MRCS Part B Microbiology & Pathology Flashcards
What is Clostridium difficile? What factors allow Clostridium difficile to cause symptoms? How does it spread so readily? What is a spore? How do you treat C.diff?
C.diff is a gram POSITIVE, spore forming ROD - facultative anaerobe. Causes symptoms by production of exotoxins - such as enterotoxin (C.diff toxin A) and cytotoxin (C.diff toxin B) that attack the walls of the bowel leading to local inflammation and diarrhoea.. The spores are highly resistant and readily transferred, able to survive in conditions other bacteria would not be able to withstand. A SPORE is a minute, one-celled, reproductive unit capable of giving rise to a new individual without sexual fusion. 1st line agent is oral metronidazole, for those who do not respond/are severely unwell the 2nd line agent is vancomycin. Fidaxomicin is a new agent that can also be tried.
A 73 year old man is admitted with diarrhoea and is found to have Clostridium difficile colitis. He is treated with oral metronidazole for 10 days. You are the surgical registrar who has been called to review him. On examination he has some right sided abdominal tenderness but his abdomen is soft. He has a recent plain film.
How would you manage him?
This man is likely to have failed medical management and has developed toxic megacolon. The correct treatment is therefore resuscitation, laparotomy and sub total colectomy and end ileostomy formation. Continued attempted antibiotic treatment is highly unlikely to improve the situation rapidly and avert spontaneous perforation.
Clostridium difficile is a Gram positive rod often encountered in hospital practice. In the UK it can be found in 3% of normal adults and up to 66% of babies. It produces an exotoxin which causes intestinal damage leading to a syndrome called pseudomembranous colitis.
Risk factors
Broad spectrum antibiotics
Use of PPI and H2 receptor antagonists
Contacted with persons infected with c.difficile
Features
Diarrhoea
Abdominal pain
A raised white blood cell count is characteristic
If severe, toxic megacolon may develop
Diagnosis is made by detecting Clostridium difficile toxin (CDT) in the stool
Management
First-line therapy is oral metronidazole for 10-14 days
If severe, or not responding to metronidazole, then oral vancomycin may be used
Patients who do not respond to vancomycin may respond to oral fidaxomicin
Patients with severe and unremitting colitis should be considered for colectomy
What is a surgical site infection? What is the commonest organism responsible for surgical site infections? What factors help to minimise the risk of surgical site infections?
A surgical site infection is the colonisation of a recent surgical wound with pathogenic bacteria that causes local and/ or systemic symptoms and local wound complications. It is important to have a clear appreciation of what constitutes a wound infection because unit outcomes are now widely reported and both over and under diagnosis can have adverse outcomes.
Staphylococcus aureus is the most common organism causing surgical site infections.
Factors Minimising Risk of SSInfections:
- Not shaving the wound
- Healthcare professionals adhering to good practice by changing clothes, washing hands and wearing gloves as appropriate
- Timely administration of perioperative antibiotics and continuing doses in those patients for whom it is justified
- Chlorhexidine skin preparation
- Avoid incise drapes, if necessary then use iodophor impregnated drapes
- A recent trial (Rossini) suggests that wound protectors do not reduce the risk of surgical site infections.
Surgical site infections may occur following a breach in tissue surfaces and allow normal commensals and other pathogens to initiate infection. They are a major cause of morbidity and mortality.
Surgical site infections (SSI) comprise up to 20% of all healthcare associated infections and at least 5% of patients undergoing surgery will develop an SSI as a result.
In many cases the organisms are derived from the patient’s own body. Measures that may increase the risk of SSI include:
Shaving the wound using a razor (disposable clipper preferred)
Using a non iodine impregnated incise drape if one is deemed to be necessary
Tissue hypoxia
Delayed administration of prophylactic antibiotics in tourniquet surgery
Preoperatively
Don’t remove body hair routinely
If hair needs removal, use electrical clippers with single use head (razors increase infection risk)
Antibiotic prophylaxis if:
- placement of prosthesis or valve
- clean-contaminated surgery
- contaminated surgery
Use local formulary
Aim to give single dose IV antibiotic on anaesthesia
If a tourniquet is to be used, give prophylactic antibiotics earlier
Intraoperatively
Prepare the skin with alcoholic chlorhexidine (Lowest incidence of SSI)
Cover surgical site with dressing
A recent meta analysis has confirmed that administration of supplementary oxygen does not reduce the risk of wound infection. In contrast to previous individual RCT’s(1)
Wound edge protectors do not appear to confer benefit (2)
Post operatively
Tissue viability advice for management of surgical wounds healing by secondary intention
Use of diathermy for skin incisions
In the NICE guidelines the use of diathermy for skin incisions is not advocated(3). Several randomised controlled trials have been undertaken and demonstrated no increase in risk of SSI when diathermy is used(4).
References
- Brar M et al.. Perioperative supplemental oxygen in colorectal patients: a meta analysis. J Surg Res 2011 (166): 227 -235.
- Pinkney T et al. Impact of wound edge protection devices on surgical site infection after laparotomy: impact of a multicentre randomised controlled trial (ROSSINI Trial). BMJ 2013 (347):10.
- http://www.nice.org.uk/CG74
- Ahmad N and Ahmed A. Meta-analysis of the effectiveness of surgical scalpel or diathermy in making abdominal skin incisions. Ann Surg 2011, 253(1):8-13.
