Joseph Hall Flashcards
What does the indented part of the monocytes nucleus signify
Golgi apparatus
How long do platelets take to make?
7-10 days
NB: Platelets bind and degrade thrombopoietin, a mechanism that regulates platelet production (liver and kidneys)
What is unique about the cytoplasm of platelets
Has cytoplasmic channels, called the invaginated membrane system, an arrangement that enables the absorption of clotting factors.
Where does hemopoiesis occur
Red bone marrow, in two microenvironmental domains, called niches:
1. The vascular niche.
2, The endosteal niche.
What are the primary lymphoid organs
- BM
2. Thymus
What are the secondary lymphoid organs
- LNDs
- Spleen
- Tonsils
- aggregates of lymphocytes and antigen-presenting cells in the lung (bronchial-associated lymphoid tissue, BALT) and the mucosa of the digestive tract (gut-associated lymphoid tissue, GALT), including Peyer’s patches.
Path of B and T cells
After leaving the two primary organs, mature B and T cells circulate in the blood until they reach one of the various secondary lymphoid organs (lymph nodes, spleen, and tonsils).
What are accessory cells?
Accessory cells include two monocyte-derived cell types:
- Macrophages
- Dendritic cells. i.e. Langerhans cell found in the epidermis of the skin.
- Follicular dendritic cell, a third type, present in lymphatic nodules of the lymph nodes. Follicular dendritic cells differ from ordinary dendritic cells in that they do not derive from a bone marrow precursor.
Specific features ofdiffuse lymphatic tissue or mucosa-associated lymphatic tissue (MALT) or lymphatic nodules
Guard the body against pathogenic substances and are the sites of initial immune response.
Accumulation of lymphatic cells that are NOT enclosed by a capsule.
Lymphocytes are found in the lamina propria (subepithelial tissue).
What are primary nodules
A nodule that contains primarily lymphocytes
What are secondaryy nodule
- Contains a germinal centre - in the central region of the nodule. Lightly stained due to the presence of large immature lymphocytes. Follicular Dendritic cells and mitotic figures are frequent.
- Mantle zone or corona: an outer ring of small lymphocytes that encircle the germinal center.
What are lymphatic tissues of the alimentary canal
Dispersed in a random manner, but in the alimentary canal are found in specific locations:
Tonsils- entrance of the oropharynx
Peyer’s patches: in the ileum
Appendix
Function of lymph nodes
- They filter the lymph, maintain and differentiate B cells, and house T cells.
- Detect and react to lymph-borne antigens.
- They are concentrated in certain regions such as the axilla, groin and mesenteries.
What are the lymphatic vessels
Afferent lymphatic vessel: bring lymph to the node.
Efferent lymphatic vessel: takes lymph away from the node.
What are the components of the lymph nodes
- Capsule: Dense connective tissue.
- Trabeculae: Dense connective tissue extending from the capsule inside the node.
- Reticular tissue: Composed of reticular cells and reticular fibers and covers the remaining of the organ
Cells of the reticular network?
- Reticular cells: secrete collagen type III
- Dendritic Cells
- Macrophages
- Follicular dendritic cells
General Architecture of the Lymph Node
- The lymph nodules are found in the outer part of the cortex, called the superficial (nodular) cortex.
- The portion between the medulla and the superficial cortex is called the Deep Cortex (paracortex). Is free of nodules. Most of the T cells are found in this region.
Features of the thymus
- Thymus is a bilobed organ.
- Site of T-cell differentiation.
- The thymus is fully formed and functional during birth.
- It persists until the time of puberty when T cell differentiation is reduced and most of the lymphatic tissue is replaced by adipose tissue.
Histology of the thymus
Connective tissue surrounds the thymus and subdivides the thymic parenchyma into thymic lobules.
Each lobule is composed of a cortical cap on top of an inner medullary tissue.
The thymic parenchyma contains developing T cells (thymocytes) in an extensive meshwork formed by epithelioreticular cells (large and pale nuclei).
On H&E stain, cortex is markedly basophilic because of the closely packed thymocytes.
Gross features of the spleen?
It filters blood and reacts immunologically to blood-borne antigens.
It is enclosed by a dense capsule of connective tissue, collagen, elastic and SM from which trabeculae extents into the parenchyma.
