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 anomalies are associated with infantile haemangiomas?
Congenital anomalies are uncommon:
Sternal non-union (cervicothoracic haemangiomas)
Spinal dysraphism (lumbrosacral haemangiomas)
Urogenital and anorectal anomalies (pelvic and perineal haemangiomas)
PHACES
Haemangiomatosis - multiple disseminated haemangiomas (often associated with liver and GIT)
How are viral infections implicated in appendicitis?
Appendix has the highest amount of gut associated lymphoid tissue in the whole intestine. Patients with viral illnesses (mumps, coxsackie virus, adenovirus) can result in appendiceal lymphoid hyperplasia –> obstruction of the appendix lumen and cascade of appendicitis.
What are the complications of infantile haemangiomas?
Ulceration and bleeding (common)
Obstruction from rapidly proliferating lesion of head and neck.
High output cardiac failure (liver)
Tissue destruction (eyelid, lip, nose)
Visual axis obstruction (periorbital)
GI haemangiomas - rare, but may present with GI bleed.
Give 5 physiological responses to laparoscopic surgery.
Respiratory:
- increased abdominal pressure → diaphragmatic elevation → compression of the lower lobes → decreased lung capacity and increased respiratory resistance.
- Increased alveolar dead space → V/Q mismatch.
- CO2 absorption → respiratory acidosis.
Cardiovascular:
- Increased systemic vascular resistance → Increased mean arterial pressure → decreased cardiac output.
- Over time, decreased preload secondary to compression of the IVC secondary to increased intra-abdominal pressure.
Renal:
- Insufflation → decreased renal cortical blood flow → decreased GFR/urine output.
- Insufflation pressures of 20mmHg → renal blood flow reduction by 75%
Describe the histological subtype alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma (ARMS) - 25-35% - late childhood (trunk and extremities)
- Mutations in MYCN and CDK-4.
- PAX-FOXO1 fusions (PAX3 or PAX7-FOXO1) occur in 80%.
- Fusion positive alveolar rhabdomyosarcoma, associated with higher rates of metastasis.
- Alveolar classified as classic or solid.
- Classic alveolar rhabdomyosarcoma - eosinophilic cytoplasm arranged in nests, separated by fibrous septae and islands of tumour cells.
- Solid alveolar rhabdomyosarcoma - lacks dividing septae, characterised by sheets of monomorphic cells with round nuclei (small round blue cells)
What are 3 early complications and 3 long term complications of OA/TOF?
Short term: anastomotic leak/mediastinitis, stricture, recurrent fistula.
Long term: GORD, anastomotic stricture, tracheomalacia, vocal cord dysfunction, disordered peristalsis → exacerbation of reflux.
Treatment related implications:
Thoracotomy (scoliosis, winged scapula, chronic pain, shoulder weakness, chest wall asymmetry)
Circular myotomy - oesophageal leak, food impaction, oesophageal pseudodiverticulum.
Colonic transposition - intrathoracic redundant colon with stasis, diarrhoea.
What are the complications of echinococcal disease?
- Mass effect - capsular stretch (pain).
- Rupture (30%) - can seed daughter cells, can cause anaphylaxis.
- Infection (25%) - can become secondarily infected with bacteria.
- Recurrence (up to 10%) - can recur post cystostomy.
What is the gene associated with cystic fibrosis?
CFTR gene (Chromosome 7, delta 508).
- Cystic fibrosis transmembrane conductance regulator)
- Codes for Cl- secreting gene in mucus secreting cells, and Cl- absorption in sweat glands.
- Autosomal recessive
What is the germline mutation associated with heriditary neuroblastoma?
Anaplastic lymphocyte kinase (ALK) oncogene activation
What are common side effects of chemotherapeutic agents? Name 8
Myelosuppression
Nausea and vomiting
Anorexia
Diarrhoea
Neurotoxicity
Renal toxicity
Hepatotoxicity
Cardiotoxicity
Hypersensitivity reactions
Ototoxicity (cisplatin)
What is 99 Tc-mercaptoacetyltriglycerine and what is it used for?
MAG3 study.
Measures the uptake and clearance of radioisotope.
