Infection/Inflammation and Neoplasia

Question 1

What are the main cytokines involved in inflammation?

Answer 1

TNF alpha

IL-1

Question 2

What causes fever?

Answer 2

• Fever occurs when prostaglandins are released by the vascular and perivascular cells of the hypothalamus.
  
  • Release of prostaglandins (particularly PGE2) → hypothalamic release of neurotransmitters which reset the temperature set point.
    
    • NSAIDs manage fever by inhibiting the synthesis of prostaglandins.
  • Fever is associated with the release of pyrogens (i.e. lipopolysaccharides (gram negative cell walls) → leucocyte mediated release of IL-1 and TNF → trigger the arachadonic acid pathway to produce prostaglandins → fever.

Question 3

How is the neonatal cellular immunity different to adults?

Answer 3

• Neonates have increased susceptibility to infection, particularly neonates, and especially to Salmonella and E. coli.
  
  • Many differences in WBCs.
    
    • Neutrophils:
      
      • Normal production at term (decreased in premature).
      • Limited scope to increase the levels of circulating neutrophils in response to inflammation/infection (smaller storage pool - 20% of that of adults)
        
        • Systemic infections often cause severe neutropenia (i.e. NEC).
      • Decreased adhesion to endothelial surface (impaired chemotaxis and migration into extravascular tissues)
    • Monocytes:
      
      • Similar concentration to adults. Once at site of inflammation/infection, efficient killing and phagocytosis.
      • Migration of monocytes is delayed (impaired chemotaxis, inability to upregulate adhesion molecules).
      • Reduced cytokines (TNF-alpha, IL-6).
    • Lymphocytes:
      
      • T-lymphocytes - higher numbers of circulating T lymphocytes. Impaired cytokines.
      • B-cells - High rates of IgM, but dependent on maternal placental transfer of IgG and IgA initially, then breast milk later.
      • NK cells - normal numbers, less lytic potential.
    • Components - reduction in complement factors.

Question 4

What is OPSI and why does it happen? Name 3 organisms associated with OPSI?

Answer 4

• OPSI - overwhelming post splenectomy infection.
  
  • Rapidly progressive infection that can cause coma/death within 24 hours and is associated with a mortality rate of 50-70% in adults.
    
    • Occurs because spleen normally contains macrophages which function to phagocytose encapsulated organisms.
    • Spleen also contains immunoglobulins responsible for generating an immune response to infection from encapsulated organisms.
• 3 organisms (encapsulated): Haemophilus influenzae B, strep. pneumonia, neisseria meningitides
• Reducing risk:
  
  • Referral to post splenectomy clinic.
  • Re-immunisation (day 14) - HiB, Strep pneumonia, meningococcal.
  • Consideration of daily lifelong prophylactic antibiotics (i.e. amoxycillin)

Question 5

Describe MAIS infection

Answer 5

• Mycobacterium avium intracellulare scrofulaceam (MAIS) is an atypical mycobacterial infection in children associated mycobacterial lymphadenitis (chronic lymphadenitis).
  
  • Usually enters via the mucous membranes of the pharynx.
  • Usually involves higher cervical nodes (submandibular, submental)
  • Typically occurs in children 1-5 years.
  • 50% respond to Abx, the rest form abscess.
    
    • 10% of abscesses are associated with formation of a sinus.
• Mx:
  
  • ABx, surgical excision of all clinically involved nodes, sinus tracts and overlying skin.
  • If nodes are in close proximity to facial nerve → TB drugs.

Question 6

What is the organism of cat-scratch disease? What is the most common vector?

Answer 6

Bartonella henselae = Cat scratch disease

• Most common vector is cat (cat tick for human transmission), dog or monkey.
  
  • Enters the skin via superficial wound caused by cat (usually).
  • Initially superficial infection or pustule - forms in 3-5 days.
    
    • Develops regional adenopathy in 1-2 weeks → chronic lymphadenitis
    • Typically single node involved, corresponding to inoculation site (i.e. axilla).
• Dx:
  
  • PCR for bartonella henselae on FNA.
• Mx:
  
  • Usually self limiting, resolves spontaneously within weeks to months.

Question 7

How does an empyema occur? What are the stages (4)?