Spleen parenchyma is divided based on the color of fresh sections into the: White pulp (appears darker histologically) Red pulp (appears lighter histologically)
Arteries and veins found in the trabecula.
No cortex, medulla, and lymphatic vessels.
What is in the stroma of the spleen
Composed of reticular fibres, supporting:
White pulp (splenic nodules with B and T cells, antigen-presenting cells and plasma cells)
Red pulp (splenic sinusoids filled with blood and plates of lymphoid tissue — splenic cords)
Features of the white pulp
- Consist of lymphatic tissue, basophilic, mostly lymphocytes.
- Two types of lymphocytes, i.e., B cells and T cells located in two different areas of the spleen.
- B cells are located in the lymphoid follicles scattered throughout the organ
- T cells aggregate around a central artery and constitute the perarterial lymphatic sheath (PALS).
Resemble the lymphatic nodule
Features of the red pulp
Red appearance due to large number of red blood cells.
- Consists of splenic sinuses separated by splenic chords:
- Consist of a sponge-like meshwork of reticular cells, reticular fibers, macrophages and dendritic cells.
- Macrophages phagocytize pathogens, cell debris, and cells that are old, abnormal, or damaged, esp. red blood cells. Phagocytosis may be increased when the spleen is enlarged
Most common type of cancer in children
Leukemia - 80% ALL
- Brain is second most common
- Solid tumours are usually embryonal tumours rather than carcinoma
Risk factors for cancer in childhoo
- Genetic condition ( anomalies)
- Family history ( Li-Fraumeni syndrome )
- Environmental (ionizing radiation,
chemicals) - Infections ( EBV (B cell lymphoma) , HIV (karposi sarcoma), HBV (hepatocarcinoma))
- Chemotherapy (second cancer )
Signs of childhood cancer
Continued, unexplained weight loss
Headaches, often with early morning vomiting
Increased swelling or persistent pain in bones, joints, back, or legs
Lump or mass, esp. in the abdomen, neck, chest, pelvis, or armpits
Development of excessive bruising, bleeding, or rash
Constant/recurrent infections
A whitish color behind the pupil
Nausea which persists or vomiting with or w/o seizures
Constant tiredness or noticeable paleness
Eye or vision changes which occur suddenly and persists
Recurrent or persistent fevers of unknown origin
Frequency of the leukemias in children
- ALL - 84%
- AML - 15%
- CML - 1%
- JMML
- CLL —- extremely rare
Ddx of presenting symptoms of leukemia
- Easy brusing/ petichiae: aplastic anaemia, ITP
- Lymphadenopathy: Bacterial infx, mump, infectious mononucleosis
- Liver and spleen enlargeent: viral infection
Systemic symptoms f leukema
Lymphadenopathy
Hepatosplenomegaly
Orthopnea, cough
mediastinal mass
tracheal compression
Facial nerve palsy
Testicular enlargement
Skin lesions
Gingival hypertrophy(AML)
Which organs does leukemia hide
- Testicles
- Brain
- These are organs where there is blood tissue barrier so therapy is different and needs to be more direct
Tx of paed cancers
Chemo is mainstay radiotherapy only used for CNS positive diseases
Dx in Tx between boys and girls for ALL
Boys 3 years and 8 weeks
Girls 2 years and 10 weeks
Induction therapies for ALL
VCR
Steroids
Asparaginase
+/- daunorubicin
IT MTX
> 95% REMISSION RATE
Maintainence therapy for ALL
Daily 6MP & weekly MTX
Monthly VCR + Steroids
3 monthly IT MTX
Boys~ 2 yrs
Girls ~ 1 yr
Tx principles of AML
Needs Intensive treatment for 4-5 months.