Radioisotope uptake in first 1-2 minutes = indication of renal function.
Washout of radioisotope = evaluates kidney drainage.
99Tc-mercaptoactetyltriglycerine is cleared by proximal tubular secretion.
What is GLUT1?
GLUT1 = Glucose transporter 1.
GLUT1 is an erythrocyte glucose transporter and placental marker. Found on infantile haemangiomas, thought to represent a placental origin for infantile haemangiomas.
What are the types of bronchiectasis?
- Cylindrical bronchiectasis
- Saccular bronchiectasis
- Fusiform bronchiectasis
List the common benign and malignant liver lesions
- Benign:
- Hepatic haemangiomas of infancy (focal, multifocal, diffuse)
- Mesenchymal hamartoma
- Focal nodular hyperplasia (more common in children > 5yrs)
- Nodular regenerative hyperplasia
- Malignant:
- Hepatoblastoma (children under 2)
- Hepatocellular carcinoma (children > 5)
- Undifferentiated embryonal sarcoma (>5yrs)
Describe the five common types of TOF/OA
Type A = isolated oesophageal atresia (often long gap) = 6%
Type B = proximal fistula, distal atresia = 5%
Type C = proximal atresia, distal fistula = 85%
Type D = proximal and distal fistula = 1%
Type E = H type fistula = 3%
What hormones are involved in descent of the testis?
-
Testosterone - produced by Leydig cells in the testis
- Acts on genital branch of genitofemoral nerve -→ calcitonin gene related peptide (essential for gubernacular migration in inguinoscrotal phase of descent).
- Acts directly on the gubernaculum via androgen receptors.
- Acts on cranial suspensory ligament - causes regression of CSL.
-
Mullerian inhibitory substance - produced by Sertoli cells in the testis.
- Stimulates the proximal end of the gubernaculum to remain short and thick.
-
Insulin-like hormone 3 - produced by Leydig cells in the testis.
- Responsible to for trans abdominal migration of the testis.
- Triggers the ‘swelling reaction’.
- Has role in normal formation of the processus vaginalis.
- Responsible to for trans abdominal migration of the testis.
-
Calcitonin gene-related peptide (aka neuropeptide) - genital branch GFN.
- Triggered by testosterone → essential for gubernacular migration during inguinoscrotal phase.
- Associated with growth of the processus vaginalis, as well as closure of processus vaginalis following testicular descent.
What is neuroblastoma and what is the histopathologic classification of neuroblastoma?
Neuroblastoma is a malignant embryonal tumour of sympathetic nervous system derived from neural crest cells.
Location of tumours can be anywhere along the migration of neural crest cells (usually adrenal medulla, paraspinal sympathetic ganglia or sympathetic paraganglia).
Classification:
Undifferentiated: lack of neuropils, unfavourable.
Poorly Differentiated: contains neuropils, <5% of tumour cells are differentiating.
Differentiating: Contains neuropils, >5% of tumour cells are differentiating toward ganglion cells.
How are vascular anomalies classified?
Vascular tumours vs Vascular malformations
Vascular tumours:
- Benign - Infantile haemangioma, pyogenic granuloma
- Locally aggressive - Kaposiform haemangioendothelioma.
- Malignant - Angiosarcoma, epithelioid haemangioendothelioma
Vascular malformations:
- Simple (capillary, lymphatic, venous, arteriovenous malformation, arteriovenous fistula,)
- Complex - combinations of the above.
Explain the embryology of the abdominal cavity.
- The abdominal wall musculature is formed from parietal lateral plate mesoderm, overlying skin if formed from ectoderm. The gut tube is formed from endoderm, covered with visceral lateral plate mesoderm.
- Lateral body folding: The lateral plate mesoderm grows laterally with ectoderm and drags the amnion ventrally to fuse in the midline (week 10/40).
- The formation of the diaphragm (weeks 4-16) separates the abdominal and thoracic cavities (diaphragm - septum transversum, pleuroperitoneal folds, oesophageal mesentery, body wall somites)
List anomalies associated with gastroschisis
- Typically not associated with syndromes.