Answer 7

Empyema occurs secondary to a pneumonic process → parapneumonic effusion → bacterial translocation → infection/inflammation → fibrin and pus = empyema.

• Four stages of empyema:
  
  • Pre-collection stage - pleuritis and inflammation associated with parenchymal inflammation.
  • Exudative stage - development of parapneumonic effusion.
  • Fibrinopurulent stage - becomes empyema, large numbers of polymorphonuclear cells and fibrin in fluid → separations.
  • Organising stage - thick exudate forms, fibroblasts invade fibrinous peel → can cause restrictive lung pathology.

Question 8

What are the most common pathogens associated with empyema?

Answer 8

1. Streptococcus pneumoniae (most common in infants and children)
2. Haemophilus influenzae B
3. Staphylococcus aureus
4. Mycobacterium tuberculosis (rarely)

Question 9

What are the aetiological theories for ulcerative colitis?

Answer 9

• Ulcerative colitis is a chronic, immune mediated inflammatory condition.
  
  • Thought to be due to an exaggerated immune response to commensal gut flora.
  • Multifactorial pathogenesis:
    
    • Immune:
      
      • HLA B27 often present.
      • Cytokine receptor imbalance in UC population (IL1, IL6).
      • Autoimmune dysregulation.
    • Microbiome:
      
      • Balance of intestinal flora plays a key role in gut health, no causative bacteria found in UC.
    • Genetic:
      
      • Higher risk in siblings.

Question 10

What are the histological findings in ulcerative colitis (5)?

Answer 10

1. Crypt architectural distortion.
2. Crypt abscesses
3. Mucosal ulceration and undermining of adjacent mucosa.
4. Mucosal bridges
5. Pseudopolyps

Question 11

What are the sequelae of acute ulcerative colitis?

Answer 11

• Acute ulcerative colitis can lead to peritonitis and megacolon
  
  • Colonic distension and decreased peristalsis (secondary to inflammation)
  • Muscularis mucosal becomes thin and haemorrhagic
  • Inflammation mediated bacterial translocation.
• Exacerbated by the use of anti motility agents (opioids) and systemic corticosteroids.

Question 12

What are the pathological changes seen in chronic ulcerative colitis (5)?

Answer 12

• Chronic inflammation → thickening and fibrosis of muscularis.
• Flattening of the haustral folds
• Reduction in meaningful peristaltic contractions.
• Mucosa becomes atrophic and may become dysplastic → malignancy.
• Colonic mesentery becomes shortened, serosa develops superficial vascularity and overabundance of adipose tissue.

Question 13

What are the complications of ulcerative colitis?

Answer 13

• Anaemia (chronic disease, malabsorption, GI blood loss)
• Diarrhoea
• Haematochezia
• Toxic megacolon (5%)
• Colorectal carcinoma (>3%) - of patients within first 10 years of diagnosis, more frequent in each subsequent decade).
  
  • Malignancy more common in those with pan colitis and those with childhood symptoms (?duration related)

Question 14

What are the short (2) and long term (5) complications of proctocolectomy for ulcerative colitis?

Answer 14

• Short term:
  
  • Wound infection
  • Anaemia
  • Electrolyte abnormalities
    
    • Diarrhoea/High output.
• Long term:
  
  • Ileo-anal stricture (10-20%)
  • Adhesive small bowel obstruction (10-30%)
  • Enterocutaneous fistula (5-13%)
  • Faecal Incontinence:
    
    • Nocturnal (40% initially) - worse in pre-adolescent age because they sleep so deeply.
    • Daytime (5%)
  • Mesenteric vein thrombosis (associated with excess tension on pull through and pro inflammatory state).

Question 15

What are 5 extra colonic manifestations of ulcerative colitis?

Answer 15

Erythema nodosum

Arthralgias

Pyoderma gangrenosa

Nephrolithiasis

Sclerosing cholangitis

Uveitis

Question 16

What are the aetiological theories behind the development of Crohn’s disease?

Answer 16

Crohn’s disease is a transmural inflammatory condition of the whole gastrointestinal tract.