A 45 year old man is admitted profoundly septic and on examination, is found to have a small wound on his right foot. There is relative anaesthesia of the surrounding skin which appears slightly pale. What is the most likely diagnosis? What is the immediate management of this condition? What is the usual cause? What are the main risk factors? What is meant by the term “Fournier gangrene” and how is it managed?
A combination of altered tissue perfusion, sepsis and cutaneous anaesthesia is suggestive of necrotizing fasciitis.
Management is Immediate administration of broad spectrum intravenous antibiotics together with radical surgical debridement. Most cases are polymicrobial with mixed infection consisting of anaerobes and gram negative aerobic organisms. The classical “flesh eating” variant is monomicrobial infection with group A haemolytic streptococcal organisms.
Main risk factors for nec fasc: DM, Immunosuppression, PVD
Fournier gangrene is a localised form of necrotizing fasciitis that affects the scrotal area and it is managed with radical debridement. The subsequent defects pose considerable reconstructive challenges.
Although it may resemble synergistic bacterial gangrene, necrotizing fasciitis is a much more acute and highly toxic infection, causing widespread necrosis and undermining of surrounding tissues. Fournier gangrene is a localised form of necrotizing fasciitis that is localised to the scrotal area. A variety of microbial causes are recognised and three sub groups are recognised;
Type I: Polymicrobial - Mixed anaerobic and gram negative aerobic organisms
Type II: Monomicrobial - Group A haemolytic streptococcal infection
Type III: Gas gangrene - Clostridium perfringens
A major risk factor for infection is underlying disease with poor tissue perfusion from peripheral vascular disease. Immunosupression and diabetes are also major risk factors. Diabetes poses a particular risk because is can result in impaired neutrophil function, poor healing following minor injury and localised tissue hypoperfusion as a result of microvascular disease.
In many cases there is an underlying injury. This can sometimes be trivial and not readily recalled by the patient. Patients are often profoundly toxic. The overlying skin may not appear overtly abnormal. However, there may be palpable crepitus and the sensation of the overlying skin can be altered as cutaneous nerves are disrupted.
The initial management is surgical with urgent, wide, radical debridement. The wounds are left open and patients are returned to theatre at 24 hour intervals until no further debridement is required. Negative pressure wound management systems (VAC dressings) have transformed the management of this patient group. Once a healthy wound bed is established, skin grafting is often required. Broad spectrum intravenous antibiotics are administered from the outset and may be adjusted according to microbiological culture of debrided tissue.
What type of organism is streptococcus pyogenes? What types of infection are linked to streptococcus pyogenes infection?
Strep pyogenes is a gram positive cocci, Lancefield Group A. These can be categorised as being invasive or non invasive. Invasive infections include; necrotising fasciitis, toxic shock syndrome and puerperal fever. Non invasive infections include pharyngitis, erysipelas and impetigo.
Streptococcus pyogenes:
Gram positive cocci Lancefield group A streptococci
Causes suppurative infections in the respiratory tract and skin
Virulence factors- adhesion to host cells by interaction between bacterial F protein and human fibronectin, cell surface M proteins allow organism to resist polymorphonuclear leucocytes. Some stains possess a capsule Streptolysins O and S produced by some strains, may play a role in development of rheumatic fever. Pyogenic exotoxins, responsible for many immune effects such as toxic shock. Hyaluronidase production, facilitates spread of infection. Streptokinase, facilitates fibrin breakdown and bacterial spread Infections
Non invasive disease; includes pharyngitis which may be complicated by the development of scarlet fever. Also causes impetigo and erysipelas
Invasive infection; these include necrotising fasciitis , toxic shock syndrome and puerperal fever. These may occur in previously healthy individuals
Non suppurative sequlae : rheumatic fever and glomerulonephritis
Which of the virulence factors possessed by streptococcus pyogenes are implicated in invasive infections? What systemic complications of non invasive streptococcal disease are you familiar with?
The production of streptolysins, hyaluronidase and streptokinase all break down tissue planes and fibrin and accounts for the spreading and invasive nature of some infections. Pyogenic exotoxins account for many of the features seen in toxic shock syndrome.
Systemic complications of non-invasive strep: These include scarlet fever, rheumatic fever and glomerulonephritis. Rheumatic fever is an autoimmune mediate event whereas glomerulonephritis is mediated by immune complex deposition.
Streptococcus pyogenes:
Gram positive cocci Lancefield group A streptococci
Causes suppurative infections in the respiratory tract and skin
Virulence factors- adhesion to host cells by interaction between bacterial F protein and human fibronectin, cell surface M proteins allow organism to resist polymorphonuclear leucocytes. Some stains possess a capsule Streptolysins O and S produced by some strains, may play a role in development of rheumatic fever. Pyogenic exotoxins, responsible for many immune effects such as toxic shock. Hyaluronidase production, facilitates spread of infection. Streptokinase, facilitates fibrin breakdown and bacterial spread Infections
Non invasive disease; includes pharyngitis which may be complicated by the development of scarlet fever. Also causes impetigo and erysipelas
Invasive infection; these include necrotising fasciitis , toxic shock syndrome and puerperal fever. These may occur in previously healthy individuals
Non suppurative sequlae : rheumatic fever and glomerulonephritis
What is the difference between cleaning and sterilisation of instruments? What is the reason behind cleaning instruments prior to sterilisation? How are the majority of surgical instruments sterilised?