- May be associated with atresia (10-25%), vanishing gastroschisis, short gut syndrome.
- Always associated with abnormal gut rotation.
- GORD
- Prematurity
- Fetal demise
What are the tumour markers of teratoma?
-
Alphafoetoprotein (AFP) - secreted by Yolk Sac Tumours.
- Normally high in newborns so can confuse things in the neonatal period.
- If elevated at diagnosis, higher risk of malignancy and higher risk of malignant recurrence post resection.
- Useful to assess the presence of residual or recurrent disease
-
beta-Human chorionic gonadotropin (BHCG) - elevated in choriocarcinomas.
- If BHCG secretion by the tumour is great enough, may be sufficiency to induce precocious puberty.
- Carcinoembryonic antigen (CEA) - produced by choriocarcinomas very rarely.
- CA125 - Valuable in the follow up of SCTs
What is the Spitz Classification?
What histological features differentiate neuroblastoma from other small round blue cell tumours of childhood?
- Neuropils = neuritic processes.
- Homer Wright rosettes (neuroblasts surrounding eosinophilic neuropil
- May also contain scattered ganglion cells or immature chromaffin cells
What syndromes are associated with Wilms’ Tumour?
Wilms’ tumour is rarely associated with syndromes (10% of all WT)
Sporadic aniridia
Isolated hemihypertrophy
Denys-trash Syndrome (nephropathy, renal failure, male pseudohermaphroditism, WT)
Beckwith-Wiedemann Syndrome (visceralomegaly, macroglossia, exomphalos, hypoglycaemia, embryonal tumours (WT, hepatoblastoma)
WAGR complex (Wilms’ tumour, aniridia, genitourinary malformation and mental retardation
Describe the pathogenesis and embryological basis of pre-auricular sinuses and cysts.
- Cysts are ectodermal inclusion cysts. - Thought to occur secondary to failed fusion of the 6 auditory hillocks (that fuse to form pinna).
What are the findings of Hirschsprung disease in anorectal manometry?
- Loss of the recto-anal inhibitory reflex
- Increased contraction in the anal canal
What is anaplasia and what does it signify in Wilms’ tumour?
Anaplasia
Multipolar, polyploid mitotic figures
Nuclear enlargement (3 times the size of adjacent cells)
Hyperchromasia
The presence of anaplasia signifies an unfavourable histology in Wilms’ tumour.
Typically occurs in children > 2yrs of age.
Associated with high rates of relapse (⅔) and death from tumour (58%)
Anaplasia associated with TP53 tumour suppressor gene deletion (chromosome 17)
What is the natural history of infantile haemangiomas (include the stages)?
Proliferative Phase:
Median age of onset 2 weeks. Rapid growth for first 6-8 months. Plateaus at 10-12 months.
Appears red/raise, may ulcerate (if in superficial dermis).
Appears bluish with slightly raised skin (if deep dermis)
Involuting Phase:
Occurs between ages 1 and 7, associated with slow regression of tumour.
Tumour colour fades from crimson to dull purple, with deflation of tumour mass.
50% involution by 5yrs, 70% by 7yrs. Complete regression by 12.
Involuted Phase:
50% will have nearly normal appearing skin.
Remainder will have lax, redundant skin or yellow/discolouration.
Previously ulcerated skin will scar.
Describe the formation of bronchiectasis
- Infection/recurrent infections cause destruction of ciliary epithelium (replaced by cuboidal epithelium)
- Infection causes bronchial oedema and inflammation, in turn causes destruction of elastic tissues of airways –> airway dilation.
- Airway dilation –> impaired clearance of bacteria, colonisation and recurrent infection/ongoing destruction.
End result is irreversible dilation of the airways secondary to inflammatory destruction of bronchial and peribronchial tissues.
Describe the development of tuberculosis.
- Airborne transmission - person to person.
- Mycobacterium tuberculosis is phagocytosed but avoids lysis within phagocyte → local infection.
- Primary infection in lung - typically asymptomatic, but may cause fever or effusion.
- Within 3 weeks of infection → cell mediated immunity walls off mycobacterium in a granuloma.