Main cytostatica (Cytarabine, Etoposide, Daunorubicin, Mitoxantrone, Amsacrine)
Acute promyelocytic leukaemia-Chemotherapy plus
al-trans-retinoic acid (ATRA)
Subtypes of lymphoma
Hodgkin’s Disease (HD)
Nonhodgkin’s Lymphoma (NHL)
- Burkitt’s
- Lymphoblastic
- Anaplastic Large Cell
Presentation of Hodgkins disease
Fevers Night sweats Weight loss Pruritus 25%
Superior Mediastinal Syndrome (SMS) - oncologic emergency
- Orthopnea, SOB, - stridor, hypoxia - Tracheal - Bronchial - Cardiac
- Superior vena cava syndrome
- Facial swelling, plethora, cyanosis, neck veins
swollen due to compression
Features of Burkitts Lymphoma
B-cell origin
> 5 y/o
Abdominal mass
Large mass + LNs
Cecum or appendix
Nasopharynx
Tumor lysis syndrome
Uric acid, phosphorus, creatinine
Treatment can precipitate renal failure
= Oncologic Emergency
Tx for lymphona
Chemotherapy- Including steroids
Role for radiotherapy for selected cases (Hodgkin’s
lympoma with partial response to chemo )
S and S of Wilms tumour
Associated anomalies, syndromes – 15%
- Hemihypertrophy
- Aniridia
WAGR syndrome:
Wilms, aniridia,
ambiguous genitalia, retardation
- GU anomalies
- Denys-Drash syndrome
- GU anomalies and renal failure
- Beckwith-Wiedemann syndrome ( both kidneys)
Neuroblastoma S & S
Paraneoplastic syndromes (substances excrided from the mass) causing
- Watery diarrhoea – Vasoactive Intestinal Peptide
- Opsoclonus-myoclonus, cerebellar ataxia
- Cross-reacting antibodies
- ↑ Urinary catecholamines
- VMA/HVA/Dopamin – 85%
- ↑ BP – 25%
- Renal compression
- Catecholamine secretion
DDx of abdominal mass after inital localisation using abdominal USG
- Renal (Wilms’ tumour - smooth unilateral flank mass that does not cross midline)
- Suprarenal (neuroblastoma irregular suprarenal mass that may cross the midline)
- Hepatic (hepatoblastoma, HCC)
- Intestinal (lymphoma)
- Pelvic ( germ cell tumour, sarcoma,teratoma)
Difference between primary and secondary immunodeficiencies
Primary: usually congenital, genetic defects in
immune system
Secondary (acquired): a result of other diseases
or conditions, such as: HIV, malnutrition,
immunosuppression
Cells of innate immunity
- Epithelial Barriers
- Phagocytic cells
- Mononuclear phagocytes
- Neutrophils
- Natural Killer (NK) cells
- Complement
- Cell Receptors
e. g. Toll- like receptors
When to suspect ID’s
- .4 new ear inf in a year
- > 2 sinus infx in 1 year
- > 2 months on antibiotics wth little affect
- > 2 pneumonias in a year
- Failure of infant to gain weight or grow normally
- Recurrent deep skin or organ abcesses
- Persistent thrush in mouth or fungal infx in skin
- Need for IV abs to clear infx
- > 2 deep deated infx. incl. epticemia
- FHX of ID
Organisms assoc. with B cell PID
Encapsulated bacteria:
- S.pneumoniae,
- H.influenzae)
- Enteroviruses.
BACTERIAL: Please SHINE my SKis (Encapsulated) Pseudommonas aerugionosa l e a s e Strep pneumoniae Haemophillus Influenza type b Neisseria menigitidis E Coli Salmonella Klesbiella pneumoniae group b Strep my Streptococcus k i s
VIRAL:
- ENTEROVIRAL ENCAPHALITIS
- POLIO
Organisms assoc. with T cell deficiencies
1 Fungi
- Viruses
- Pneumocystis carinii
How does a phagocyte defect present
infections of the skin and reticuloendothelial
system.
How does C’ deficiencty present
blood-borne infections, such as bacteraemia
and meningitis, caused by encapsulated
bacteria.