The process of cleaning instruments refers to the systematic removal of foreign material and visible debris from a device. Sterilisation involves the removal of all viable micro-organisms from a device. Disinfection involves the reduction in the number of viable micro-organisms from a surface, but does not remove them all.
The process of sterilisation does not, in itself, involve the removal of debris from the surface of an instrument. If a device is not cleaned prior to sterilisation then there will still be proteinaceous material and other debris present on the surface following use. Apart from being aesthetically displeasing this can impair the function of the instrument and may introduce foreign material, albeit denatured, into a new wound.
Sterilisation: The usual practice is to autoclave them. This involves placing clean instruments into a specialised unit that delivers high pressure and temperature steam into a closed unit. A median treatment time of three minutes at 134 degrees oC is the usual strategy.
Surgical equipment has to be cleaned and sterilised prior to use. The extent to which these processes will be required varies according to the type of equipment and the purpose for which it will be used. In general, the three processes are relevant; cleaning, disinfection and sterilisation.
Cleaning refers to removal of physical debris.
Disinfection refers to reduction in numbers of viable organisms.
Sterilisation is removal of all organisms and spores.
Autoclaving: Air removed and high pressure steam used (usually 134 oC for 3 minutes)Most reusable surgical equipment, must be physically cleaned prior to autoclaving, unsuitable for fragile items
Glutaraldehyde solution (2%): Colourless oily liquid, directly cytocidal and virucidal even at low temperaturesSpecifically used for endoscopes and some laparoscopic items, staff can rapidly develop allergy to this substance which has limited its more widespread use
Ethylene oxide: 3% mixture of gas with carbon dioxide usedUsed for packaged materials that cannot be heated, the gas is explosive and environmentally toxic, it is used mainly in the industrial setting
Gamma irradiation: Gamma rays emitted from radioactive substance such as cobalt 60 or caesium 137Suitable for batch treatment of relatively thermostable items, typically an industrial process
What is the Bowie-Dick test and how does it relate to autoclaves? Name all the known prion diseases? What precautions must be taken when undertaking surgery or an invasive procedure on a patient with a known or suspected prion disease?
During autoclaving the usual practice is to create a vacuum at the beginning and the end of each sterilisation cycle. The Bowie-Dick test consists of a unit containing indicator strips that change colour when the autoclave cycle, including the vacuum phases is working correctly. These units are placed into an autoclave and a cycle is run. The unit and its indicators are then checked at the conclusion of the cycle. It provides a warning of device malfunction.
Known prion diseases: Kuru, Creutzfeldt-Jacob Disease, variant Creutzfeldt-Jacob Disease, fatal familial insomnia and Gerstmann-straussler-scheinker-syndrome (GSS).
All patients irrespective of known or suspected prion disease: Single use devices must be used for lumber punctures and surgery relating to the eye, tonsils, brain or spinal cord.
For known and suspected cases of CJD for all types of surgery: it is important that the Infection Prevention & Control Team and Hospital Sterilising and Disinfection Unit Manager are informed by clinicians of all suspected or known patients with CJD, so that disposable instruments can be used for all surgery on those patients (wherever possible). All non-disposable instruments on such patients must be quarantined (suspected cases) or destroyed (known cases).
Surgical equipment has to be cleaned and sterilised prior to use. The extent to which these processes will be required varies according to the type of equipment and the purpose for which it will be used. In general, the three processes are relevant; cleaning, disinfection and sterilisation.
Cleaning refers to removal of physical debris.
Disinfection refers to reduction in numbers of viable organisms.
Sterilisation is removal of all organisms and spores.
Autoclaving: Air removed and high pressure steam used (usually 134 oC for 3 minutes)Most reusable surgical equipment, must be physically cleaned prior to autoclaving, unsuitable for fragile items
Glutaraldehyde solution (2%): Colourless oily liquid, directly cytocidal and virucidal even at low temperaturesSpecifically used for endoscopes and some laparoscopic items, staff can rapidly develop allergy to this substance which has limited its more widespread use
Ethylene oxide: 3% mixture of gas with carbon dioxide usedUsed for packaged materials that cannot be heated, the gas is explosive and environmentally toxic, it is used mainly in the industrial setting
Gamma irradiation: Gamma rays emitted from radioactive substance such as cobalt 60 or caesium 137Suitable for batch treatment of relatively thermostable items, typically an industrial process
What is tetanus? What are the features, present in a wound, that increase the risk of tetanus? How is it prevented? How would you manage a high risk tetanus prone wound in a non immunised patient? How would you manage a clean wound in a person who was fully immunised against tetanus more than ten years ago?
Tetanus is a condition characterised by generalised muscular spasms that occur as a result of the infection of a wound with the spore producing Clostridium tetani. The organism produces a neurotoxin (tetanospasmin) that is transported to the CNS and inhibits the release of inhibitory neurotransmitter molecules that results in unopposed neuronal motor discharge.
Wound risk factors: Heavy contamination with soil or faeces, Devitalised tissue, Infected or old neglected wounds, Puncture wounds
Tetanus is prevented by wound managment and immunisation programmes.
High risk non-immunised wound Debride and clean wound. Administer human anti tetanus immunoglobulin and start an immunisation course of tetanus toxoid
Clean wound, immunised >10years ago: wound care and tetanus toxoid booster.