- Tissue within granuloma dies → caseous necrosis → Ghon focus → fibrosis and calcification (Range complex)
- Fibrocalcific nodule can lay dormant with viable organisms (latent disease) and become reactivated when immunocompromised.
- Reactivation → response of memory T cells → cytokine release → extensive caseous necrosis in lungs with cavitating lesions.
- If disseminates, can affect kidneys, spine, cervical lymph nodes, adrenal glands, liver, meninges.
Describe the pathophysiology of appendicitis
- Luminal obstruction (faecolith, lymphoid hyperplasia, neoplasm) creates closed loop obstruction.
- Ongoing mucus secretion from appendiceal mucosa –> increased intraluminal pressure and accordingly increased intramural pressure –> obstruction of lymphatic drainage –> worsening swelling and oedema.
- Veinous congestion/obstruction –> secondary arterial insufficiency –> ischaemia and necrosis.
- Associated bacterial overgrowth and translocation.
How is cystic nephroma distinguished from cystic Wilms’ tumour?
Grossly and radiographically indistinguishable.
Both will contain purely cystic masses, characterised by thin walled septation.
Cystic nephroma contains ONLY entirely differentiated tissues in the septations without blastemal or embryonal elements (these are characteristic of Wilms’ tumour)
Discuss MAIS
Atypical mycobacterium infection - usually associated with cervical lymphadenitis.
- Mycobacterium avium intracellulare scrofulaceam
MAIS lives in soil, enters the hose via the mucous membranes of the pharynx.
- Typically involves the higher cervical nodes (submandibular, submaxillary).
- Typically occurs in children aged 1-5.
Develops as minimally tender nodal swelling with eventual overlying skin thinning and discolouration –> ulceration and sinus formation in 10%.
Describe the key histological findings in Crohn’s disease
- Acute: Transmural inflammation, mucosal ulceration, submucosal and lymphatic granulomas, serosal fat wrapping. May have fistulous tracts.
- Chronic: Fibrosis, bowel wall thickening and stricture formation.
List 4 possible diagnoses associated with small blue cell tumour finding in a biopsy of a chest wall lesion.
The small round blue cell tumours of infancy and childhood are:
Ewing sarcoma
Rhabdomyosarcoma
Neuroblastoma
Non-Hodgkins Lymphoma (Burkitt Lymphoma, Lymphoblastic lymphoma)
What is meant by triphasic in regards to Wilms’ tumour?
Wilms’ tumour with favourable histology are triphasic if they contain all 3 elements.
Blastemal
Stromal
Epithelial tubules
Discuss the processes involved in the clinical picture of CARS
CARS = Compensatory anti-inflammatory response syndrome
Thought to balance the effects of SIRS, but can lead to secondary infection. Best example is in major trauma or burns where there is a known immunocompromise following initial systemic inflammatory response.
- Cutaneous anergy
- Reduction of lymphocytes (apoptosis)
- Decreased cytokine response by monocytes
Associated with IL10
Describe the genitourinary manifestations of cystic fibrosis
Male infertility
Bilateral absence of the vas deferens
Subvertility in females
Describe OPSI
OPSI - Overwhelming post splenectomy infection.
Seen in patients with asplenia (functional or post splenectomy).
Susceptibility to infections from encapsulated bacteria.
- Streptococcus pneumonia
- Haemophilus influenzae B
- Neisseria meningitidis.
Which hepatic haemangiomas stain positive for GLUT1?
Multifocal and diffuse hepatic haemangiomas are true infantile haemangiomas and they therefore stain positive for GLUT1.
Focal hepatic haemangioma DOES NOT stain positive for GLUT1 as it is a variant of the rapidly involuting congenital haemangioma.
Describe the gastrointestinal manifestations of cystic fibrosis.
- Meconium ileus - inspissated meconium causing intraluminal obstruction.
- Pancreatic insufficiency - inspissated exocrine secretions cause obstruction of pancreatic ducts –> auto digestion of acing cells and fatty replacement of pancreatic parenchyma –> fibrosis.
- Biliary system - thick, viscous bile –> small duct obstruction, increased activity of free radicals –> hepatocellular damage. Cholelithiasis.