Encapsulated if the deficiency is in the early components of C’
Neisseria if its in the late components of C’ i.e. c5-c9 deficiencies (MAC attack)
Features of X-linked Agammaglobulinaemia
Bruton’s disease
- defect in btk gene (X chromosome)
- encodes Bruton’s tyrosine kinase
-Block in B-cell development
(Pre-B cells cannot develop into mature B cells)
-Presentation in 2nd half of first year with recurrent sinopulmonary pyogenic infections
- Scanty LNDs
- Absent B cells
- Global lack of immunoglobulins of all classes
- Live vaccines contraindicated
- Absence of germinal center and primary lymphoid follicle in the lymph node. outer cortex which contain primary and sencondary lymphoid fillicle also contain prominent number of CD4 T-cells within interfollicular regions (allowing for T-B cell interaction). in patients with agammaglobulinemia ,the outer cortex is present but diminshed. 1134
Lab presentation of XLA
Investigations:
- all Igs absent / very low
- B cells absent / very low
- T cells normal
Tx of XLA
- IVIG to prevent infx and minimise bronchiectasis
Features of Common Variable ID
- Commonest symptomatic Ab deficiency
- presentation: any age childhood to old age (m=f)
- Peak: early childhood (1-5y)/early adulthood (16-20y)
- Recurrent sinopulmonary infections, bronchiectasis
- Chronic enterovirus, arthritis, giardiasis
- May also have autoantibodies, SLE
- Higher incidence of cancer (gastric Ca and lymphoma-300 fold increased risk)
- Usually missed => late diagnosis =>
complications (structural lung/sinus damage)
Clinical features of CVID
Hyppogammaglobulinemia
(Marked reduction in serum IgG and IgA,
IgM reduced in 50% of pts)
Familial inheritance observed in 25% of cases
B cells normal or low
T cells normal
Treatment: IVIG, prophylactic antibiotics
Presentations and organisms associated with them in CVID
+++ Sinusitis
- (Hemophilus influenza, Streptococcus pneumoniae)
+++ Pneumonia
- (Hemophilus influenza, Streptococcus pneumoniae)
++ Bronchiectasis
+ Gastrointestinal infections
- (Giardia lamblia, Campylobacter jejuni)
+ Meningitis (ECHO virus)
+ Splenomegaly, lymphadenopathy, conjunctivitis, autoimmune disease and increased risk of cancer
Feautres of IgA deficiency
- Most common: incidence~1:500
- Usually asymptomatic
- Lack of serum and mucosal IgA (<7mg/dl)
- Normal IgG, IgM
- Associated with:
- chronic lung disease (bronchiectasis)
- allergy, autoimmunity
- Etiology unknown, but familial associations and
linkage with CVID
Broad spectrum antibiotics
Tx of IgA def
IVIG
Causes of SCID
Predominant T cell deficiencies:
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- Ataxia-Telangiectasia
- RAG 1 and RAG 2 deficiency
- IL - 2R gamma chain (most common and X linked)
- Adenosine deaminase deficiency - usually degrades excess adenosine in the cell - without this enzyme, adenosine builds up and is toxic to lymphocytes (T and B) (second most common)
Features of SCID
Involves both T and B cells
- 50% X-linked
Presentation:
- well at birth; problems >1st month
- diarrhoea; weight loss; persistent candidiasis
- life threatening bacterial / viral infections
- failure to thrive
- failure to clear vaccines
- unusual infections
Investigation of SCID
-Lymphocyte subsets: T, B, NK (% and numbers)
=> low total lymphocyte count => SCID sign!
- Pattern: very low/absent T ; normal/absent B
- Igs low
- T cell function ↓ (proliferation, cytokines)
Tx of SCID
- isolation => to prevent further infections!
- Avoid live viral vaccines!