• Unknown, but likely multifactorial aetiology:
  
  • Complex integration between environmental, genetic and immune factors
    
    • Genetic:
      
      • More common in family members and siblings (identical twins 35-50%, non-identical twins 4%).
      • Gene mutations (30-40%)
        
        • NOD2/CARD15 (Overexpression in proinflammatory cytokine transcription)
        • IBD5 gene mutation associated with Crohn’s disease linked perianal disease.
    • Environmental:
      
      • Increasing use of ABx in the community corresponds to increasing rates.
      • Altered microbiome (Crohn’s patients = dysbiotic) → more total bacteria including more pathogenic microbes and less bacterial diversity.

Question 17

What are the histopathological findings associated with Crohn’s disease (5)?

Answer 17

• Transmural inflammation
• Granuloma formation
• Intestinal wall thickening
  
  • Submucosal oedema
  • Fibrosis
  • Lymphatic dilatation.
• Skip lesions
  
  • Fissures and ulcerations interspersed with areas of normal mucosa.
  • Ulcers may penetrate deep into the muscularis → can progress to perforation, abscess, fistulae.
• Fat wrapping and thickening of the mesentery - response to transmural inflammation.
• Chronic inflammation → fibrosis, bowel wall thickening, stricture.

Question 18

What virus causes the common wart?

How long is incubation?

What is the histopathology?

Answer 18

Common wart (verruca vulgaris) is caused by the human papilloma virus.

Incubation can be up to 12 months. Spontaneous resolution in 2 years.

Histology - hyperkeratotic, containing verrucous papules and nodules.

Question 19

What virus causes molloscum contagiosum?

How long is incubation?

What are the clinical characteristics?

Answer 19

Molloscum contagiosum is caused by the poxvirus, molloscum contagiosum virus.

Incubation = 2 weeks to 6 months. Duration = persist for 2 or more years (50% resolve by 12 months).

Clinical characteristics = Age < 10yrs, warm and moist areas - axilla, popliteal fossa, groin, genitalia. Presents as clusters of small round papules with central pit (umbilicated) → contain cheesy white material.

Question 20

What are the three most common pathogens in necrotising fasciitis?

Answer 20

Group A strep - usually Strep Pyogenes

Staph aureus

Pseudomonas aeruginosa (usually in the immunocompromised)

Single organism - 88%

Polymicrobial - 8%

Fungal - 2%

Question 21

What are the four pathologic characteristics of necrotising soft tissue infection?

Answer 21

• Toxin producing bacteria:
  
  • Proteases break down extracellular matrix
  • Toxins inhibit influx of neutrophils
    
    • Cause platelet aggregates → intravascular thrombosis and occlusion → ischaemia and obstruct WBC access.
• Tissue destruction:
  
  • Liquefactive necrosis (toxin mediated)
  • Ischaemia secondary to occlusive intravascular aggregates of platelets and leucocytes.
• Fulminant progression of the inflammatory process.
• Early systemic toxicity → sepsis → MODS → septic shock → death.

Question 22

What is graft versus host disease?

Answer 22

• Graft versus host disease occurs when immunologically competent cells (or precursors) are transplanted into immunocompromised hosts.
  
  • Graft T-cells (within transplant inoculum) recognise host/recipient HLA antigens as foreign and react to them → immune reaction and inflammation.
    
    • T cells from the graft infiltrate the host and cause tissue destruction and apoptosis.
    • Engages the innate immune system (macrophages and NK cells) → production of cytokines → promote systemic inflammation.
  • Occurs most commonly following haematopoeitic stem cells transplant.

Question 23

How does graft versus host disease present (acute versus chronic)?

Answer 23

• Acute GVHD (occurs within 100 days) - usually days to weeks after transplant.
  
  • Major manifestations - involvement of the immune system and epithelial of the skin, liver and intestines.
    
    • Skin - rash and desquamation
    • Liver - lymphocyte mediated destruction of the epithelial cells of the liver → jaundice and hepatitis.
    • Intestine - mucosal ulceration and diarrhoea.
    • Eyes - haemorrhagic conjunctivitis
    • Kidneys - glomerulonephritis
    • Lungs - interstitial pneumonitis
• Chronic GVHD (occurs > 100 days) - may continue on from acute GVHD or may be insidious.
  