- Increased rates of GORD.
What triggers typical haemolytic uraemic syndrome?
Typical haemolytic uraemic syndrome occurs following a gastrointestinal infection with E. Coli (verocytotoxin producing) or Shigella.
HUS often follows a prodrome of bloody diarrhoea associated with the E Coli infection.
Give an example of 46XX DSD
46XX DSD - refers to overandrogenisation - most commonly congenital adrenal hyperplasia.
Normal paramesonephric duct system (upper vagina, uterus, Fallopian tubes).
External genitalia/phenotype depends on timing and amount of androgen exposure (clitoromegaly to normal male appearance).
What are the pathophysiogical stages of infantile haemangioma?
- Proliferative phase: expression of multiple growth factors (fibroblast growth factor - FGF, matrix metalloproteinases - MMP, vascular endothelial growth factor) that play critical roles in the formation of blood vessels. Tumour is composed of plump, rapidly dividing endothelial cells that form a mass of sinusoidal vascular channels with feeding and draining artery/veins.
- Involuting phase: decreased angiogenesis, endothelial cell apoptosis (expression of angiogenesis inhibitors such as interferon-beta and tissue inhibitor of metalloproteinase (TIMP1).
- Involuted phase
How do chemotherapeutic alkylating agents work? Name 2.
Alkylating agents interfere with cell growth by covalently cross linking DNA.
Examples of alkylating agents include -
Cyclophosphamide: lymphoma, leukaemia, neuroblastoma, sarcoma.
Cisplatin: testicular and germ cell tumours, brain tumours, osteosarcoma, neuroblastoma
Carboplatin: Brain tumours, germ cell tumours, neuroblastoma, sarcoma, colorectal cancers
What are the mutations associated with Li Fraumeni syndrome and what cancers is it associated with?
Li-Fraumeni syndrome is associated with inactivation of the p53 tumour suppressor gene.
Risk of:
Osteosarcoma
Rhabdomyosarcoma (when coupled with overactivation of the RAS oncogene)
Adrenocortical carcinomas
Pre-menopausal breast cancer.
Brain tumours
What immune complex causes Henoch Schönlein Purpura and what paediatric surgical conditions does it affect?
Immune Complex = IgA
Symptoms associated with HSP correspond to deposition of IgA within tissues.
- Colicky abdominal pain (deposition of IgA in walls of GI vessels → inflammation → pain)
- GI bleed (IgA deposition in GIT vasculature → inflammation of mucosa → bleeding).
- Intussusception - oedema or bleeding in gut wall associated with HSP → pathological lead point.
- Can mimic testicular torsion - IgA deposition in skin of scrotum → inflammation
How do congenital haemangiomas differ from infantile haemangiomas?
Congenital haemangiomas:
Fully developed at birth
Display no post natal growth.
Congenital haemangiomas don’t stain positive for GLUT1 (infantile haemangiomas do)
More commonly found on the limbs (RICH).
Involution occurs more quickly (by 6-14 months) - RICH
Non-involuting congenital haemangiomas don’t involute but will grow with the child (NICH).
Name 5 factors associated with worse prognosis in rhabdomyosarcoma.
Alveolar subtype
PAX3 or PAX7-FOXO1 fusion
Age > 10years or age <1yr
Trunk, paraspinal, pelvic/retroperitoneal, perianal sites
Immunohistochemical staining for myogenin
Size of tumour (>5cm)
Presence of lymph node or distal metastases.
What is graft versus host disease?
Graft versus host occurs when immunologically competent T cells are transplanted into immunologically crippled recipients (most commonly occurs with haemotopoietic stem cell transplantation).
- T cells in the donor inoculum recognise the recipients HLA antigens as foreign and react to them.
- Immune mediated damage to skin, liver and intestines.
- Skin: Generalised rash → can lead to extensive desquamation.
- Liver: Destruction of the small bile ducts → jaundice
- Intestine: Mucosal ulceration → bloody diarrhoea.
What are the roles of the WT1 gene?
- Associated with normal gonadal and kidney development.
