Cervical cancer was at one stage, the leading cause of death among females. Now, it ranks low on the ladder of cancer deaths, thanks to the Pap smear.

Pathogenesis / Risk factors: The pathogenesis of cervical cancer largely relates to the risk factors and the HPV. The cardinal risk factors are: 1) Early age of intercourse, 2) Multiple sexual partners, 3) A male partner who has had multiple sexual partners previously. HPV is also related to the pathogenesis in the following ways (I doubt you need to know this, but makes perfect sense): 1) HPV DNA has been isolated from cervical cancers & precancerous lesions, 2) HPV have oncogenes which can transform keratinocytes into cells found in precancerous lesions, 3) HPV has oncoproteins that bind to p53 tumour suppressor gene. There are various types of HPV, which produce lowhigh risk lesions (remember that 16, 18, 31, 33 are all high risk types). It is important to note that a vast number of women with HPV infection DO NOT develop CIN or CERVICAL CANCER.

Cervical Intraepithelial Neoplasia (Robbins pp 1049, Figs: 24-19 – 24-21)

General: The majority of cervical cancer lesions are preceded by a precancerous lesion. The thing about these precancerous lesions is that: they may regress spontaneously or become invasive carcinomas, and they are associated with HPV. These are classified according to the cervical intraepithelial neoplasia 1-3 (mild, moderate, severe dysplasia) classification. The higher the classification, the more risk of progression to carcinoma. The squamocolumnar junction (transformation zone) is the most common place where CIN arises.

Morphology: CIN I: Very similar to condylomata acuminata. There is very few alterations of the epithelial cells. HPV nucleic acid is prominent under certain stains. CIN II: There is atypical cells in lower layers of squamous epithelium. These cells show changes such as: high nuclear/cytoplasmic ratio, hyperchromasia, loss of polarity, increased mitotic figures, abnormal mitoses. CIN III: This is when there are atypical cells are seen throughout all layers of epithelium.

Interesting points: If the CIN is of squamous type ≫ it is easier to detect on Pap smear. If it is made up of glandular cells ≫difficult to detect on Pap smear.

General: 80% of the cancers of the cervix are of the squamous type. 15% are adenocarcinomas, & 5% are other types.

Epidemiology: Peak incidence is @ 45 years for invasive cancer, and @ 30 years for CIN III.

Clinical features / course: The clinical course of the disease is over many years. Patients may be asymptomatic. Pap smears are recommended every year after sexually active. Cytologic examination merely detects an abnormality, whether it be cancer or CIN. Diagnosis comes after specimens are retrieved for histological examination. Colposcopic examination also reveals the macroscopic view: punctuated irregularities of mucosa. When disease is obvious symptomology is: irregular vaginal bleeding, leukorrhea (whitish discharge), pain on coitus, dysuria.

Morphology: Cervical carcinomas exists in three forms: 1) exophytic, 2) infiltrative, 3) ulcerative. Microscopically: You can see large squamous cells with atypia throughout all layers of the epithelium (squamous variety). The cancer is of squamous (arise from epithelium), adenocarcinoma (arise from endocervical glands), adenosquamous (arise from reserves cells of basal layer of epithelium) variety. There are various staging classifications (Read Robbins pp 1052/3). Cervical cancer (like other structures) can spread locally (vagina, uterus, bladder, rectum) or distally (bones, lungs, liver, brain, lymph nodes).

Treatment: Invasive cancers result in hysterectomy with radiation.

General: Most common cancer of female genital tract, more common than cervical carcinoma.

Epidemiology/At risk individuals: peak incidence: 55-65 year old. At risk individuals: endogenous factors: 1) obesity, 2) diabetes, 3) hypertension, 4) infertility, 5) ovarian abnormalities (polycystic disease, ovarian cancer ≫ esp oestrogen secreting), exogenous factors: 1) unopposed oestrogen administration (i.e.: treatment of menopausal symptoms ≫ increased risk by 5X), Tamoxifen (antioestrogen used in Breast Ca ≫ 4X increased risk).

Clinical features / course: There are two clinical settings evident: 1) younger aged patients that are perimenopausal, 2) older age patients that are post-menopausal. Symptoms include: irregular vaginal bleeding, leucorrhea. The cancer can be divided into various stages, the more advanced the stage ≫ the poorer the prognosis.

