Infection/Inflammation Flashcards
What are the proposed mechanisms in the pathogenesis of malignancy?
Malignancy occurs when there is imbalance between cell proliferation and cell death. Factors that contribute to the pathogenesis of malignancy are:
- Activation of proto-oncogones (point mutation on RAS → continuous activation → upragulation of proliferation).
- Inactivation of tumour suppressor genes (RB inactivation → allows unregulated cell division. TP53 inactivation associated with many paediatric malignancies).
- Chromosomal translocations (EWS - FLI-1 translocation → Ewing sarcoma. PAX7-FKHR → alveolar rhabdomyosarcomas)
- Abnormal DNA content (triploid vs near diploid vs near tetraploid chromosomes - neuroblastoma)
- Epigenetic alterations
What is Kasabach-Merritt Phenomenon?
Kasabach-Merritt phenomenon occurs only with tufted angiomas and kaposiform haemangioendotheliomas.
Characteristics:
Enlarging vascular lesion and thrombocytopaenia (unresponsive to platelet transfusion as platelets become trapped in the lesion)
Microangiopathic anaemia
Mild consumptive coagulopathy
Risk of intracranial, pleural/pulmonary, peritoneal or GI haemorrhage.
Describe the embryological basis, pathological findings and natural history of dermoid cysts.
- Often midline or paramedian (sites of embryonic fusion). - Occur due to ectodermal elements become trapped beneath the skin during development. - May contain sebaceous glands, increase in size over time due to sebum. - May rupture or develop infection. - Those in the skull and spine may have deep extension and must always be appropriately imaged prior to resection (failed separation of ectodermal cells from neural tube). - Most common site superior palpebral ridge (external angular dermoid)
What is the treatment of tumour lysis syndrome?
- Treatment involves identifying those who are high risk of developing tumour lysis.
- Hyperhydration and allopurinol (xanthine oxidase inhibitor - purines don’t get converted to uric acid)
- Electrolyte management (may require haemodialysis)
What are the definitive and intermediate hosts of the Echinococcus granulosus?
Definitive hosts: dogs, wolves, foxes.
Intermediate hosts: Sheep, cattle.
Accidental intermediate host: Humans
Describe the two phases of testicular descent
Trans-abdominal phase (weeks 10-15):
The testis is supported by the cranial suspensory ligament (cranial end) and the directed by the gubernaculum (caudal end). Testis descends to the deep inguinal ring.
- Insulin like hormone 3 (INSL3) is released from the Leydig cells of the testis → causes the ‘swelling reaction’ in the gubernaculum - it swells and dilates the future inguinal canal.
- The proximal end of the gubernaculum becomes short and fat, holding testis near deep ring.
- Testosterone (released by the Leydig cells of the testis) cause regression of the cranial suspensory ligament.
Inguinoscrotal phase (weeks 15-25):
- The gubernaculum bulges out of the inguinal abdominal wall at the site of future superficial inguinal ring.
- Gubernaculum migration drags an evagination of peritoneum with the testis inside it, to the scrotum.
- Gubernaculum migration is mediated by the genital branches of the genitofemoral nerve (androgen mediated release of calcitonin gene-related peptide)
Describe the histological subgroup embryonal rhabdomyosarcoma.
Embryonal rhabdomyosarcoma (ERMS) - accounts for 65-75% - early childhood (head, neck, genitourinary)
- Associated with loss of heterozygosity at the 11p15 in 80% of patients (insulin growth factor 2 becomes over-expressed). Also fibroblast growth factor (GHGR1) and neuroblastoma RAS viral oncogene (NRAS)
- Embryonal rhabdomyosarcoma contain:
- Botryoid tumours (grape like) = hollow viscous - bladder, vagina, biliary tree
- Spindle cells = paratesticular lesions.
- Dense patterns.
- Botryoid and spindle cell histology associated with better prognosis.
ESSAY: Outline the genetic and cytological factors that are utilised in risk stratification of neuroblastoma
Risk stratification models: INSS=post treatment, INRG=pre-treatment, radiologically guided.
Factors that are considered in risk stratification:
- MYCN amplification (if present, increased risk)
- DNA content - near diploid or near tetraploid (associated with increased risk)
- Modified Shimada - undifferentiated vs poorly differentiated vs differentiating.