Tetanus is an acute and often fatal disease which is relatively rare in the Western world because of immunisation programmes and ready access to healthcare. It is caused by the organism Clostridium tetani which is commonly found in soil and animal faeces. The tetanus bacillus is a straight slender gram positive rod. A fully developed terminal spore gives the organism its classical drumstick appearance. It is an obligate anaerobe, the spores are highly resistant to adverse conditions. Clostridium tetani produces a number of toxins. However, the organisms neurotoxin (tetanospasmin) is the main pathogenic product. The toxin diffuses to the relevant level of the spinal cord to produce local tetanus and then affects the entire CNS. Infection to the key aspects of the CNS is via retrograde axonal transport. Once the entire toxin molecule is internalised into the presynaptic cells it affects the membrane of the synaptic vesicles and prevents the release of the neurotransmitter γ aminobutyric acid. Motor neurones are thus left under no inhibitory control and undergo sustained excitatory discharge causing the classical motor spasms of tetanus. The incubation period is usually 4-14 days. Management of established tetanus consists of providing full supportive care in the ITU as autonomic disturbance and cardiac arrhythmias are common. Penicillin, metronidazole and human tetanus immunoglobulin should be administered. Any wounds should be debrided. Tetanus immunisation programme The standard active immunisation programme consists of 3 IM doses of 0.5ml of tetanus toxoid given at monthly intervals from 2 months of age. Booster doses are given at 4 and 14 years of age. Immunisation following injury depends upon the immunisation status of the patient.
The following features render a wound at high risk of tetanus:
Heavy contamination with soil or faeces
Devitalised tissue Infection or old neglected wounds
Puncture wounds
DOH guidance
Immunisation statusClean woundTetanus prone wound
Full course or less than 10 yearsNilGive tetanus toxoid booster
Full course but more than 10 years agoGive tetanus toxoid booster (may be omitted if full five doses given at correct intervals)Give tetanus toxoid booster and human (may be omitted if full five doses given at correct intervals) anti tetanus immunoglobulin
Not immunised or unknownStart tetanus toxoid courseStart tetanus toxoid course and give human anti tetanus immunoglobulin
What is the difference between a community acquired infection and a nosocomial infection? What factors increase the risk of nosocomial infections? What is meant by the term ventilator acquired pneumonia? What aetiological factors contribute to the development of ventilator associated pneumonia?
Community acquired infections are those which originate in the community. These are, therefore, either present on admission or occur more than 10 days following discharge from hospital. They typically are not related to and surgical site or indwelling device inserted during that hospital admission, or in the case of prostheses, up to 1 year following implantation. The causative agent will usually be one that is present in the community and be sensitive to standard community based interventions. Nosocomial infections are those which are acquired in hospital or within 10 days following discharge. They are typically caused by different pathogens to community infections and have differing antimicrobial sensitivities.
Risk increased by: High patient occupancy levels
Poor infection control practice
Excessive use of indwelling devices or delayed removal of such devices
Failure to use infection control bundles, where these exist
Poor equipment handling (increasing risks of contamination)
It is defined as a pneumonia that occurs 48 hours after commencement of invasive ventilation or within 24 hours of extubation.
Aetiological factors contributing to VAP: Bacterial overgrowth of the oropharynx and stomach
Impaired mucociliary clearance and coughing
Impaired glottis closure with pooling of secretions above endotracheal tubes
Microaspiration or oropharyngeal contents
Healthcare associated infections
As many as 1 in 10 patients may have a healthcare associated infection (HCAI) at any one time. Up to 5000 deaths occur in the UK each year as a result of HCAI.
A number of different terms are used to describe infections that occur in hospitalised patients:
Nosocomial: Acquired as a result of admission to a healthcare facility
Infection not present on admission, commencing 48 hours following admission, or up to 10 days following discharge
Surgical site infections are those which occur up to 30 days following a procedure (1 year if prosthesis used)
HCAI: Used to describe situations of increased infection risk with pathogens found in hospitals
Affected by antibiotic policy
Vary according to site, illness, devices, concomitant therapy
Types of HCAI
UTIs are the most common, septicaemia has the highest mortality.
Bacterial:
UTI- device related
Pneumonia- use of ventilators
Surgical site infections
Bloodstream infections- use of central venous catheters
Clostridium difficle colitis
Viruses:
Gastroenteritis
Respiratory tract infections
Hepatitis B and C/ HIV
Prion disease
Reducing risk
Preoperative MRSA screening and decontamination if colonised
Hair removal with clippers
Correct antimicrobial prophylaxis (dose, drug, time)
Normoglycaemia
Normothermia
What diseases are associated with Helicobacter Pylori infection? What type of organism is H.pylori? How is a H pylori infection diagnosed? How is infection treated?
Associated with H.pylori infection: Peptic ulcers, Gastric cancer, MALT lymphoma
H. pylori is a gram negative, slightly curved rod, it is microaerophilic.
Diagnosis H pylori: Culture (difficult, slow, but accurate), Microscopy (accurate but invasive), Serology (difficult to establish eradication), Biopsy rapid urease tests (Clo, invasive but quick)
Infection is treated with triple therapy: Abx, PPI
Infection with Helicobacter Pylori is implicated in many cases of duodenal ulceration and up to 60% of patients with gastric ulceration.
It is a gram negative, helical shaped rod with microaerophillic requirements. It has the ability to produce a urease enzyme that will hydrolyse urea resulting in the production of ammonia. The effect of ammonia on antral G cells is to cause release of gastrin via a negative feedback loop.