Morphology: Macroscopically, the tumour can be locally polypoid or diffuse over entire endometrium. Microscopically: 85% are adenocarcinomas, proliferating glands with malignant epithelial cells, sometimes squamous metaplasia of epithelium present (adenocarcinoma with squamous metaplasia). Three grades of differentiation are evident (i.e.: mild, moderate, well).

Treatment: Hysterectomy + radiation.

Definition

The QT interval is the time from the start of the QRS complex to the end of the T wave, and it represents the total duration of electrical activity in the ventricles

Usually measured in aVL where the U waves are least prominent (U waves can be mistaken for T waves)

The QT interval is rate dependent, and the corrected QT interval needs to be calculated

QTc = QTm / square root of RR

Where QTm is the measured QT interval, QTc the calculated QT interval, and RR is the measured RR interval (all measurement in seconds)

Upper limit of QTc is 0.42 seconds (10.5 small squares)

QT prolongation is associated with ventricular arrhythmia, esp.Torsade de Pointes, syncope and sudden death.

QT prolongation – causes

Congenital: Romano-Ward (Autosomal dominant, normal hearing)

Lange-Nielsen (Autosomal recessive, deafness)

Hypokalaemia, Hypocalcaemia, Hypomagnesaemia

Hypothermia

Drugs antiarrhythmics (quinidine, sotalol, amiodarone etc)

antihistamines: terfenadine, astemizole

antimalarials: esp. halofantrine

antibiotics: erythromycin, co-trimoxazole

antipsychotics: esp. droperidol, thioridazine

misc: tricyclics, cisapride

QT prolongation – principles of management

Exclude congenital syndrome (FHx of sudden death, deafness)

Avoid drugs in underlying cardiac disease

Avoid high doses of drugs that prolong QT

Avoid giving two drugs concurrently that prolong QT

Avoid giving a drug that raises the concentration of a QT interval prolonging drug

If patient at risk then monitor calcium, potassium, magnesium, and thyroid function, and maintain in normal range

?Routine ECG

Investigate symptoms and signs of arrhythmia whilst on drugs

Liase with cardiologists

References

Royal College of Psychiatrists, Council Report CR57

‘The association between antipsychotic drugs and sudden death’ 1997

Reilly et al, ‘Recent studies of ECG changes, antipsychotic use and sudden death in psychiatric patients’ Psychiatric Bulletin (2002), 26, 110-112

Current Problems in Pharmacovigilance, Volume 27, February 2001

‘QT prolongation in antipsychotics’

O’Brien and Oyebode, ‘Psychotropic medication and the heart’ Advances in Psychiatric Treatment (2003), 9, 414-423

1. Delay and Deniker first isolated dopamine receptors.
2. Carlsson and Lindquist first used ECT
3. Sakel is a name associated with insulin coma therapy
4. Yohimbine is an Alpha 2 noradrenergic receptor antagonist.
5. Noradrenaline is a precursor of dopamine
6. Dopamine is a precursor of nor adrenaline
7. Tetrabenazine causes depletion of dopamine.
8. Risperidone is a strong antagonist of the 5HT2A receptors
9. Second messengers are characteristic of ion-channel receptors.
10. D1 and D5 belong to same family
    
11. Glutamate is a NMDA antagonist
12. Memantine blocks NMDA receptors
13. Nicotinic receptors control cation channels
14. Heteroreceptors cause decrease neurotransmitter release through presynaptic mechanisms
15. Heteroreceptors can be ionotropic or metabotropic.
16. α₂ receptors are excitatory and use inositol phosphate as a second messenger
17. 5-HT3 receptors are linked to Na-Ion channels
18. All 5HT₁ and 5HT₂ receptors are G-protein coupled.
19. 5HT3 is an anion channel
20. Serotonin receptors are all metabotrophic

Acute Mastitits: This occurs during nursing as cracks begin to appear in the nipples. This allows Staph + Strep to invade --> acute inflammation --> breast abscess.

Fat Necrosis: Occurs 2nd to trauma
Macroscopy: irregular hard mass of orange/brown colour (haemoglobin derived pigments). Microscopy: central necrotic fat surrounded by lipid laden macrophages and neutrophilic infiltration. Later on: fibrovascular changes wall it off. Later on: fibrosis associated with foamy macrophages laden with haemosiderin.

Breast abscess: Results from acute mastitis or rupture of a duct.
Microscopy: central cavity filled with neutrophilic debris surrounded by inflamed tissue --> eventually fibrosis occurs.