- Mitosis:karryorrhexis index (MKI) - higher ratio → higher risk.
- Segmental chromosomal aberrations (loss of heterogeneity) - point deletions on short arm chromosome 1p or 11q (higher risk)
- Presence of mutation in anaplastic lymphoma kinase (ALK) → higher risk
- Presence of Schwannian stroma - nodular ganglioneuroblastoma = higher risk.
Factors are taken into account by Children’s Oncology Group for treatment guidelines, both INSS and INRG are used simultaneously for risk stratification.
What is the natural history of molluscum contagiosum?
- Incubation - 2 weeks to 6 months.
- Clusters of small, round, waxy papules with central pit (umbilicated) in warm, moist areas (axilla, elbows, behind knees, groin, genitals.
- Papules may persist for 2 years (50% will resolve within 12 months).
What is tumour lysis syndrome? Name 3 manifestations
Tumour lysis syndrome occurs when tumour cells release of large volumes of intracellular components into the blood (usually associated with chemotherapy - Acute lymphoblastic leukaemia, Hodgkin lymphoma)
Manifestations:
Hyperkalaemia → life threatening arrhythmias
Hyperphosphataemia → calcium chelating agent, binds with intravascular Ca2+
Hypocalcaemia (secondary to hyperphosphataemia) → numbness, tingling, tetany, seizures, arrhythmias
Increased purines (DNA components) → Hyperuricaemia (xanthine oxidase) → uric acid crystal deposition in kidney → Acute kidney injury
How does FDG (F18 - fluorodeoxyglucose) PET work?
- A radioactive isotope is attached to FDG carrier molecule (FDG is a glucose analogue).
- The FDG/isotope is injected into the blood where the glucose analogue is taken up my tissues with high metabolic activity (esp. malignancies)
- Once absorbed by the malignant tissues, the radioisotope begins to break down, releasing positrons that collide with electrons nearby and release gamma rays that are recorded by the PET machine.
- Allows to localise areas of high uptake of FDG and therefore locate occult cancers and metastases
FDG PET is useful in diagnosis, staging and surveillance/treatment response.
What is the chronology of appendicitis if left untreated?
- Initial obstruction of lumen and associated appendiceal swelling/oedema –> vague abdominal pain.
- A small proportion of these are thought to spontaneously resolve.
- Progressive swelling, ischaemia and peritoneal irritation –> Localised peritonism.
- If progresses to full thickness necrosis and perforation –> fevers, peritonitis (usually occurs 36-48hrs after onset of symptoms.
- Perforation my occur earlier or later, or not at all.
Discuss the processes involved in the clinical picture of SIRS including the role of cytokines.
SIRS - systemic inflammatory response syndrome. Generalised inflammatory response associated with infection or trauma/burn.
Largely regulated by cytokines TNF and IL-1.
Defined as two or more:
- Fever > 38 or < 36
- HR > 90
- RR> 20
- PaCO2 < 32mmHg
- WCC >12 or <4
(2020 exam ) What is epignathus?
Refers to a teratoma protruding from the mouth (usually palate in the region of Rathke’s pouch) but can originate in the nasopharynx.
Usually benign, unlikely to recur.
DDx: Large epulis
Name 3 post-natal pathological causes of varicocoele.
Development of a right sided varicocoele in a young child is concerning for a tumour obstructing the right renal vein.
Wilms’ Tumour
Neuroblastoma
Hydronephrotic kidney obstructing the right renal vein.
Explain the mechanism of GVHD and what are the clinical manifestations (ESSAY QUESTION 2019)
Mechanism:
- Immunocompetent donor T cells recognise HLA antibodies in immunologically crippled host as foreign and react with them.
- Occurs most typically in haematopoietic stem cell transplants.
- Donor T cells tissue destruction and trigger an inflammatory response (further tissue damage).
- May be acute (from days to weeks after transplant) or chronic (typically > 100 days)
Manifestations:
- Skin: generalised rash → desquamation. In chronic, can cause severe cutaneous damage.
- Liver: T cells attack liver epithelial cells → hepatitis → necrosis of hepatocytes and bile duct epithelial cells → destruction of small bile ducts → jaundice.
- Intestine: mucosal damage → bloody diarrhoea.