  • Skin - extensive cutaneous injury with destruction of appendages and dermal fibrosis.
  • Liver - chronic liver disease → cholestatic jaundice.
  • Gastrointestinal tract - strictures secondary to mucosal inflammation (especially oesophageal).
  • Immune - involution of the thymus and depletion of lymphocyte stores in lymph nodes (can lead to recurrent severe infections).

Question 24

Name 5 complications associated with immune system ablation and immunosuppression for transplant.

Answer 24

• Intestinal
  
  • Abdominal pain and diarrhoea (⅔ of all patients) - more severe diarrhoea associated with increased rates of acute GVHD.
  • Typhlitis:
    
    • Necrotising inflammation of the colon in the severely immunocompromised patient.
      
      • Presents with fever, abdominal pain, tenderness, neutropaenia.
• Hepatobiliary
  
  • Deranged LFTs are common.
  • Increased rates of cholelithiasis (due to haemolysis)
  • Hepatic veno-occlusive disease (common complication after stem cell transplant).
    
    • Triad of painful hepatomegaly, hyperbilirubinaemia, unexplained fluid retention.
    • Occurs due to hepatocellular toxicity associated with high dose alkylating chemotherapeutic agents.
• Pulmonary
  
  • Increased rates of opportunistic infections.
  • Possible bronchiectasis.
• Genitourinary
  
  • Haemorrhagic cystitis (up to 20% of transplant patients)
  • Often self limiting, may need endoscopic surgical intervention if severe/obstructing.

Question 25

What is PHACES?

Answer 25

• P: Posterior fossa brain malformations
• H: Haemangiomas of the face
• A: Arterial abnormalities (coarctation etc)
• C: Cardiac
• E: Eye and endocrine problems
• S: Sternal malunion, supraumbilical rappe.

Question 26

What are the PIK3A-related overgrowth syndromes (PROS)?

Answer 26

• PROS incorporates all the overgrowth conditions associated with somatic mutations of the PIK3CA gene.
  
  • Klippel-Trenaunay Syndrome - large slow flow mixed venous, capillary, lymphatic malformation and limb overgrowth.
  • CLOVES Syndrome (Congenital Lipomatous overgrowth, Vascular malformations, Epidermal naevi, Scoliosis/Spinal Syndrome)
  • FAVA Syndrome (Fibroadipose vascular anomaly)

Question 27

Name 3 vascular malformation syndromes evident in the neonatal period.

Give 3 components of each syndrome.

Answer 27

• PIK3CA-related overgrowth syndromes (PROS)
  
  • Klippel-Trenaunay Syndrome -
    
    • Combined capillary lymphatic, venous malformation (CLVM)
    • Limb overgrowth (present from birth)
    • Pelvic/perineal lymphatic/venous malformation can predispose to pain and PR bleeding/dysuria
  • CLOVES Syndrome -
    
    • Congenital lipomatous overgrowth - usually truncal.
    • Vascular malformation - fast flow vascular malformations often within lipomatous overgrowth
    • Eye/endocrine problems
    • Sternal non-union, supra umbilical raphe, skeletal (macrodactyly, wide triangular feed, widened sandal gap.
    • HIGH risk of Wilm’s tumour
  • FAVA -
    
    • Fibroadipose vascular anomaly - usually fibrofatty replacement of affected muscle - usually calf - and slow flow vascular malformations.
    • Pain
    • Joint contractures.
  • Diffuse capillary malformation with overgrowth (DCMO)
• Parkes-Weber Syndrome
• Proteus syndrome

Question 28

How does the lymphatic system develop?

What are the 6 lymphatic sacs?

Answer 28

• Lymphatics develop from the venous endothelium.
• Week 5/40, sac like projections form as outpouch from veinous channels.
• 6 lymphatic sacs
  
  • Jugular x2
  • Iliac x2
  • Retroperitoneal
  • Cisterna chyli

Question 29

What are the two types of rhabdomyosarcoma?

Answer 29

1. Embryonal Rhabdomyosarcoma (65-75%) - 2-6yrs - head, neck and genitourinary - better prognosis
2. Alveolar Rhabdomyosarcoma (25-35%) - 10-18yrs - trunk, limbs - worse prognosis (PAX/FOXO1 fusion)

Question 30

What cells does rhabdomyosarcoma arise from?