Fibroadenoma:

• This is a benign breast tumour composed of new fibrous + glandular tissue. It affects young people (20-35)
• Macroscopy: firm mass, cut surface: sharply demarcated, gray-white.
• Microscopy: glands present lined by cuboidal/low columnar cells & are surrounded by stroma (fibrous tissue). Glands appear distorted as stroma compresses them.
• Risk of breast Ca: 0.1% cases progress to malignancy.
  

Intraductal papilloma (48yrs):

• Papillomas are tumours that extend into the lumen of ducts. Two types: 1) small duct, 2) large duct (bloody nipple discharge).
• Macroscopy: palpable mass in some cases only
• Microscopy: central core of fibrovascular tissue surrounded by 2 cell epithelial layer.
• Risk of breast Ca: depends on the microscopic appearance. If: presence of 2 cell layer, lack of cribiform/trabecular pattern, low mitotic activity etc --> benign.
  

Fibrocystic disease (25-45yrs):

• This is a disease where the stroma becomes increasingly fibrotic and there are cysts within the breast. The pathogenesis is related to hormonal imbalances.

• Macroscopy: numerous microcysts + large cysts

• Microscopy: Components are:
  
• 1) Cysts: cystic dilatation of lobules and ducts produces numerous cysts,
  
• 2) apocrine metaplasia: cysts are lined by cells that look like those in apocrine sweat glands: polygonal cells, abundant granular cytoplasm, central nucleus,
  
• 3) Fibrosis: cysts rupture and release their contents --> result in chronic inflammation --> scarring/fibrosis of stroma,
  
• 4) epithelial hyperplasia: papillary projections of epithelium are common,
  
• 5) sclerosing adenosis: number of acini per lobule is increased 2 fold and the stroma compresses the glands distorting them --> mimicks Ca --> but staining for myoepithelial cells is reassuring.

Ductal hyperplasia:

• Usually the epithelium of ducts are 2 layers (columnar + myoepithelial cells). In this disease there is hyperplasia of epithelium --> more than 2 layers present. > 4 layers = increased risk of Ca but most often not.
• Microscopy: The lumen is filled with populations of epithelial cells, leaving uneven fenestrations. If fenestrations are more regular/even --> more chance that is atypical.
  
• In addition: look for signs of atypicalness: hyperchromatic nuclei, loss of polarity, regular spaces, absence of myoepithelial cells etc.
  

Breast cancer - General notes.

Risk factors: family Hx (genes BRAC1 & BRAC2 are major factors), age, proliferative breast disease, personal Hx, radiation, oestrogen exposure (early menarche/late menopause), nulliparity, obesity, HRT (exogenous oestrogen therapy).

Incidence in breast quadrants: Left breast affected more (110:100), upper outer quadrant accounts for 50% of tumours.

Classification: In situ or Invasive. In situ (15-30%): ductal, lobular. Invasive (70-85%): ductal (no special type), lobular, tubular, colloid, medullary, papillary.

All breast Ca arise from the terminal duct lobular unit (TDLU).

1. IN SITU CARCINOMA

a) Duct carcinoma in situ: In this cancer, the epithelial cells lining the ducts show malignant characteristics: loss of polarity, pleomorphism, hyperchromasia, high nuclear/cytoplasmic ratio, increased mitotic activity, prominent nucleoli. The cancer is in situ, meaning there is NO invasion through basement membrane. The epithelium is more than 2 cell layers thick.
Morphology:

• Microscopy:
  
• Architecture:
  
• solid (lumen filled with malignant cells),
  
• cribiform/tubular (round regular spaces within glands --> indicates malignancy),
  
• papillary (epithelial projections into lumen without fibrovascular stroma).
  
• Cytological grade: a) low, b) intermediate, c) high. Low grade --> High grade just means cell atypia worsens (refer to above).
  
• Comedo (central) necrosis: present / absent. If present --> then its more likely to be high cytological grade --> worse.

Lobular carcinoma in situ is not discussed in the notes. You can read about it on Pg 1109, Robbins, Fig 25-19.