- Eyes: haemorrhagic conjunctivitis
- Kidneys: GN
- Lungs: interstitial pneumonitis
Discuss the processes involved in the clinical picture of MODS including the role of cytokines.
MODS = detection of organ dysfunction in acutely ill patient.
Primary MODS - well defined insult to an organ resulting in dysfunction.
Secondary MODS - organ dysfunction occurs secondary to the host response (SIRS) in organs remote from the initial insult.
How does positron emission topography work?
- A tracer isotope, bound to a carrier molecule is injected intravenously.
- Depending on the type of carrier molecule, the tracer/molecule combination is taken up by the body.
- The radioactive tracer releases positrons that react with electrons in the nearby tissues.
- Reaction between positrons and electrons causes desctruction of the subatomic particles and release of gamma rays/photons.
- The PET machine analyses these gamma rays and maps the source location in 3D.
What is the significance of PAX-FOXO1 fusion and why?
PAX3-FOXO1 or PAX7-FOXO1 fusion is seen in 80% of alveolar rhabdomyosarcoma and is associated with worse prognosis due to higher rates of metastasis.
Fusion between FOXO1 and PAX results in over-expression of PAX activity - dedifferentiation and proliferation of myogenic cells.
What is MIBG and how is it used in paediatric surgery?
MIBG = Meta-iodo-benzyl-guanadine
Meta-iodo-benzyl-guanadine is a scintographic study that binds radioactive iodine.
Diagnostic: The MIBG is taken up by neuroblastoma cells (as well as phaeochromocytoma) and when used with low dose radioactive iodine may be used in the diagnosis of neuroblastoma.
Therapeutic: When MIBG is bound to a high dose of radioactive iodine, the MIBG is taken up by the neuroblastoma cells and the high dose of radioactivity causes localised and specific cell destruction.
What are the pathological findings associated with thyroglossal duct remnants (histopathology, microbiology where possible).
Thyroglossal duct cysts: - Lined with stratified squamous epithelium or ciliated pseudo stratified columnar epithelium. - May contain mucus secreting glands. - Contains ectopic thyroid tissue in 10-45%. Microbiology: - Can become infected, usually from an oral source. - Haemophilus influenzae, Staph aureus, Staph epidermidis.
How can you differentiate Wilms’ Tumour from clear cell carcinoma of the kidney radiographically?
Clear cell carcinoma is highly malignant, it invades the renal parenchyma rather than compressing the margin into a pseudocapsule like Wilms’ tumour.
How do chemotherapeutic plant alkaloids work? Give an example.
Plant alkaloids inhibit microtubule function
Example of a plant alkaloid - vincristine (inhibits tubulin polymerisation, block mitosis)
Name a syndrome associated with Wilms’ tumour and the associated gene.
WAGR syndrome (Wilms’ tumour, aniridia, genitourinary abnormalities, mental retardation).
Associated with a delegation from chromosome 11p13, gene WT1.
What is the organism involved in cat scratch disease?
Bartonella hensalae (gram negative rickettsial organism)
Described the pathophysiology of bronchiectasis
Bronchiectasis is irreversible dilatation of the airways secondary to destruction of bronchial and peribronchial tissue.
- Infection/recurrent infections –> inflammatory destruction of the ciliary epithelium –> replaced by cuboidal squamous epithelium.
- Damage to the elastic tissue of the bronchi and destruction of the peribronchial tissue.
- Dilatation of the airways and further impairment in clearance of mucus and bacteria.
- Anastomoses form between pulmonary and bronchial arteries in areas of saccular dilation.
What factors contribute to unfavourable prognosis in neuroblastoma?
International Neuroblastoma Risk Group Pretreatment Classification (COG)
MYCN amplification
Age > 18 months
Tumour ploidy - near diploidy or near tetraploidy (represent structural genetic abnormalities)
Segmental chromosomal aberrations (1p, 11q)
Nodular ganglioneuroblastoma
International Neuroblastoma Pathology Classification
Undifferentiated histology.
Nodular gangioneuroblastoma.
High mitosis-karryohexis index (>200)
Age > 18 months OR Age > 5yrs
What are the theories of pathogenesis of Hirschsprung Disease?