What are the genetic mutations associated with rhabdomyosarcoma (3)?

Name one mutation associated with each subtype of rhabdomyosarcoma

Answer 30

• Rhabdomyosarcoma arise from pluripotent mesenchymal cells with disrupted cell growth and differentiation.
• Genetic mutations:
  
  • MET oncogene
  • Macrophage inhibitory factor (MIF)
  • p53 tumour suppressor (germline mutation in Li Fraumeni syndrome)
• Embryonal - Loss of heterozygosity at 11p15 (80%) - affects insulin growth factor 2 (IGF-2), also aberrations in fibroblast growth receptor 1 (FGFR1) and neuroblastoma TAS viral oncogene homolog (NRAS)
• Alveolar - PAX3 or PAX7 fusion with FOXO1 (i.e. PAX7/FOXO1 fusion) - worse prognosis - 80%.
  
  • Also frequently associated with MYC-N, CDK-4

Question 31

Describe the risk stratification of rhabdomyosarcoma

Answer 31

1. Pre treatment - TNM stage + Size + Site → Stage 1-4
2. Post excision - Clinical group 1-4 (depending on residual disease post excision)
3. Age <10 vs Age >10
4. PAX/FOXO1 fusion

Question 32

Outline the genetic and cytological factors that are utilised in risk stratification of neuroblastoma (Essay 2017)

Answer 32

Since 2018, neuroblastoma risk stratification has followed COG guidelines and has moved towards pre-operative staging and risk stratification.

• INRGSS = preoperative stage as per sectional imaging.
• COG risk stratification combines INRGSS plus the following genetic/cytological factors
  
  • MYCN amplification - high risk
  • Chromosomal aberrations - 1p LOH, 11q LOH associated with worse outcomes (MYCN negative)
  • Age <18 lower risk.
  • Tumour ploidy: near diploid or near tetraploid associated with worse outcomes vs near triploid.
  • Ganglioneuroblastoma (nodular) - universally higher risk
• Previously utilised markers used in risk assessment (INPC)
  
  • Mitosis Karyorrhexis Index (MKI) - number of cells undergoing mitosis or karyorrhexis (high = higher risk)
  • Degree of differentiation (undifferentiated = worst prognosis, poorly differentiated, differentiating)
  • Anaplastic lymphoma kinase (ALK) = worse prognosis.

Question 33

Describe the molecular/genetic abnormalities associated with neuroblastoma (4)

Answer 33

• MYC-N amplification - worse prognosis - 25% of all neuroblastoma
  
  • MYC-N proto-oncogene → when amplified → increased rates of DNA synthesis and cell proliferation, as well as shorter G1 phase of the cell cycle.
  • MYC-N can also transform normal cells into tumour cells (via cooperation with activated RAS complex).
• DNA ploidy - 55% triploid or near triploid = better outcomes.
  
  • Diploid/near diploid or tetraploid chromosomes = worse prognosis.
  • Only relevant for patients under 2 years of age.
• Segmental chromosomal aberrations - worse prognosis
  
  • 1p deletion (short arm of chromosome 1) - 35% of all neuroblastoma (higher in advanced disease) - thought to represent loss of a tumour suppressor gene.
  • 11q deletion (long arm of chromosome 11) - common - worse prognosis.
• Anaplastic lymphoma kinase mutation - proto-oncogene (short arm chromosome 2) - worse outcome.
  
  • Germline mutation associated with hereditary neuroblastoma.
• Loss of function mutation on PHOXB2 (chromosome 4) - also associated with familial neuroblastoma (and Hirschsprung disease).

Question 34

What are the common sites of neuroblastoma?

Answer 34

• Neuroblastoma arises from sympathetic cells (precursors of sympathetic cells from neural crest cells). Neuroblastoma can occur anywhere neural crest cells migrate.
  
  • Abdominal (75%) - present with mass or abdominal pain.
    