- CMV- / irradiated / low WBC blood transfusions
- IVIG replacement if necessary
- Treat infections, supportive care
- Bone marrow / stem cell transplant
Prognosis of SCID
- Dependent on promptness of diagnosis
- Survival >80% (early diagnosis, good donor match, no infections pre-transplant)
- Survival <40% (late diagnosis, chronic infections, poorly matched donors)
- Regular monitoring post BMT => engraftment
Features of Di George (T Cell def)
Congenital thymic aplasia – thymus does not develop normally (neither does parathyroid) 1:4000
Results from deletion in chromosome 22q11, but is
not inherited
Few to no mature T cells in periphery
Hypocalcaemia (hypocalcaemic tetany of the neonate)
Congenital cardiac abnormalities
Recurrent or chronic infections with viruses,
bacteria, fungi, protozoa
Presentation of Di George
Dysmorphic features: micrognathia, cleft palate,
low-set ears, fish shaped mouth
Features of Wiskott-Aldrich Sybdrome (predominant t cell def)
X linked mutation in gene encoding protein that
interacts with cytoskeleton
Thrombocytopaenia, bleeding diathesis, petechia
Severe eczema, allergic reactions
Recurrent bacterial infections
Abnormal B and T cells, low T cell count
Can be treated with antibiotics, antivirals, bone
marrow transplant
Features of Ataxia Telangiectasia (predominant T cell def)
Mutation in ATM gene
Manifests as staggering gait
with abnormal vascular dilation
Typical telangiectasia (ear lobes, conjuctivae)
Progressive cerebellar ataxia
Increased susceptibility to infection, lymphopenia,
depressed Ig and T cell response
- Ataxia (cerebellar defects)
- Angiomas (telangiectasia)
- IgA deficiency
What are the findings in ataxia telangiectasia? /
- Increase alpha fetoprotein
- Decreased IgA , E and G - due to effectshumoural and cell mediated immune system
- Increased sinopulmonary infection (IgA deficiency)
- Lyphopenia (low WBCs)
- Cerebellar atrophy
- Increased risk of leukemia and lymphoma
Types of phagocyte defects
Affect the innate and acquired response to
pathogens
Defects in:
- Action required to phagocytize
- Migration and adhesion of phagocytic cells
- Leucocyte adhesion defects (LADs)
- Chediak-Higashi syndrome
- Chronic granulomatous disease
Features of LAD
Autosomal recessive
Group of disorders in which the leukocyte
interaction with vascular endothelium is disrupted
- defect in β- chain of integrins or selectin ligands
Consequences:
- Increased WBC counts
- Recurrent bacterial skin infections, intestinal & perianal ulcers
- No pus formation or effective wound healing
- Recurrent skin and mucosal non pyogenic bacterial infections
- Impaired wound healing
- Delayed separation of the umbilical cord (>30 days)
- Increased neutrophils but absence of neutrophils at the infection site
Features of Chediak-Higashi syndrome
Autosomal recessive
Abnormal giant granules and organelles in neutrophils
Defective killing of phagocytosed microbes ( defect
phagosome-lysosome fusion), leading to massive
infiltration of lymphocytes and macrophages in liver,
spleen, lymph nodes
Strep and Staph main problem- recurrent infections
Poor prognosis
- Recurrent pyogenic infections with strep and staph
- Partial albinism
- Peripheral neuropathy
- Progressive neurodegeneration
- Infiltrative lymphohistiocytosis
- Pancytopenia
- Mild coagulation defects (due to abnormal dense granules in platlets)
Features of Chronic granulomatous disease
X-linked, autosomal recessive
Skin, lymph node, lung infections
High WBC counts
Defective killing of phagocytosed microbes
(defect in oxidation due to mutation in NADPH)
Treatments include: antibiotics, antifungals, IFNγ
Presentation of C’ deficiencies
Early complement protein deficiencies (C1, C2,
C3 or C4):
-pyogenic infections
-autoimmunity - SLE very common
-hereditary angioedema (C1 inhibitor deficit): failure
to inactivate complement and bradykinin systems
Late component protein deficiencies (C5-C9):
- prevents formation of membrane attack complex
- gram-negative (Neisseria) bacterial infections
Causes of secondary ID’s
- Malnutrition
- Malignancy:
- Chronic Lymphocytic Leukemia
- Immunodeficiency with Thymoma(Good’s syndrome)
- Non-Hodgkin and Hodgkin Lymphomas
- Multiple Myeloma - Immunosuppressive-Immunomodulatory drugs:
-Cyclophosphamide, Azathioprine, Rituximab,
Infliximab, Alemtuzumab - Infections:
- Bacterial: Mycobacterium tuberculosis
- Viral: HIV, Epstein Barr, HSV, CMV - Untreated autoimmunity (RA, SLE)
- Protein loss:
- Nephrotic syndrome, protein-losing enteropathy, severe burns, trauma - Metabolic disease:
- Diabetes mellitus, severe liver disease, uremia - Asplenia, sickle cell disease
Features of HIV
Secondary ID
- Dysfunction and deficiency of B cells
- Dysfunction and deficiency of T cells
- Decreased phagocytosis and intracellular killing by
monocytes and neutrophils
-Decreased cell-mediated cytotoxicity by NK cells
Cisterna Chyli location
L1
Thoracic duct location
T12
Induction therapy leukemia
VCR
Steroids
Asparaginase
+/- daunorubicin
IT MTX
Summary - (CTX plus steroids)
Tx principles of AML
- Needs Intensive treatment for 4-5 months.