- Failed migration - neural crest cells fail to migrate to the anus due to early maturation or differentiation into ganglion cells.
- Failure to survive - neural crest cells migrate appropriately but fail to survive due to an inhospitable microenvironment.
What organisms are associated with cystic fibrosis in childhood?
Pseudomonas aeruginosa (remember biofilm)
Staphylococcus aureus
Haemophilus influenzae B
Burkholderia cepacia
What genetic mutations are associated with Wilms’ tumour?
WT1 - 11p13 - loss of tumour suppressor gene.
WT2 - 11p15 - Seen in Beckwith-Wiedemann Syndrome.
WTX - Xq11.1
TP53 - inactivation of tumour suppressor gene (associated with anaplastic WT)
Loss of heterozygosity (especially 1p, 11p or 16q) - 5% of WT
Gain of chromosome 1q - 30% of WT
Describe the key histological findings in ulcerative colitis.
- Acute: Disruption of the crypt architecture - crypt dysplasia, micro abscesses+ mucosal ulceration and undermining of adjacent mucosa –> pseudopolyps. Thinning of the muscularis. Inflammation limited to superficial layers.
- Chronic: Muscularis thickening, shortening of the mesentery, increased serosal vascularity and overabundance of adipose tissue.
- May develop dysplasia/malignancy (3% of patients within 10years of diagnosis)
Elucidate the embyrological basis for thyroglossal remnants.
Thyroglossal remnants include (thyroglossal duct cyst, thyroglossal duct sinus). 1. Thyroglossal duct is associated with the descent of the thyroid. 2. The thyroid forms in the foramen caecum at the base of the tongue (tuberculum impair) and descends along the thyroglossal duct in the midline of the neck to lie on the thyroid cartilage in its orthotopic position. 3. During descent, passes the developing hyoid bone anteriorly or posteriorly and may travel straight through hyoid. 4. Thyroid maintains connection to foramen caecum throughout descent. 5. Once thyroid reaches its position on the thyroid cartilage, the thyroglossal duct should obliterate.
Name 3 organisms responsible for OPSI
- Streptococcus pneumonia
- Haemophilus influenzae B
- Neisseria meningitidis.
Explain when and how gastroschisis occurs
Theories of gastroschisis - unknown:
- Failure of lateral abdominal wall folding and closure (TEXTBOOK ANSWER).
- Persistence of physiological mid gut herniation.
- Yolk sac failure - abnormal body wall folding results in an inability of the yolk sac to fuse with the umbilical cord. The gut attached to the yolk stalk by the vitelline duct would develop in the amniotic cavity (displaced to the right of the body stalk)
Describe the histological subtypes of Wilms’ Tumour
Favourable histology (90% of tumours)
Contain 3 components - blastemal, stromal and epithelial.
Most are triphasic, but can be biphasic or monophasic.
Unfavourable histology - contains focal or diffuse anaplasia
Anaplasia = multipolar polploid mitotic figuers with marked nuclear enlargement and hyperchromasia.
Focal anaplasia - presence of one or a few sharply localised regions of anaplasia within a tumour.
Diffuse anaplasia - may have anaplasia outside the kidney, or diffusely within the kidney.
What are nephrogenic rests and what are their prognostic implications?
Nephrogenic rests refer to persistence of metanephric tissue beyond 36 weeks gestation. They are uncommon in the normal population (0.1%-0.9%), but are considered a precursor for Wilms’ tumour.
Presence of nephrogenic rests in Wilms’ tumour surgical resection specimens suggest higher chance of metachronous tumour in the other kidney. Nephrogenic rests are seen in 100% of bilateral WTs.
What are the effects of diathermy on tissues?
Diathermy - coagulation, fulguration, cutting.
Coagulation = Heat generated by current from small electrode leads to cell death by dehydration and protein denaturation.
Fulgaration = higher voltage coagulation → allows sparks to arc and jump an air gap to fulgurate the tissue.
Cutting = voltage and frequency that generates high head and cuts tissue by causing cell water to explode to steam.
Give an example of 46XY DSD
46XY DSD - undervirilisation
- Usually due to insufficient testosterone production, androgen receptor deficiency or inability to convert testosterone to dihydrotestosterone (5 Alpha reductase dependent)
-
Androgen deficit:
- Adrenal synthesis - 17 alpha-hydroxylase deficiency
- Testicular synthesis - 12,20-desmolase deficiency.