2. INVASIVE CARCINOMA
a) Invasive duct carcinoma of no special type (70-80%): In this cancer, the epithelial cells are malignant and invade into the stroma. Clinically, you will feel a mass of stony hard consistency.
Morphology: Microscopy: 1) tumours cells grow in sheets, cords, nests, individually, invade into stroma + fat 2) tumour cells vary from small - large, but are generally larger + prominent nuclei/nucleoli than their lobular counterparts, 3) absence of myoepithelial cells (special staining).

b) Tubular carcinoma: This cancer has lots of tubules lined with ductal epithelium.
Morphology: Microscopy: 1) tumour cells are arranged tubular fashion, absence of myoepithelial cells (special staining), 2) apocrine snouts.
Prognosis: excellent

c) Mucinous (colloid) carcinoma: This cancer usually occurs in post-menopausal women. Neuroendocrine differentiation occur in 25-50% of cases.
Morphology: Microscopy: 1) Small clusters of cells (solid/acinar formation) floating in a sea of mucin
Prognosis: excellent (no nodal mets)

d) Medullary carcinoma: This cancer is always 'pushing' the border type --> i.e: non infiltrative border.
Microscopy: 1) solid syncytium like sheets of large cells with pleomorphic nuclei, prominent nucleoli, high mitoses, 2) marked lymphoplasmacytic infiltrate at peripheral of tumour
Prognosis: mets to lower axillary lymph nodes + prognosis is better than invasive duct carcinoma

e) Invasive lobular carcinoma: This cancer has high proportion of bilaterality.
Morphology: 1) tumour cells growing in single file + invade into stroma, 2) tumour cells are not arranged in gland form, 3) signet ring configuration: if mucin abundant. Sometimes tumour cells do not grow in single file --> called variants (alveolar, trabecular, solid).
Prognosis: Although chances of bilaterality is high --> prognosis is same as invasive duct carcinoma. Particular mets to: abdominal cavity (GI tract, ovaries, serosal surfaces).

f) Paget's disease: This disease is characterised by eczema of the nipple. Paget's disease is like ductal carcinoma in situ where the cancer extends via the ducts into the nipple. Usually is accompanied by underlying duct carcinoma in situ
Morphology: Microscopy: 1) skin of the nipple ulcerated, ozzing, 2) large clear cells with atypical nuclei

SPREAD AND METASTASES

Routes of invasion: direct, lymphatics (axillary nodes, supraclavicular, internal mammary), haemotogenous
Distal metastases: skeletal system, lung, liver, ovary, adrenal, CNS.

PROGNOSIS
Stage: The higher stage --> worse prognosis
Size: Bigger --> badder, more chance of spreading --> even badder
Cytoarchitecture: Metaplastic = bad, Duct vs Lobular = same prognosis, Medullary / tubular / colloid: good prognosis.
Microscopic grade: The higher grade --> worse prognosis. Bloom-Richardson system is used for grading --> no need to know.
Skin/Nipple invasion: worse prognosis
Axillary lymph node mets: most important prognostic factors --> involvement = worse prognosis (factors: how many, extent of invidual node involvement etc)
Local recurrence: bad prognosis.

NON-EPITHELIAL BREAST MALIGNANCIES

Phylloides tumourL Basically this tumour is a cancer arising from intralobular stroma
Read Robbins pp 1103

Benign renal tumours do not have much clinical significance because most are found at autopsy.

Renal papillary adenoma (adenoma)

Morphology: Macroscopic: discrete nodules found in cortex, Microscopically: papillary structures, regular cells free of atypia, look exactly like renal cell adenocarcinoma.

Oncocytoma

This is an epithelial tumour arising from intercalated cells of collecting ducts. An oncocyte is a large epithelial cell, with granular cytoplasm, and abundant mitochondria.

Morphology: Macroscopic: encapsulated tumour, Microscopically: eosinophilic cells with abundant mitochrondria

Angiomyolipoma

This is a tumour consisting of: blood vessels (angio), muscle (myo), fat (lipoma). 25%-50% of tuberous sclerosis patients have this ≫ tuberous sclerosis = lesion in cerebral cortex that causes epilepsy, retardation, skin lesions.

General: Tumours arise from tubular epithelium

Epidemiology: Occur in 6^th-7^th decades of life, male: female / 3:1, Risk factors: smoking, obesity, hypertension, unopposed oestrogen therapy, asbestos, chronic renal failure, polycystic disease, tuberous sclerosis.