- Main cytostatica (Cytarabine, Etoposide,
Daunorubicin, Mitoxantrone, Amsacrine) - Acute promyelocytic leukaemia-Chemotherapy plus
al-trans-retinoic acid (ATRA)
Tx of lymphoma
- Chemotherapy- Including steroids
- Role for radiotherapy for selected cases (Hodgkin’s
lympoma with partial response to chemo
Which type of abdominal masses are typical of certain age groups
Infant:
- Neuroblastoma, Wilms’ tumour,
hepatoblastoma,
2-6 years:
- Neuroblastoma, Wilms’ tumours
7-10years:
- NHL, Germ cell tumours
10-16 years:
- Lymphoma, hepatocellular carcinoma,
Ovarian Tumour
Sites of metastasis in Wilms tumour
Lung (Chest X-ray, CT)
Rare: Liver, Bone, Brain
Site of metastases in neurblastoma
Bone marrow
Bone
Liver
Distant lymph nodes
Skin
Nuclear medicine scans for Dx of neuroblastoma
MIBG scan
Bone scan
Describe the MIBG scan
- Meta-iodobenzyl guanidine
- Strong affinity for adrenal medulla and adrenergic nerve
tissue. - Uptake by NB, ganglioneuroma, pheochromocytoma,
paragaglioma, retinoblastoma and medullary thyroid
tumour - Follow up investigation
Features of neuroblastoma
- Commonest cancer of
infancy - Tumour of sympathetic
nervous system from neck –
pelvis
Metastases
- Bone, bone marrow,
- lymph node,
- Liver , skin
Secretion of catecholamines
Uptake of MIBG
Signs of metastases
- Rapidly enlarging liver- abd. distension, respiratory
compromise(usually in infants), - Bluish coloured skin nodules
- Signs of bone and bone marrow involvement–bone pain,
limp, anaemia, skin or mucosal haemorrhage - Proptosis and periorbital ecchymosis (tumour infiltration of
periorbital bone)- Racoon eyes - Constituional: failure to thrive and fever
Aetiology of ALL
- trisomy 21 after the age of 5
- Klinefelter’s syndrome - XXY
inherited diseases with excessive chromosomal fragility such as
3) Fanconi anaemia - inherited disorder that leads to BM failure
4) Bloom’s syndrome - inherited disorder characterized by short stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer.
5) Ataxia-telangiectasia - primary ID disorder
B cell ALL:
Children t12:21 - good prognosis
Adults t9:22 (Philadelphia chromosome bcr:abl mutation also associated with CML)
T cell ALL:
NOTCH1 mutation
Environmental factors: include exposure to atomic bomb explosions, radiation, smoking, use of hair dyes, and employment in electrical occupations
Viral
Folate metabolism polymorphisms
Risk factors for ALL
- <6, late 30s, mid 80s *CLL = 60’s
- Hx malignancy
- Tx w/ cheo
- Exposure to radiation or environmental toxins
- Smoking
- Genetic disorders - Klinefelters, trisomy 21
FHx ALL
Read disease lob of ALL in notes
Read disease lob of ALL in note
Paediatric oncologic emergencies
see notes
ALL Prognostic factors
Negative prognostic features include:
1. older age
- elevated WBC at presentation above 100 x 10^9/L
(100,000/microlitre) - failure to achieve complete remission within 4 weeks of treatment
- adverse cytogenetic abnormalities (t(9;22), 11q23 rearrangements, t(1;19), t(8;14), t(12;21), and chromosome band 14q11-13) abnormalities.
- Complex karyotypes: 5 or more chromosomal abnormalities
- Low hypodiploid (30-39 chromosomes) or near triploidy (60-78 chromosomes).
- Del (9q) and high hyperdiploidy (51-65 chromosomes) are associated with a more favourable outcome compared with those mentioned above.
- Presence of minimal residual disease (MRD): a marker of adverse outcome