-
Receptor deficit:
-
Complete androgen insensitivity syndrome (CAIS)
- Point mutation on androgen receptor gene on X chromosome.
- AMH production intact → paramesonephric duct regression normal.
- Phenotypically normal female anatomy, blind ending vagina, but impalpable testes. No uterus, or Fallopian tubes.
- Partial androgen insensitivity
-
Complete androgen insensitivity syndrome (CAIS)
-
Failure of testosterone conversion to dihydrotestosterone:
- 5 alpha reductase deficiency.
What gene is amplified in neuroblastoma? What is the clinical implication?
MYCN is the gene amplified in neuroblastoma.
The gene encodes for transcription factors for DNA synthesis and cell proliferation, plus shorter G1 phase.
Describe the natural history of human papilloma virus skin infection in children.
- Incubation - up to 12 months.
- Warts appear and may be solitary, multiple, or clustered (usually on hands and feet).
- Resolve spontaneously within 2 years, reinfection unlikely (from same strain of HPV, but many strains)
What are the small round blue cell tumours of infancy and childhood?
Neuroblastoma
Rhabdomyosarcoma
non-Hodgkin lymphoma (Burkitt Lymphoma, lymphoblastic lymphoma)
Ewing sarcoma
Name 4 risk factors for testicular cancer
- Undescended testis (UDT)
- History of germ cell tumour in contralateral testis.
- Family history of germ cell tumours
- Gonadal dysgenesis
Describe how was Echinococcus eradicated in New Zealand
4 phase program since the 1950s, with initial treatment of dogs with antihelmthics as well as dog control measures, followed by surveillance of all slaughtered livestock in NZ → traceback to farms + further treatment/eridacation, regulation of slaughter of animals on farms, and banning feeding offal to dogs. Now relies on surveillance and traceback plus mandatory prophylactic dog treatment and nil importation of intermediate hosts from international areas.
Give 2 examples of genetic mutations of translocations in paediatric malignancies and how they affect prognosis.
Ewing sarcoma - t(11;22)(q24;12) translocation makes the EWS - FLI-1 → potent oncogene.
EWS - FLI-1 is found in 90% of Ewing sarcoma and is associated with a better prognosis.
Alveolar rhabdomyosarcomas - chromosomal translocation results in PAX7/FKHR or PAX3/RKHR fusion → potent transcriptional activators
Presence of PAX7-FKHR in alveolar rhabdomyosarcoma is associated with better prognosis.
Neuroblastoma - associated with abnormal DNA content. Most commonly triploid or near triploid (55%). Others associated with worse prognosis.
Describe the pathogenesis of empyema formation
Four stages of empyema formation:
- Pre-collection phase (Pleurites and inflammation associated with parenchymal inflammation - pneumonia).
- Exudative phase: parapneumonic effusion develops (fluid is thin, low cellular count).
- Fibropurulent stage - empyema forms - large numbers of polymorphonuclear cells and fibrin –> progressive impairment in lung expansion and formation of fluid loculations.
- Organising stage - thick exudate forms, fibroblasts invade fibrinous peel on lung –> can cause entrapment of restrictive lung disease.
How do you classify lymphatic malformations? What are associations?
Macrocystic (>1cm)
Microcystic (<1cm)
Combination of macro and microcystic.
Lymphatic malformations are associated with underlying soft tissue and skeletal hypertrophy.
List 4 USS findings that would support the diagnosis of appendicitis. List 12 clinical findings (on history and physical examination) that would support a diagnosis of appendicitis.
USS:
- Dilated appendix (>6mm diameter) blind ending structure in the right iliac fossa.
- Hyperaemia
- Periappendiceal free fluid.
- Periappendiceal abscess.
- Faecolith
- Appendix non-compressible
Clinical:
- History: Migratory abdominal pain (generalised, to RIF).
- History: Associated anorexia
- History: Family history of appendicitis (3 times more likely)
- History: Low volume diarrhoea
- History: Nil sick contacts/family members.
- History: Abdominal dysuria
- History: Nil preceding URTI
- Exam: Tachycardia
- Exam: Fever (>38)
- Exam: Abdominal tenderness - McBurney’s point
- Exam: Localised or generalised peritonitis.