Once infection is established the organism releases enzymes that disrupt the gastric mucous layer. Certain subtypes release cytotoxins cag A and vac A gene products. The organism incites a classical chronic inflammatory process of the gastric epithelium. This accounts for the development of gastric ulcers. The mildly increased acidity may induce a process of duodenal gastric metaplasia. Whilst duodenal mucosa cannot be colonised by H-Pylori, mucosa that has undergone metaplastic change to the gastric epithelial type may be colonised by H- Pylori with subsequent inflammation and development of duodenitis and ulcers.
In patients who are colonized, there is a 10-20% risk of peptic ulcer, 1-2% risk gastric cancer and <1% risk MALT lymphoma.
You have just performed a radical orchidectomy for a suspected testicular cancer. Outline the steps involved in the pathological processing of this specimen such that the pathologist may be in a position to issue a histopathology report.
The specimen should be placed in a contained of adequate size and covered with saline/ formalin combination. The specimen should be clearly labeled with patient details and a request card completed with adequate clinical information. It should be transported to the hospital pathology department and the tissue allowed to fix prior to being cut by a pathologist.
Sites of interest will then be processed and impregnated with wax before being embedded and cut using a microtome. A number of basic (H&E) and advanced (immunohistochemistry) stains will be applied to multiple sections to allow the pathologist to assess the tumour and provide useful prognostic information.
What would be the best method for assessing whether a peritoneal nodule encountered during the trial dissection phase of a Whipples procedure contained metastatic cancer or not?
In this situation a rapid diagnosis is required. If the nodule is indeed metastatic cancer then it represents peritoneal disease and attempts to proceed with definitive resection aborted. The surgeon should telephone the pathology department and warn then that a frozen section is about to be requested. The tissue should be taken immediately to the department, cut into small pieces and then frozen in liquid nitrogen. It is then cut into thin sections using a cryostat and stained. The pathologist can then view the specimen and attempt to determine whether there are cancer cells present or not.
Principles of pathological specimen processing
Surgeons frequently submit human tissues for histological assessment. In some cases the intention is to confirm a know or suspected diagnosis. At other times the diagnosis may have been elusive and only by direct analysis of tissue cellular composition and architecture can it be achieved.
Histological assessment of tissue involves processing it such that it can be visible microscopically. There are two main methods for achieving this, the first involves frozen sections and the second, paraffin embedded ones.
Frozen sections are usually performed when tissue microscopy is required urgently, such as intra operatively. The tissue is cut up and then snap frozen using liquid nitrogen and cut into thin sections using a cryostat microtome. The thin tissue sections thus obtained are placed onto a glass microscope slide and stained with haematoxyllin and eosin. The advantage of the technique is speed. The main disadvantages of the technique are that it is very labour intensive and the quality of the sections obtained does not equate with those that are obtained following formalin fixation and wax embedding. On occasion the specimen quality may be so poor that a pathologist cannot make a robust diagnosis.
The other method of specimen preparation for histology involves formalin fixation of the tissue specimen. Formalin cross links collagen fibres and maintains the structural and cellular integrity of tissues that facilitates subsequent analysis. This process takes between 24 and 72 hours depending upon the size of the tissue sample.Once fixed, the tissue is cut up by a pathologist into small blocks that represent regions of interest. These blocks are processed by impregnating the tissues with wax. They are eventually embedded in wax and cut into thin sections using a microtome. They can be stained with a number of different tissue stains. The advantage of this technique is that it provides specimens that are long lasting and require little special storage precautions. The main disadvantage is the time taken to prepare the tissues. Even in an efficient laboratory a turnaround time of less than 48-72 hours for small specimens would be unusual.
There are some special histological immunohistochemistry tests that are impeded by the tissue fixation process with formalin. Renal biopsies and lymph nodes are two tissue types for which it is often best to check with the laboratory first. Particularly if there is any intention to submit part of a lymph node for culture.
What are the key differences between histology and cytology?
Histology allows determination of cell types in relation to their surrounding structures. This usually requires pieces of tissue for analysis. Cytology is concerned with analysis of individual cells. Whilst this may convey important clinical information, there are some situations where it is not possible to determine with certainty whether a pathology is present or not. This is well demonstrated by follicular lesions of the thyroid, where it is impossible to state whether cancer is present without histological assessment of the capsule.
Principles of pathological specimen processing
Surgeons frequently submit human tissues for histological assessment. In some cases the intention is to confirm a know or suspected diagnosis. At other times the diagnosis may have been elusive and only by direct analysis of tissue cellular composition and architecture can it be achieved.
Histological assessment of tissue involves processing it such that it can be visible microscopically. There are two main methods for achieving this, the first involves frozen sections and the second, paraffin embedded ones.
Frozen sections are usually performed when tissue microscopy is required urgently, such as intra operatively. The tissue is cut up and then snap frozen using liquid nitrogen and cut into thin sections using a cryostat microtome. The thin tissue sections thus obtained are placed onto a glass microscope slide and stained with haematoxyllin and eosin. The advantage of the technique is speed. The main disadvantages of the technique are that it is very labour intensive and the quality of the sections obtained does not equate with those that are obtained following formalin fixation and wax embedding. On occasion the specimen quality may be so poor that a pathologist cannot make a robust diagnosis.
