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Pathophysiology > Infection/Inflammation and Neoplasia > Flashcards

Infection/Inflammation and Neoplasia Flashcards

1
Q

What are the main cytokines involved in inflammation?

A

TNF alpha

IL-1

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2
Q

What causes fever?

A
  • 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.
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3
Q

How is the neonatal cellular immunity different to adults?

A
  • 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.
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4
Q

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

A
  • 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)
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5
Q

Describe MAIS infection

A
  • 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.
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6
Q

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

A

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.
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7
Q

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

A

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.
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8
Q

What are the most common pathogens associated with empyema?

A
  1. Streptococcus pneumoniae (most common in infants and children)
  2. Haemophilus influenzae B
  3. Staphylococcus aureus
  4. Mycobacterium tuberculosis (rarely)
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9
Q

What are the aetiological theories for ulcerative colitis?

A
  • 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.
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10
Q

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

A
  1. Crypt architectural distortion.
  2. Crypt abscesses
  3. Mucosal ulceration and undermining of adjacent mucosa.
  4. Mucosal bridges
  5. Pseudopolyps
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11
Q

What are the sequelae of acute ulcerative colitis?

A
  • 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.
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12
Q

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

A
  • 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.
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13
Q

What are the complications of ulcerative colitis?

A
  • 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)
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14
Q

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

A
  • 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).
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15
Q

What are 5 extra colonic manifestations of ulcerative colitis?

A

Erythema nodosum

Arthralgias

Pyoderma gangrenosa

Nephrolithiasis

Sclerosing cholangitis

Uveitis

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16
Q

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

A

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.
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17
Q

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

A
  • 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.
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18
Q

What virus causes the common wart?

How long is incubation?

What is the histopathology?

A

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.

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19
Q

What virus causes molloscum contagiosum?

How long is incubation?

What are the clinical characteristics?

A

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.

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20
Q

What are the three most common pathogens in necrotising fasciitis?

A

Group A strep - usually Strep Pyogenes

Staph aureus

Pseudomonas aeruginosa (usually in the immunocompromised)

Single organism - 88%

Polymicrobial - 8%

Fungal - 2%

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21
Q

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

A
  • 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.
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22
Q

What is graft versus host disease?

A
  • 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.
23
Q

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

A
  • 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).
24
Q

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

A
  • 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.
25
Q

What is PHACES?

A
  • 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.
26
Q

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

A
  • 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)
27
Q

Name 3 vascular malformation syndromes evident in the neonatal period.

Give 3 components of each syndrome.

A
  • 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
28
Q

How does the lymphatic system develop?

What are the 6 lymphatic sacs?

A
  • 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
29
Q

What are the two types of rhabdomyosarcoma?

A
  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)
30
Q

What cells does rhabdomyosarcoma arise from?

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

Name one mutation associated with each subtype of rhabdomyosarcoma

A
  • 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
31
Q

Describe the risk stratification of rhabdomyosarcoma

A
  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
32
Q

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

A

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.
33
Q

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

A
  • 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).
34
Q

What are the common sites of neuroblastoma?

A
  • 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.
35
Q

What is a triphasic nephroblastoma?

A
  • 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).
36
Q

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

A
  • 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.
37
Q

How is anaplasia in Wilms Tumour defined (3)?

A
  • 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
38
Q

What are 5 gene mutations associated with Wilms Tumour?

A
  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)
39
Q

How does PRETEXT staging work for hepatoblastoma?

A
  • 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.
40
Q

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

A
  • 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)
41
Q

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

A
  • 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
42
Q

Name 3 benign testicular masses

A
  • Germ cell:
    • Teratoma (usually benign in prepubertal)
  • Stromal:
    • Leydig Cells Tumours
    • Granulosa cell tumours
  • Epithelial:
    • Epidermoid cysts
43
Q

Describe the histological classifications of lymphomas

A
  • 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)
44
Q

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

A
  • 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.
45
Q

What are the three theories of embryology of teratomas?

A
  • 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.
46
Q

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

A

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%
47
Q

What are the tumour markers for teratomas?

A

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
48
Q

Define hamartoma

A

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

49
Q

Describe the histology of fibrous hamartomas of infancy

A
  • 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.
50
Q

Describe the histological features of mesenchymal hamartomas

A
  • 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.
51
Q

Describe the histolopathology of hamartomatous polyp of Peutz-Jehger syndrome

A
  • Peutz-Jehger polyps are hamartomas of the muscularis mucosa.
    • They demonstrate strands of smooth muscle fibres that divide polyp into sectors.
52
Q

What are 2 causes of hypothyroidism in children?

A
  • 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)
53
Q

What is the pathogenesis of medullary thyroid cancer?

A
  • 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).

Pathophysiology (7 decks)

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