- Exam: Rovsings sign positive.
- Exam: Psoas sign, obturator sign.
- Exam: Right lower quadrant mass/phlegmon
Describe histological findings in Hirschsprung disease
Haematoxylin and Eosin:
- Submucosal and myenteric plexus aganglionosis.
- Nerve trunk hypertrophy
Acetylcholineresterase histochemistry:
- Increased cholinergic mucosal innervation (due to abnormal extrinsic innervation in the aganglionic rectum).
Immunohistochemical staining for calretinin:
- Absence of calretinin
Describe the abnormal molecular biology in neuroblastoma.
- Abnormal DNA content - Triploid or near triploid chromosomes in 55% of primary neuroblastoma. Remainder is near diploid or near tetraploid (both associated with worse prognosis)
- MYCN gene amplification - Short arm of chromosome 2, MYCN proto-oncogene causes increased rates of DNA synthesis, cell proliferation and shorter G1 phase of cell cycle.
- Segmental chromosome aberrations - Frequent deletions in short arm of chromosome 1 (35%), or chromosome 11. Both associated with more advanced disease, worse outcome.
- Mutations - Anaplastic lymphoma kinase (ALK) and PHOXB2 are associated with hereditary neuroblastoma.
What is the triad of haemolytic uraemic syndrome?
Thrombocytopaenia
Microangiopathic haemolytic anaemia
Acute kidney injury
What are the most common sites of extragonadal teratoma?
- Sacrococcygeal Teratoma - 45%
- Head and neck - 10%
- Mediastinal (anterior) - 6%
- Retroperitoneal (usually suprarenal) - 4%
- Central nervous system - 5%
What is Beckwith-Wiedemann syndrome?
Multiple tumours, hemihypertrophy, macroglossia, hyperinsulinism.
Associated with WT2 tumour suppressor gene loss → Wilms’ tumour, hepatoblastoma, adrenal malignancy
Associated with increased risk of rhabdomyosarcoma
How do topoisomerase inhibitors work? Give an example
Topisomerase inhibitors block toposiomerases and therefore block normal transcription and replication of DNA.
Topoisomerses regulate transcription and replication of DNA by transiently cutting the strands of DNA to relax the superocoil and extend the molecule. Essential for DNA transcription and replication.
Examples of topoisomerase inhibitors:
Doxorubicin (intercalation, DNA strand breaks, free radical formation ) - leukaemia, lymphoma, solid tumours.
Dactinomycin (intercalation, DNA strand breaks) - Wilms tumours, sarcomas
What is typhlitis and how is it treated?
Typhlitis is a necrotising enterocolitis that occurs in association with severe neutropaenia (also called neutropaenic enterocolitis)
Typhlitis symptoms:
Fever, abdominal pain, tenderness and neutropaenia.
Rx:
IVABx, NBM + TPN, G-CSF may help, surgical intervention if perforation.
Describe the life cycle of the Echinococcus granulosus
- Mature worms live in the intestine of the definitive host (usually dogs). They shed eggs in their faeces. They are immediately infectious.
- Accidental ingestion of the eggs by intermediate host (usually sheep, accidental intermediate host = humans).
- The eggs hatch in the small intestine of the intermediate host, develop hook like oncospheres that allow them to penetrate the intestinal wall and move into the blood stream -→ reach organs (esp liver, lungs).
- The oncospheres become thick walled hydatid cysts that become filled with protosolices and daughter cysts.
- The definitive host eats the organs of infected intermediate host and the cycle begins again (30-80 days to develop into adults stages).
Describe the pathophysiology of congenital adrenal hyperplasia.
- CAH results from an inability of the adrenal gland to form cortisol (enzyme deficiency, usually 21-hydroxylase deficiency - converts progesterone to deoxycorticosterone → corticosteroid or aldosterone).
- Substrates are shunted to mineralocorticoid or sex hormone pathways.
- There is no negative feedback to pituitary and excess ACTH continues to be secreted → excess mineralocorticoid or sex hormones (as cortisol can’t be produced).
- Adrenal differentiation occurs at 11 weeks gestation (after gonadal differentiation) therefore only external genitalia are affected.
What is the Spitz Classification?