The other method of specimen preparation for histology involves formalin fixation of the tissue specimen. Formalin cross links collagen fibres and maintains the structural and cellular integrity of tissues that facilitates subsequent analysis. This process takes between 24 and 72 hours depending upon the size of the tissue sample.Once fixed, the tissue is cut up by a pathologist into small blocks that represent regions of interest. These blocks are processed by impregnating the tissues with wax. They are eventually embedded in wax and cut into thin sections using a microtome. They can be stained with a number of different tissue stains. The advantage of this technique is that it provides specimens that are long lasting and require little special storage precautions. The main disadvantage is the time taken to prepare the tissues. Even in an efficient laboratory a turnaround time of less than 48-72 hours for small specimens would be unusual.
There are some special histological immunohistochemistry tests that are impeded by the tissue fixation process with formalin. Renal biopsies and lymph nodes are two tissue types for which it is often best to check with the laboratory first. Particularly if there is any intention to submit part of a lymph node for culture.
What are the main features of the acute inflammatory process?What is an abscess? Why do abscesses form? What is an empyema?
The key features of acute inflammation are vasodilatation, formation of a protein rich exudate and the accumulation of neutrophil polymorphs at the site. The process concludes by resolution, abscess formation or progression to chronic inflammation.
An abscess is a collection of tissue flid and white cells within a contained space
Abscesses: usually arise because there is a significant microbial load at a specific anatomical site. This in turn results in the accumulation of a significant quantity of neutrophil polymorphs. Tissue fluid will extravasate into the site. The centre of abscesses is usually hypoxic and this can impede oxygen free radical dependent killing mechanisms and cellular phagocytic functions. This therefore impedes clearance of pus. Finally, there needs to be confinement of this process. This typically occurs as a result of anatomical factors such as the presence of skin or connective tissue which anatomically confines the process.
Empyema: collection of pus within a hollow viscus
Inflammation is the reaction of the tissue elements to injury. Vascular changes occur, resulting in the generation of a protein rich exudate. So long as the injury does not totally destroy the existing tissue architecture, the episode may resolve with restoration of original tissue architecture.
Vascular changes: Vasodilation occurs and persists throughout the inflammatory phase. Inflammatory cells exit the circulation at the site of injury. The equilibrium that balances Starlings forces within capillary beds is disrupted and a protein rich exudate will form as the vessel walls also become more permeable to proteins.
The high fibrinogen content of the fluid may form a fibrin clot. This has several important immunomodulatory functions.
Sequelae:
Resolution: Typically occurs with minimal initial injury. Stimulus removed and normal tissue architecture results
Organisation: Delayed removal of exudate, Tissues undergo organisation and usually fibrosis
Suppuration: Typically formation of an abscess or an empyema. Sequestration of large quantities of dead neutrophils
Progression to chronic inflammation: Coupled inflammatory and reparative activities. Usually occurs when initial infection or suppuration has been inadequately managed
Causes
Infections e.g. Viruses, exotoxins or endotoxins released by bacteria
Chemical agents
Physical agents e.g. Trauma
Hypersensitivity reactions
Tissue necrosis
Presence of neutrophil polymorphs is a histological diagnostic feature of acute inflammation
What is amyloid? What types of amyloidosis are you familiar with? What organs are most commonly affected by amyloidosis? How is it diagnosed? How is it treated?
Amyloid: extracellular protein deposit which is insoluble. It is usually linked to a deposition of a specific fibrillar protein.
Both AA and AL types of amyloidosis are well described. AL is the most common type and related to conditions such as myeloma. AA amyloidosis is typically associated with chronic inflammatory states.
The heart and kidneys are the most common sites. However, amyloidosis is a multisystem disorder.
By biopsy of an affected organ. Histologically, the insoluble proteinaceous deposit will cause the birefringence of polarised light.
There is no specific treatment for amylosis per se, treatment is directed at the underlying cause.
Amyloid is an extracellular protein deposit which is insoluble. These deposits disrupt normal tissue structure and if excessive may affect function. All types of amyloid consist of a major fibrillar protein that defines the type of amyloid (approximately 90%) plus various minor components.
Amyloid is classified with the prefix A (for amyloid) and the suffix depending upon the fibrillary protein present. The main clinical types are AA and AL amyloidosis. Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders - e.g. rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, malignancies and conditions predisposing to recurrent infections. AL amyloidosis results from extra-cellular deposition of fibril-forming monoclonal immunoglobulin light chains (most commonly of lambda isotype). Most patients have evidence of isolated monoclonal gammopathy or asymptomatic myeloma, and the occurrence of AL amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusual. AL type amyloidosis is the most common variant. The kidney and heart are two of the most commonly affected sites. Diagnosis is based on surgical biopsy and characteristic histological features which consist birefringence under polarised light. Immunohistochemistry is used to delineate the subtype. Treatment is usually targeted at the underlying cause.
What is meant by the term “metaplasia”? Describe the metaplastic processes involved in the development of Barrett’s oesophagus.
What process may complicate Barrett’s oesophagus that can result in the development of oesophageal cancer?
Metaplasia : transformation of one type of specialised epithelium to another, usually in response to a external stimulus.
Barrett’s oeosphagus is characterised by long standing gastro-oesophageal reflux. This results in recurrent oesophagitis. Eventually, the squamous epithelium that lines the oesophageal lumen becomes replaced by goblet cells that are usually found in the stomach.