Clinical features / course: classic: costovertebral pain, palpable mass, haematuria (classic tri-symptoms in 10% of cases only). Usually, tumour is silent until very large (10cm) ≫ systemic symptoms (LOW, LOA). Renal cell carcinoma also produces paraneoplastic syndromes such as: hypercalcaemia, hypertension, polycythaemia, Cushings etc.

Morphology: Macroscopic: upper pole nodules, yellow-white colour, areas of haemorrhage + necrosis. Microscopic: There are three types of renal cell carcinomas: clear cell, papillary, chromophobes. Clear cell (80%): rounded cells, clear cytoplasm, well differentiated/marked nuclear atypia (depends on cancer). Papillary (10-15%): tumour cells (cuboidal/columnar cells) arranged in papillary form, interstitial foam cells, psammoma bodies. Chromophobe (5%): sheets of pale cells, perinuclear halo.

Genetics / Cytogenetics: Clear cell carcinoma: There is deletion of the VHL gene from chromosome 3. VHL gene acts as a tumour suppressor gene. Papillary: Trisomies 7, 16, 17 and loss of Y in male patients≫ sporadic forms, and trisomy 7 ≫ familial form. Chromophobe: multiple chromosome losses.

Behaviour: Unfortunately, most patients are asymptomatic ≫ and by the time it produces local symptoms it has already metastasized. Metastatic locations: lungs, bone, nodes, liver, brain. Striking patterns is invasion into renal vein (varicosities of scrotal veins).

Prognosis & Treatment: Chromophobe renal carcinoma has best prognosis compared to other two. Treatment is usually nephrectomy.

General: Wilms tumour is renal cancer of childhood.

Epidemiology: 2-5 age group.

Pathogenesis/Genetics/Aetiology: The risk of Wilms tumour increases in association with 3 congenital malformations:

1. WAGR syndrome (WT-1 gene deleted),
   
2. Denys-Drash syndrome (WT-1 gene mutation),
   
3. Beck-with-Wiedemann syndrome (WT-2 abnormal).

Morphology: A risk factor for Wilms tumour is: nephroblastomatosis (i.e.: nephrogenic elements in kidney). Microscopy shows triphasic histology: stromal area (less cellular, spindle shaped cells), epithelial area, blastemic (tightly packed basophilic cells).

Clinical features: palpable mass, haematuria, costovertebral pain.

Prognosis / Treatment: Prognosis was poor in the 60s. Modern treatment of: chemotherapy, radiotherapy, surgery has lifted 5-year survival rate to 90%.

Transitional cell tumors

• General: Represent 90% of all bladder tumours. Tumours classifed into low-grade / high-grade categories.
• Risk factors: smoking, exposure to dyes, schistosoma haematobium, cyclophosphamide (immunosuppressive agent), analgesic abuse
• WHO Classification:
  
• papilloma,
  
• Grade 1: papillary non-invasive,
  
• Grade 2: papillary, may be invasive,
  
• Grade 3: solid + invasive.
  
• If the tumour is graded as invasive, it is critical to stage the tumour also ≫ to obtain a prognosis.
• Clinical features: painless haematuria (classic)
• Morphology: 4 morphologic patterns ≫ Fig 22-8 pp 1004.
  
• Papilloma: finger like papilla arising from mucosa with fibrovascular stroma surrounded by normal transitional epithelium,
  
• Grade 1 TCC: closely resemble normal transitional cells, increased no. of cell layers,
• Grade II TCC: papillary/flat: increased no. of layers + mitotic activity, loss of polarity, pleomorphic cells,
  
• Grade III TCC: papillary/flat/both: invade into muscularis, cells flatten out resembling squamous cells, sometimes foci of glandular differentiation.

OTHER TUMOURS (Robbins Table 22-2)

SCC, adenocarcinoma (primary or direct invasion from rectum), small cell carcinoma, sarcoma.

ENDOMETRIOSIS (Robbins pp 1057)

• Endometriosis is defined as the presence of endometrial tissue outside the uterus.
  
• Adenomyosis is defined as presence of endometrial glands in the myometrium.
  
• The ovaries (36%) are most frequent areas of ectopic tissue.
  
• The endometriotic tissue is still under influence from hormones.
• Pathogenesis:
  
• 1) Regurg theory: Retrograde menstruation into fallopian tubes + ovaries may also take some endometrial tissue,
  
• 2) Metaplastic theory: Endometrium arises from coelomic epithelium, and can arise in odd places,
  
• 3) Vascular/Lymphatic dissemination theory: endometrial tissue dessiminates through blood/lymph.
  