- Tumour suppressor gene
- Mutations are associated with Wilms’ tumour and associated syndromes (WAGR syndrome, Denys-Drash syndrome)
Name 2 ovarian pathologies that occur in neonatal period, childhood and adolescents
Neonatal -
- Simple: Follicular cysts (associated with maternal oestrogens) - usually involute in first year of life.
- Complex: may represent ovarian torsion (in utero OR neonatal period.
Childhood -
- Simple: usually physiological follicular cysts.
- Complex: large, complex cysts that don’t regress = ovarian tumours (mature teratomas far more likely than stromal tumours).
Adolescents -
- Benign: follicular cyst, ovarian torsion, corpus luteal cyst.
- Malignant:
- Germ cell tumours (immature teratomas, dygerminomas)
- Epithelial-stromal tumours (serous carcinoma, mucinous carcinoma)
- Sex cord-stromal tumours (granulosa cell tumours, Sertoli-leydig cell tumours)
How to chemotherapeutic antimetabolites work? Name 2.
Antimetabolites are cell-cycle specific, they interfere with the use of normal substrates for DNA/RNA synthesis.
Antimetabolite examples:
Methotrexate (interferes with folate metabolism) - Leukaemia, lymphoma, osteosarcoma
Mercaptopurine (incorporated into DNA/RNA, blocks purine synthesis) - Leukaemia
Gemcitabine (incorporated into DNA, inhibits DNA polymerase) - Hodgkin lymphoma
Describe the pulmonary manifestations of cystic fibrosis
Inspissated mucus impairs effectiveness of mucuciliary elevator (impaired clearance of mucus and bacteria)
- Recurrent infections.
- Bronchiectasis
- Mucus plugging
Explain the pathophysiology of necrotising fasciitis
Four components of necrotising fasciitis:
- Bacterial toxins - allow for rapid spread via destruction of ECM, impair neutrophil migration and phagocytosis.
- Local tissue destruction - toxin induced obstructing bacterial platelet/neutrophil/endothelial cell clusters → ischaemia.
- Fulminant progression of the inflammatory process
- Early systemic toxicity, SIRS → sepsis → MODS → septic shock → death
List the causative organisms for empyema
Staphylococcus aureus, Haemophilus influenzae, Stretococcus pneumonia, Mycobacterium tuberculosis (RARE)
Describe histological findings in hepatocellular carcinoma
- Associated with surrounding cirrhosis in 60%.
- Tumour made up of trabeculae.
- Tumour cells larger than normal hepatocytes
- Hypochromasia.
- Frequent and bizarre mitosis
- Vascular invasion
- Differentiation:
- <2cm well differentiated.
- Larger tumours - poorly differentiated cell clones.
- Associated with neovascularisation and hyper vascular pattern.
Describe histological findings on hepatoblastoma
Low risk = foetal histology, low mitotic rate
Intermediate risk = epithelial and mixed histology
High risk = embryonal histology with associated anaplasia or macrotrabecular pattern (similar to HCC)
What is Kasabach-Merritt phenomenon?
- Rapidly expanding vascular tumour (usually kaposiform haemangioendothelioma or tufted angioma)
- Thrombocytopaenia (refractory to platelet transfusion)
- Consumptive coagulopathy
- Microangiopathic haemolytic anaemia
Name 3 tumours of the mediastinum
Non-Hodgkin Lymphoma (most common - usually anterior mediastinum)
Hodgkin Lymphoma (usually anterior and middle mediastinum)
Germ cell tumours (teratomas - usually anterior mediastinum)
Neuroblastoma (posterior mediastinum)
What anaesthetic risks are associated with mediastinal tumours?
Induction of anaesthesia can cause rapid and profound cardiorespiratory collapse in children with mediastinal tumours.
- Anterior mediastinal tumours (usually NHL or HL) may cause compression of trachea/bronchus or obstruction of venous return to the heart.
- Loss of intrinsic muscle tone with induction of anaesthesia can cause profound cardiorespiratory collapse.
Main signs/symptoms that suggest high risk of collapse:
- Orthopnoea
- Head and neck swelling (SVC obstruction)
- Loss of >50% of tracheal or bronchial diameter on pre-op imaging.