    • 50% adrenal medulla
    • 25% paraspinal ganglion
  • Posterior mediastinum (20%) - respiratory distress, dysphagia.
  • Cervical region (1%) - may present with Horner’s syndrome
  • Pelvis - Organ of Zuckerkandl (4%) - present with altered defecation or urination (spinal cord compression).
• May present with non-specific symptoms associated with excess catecholamine or VIP secretion:
  
  • Catecholamines - flushing, sweating, irritability
  • VIP - diarrhoea, weight loss, hypertension
• Metastases (40% at diagnosis)
  
  • Older patients - bone marrow, lymph nodes and bony mets.
  • Mets to brain, spinal cord, heart or lungs VERY RARE.

Question 35

What is a triphasic nephroblastoma?

Answer 35

• Triphasic refers to a nephroblastoma containing the three main cell types - blastemal, stromal, and epithelial. These usually represent favourable histology (accounting for 90% of Wilms tumours).

Question 36

What makes a Wilms Tumour unfavourable and why (3)?

Answer 36

• Unfavourable Wilms Tumour histology determined by the presence of anaplasia.
  
  • May be focal or diffuse.
• Presence of anaplasia associated with:
  
  • Limited response to preoperative chemotherapy
    
    • High rates of relapse
    • Higher rates of death
      
      • Diffuse anaplasia associated with highest rates of relapse and death.

Question 37

How is anaplasia in Wilms Tumour defined (3)?

Answer 37

• Anaplasia defined as tumour cells containing:
  
  • Hyperchromasia
  • Giant cell nuclei (diameter > 3 times normal cells)
  • Atypical mitotic figures
• Unfavourable Wilms tumours
  
  • Focal anaplasia
  • Diffuse anaplasia

Question 38

What are 5 gene mutations associated with Wilms Tumour?

Answer 38

1. WT1 gene (Chromosome 11p13) - 20% of WT - associated with Denys Drash Syndrome
2. WT2 gene (Chromosome 11p15.5) - Typically seen with Beckwith-Wiedemann Syndrome
3. WTX gene (Chromosome Xq11.1) - 20-30%
4. CTNNbB1 (Chromosome 3p21) - 15% of WT
5. TP53 - 5%
6. Loss of heterozygosity (1p, 11p, 16q) - 5%
7. Gain of genetic material (chromosome 1q) - 30%
8. MYCN
9. MicroRNA biogenesis mutations (DROSHA, DGCR8)

Question 39

How does PRETEXT staging work for hepatoblastoma?

Answer 39

• PRETEXT refers to pre-treatment extent of disease staging system.
  
  • Requires: anatomical location of tumour/tumours (4 sectors - LEFT = lateral sector [segments II and III], medial sector [segments IVa and IVb]. RIGHT = anterior sector [segments V and VIII], posterior sector [segments VI and VII])
    
    • PRETEXT 1 = 3 adjoining sectors free of disease
    • PRETEXT 2 = 2 adjoining sectors free of disease
    • PRETEXT 3 = only 1 sector is disease free
    • PRETEXT 4 = No tumour free sectors.
  • PRETEXT Annotations (VPEFRNCM) - involvement of these upstages the PRETEXT stage
    
    • V+ = IVC or hepatic vein involvement
    • P+ = portal vein involvement
    • E+ = Extrahepatic tumour
    • F+ = Multifocal tumour nodules
    • R+ = tumour rupture
    • N+ = lymph node metastasis
    • C+ = caudate involvement
    • M+ = distant metastasis
  • Also looks at AFP > 100 or <100, Age >8 or < 8.

Question 40

Name 3 causes of antenatal (6) and postnatal (6) pathological elevations in AFP.

Answer 40

• Antenatal:
  
  • Abdominal wall defects
    
    • Gastroschisis
    • Exomphalos
  • Spinal dysraphism
  • Hepatic disease
    
    • Hepatic haemangiomas of infancy
    • Hepatoblastoma (only 4% present at birth)
• Post natal:
  
  • Hepatoblastoma
  • Gonadal tumours
    
    • Yolk sac tumours
    • Embryonal carcinoma
    • Dysgerminoma
  • Sacrococcygeal teratomas (may represent yolk sac component)

Question 41

Give 5 differential diagnoses for a mass in the scrotum (7).