• Clinical features: painful menstruation, painful coitus, pelvic pain.
• Morphology:
  
• Macroscopically: haemorrhagic spots, scarring (from bleeding), ovaries have chocolate cysts (filled with brown blood debris).
  
• Microscopically: endometrial glands, stroma, hemosiderin pigment.

Why isn’t endometriosis cancer?

1) Under influence of hormone,

2) 2 cell proliferation (not monoclonal),

3) mortality rate none.

ENDOSALPINGIOSIS

• The fallopian tubes have a simple columnar epithelium and are ciliated.
  
• Sometimes, you get this tubal epithelium in sites other than the fallopian tubes.
  
• Common sites are: pelvic peritoneum, ovaries etc.
• Morphology: Macroscopically: not under influence of hormones, so no scarring. Microscopically: You see tubal epithelium with fibrous tissue surrounding it, no glands.

Tumours of surface (coelomic) epithelium

There are various types of these tumours. Each of these types can be benign, borderline, or highly malignant.

Serous tumours:

• General: The tumour is filled with clear serous fluid. Most bilateral.
  
• Epidemiology: Account for about 30% of all ovarian tumours, 25% malignant.
  
• Morphology: Macroscopically: cystic neoplasms lined with tall columnar cells, neoplasm filled with serous fluid, papillary projections seen in malignant cases. Microscopically: benign tumours (cystadenomas) have little/no papillae, borderline malignant tumours have increased papillae and show signs of epithelial stratification, malignant tumours (cystadenocarcinomas) have complex papillae with malignant cell features (atypia etc), psammoma bodies a characteristic of serous tumours.
• Clinical course: Transcoelomic/lymphatic spread are common. Prognosis is poor if peritoneum is involved, otherwise close to 100%.

Mucinous tumours:

• General: Sticky mucin present within cysts. Most not bilateral.
  
• Epidemiology: 25% of all ovarian neoplasms, most are benign/borderline.
  
• Morphology: Macroscopically: large multicystic tumour, sticky mucin inside, Microscopically: benign tumours: tall columnar epithelium, borderline: papillary structure, epithelial stratification beginning, malignant (cystadenocarcinoma): epithelial stratification, loss of glandular structure, necrosis.
• Clinical course: Pseudomyxoma peritonei is a condition associated with mucinous ovarian tumours: involves mucinous ascitis, peritoneal cysts, adhesions.
  
• Ovarian tumours spread: transcoelomic/lymphatic.

Endometroid tumours:

• General: Tubular glands resembling endometrium present.
• Epidemiology: 20% of all ovarian tumours, 10-15% coexist with endometriosis, up to 30% associated with endometrial carcinoma.
• Morphology: Macroscopically: solid & cystic areas, Microscopically: glandular pattern similar to endometrium.
• Clinical course: 40-50% 5 year survival rate.

Clear cell tumours:

• General: epithelial cells that line tumours have lots of clear cytoplasm.
• Morphology: Microscopically: clear cells arranged in sheet form (solid tumours), tubular form (cystic tumours).

In MMMT (these are highly malignant) – there is a bit of both types of tumours: epithelial, and mesenchymal. There is malignant glandular pattern and malignant stromal elements. The stromal elements may be: cartilage, muscle, osteoid etc. Both types of tissue derive from one cell (monoclonal) – because epithelial markers are present in stromal cells. These tumours occur in post-menopausal women.

PROLIFERATING / BORDERLINE TUMOURS

In these types of tumours, there is evidence of proliferation and spread but all of this is benign. Serous tumours are most common. In serous tumours, the epithelium proliferates uncontrollably, but don’t invade stroma. They are cystic tumours with luminal/surface papillae. These tumours are not cancer! (i.e.: malignant). The mucinous variety is similar in that epithelium is uncontrollably proliferating, except now there is mucin. Arrangement is multicystic.

IMPLANTS

These are just spreads of primary cancers.

PSEUDOMYXOMA PERITONEI

Refer above. Refer to pp 1071.

General Information (Abbas pp 201)

Immune responses are considered to defend the host against infections. Sometimes, immune responses are themselves capable of causing tissue injury and disease. There are two main types of hypersensitivities:

1) an immune response towards a foreign antigen that is uncontrolled and dysregulated,

2) immune responses can be directed against self antigens – therefore tolerance is reduced/impaired.