What are the effects of hypothyroidism on children?
- Intellectual impairment (T4 essential for myelinisation of the CNS in the first 3 years of life).
- Growth retardation
- Fatigue
- Constipation
- Poor school performance
- Weight gain
- Irregular menses
What genetic conditions or mutations are associated with thyroid malignancies?
-
RET proto-oncogene: seen in well differentiated thyroid carcinoma AND medullary thyroid cancer.
- Germline mutations of RET oncogene → affects all tissues in which RET is produced = MEN2 or familial medullary thyroid cancer.
- Somatic mutations of RET in thyroid → sporadic medullary thyroid cancer.
- Mutation in BRAF (B isoform of Raf kinase) is common in well diffferentiated thyroid carcinoma (papillary, follicular). Associated with worse prognosis.
- APC gene mutation (Familial adenomatous polyposis) associated with papillary thyroid cancer.
What serum markers are elevated in medullary thyroid carcinomas?
- Calcitonin
- Carcinoembryonic antigen (CEA)
Both calcitonin and CEA are secreted by thyroid parafollicular C cells.
What familial factors are involved in paediatric thyroid disease?
Medullary thyroid carcinoma is particularly associated with hereditary pattern (sporadic cases also occur).
- Associated with MEN2 (MEN2A, MEN2B, familial medullary thyroid carcinoma)
- All MEN2 associated with mutation in the RET proto-oncogene
- MEN2A = 90% develop MTC from age of 5 years.
- Also associated with phaeochromocytomas.
- MEN2B = accounts for 5% of hereditary MTC. Usually occurs at earlier age and is more aggressive.
- Also associated with phaeochromocytoma and marfanoid features.
- Familial MTC = MTC sole manifestation, least aggressive variant of all MEN2.
- MEN2A = 90% develop MTC from age of 5 years.
- All MEN2 associated with mutation in the RET proto-oncogene
Describe the molecular genetics of MEN2
- Autosomal dominant condition
- Gain of function germline mutation in the RET oncogene. Mutations in RET cause activation of the signal transduction pathway.
- MEN2B consistently has the highest risk, followed by MEN2A and then FMTC
What are major risk factors for thyroid malignancy?
- Family history
- MEN2 syndrome (MEN2A, MEN2B and familial medullary thyroid carcinoma) - MTC
- Familial adenomatous polyposis (APC mutation) - papillary thyroid carcinoma
- Previous cancers
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Leukaemias
- Radiation exposure
- Radiotherapy
- Chemotherapy with alkylating agents (carboplatin, cisplatin)
What is Tc99 sodium pertechnetate scintigraphy?
Tc99 sodium pertechnetate scintigraphy is also known as a Meckel scan.
- The radio-isotope has a high affinity for parietal cells in gastric mucosa.
- Gastric mucosa is the most common ectopic tissue in Meckel diverticulum.
- When gastric mucosa present, the scan shows uptake in the stomach and focally in the distal small bowel.
- Sensitivity 25 - 92%, 33% false negative rate (occurs when either no gastric mucosa, or when there is rapid transit through GIT such as when there is a high volume bleed.
What is 99m Tc-dimercaptosuccinic acid used for?
99m Tc-dimercaptosuccinic acid = DMSA = used for static renal scintigraphy.
- Used to assess renal structure and morphology (renal parenchyma).
- Binds to proximal tubules in renal cortex.
- Gives excellent assessment of differential renal function, renal cortical scarring, acute pyelonephritis.
- Gives NO assessment of excretion/drainage of the kidney
What is 99m Tc-mercaptoacetyltriglycine used for?
99m Tc-mercaptoacetyltriglycine = MAG3 = dynamic renal scintigraphy.
- Useful in assessment of renal perfusion, extraction of tracer from blood and excretion of tracer through collecting system.
- MAG3 is secreted by the distal part of the proximal tubule active secretion.
- Used to assess for differential function and drainage of kidney (esp PUJ obstruction, VUJ obstruction - when used with free draining catheter).
What is 99m Tc-diethylenetriamine penta-acetic acid used for?