Answer 41

• Neoplastic
  
  • Benign
    
    • Germ cell:
      
      • Seminoma (usually associated with history of UDT)
      • Teratoma (usually benign in prepubertal)
    • Stromal:
      
      • Leydig Cells Tumours
      • Granulosa cell tumours
    • Epithelial:
      
      • Epidermoid cysts
  • Malignant
    
    • Primary
      
      • Yolk sac tumour
      • Embryonal carcinoma - aggressive, often associated with metastastasis
      • Teratoma (treated as malignant in post pubertal)
      • Gonadoblastoma (usually associated with mixed gonadal dysgenesis) - may be bilateral.
      • Choriocarcinoma
      • Paratesticular rhabdomyosarcoma (usually embryonal subtype)
    • Metastatic
      
      • Testes most common site for leukaemic deposits, may be bilateral.
      • Also occurs with lymphoma (follicular, ALL, Burkitt Lymphoma)
• Non-neoplastic
  
  • Hydrocoele
  • Hernia

Question 42

Name 3 benign testicular masses

Answer 42

• Germ cell:
  
  • Teratoma (usually benign in prepubertal)
• Stromal:
  
  • Leydig Cells Tumours
  • Granulosa cell tumours
• Epithelial:
  
  • Epidermoid cysts

Question 43

Describe the histological classifications of lymphomas

Answer 43

• Broadly separated into Hodgkin Lymphoma and Non-Hodgkin Lymphoma
  
  • Hodgkin Lymphoma - characterised by Hodgkin Cells and Reed-Sternberg Cells
    
    • Classical Hodgkin Lymphoma (4 subtypes)
      
      • Nodular sclerosis - NS (most common type in children)
      • Mixed cellularity (MC)
      • Lymphocyte rich (LR)
      • Lymphocyte depleted (LD)
    • Nodular Lymphocyte Predominant Hodgkin Lymphoma (nodular LPHL)
  • Non-Hodgkin Lymphoma (4 subtypes)
    
    • Burkitt Lymphoma (40%) - associated with translocation involving the MYC gene on chromosome 8
    • Lymphoblastic lymphoma - 30%
    • Diffuse large B-cell lymphoma (DLBCL) - 20%
    • Anaplastic large cell lymphoma (ALCL) - 10% - ALK gene translocation (chromosome 2)

Question 44

How do the two main subgroups of lymphoma differ in their presentation.

Answer 44

• Two main subtypes of lymphoma in children are Hodgkin Lymphoma and Non-Hodgkin Lymphoma
  
  • Hodgkin Lymphoma is usually indolent and slow to progress. May present with cervical or supraclavicular lymphadenopathy.
    
    • Rarely presents with complications from tumour size/lyisis.
    • Usually presents with cervical pathology
  • Non-Hodgkin Lymphoma is rapidly expanding, rapidly progressive.
    
    • Often presents with complications of the rapidly expanding tumour
      
      • Often presents with abdominal Burkitts (30%), or head and neck (30%) or mediastinal (27%).
        
        • Mediastinal: Stridor/wheeze, SOB, chest pain, jugular engorgement - usually lymphoblastic
        • Abdominal: Bowel obstruction or intussusception.
        • Tumour lysis:
          
          • Breakdown of large volumes of cells and release of intracellular products into bloodstream.
            
            • Hyperkalaemia → arrhythmias
            • Hypocalcaemia (secondary to hyperphosphataemia) → paraesthesias, tetany, seizures
            • Hyperuricaemia → uric acid crystal deposition in kidneys → AKI.

Question 45

What are the three theories of embryology of teratomas?

Answer 45

• Theory 1 - failed migration of totipotent primordial germ cells
  
  • Failed migration of the the totipotent primordial germ cells from the allantois to the yolk sac to the gonadal ridge during weeks 4/5 of gestation.
    
    • Explains the extragonadal sites.
• Theory 2 - primitive streak remnants
  
  • Gastrulation (week 3) - cells migrate between the ectoderm and endoderm via the primitive streak to form the mesoderm. Following migration, the primitive streak shortens and disappears.
  • Remnants of the pluripotent primitive streak cells → teratomas (site at caudal end of bilaminar disc may explain the incidence of sacrococcygeal teratoma as the most common teratoma.
• Theory 3 - incomplete twinning
  
  • Teratomas are a form of incomplete twinning.

Question 46

Where are the most common sites of teratoma (6)?