Type I Hypersensitivity – Humoral – 2-30 mins (Abbas pp 202, Fig 11-1)

These types of hypersensitivities are also called allergies. Individuals that develop such reactions are said to be “atopic”. It often follows inflammation and results in the production of IgE. This triggers release of mediators from mast cells. It is important to note, that for immediate hypersensivity reactions to occur – the host must have had previous exposure to the antigen. Common types of Type I reactions include: hay fever, food allergies, bronchial asthma, and anaphylaxis.

Steps in immediate hypersensitivity (Abbas pp 202)

Production of IgE antibody

• Normal individuals do not mount a strong TH2 response to most foreign antigens. For some unknown reason, some individuals mount this abnormally sensitive response

• Immediate hypersensitivity therefore develops when an “atopic” individual is exposed to an allergen (protein antigens) ≫ causes the activation of TH2 cells.

• TH2 begin secreting cytokines. Of these, Il-4 & IL-13 stimulate B lymphocytes specific for the particular foreign antigen to start producing IgE antibodies.

• “Atopic” individuals begin to produce large amounts of IgE compared to normal individuals. It has been established that “atopy” has a genetic link.

Activation of Mast cells and secretin of mediators

• Once IgE is produced in response to a particular allergen, it binds to the FcRI receptors expressed on the cell membrane of mast cells. The mast cells are now coated with IgE antibody that is specific that particular allergen. This coating process is called “sensitisation” because now the mast cells are sensitive (“loaded” with IgE) to activation upon contact with that allergen.

• Mast cells are present in all connective tissues of the body, so which mast cells are activated depends on the route of entry of the allergen.

• Thus, when the allergen presents again at a later stage the mast cells get activated. This occurs due to binding of the allergen to 2 or more IgE antibodies on the mast cell.

• This causes IgE and Fc receptors (carrying the IgE) to cross link. This triggers biochemical signals from signal transducing chains of the FcRI receptor. This causes the production of mediators.

• The most important of these mediators are: vasoactive amines (i.e: histamine) and proteases released from granules, products of arachidonic acid metabolism and cytokines. For fⁿ of these mediators refer to: Abbas pp 205. Generally, mast cell mediators cause acute vascular and smooth muscle reactions + inflammation.

• The cytokines produced by the mast cells stimulate leukocytes to be activated  late phase reaction. The leukocytes are: eosinophils + neutrophils (both stimulated by TNF and IL-4), and TH2 cells. Chemokines produced by mast cells and tissue cells also cause leukocytic recruitment. TH2 cells can further release cytokines which exacerbate the reaction.

The dose and route of allergen administration determines the type of IgE-mediated allergic reaction that results. I.e.: Whether it is serious or not so serious.

The allergen can enter the body via 1 of 4 ways:

• Intravenously, directly into the blood stream (i.e.: injected drugs, snake bites)

• Subcutaenously – low dose

• Inhalation – low dose

• Ingestion

All Immediate hypersensitivity reactions require mast cell activation upon a re-presentation of that particular allergen. Mast cells are found throughout the body. Generally, they are divided into mast cells associated with blood vessels and those found in connective tissue. In an allergic individual, all of these cells are loaded with IgE antibodies. Thus, the allergic response initiated upon re-presentation depends on which mast cells are activated. Allergen administration intravenously results in systemic histamine release due to systemic mast cell activation, subcutaneous administration results in local inflammatory reaction, inhalation causes mucosal mast cell activation resulting in excess mucous produced, and smooth muscle contraction of lower airways. Ingestion of an allergen activates gut mucosal mast cells, therefore smooth muscle contraction ≫ vomiting. The allergen is also absorbed into the blood ≫ back to intravenous administration.

Detection / Therapy for Immediate Hypersensitivity (Abbas pp 208)

Detection is simply done by skin test, RIST test (for IgE levels) and RAST (for antigen specific IgE levels). Therapy is aimed at inhibiting release of mediators of mast cells, inhibiting effects of mast cell mediators, and reducing inflammation. Firstly, you remove the allergen causing the allergic reaction. Commonly used drugs include: anti-histamines (hay fever), bronchial smooth muscle relaxants, adrenaline (anaphylaxis), corticosteroids (anti-inflammatory). Repeated administration of the allergen in small doses makes the host desensitised ≫ de-sensitisation/hyposensitisation.