Dysplasia may complicate Barrett’s oesophagus and can result in the development of oesophageal cancer
What is the main concern when severe dysplasia is identified in a segment of Barrett’s oesophagus? What treatments are available for Barrett’s oesophagus complicated by severe dysplasia? How is Barrett’s oeosphagus without dysplasia managed?
The main concern is that a foci of invasive cancer has already developed and been missed through sampling error.
The treatment depends upon the fitness of the patient and patient wishes. Treatment options include photodynamic therapy, laser ablation and segmental resection.
Barrett’s without dysplasia: managed with long term proton pump inhibitor therapy. Endoscopic surveillance is also required.
Barretts oesophagus is a condition characterised by the metaplastic transformation of squamous oesophageal epithelium to columnar gastric type epithelium. Three types of this metaplastic process are recognised; intestinal (high risk), cardiac and fundic. The latter two categories may cause difficulties in diagnosis. The most concrete diagnosis can be made when endoscopic features of Barretts oesophagus are present together with a deep biopsy that demonstrates not just goblet cell metaplasia but also oesophageal glands.
Barrett’s can be sub divided into short (<3cm) and long (>3cm). The length of the affected segment correlates strongly with the chances of identifying metaplasia. The overall prevalence of Barrett’s oesophagus is difficult to determine but may be in the region of 1 in 20 and is identified in up to 12% of those undergoing endoscopy for reflux.
A proportion of patients with metaplasia will progress to dysplasia and for this reason individuals identified as having Barrett’s should undergo endoscopic surveillance (every 2-5 years). Biopsies should be quadrantic and taken at 2-3cm intervals. Biopsies need to be adequate. Where mass lesions are present consideration should be given to endoscopic sub mucosal resection. Up to 40% of patients will be upstaged from high grade dysplasia to invasive malignancy with such techniques.
Treatment
Long term proton pump inhibitor
Consider pH and manometry studies in younger patients who may prefer to consider an anti reflux procedure
Regular endoscopic monitoring (more frequently if moderate dysplasia). With quadrantic biopsies every 2-3 cm
If severe dysplasia be very wary of small foci of cancer
What are the key pathological features of Crohns disease? What is the commonest extra intestinal complication of Crohns disease and why does it occur? Why do people with Crohns disease develop diarrhoea? What skin lesions are typically associated with Crohns disease?
It is a chronic inflammatory condition affecting the gastrointestinal tract. Focal inflammatory inflammation occurs in a non confluent fashion with a patchy distribution. Whilst the terminal ileum is the commonest site, any site can be affected. Macroscopically, the inflammation is transmural and typically heals by fibrosis, which accounts for the stricturing that occurs. On internal inspection, the transmural inflammation appears as cobblestones on the mucosa. Histologically, there are stigmata of chronic inflammation, particularly with the presence of granulomas.
Diarrhoea in Crohns may be multifactorial since actual inflammation of the colon is not common. Causes therefore include the following:
Bile salt diarrhoea secondary to terminal ileal disease
Entero-colic fistula
Short bowel due to multiple resections
Bacterial overgrowth
The commonest extra intestinal complication of Crohns disease is the development of gallstones. This is seen in up to 30% of cases. The pathogenesis of this relates to the high degree of terminal ileal involvement with Crohn’s disease. Following resection or even healing with extensive fibrosis, there is an impairment of bile salt recycling, which then results in salt imbalance within bile and gallstone deposition.
The causes of diarrhoea in patients with Crohns disease are multifactorial. The inflammatory activity in the acute phase results in secretion of mucous into the bowel lumen and increased fluid volume that makes for a more watery stool. In addition, terminal ileal disease, results in bile salt malabsorption that can result in bile salt diarrhoea. Patients who have undergone extensive resections or even those with loss of absorptive surface area due to extensive disease have a mal absorptive state that is characterised by diarrhoea. Finally, some patients develop entero-colic fistulas that result in small bowel content entering the distal colon and presenting a fluid load that is then not absorbed.
Skin lesions: Erythema nodosum, an acute nodular erythematous eruption usually affecting the legs is sometimes seen. So too is pyoderma gangrenosum, which is a painful ulcerated lesion that can occur anywhere in the body but not infrequently occurs in close proximity to any stomas that may be constructed. It is challenging to treat.
A 38 year old male with long standing terminal ileal Crohns disease has recurrent episodes of small bowel obstruction. He has been investigated with colonoscopy which demonstrated a normal colon (but the ICV could not be entered) and MRI enteroclysis which demonstrates a 7cm terminal ileal stricture. What is the best treatment option? When performing a laparotomy for a patient with Crohns disease what external features of the affected segment are often present?
Long standing strictures like this are often fibrotic and seldom respond to medical management. The best management therefore involves optimising his nutritional state and once this is achieved proceed to surgery. The usual option here would be an ileocaecal resection. 7cm would be slightly too long for a stricturoplasty. In the event that he is smoker he should be given every encouragement to stop since smoking significantly increases his risk of recurrent disease.
Features of external segment on laparotomy: It may be obviously inflamed and the bowel is often thick walled and may feel fibrotic. It is the friable, fatty mesentery that is usually one of the most striking and surgically challenging features.
Surgical interventions in Crohns disease
The commonest disease pattern in Crohns is stricturing terminal ileal disease and this often culminates in an ileocaecal resection. Other procedures performed include segmental small bowel resections and stricturoplasty. Colonic involvement in patients with Crohns is not common and, where found, distribution is often segmental. However, despite this distribution segmental resections of the colon in patients with Crohns disease are generally not advocated because the recurrence rate in the remaining colon is extremely high. As a result, the standard options of colonic surgery in Crohns patients are generally; sub total colectomy, panproctocolectomy and staged sub total colectomy and proctectomy. Restorative procedures such as ileoanal pouch have no role in therapy.