Answer 46

Teratomas may be gonadal or extra-gonadal.

• Gonadal:
  
  • Ovary = 27%
  • Testis = 5%
• Extra-gonadal:
  
  • Sacrococcygeal teratoma = 35-60%
  • Mediastinal (usually anterior mediastinum) = 6%
  • CNS = 5%
  • Cervical, head (epignathus - oropharyngeal/palatine teratoma protruding from mouth), hepatic pericardial, umbilical = less than 3%

Question 47

What are the tumour markers for teratomas?

Answer 47

Tumour markers for teratomas include alpha foetoprotein (AFP) and BHCG

• Presence of elevations in tumour markers often suggests a malignant component.
  
  • AFP is secreted by yolk sac tumours and embryonal carcinomas.
    
    • If elevated in SCT, associated with high risk of malignant recurrence.
    • If elevated in mediastinal teratomas higher risk of malignant component.
    • AFP can be used to monitor recurrence.
  • BHCG is secreted by choriocarcinomas.
    
    • Elevations in BHCG may be seen in mediastinal teratomas associated with Klinefelter’s (47XXY) which is strongly suggestive of choriocarcinoma component.
• CEA is rarely produced by choriocarcinomas
• CA125 can be used in the follow up/surveillance of SCTs

Question 48

Define hamartoma

Answer 48

A hamartoma is a disorganised collection of benign cells native to the location in which they arise.

Question 49

Describe the histology of fibrous hamartomas of infancy

Answer 49

• Fibrous hamartomas of infancy are benign ‘tumour-like’ growth of myofibroblastic derivation.
  
  • Usually occur in first 2 years of life.
  • Usually present as a solitary mass on the limbs, trunk, sacrum and scrotum.
• Histology:
  
  • Bundles of well-defined thick connective tissue which branch, interweave and project into adjacent fat.
  • 3 elements:
    
    • Adipose tissue
    • Myofibroblasts
    • Primitive mesenchymal cells.
  • Mesenchymal tissue is organised into distinct whorls, bands or nests.

Question 50

Describe the histological features of mesenchymal hamartomas

Answer 50

• Accounts for ⅓ of all benign hepatic lesions.
  
  • Mostly occur within the first two years of life.
• Histology:
  
  • Macro -
    
    • Large, well circumscribed lesions 8-10cm minimum.
    • 75% right sided.
    • Cross section reveals multiple cysts filled with serous fluid, separated by loose fibrous myxoid tissue.
  • Micro -
    
    • Mixture of bile ducts, liver cells (usually normal hepatocytes) and mesenchyme.
    • Cysts may represent dilated bile ducts or lymphatics, or amorphous cysts surrounded by mesenchyme.
      
      • Bile ducts in the periphery show active proliferation.
    • In older patients, cysts may be lined with cuboidal epithelium.

Question 51

Describe the histolopathology of hamartomatous polyp of Peutz-Jehger syndrome

Answer 51

• Peutz-Jehger polyps are hamartomas of the muscularis mucosa.
  
  • They demonstrate strands of smooth muscle fibres that divide polyp into sectors.

Question 52

What are 2 causes of hypothyroidism in children?

Answer 52

• Effects of hypothyroidism:
  
  • T4 is essential for myelinisation of the CNS within the first 3 years of life → deficiency of T4 can lead to intellectual impairment/disability.
  • Older children - decline in growth, fatigue, constipation and poor school performance.
  • Teenagers - dry skin, thin hair, weight gain
• Congenital causes:
  
  • Congenital hypothyroidism - associated with abnormal development of the thyroid gland (dysgenesis or agenesis, occasionally from defects in thyroid hormone synthesis.
• Acquired:
  
  • Hashimotos Thyroiditis (chronic lymphocytic) - autoimmune production of anti-thyroid antibodies)

Question 53

What is the pathogenesis of medullary thyroid cancer?

Answer 53

• Medullary thyroid cancer arises from parafollicular cells (C cells) which are derived from neural crest cells.
  
  • Often associated with inherited syndromes:
    
    • MEN2A/MEN2B/Familial MTC
      
      • Associated with mutations in the RET proto-oncogene.
  • C cells secrete calcitonin, and CEA (the two tumour markers in MTC).