99m Tc-diethylenetriamine penta-acetic acid = DTPA = dynamic renal scintigraphy.
- Assess perfusion of kidneys, extraction of tracer from blood and excretion of tracer through the collecting system.
- Removed from blood via glomerular filtration → can be used to calculate GFR in each kidney
- Similar use to MAG3 in paediatric urology but not used as often as less accurate.
What are the types of posterior urethral valves and what is their underlying aetiology?
Type 1: Membranes that run obliquely from the verumontanum and insert into the proximal membranous urethra.
- Aetiology: thought to be due to abnormal insertion of the mesonephric duct into the cloaca and failed migration of the ejaculatory ducts.
Type 3: Ring type membrane distal to the verumontanum with a central perforation .
- Aetiology: incomplete dissolution of the urogenital membrane.
What is the formula for bladder compliance and how is it measured?
Bladder compliance = change in pressure/change in volume.
Measured with cystometrogram (CMG)
What develops from the mesonephric ducts in males and females?
BOTH: ureter, collecting systems.
Males: vas deferens, epididymis
Females: Gartner’s duct.
From mesonephric tubules (primitive functional mesonephros)
Males: efferent ductules of testes
Females: Broad ligament.
What forms from the metanephric cap and what forms from the ureteric bud?
Ureteric bud: ureter, collecting ducts, calyces, pelvis.
Metanephric cap: glomerulus, proximal tubule, loop of Henle, distal tubule.
What are the findings on liver biopsy for biliary atresia?
- Expansion of the portal tracts.
- Oedematous fibroplasia and bile duct proliferation, with intraluminal bile plugs.
- Periportal oedema
What are the types of biliary atresia?
Which type is the most common?
- Type 1: CBD atresia
- Type 2a: atresia of the common hepatic duct
- Type 2b: atresia of the CBD and common hepatic duct
- Type 3: of all extra-hepatic ducts up to the porta hepatis (accounts for 90%)
What are the major determinants of satisfactory outcome after portenterostomy?
- Age at initial operation (ideally < 60 days (cirrhosis begins to occur at 3 months)
- Successful achievement of postoperative bile flow
- Presence of microscopic ductal structures at the porta hepatis
- Extent of liver parenchymal disease at the time of diagnosis
- Technical factors involving the anastomosis
- List the key histological findings of lichen sclerosis, when is this most commonly encountered in paediatric practice?
Lichen sclerosis most commonly occurs in paediatric males as the condition balanitis xerotica obliterans - a chronic inflammatory condition of the prepuce and glans that causes fibrosis (phimosis), and meatal stenosis.
Histology: hyperkeratosis, epidermal atrophy, dermis contains abundant collagen and lympho-plasmacytic infiltrate.
What conditions are associated with cholelithiasis in the paediatric population?
Obesity - cholesterol stones
Haemolytic anaemias - sickle cell anaemia, hereditary spherocytosis - pigmented stones
Long term TPN
Cystic fibrosis
Ileal resection
Mast cell activation
What system is used to classify choledochal cysts?
What are the types of choledochal cyst?
Todani classification
There are 5 main types:
Type Ia: Cystic dilatation of the CBD
Type Ib: Fusiform dilatation of the CBD
Type II: Diverticulum off CBD
Type III: Choledochocoele (cystic swelling of CBD within wall of duodenum)
Type IVa: Both intrahepatic and extra hepatic biliary cysts
Type IVb: Multiple extra hepatic duct cysts
Type V: multiple intrahepatic duct cysts (I.e Caroli disease)
What is the pathophysiology of infarction of an intussusceptum?
- The mesentery of the intussceptum is pulled into the intussuscipiens, compressing it.
- Venous stasis/obstruction occurs → intussusceptum becomes swollen and engorged (bowel wall oedema).
- If remains un-reduced, arterial insufficiency follows resulting in ischaemia and eventually necrosis/infarction of the intussusceptum
What are five lead points in intussusception?
- Meckel Diverticulum
- Polyp
- Duplication cyst
- Lymphoma
- Haemorrhage into bowel wall from HSP.
- Appendix stump
- Tumours
