normochromic anaemia
- Symptomatic splenomegaly
- B symptoms
- Gout secondary to hyperuricaemia
- Initially normal or increased Plt count, thrombocytopaenia as disease progresses (risk of thrombosis and bleeding)
What is the source of antibodies directed against platelets and RBCs in ITP and immunohaemolytic anaemias?
Spleen
What is the typical adult weight of the spleen?
150g
Describe the macroscopic appearance of the spleen
Enclosed by connective tissue capsule
Cut surface: red pulp dotted with white pulp follicles
Describe the structure of a white pulp follicle
- Central artery
- Periarteriolar sheath: collar of T-cells
- Lymphoid nodules composed mostly of B-cells: capable of developing into germinal centres
Describe the two types of circulation seen in the spleen
- Open circulation: blood travels through capillaries into dendritic-cell-lined splenic cords to the sinusoids
- Closed circulation: blood travels directly from capillaries to splenic veins
Four functions of the spleen
- Phagocytosis of RBCs and particulates
- Antibody production
- Haematopoiesis: normally ceases prior to birth but can be reactivated in severe anaemias or in myeloproliferative disorders
- Sequestration of formed blood products
How is antibody production stimulated in the spleen?
Antigens are trapped by dendritic cells in the periarteriolar sheath and presented to T lymphocytes
Under normal conditions, what volume or percentage of RBCs and platelets are sequestered in the spleen?
RBCs: 30-40ml
Platelets: 30-40%
What percentage of platelets may be sequestered in the spleen in splenomegaly?
80-90%
What is the clinical significance of anatomic or functional asplenia?
Increased susceptibility to infection by encapsulated bacteria (e.g. pneumococcus, meningococcus, Haemophilus influenzae)
Three features of hypersplenism
Anaemia
Thrombocytopaenia
Leukopenia
May be alone or in combination
Six broad causes of splenomegaly
- Infection
- Portal HTN
- Lymphohaematogenous disorders
- Immunological/inflammatory
- Storage diseases
- Miscellaneous
12 infectious causes of splenomegaly
- Non-specific splenitis of various blood-borne infections (e.g. IE)
- Infectious mononucleosis
- TB
- Typhoid
- Brucellosis
- CMV
- Syphillis
- Malaria
- Histoplasmosis
- Toxoplasmosis
- Leishmaniasis
- Schistosomiasis
Three causes of portal HTN which may lead to splenomegaly
- Hepatic cirrhosis
- Portal or splenic vein thrombosis
- Cardiac failure
Four lymphohaematogenous disorders which may cause splenomegaly
- Lymphoma and lymphoid leukaemias
- Multiple myeloma
- Myeloproliferative disorders
- Haemolytic anaemias
Two inflammatory disorders which may cause splenomegaly
- RA
- SLE
Two storage diseases which may cause splenomegaly
- Gaucher disease
- Niemann-Pick disease
Three miscellaneous causes of splenomegaly
- Amyloidosis
- Primary neoplasm or cyst
- Secondary neoplasm
Morphological appearance of spleen in non-specific acute splenitis (infective)
Enlarged (200-400g)
Acute congestion of red pulp
Effacement +/- necrosis of lymphoid follicles (necrosis more common with haemolytic Strep i.e. GAS)
Abscess rarely
Morphological appearance of spleen in congestive splenomegaly
Marked enlargement (1000-5000g)
Firm with thickened fibrous capsule
Early congestion of red pulp with later fibrosis and hypercellularity
Rigid, dilated sinusoids
Morphological appearance of splenic infarcts
Pale, wedge-shaped, subcapsular
Overlying fibrinous capsule
Large depressed scars
If septic: suppurative necrosis
Four most common predisposing conditions to “spontaneous” splenic rupture
- Infectious mononucleosis
- Malaria
- Typhoid fever
- Lymphoid neoplasms
Why are chronically enlarged spleens less likely to rupture?
Thick fibrotic capsule keeps bleed contained
Describe the main location of haematopoiesis from foetal to adulthood
3rd month of development until birth: chief site of haemtopoiesis is hepatic (HSCs migrate here during 3rd month of development)
4th month of development: HSCs begin to move to bone marrow (chief site of haematopoiesis still hepatic)
At birth: marrow throughout skeletal is haematopoietically active, hepatic haematopoeisis ceases soon after birth
At puberty: haematopoiesis becomes restricted to axial skeleton only (in normal adults ~half of marrow space is haematopoietically active)
Define leukaemia vs lymphoma
Leukaemia: widespread involvement of bone marrow +/- peripheral blood
Lymphoma: discrete tissue masses
Typical presentation of lymphoma
2/3 of NHL and all HL: enlarged non-tender lymph nodes
Remaining 1/3 NHL: symptoms related to involvement of extranodal sites (e.g. skin, stomach, brain)
Typical presentation of leukaemia
Signs and symptoms related to suppression of normal haematopoiesis by tumour cells in bone marrow (e.g. anaemia, thrombocytopaenia, neutropenia)
Most common plasma cell neoplasm
Multiple myeloma
Describe the embryological origin of the thymus
3rd and 4th pharyngeal pouches
Describe the changes seen in the thymus throughout birth to adulthood
Weighs 10-35g at birth
Grows to max weight of 20-50g through childhood
Post puberty begins to involute
5-15g in elderly
What condition is associated with thymic hypoplasia/aplasia? What are the clinical consequences?
DiGeorge syndrome (22q11 deletion syndrome)
Decreased cell-mediated immunity, hypoparathyroidism
What are the two types of thymic hyperplasia?
- Thymic follicular hyperplasia: appearance of B-cell germinal centres in thymus (small numbers of B-cells in the normal thymus)
- Morphologically normal thymus that is large for age
What is the clinical significance of a large (for age) thymus that is otherwise morphologically normal?
Risk of being misidentified as thymoma and surgically removed
What is the most common cause of thymic follicular hyperplasia? What are some other causes?
Myasthenia gravis most common
Others: Graves’ disease, RA, SLE, scleroderma
Three classifications of thymoma
- Non-invasive
- Invasive
- Carcinoma
Morphological features of non-invasive thymoma
Medullary- +/- cortical-type epithelial cells
Spare thymocytes
What are thymocytes?
Benign immature T-cells found in the thymus
Morphological features of invasive thymoma
Cytologically benign but invasive with capacity to metastasise
Mostly cortical-type epithelial cells
Numerous thymocytes
Morphological features of thymic carcinoma
Typically SCC
Fleshy, obviously invasive tumours
Can metastasise (e.g. to lung)
What virus plays a role in the pathogenesis of thymic carcinoma?
EBV
Describe the typical presentation of thymoma
Adult >40yo
May present either with symptoms related to impingement of mediastinal structures (e.g. SVC syndrome, dysphagia, cough, chest pain) or be detected as part of work-up for myaesthenia gravis
Name seven autoimmune disorders linked to thymoma
- Myaesthenia gravis
- Hypogammaglobulinaemia
- Graves’ disease
- Cushing syndrome
- Pure red cell aplasia
- Pernicious anaemia
- Dermatomyositis-polymyositis