Crohns disease is notorious for the developmental of intestinal fistulae; these may form between the rectum and skin (peri anal) or the small bowel and skin. Fistulation between loops of bowel may also occur and result in bacterial overgrowth and malabsorption. Management of enterocutaneous fistulae involves controlling sepsis, optimising nutrition, imaging the disease and planning definitive surgical management.
Extraintestinal manifestations of Crohns
Related to disease extent: Aphthous ulcers (10%), Erythema nodosum (5-10%), Pyoderma gangrenosum (0.5%), Acute arthropathy (6-12%), Ocular complications (up to 10%)
Unrelated to disease extent
Sacroiliiitis (10-15%), Ankylosing spondylitis (1-2%), Primary sclerosing cholangitis (Rare), Gallstones (up to 30%), Renal calculi (up to 10%)
Crohn’s disease: Mouth to anus. Macroscopic changes: Cobblestone appearance, apthoid ulceration. Depth of disease: Transmural inflammation. Distribution pattern: Patchy. Histological features: Granulomas (non caseating epithelioid cell aggregates with Langhans’ giant cells)
Ulcerative colitis: Distribution: Rectum and colon. Macroscopic changes: Contact bleeding. Depth of disease: Superficial inflammation. Distribution pattern: Continuous. Histological features: Crypt abscesses, Inflammatory cells in the lamina propria
A 73 year old man presents with the knee pain and the following x-ray is obtained. What are the main abnormalities? What is the most likely diagnosis? Describe the main features of this condition.
This is an x-ray of the knee and the following abnormalities are demonstrated:
Joint space narrowing
Osteophyte formation
Increased subchondral bone density
Bone cyst formation
In keeping with OA of the knee
Osteoarthritis is a degenerative condition affecting synovial joints. It may be primary, where there is no overt antecedent cause, or secondary where there is an underlying reason (such as deformity or trauma). It is characterised by the destruction of hyaline cartilage in the early phases and then progressive destruction of the underlying cortical bone. In contrast to rheumatoid disease, there is a minimal inflammatory response and almost no systemic disturbance.
Diagnosis: It is largely a clinical diagnosis, a good history, compatible clinical examination and supportive plain films are usually supportive. In most cases, more specialised imaging is unnecessary. Blood testing for inflammatory markers is generally used to exclude rheumatoid disease.
Osteoarthritis is a very common degenerative joint disorder that arises as a result of hyaline cartilage destruction in synovial joints. The commonest presentation is with pain in the affected joint which is worse on movement. Osteoarthritis typically affects weight bearing joints and is less common in those that are not subjected to mechanical loads. In some cases there is a history of antecendant trauma. Where this is the case, the condition is termed secondary. More rarely, there is not and the condition occurs without an obvious primary cause, and is then termed primary.Osteoarthritis of the hands usually falls into this primary category.
Pain in osteoarthritis
Pain, the main presenting symptom of osteoarthritis, is presumed to arise from a combination of mechanisms, including the following:
Osteophytic periosteal elevation
Vascular congestion of subchondral bone, leading to increased intraosseous pressure
Synovitis with activation of synovial membrane nociceptors
Fatigue in muscles that cross the joint
Overall joint contracture
Joint effusion and stretching of the joint capsule
Torn menisci
Inflammation of periarticular bursae
Periarticular muscle spasm
Psychological factors
Crepitus (a rough or crunchy sensation)
Central pain sensitization
Investigation
Plain x-rays often demonstrate classical features in weight bearing joints including, loss of joint space, sub chondral bone sclerosis and bone cyst formation.
Laboratory investigations are of limited value and where they are undertaken are usually normal. Indeed, raised inflammatory markers are strongly suggestive of an alternative diagnosis.
Management
Early cases respond to simple analgesia and physiotherapy. Once established, the only realistic definitive treatment option is arthroplasty or arthrodesis.
What are the cells of origin of carcinoid tumours? What is the most common site of carcinoid tumours? What are the typical luminal macroscopic features of carcinoid tumours ?
Carcinoid tumours are derived from neuroendocrine cells. The vast majority of tumours are identified within the appendix. They are most common in the terminal ileum, appendix and caecum. More rarely, they may be found in other sites such as the rectum and bronchi.
Luminal macroscopic features of carcinoid of sites such as the rectum: They typically appear as a mass lesion with normal overlying gastrointestinal mucosa and fell firm and smooth. This is because the neuroendocine cells from which they are derived as located beneath the mucosal layer. Invasion of the mucosal layer to form a classical exophytic growth is a late feature.
Carcinoid tumours secrete serotonin. They originate in neuroendocrine cells mainly in the intestine (midgut-distal ileum/appendix), but can occur in the rectum, bronchi. Hormonal symptoms mainly occur when disease spreads outside the bowel
Clinical features
Onset: insidious over many years
Flushing face, Palpitations, Pulmonary valve stenosis and tricuspid regurgitation causing dyspnoea, Asthma, Severe diarrhoea (secretory, persists despite fasting)
Investigation: 5-HIAA in a 24-hour urine collection, Somatostatin receptor scintigraphy, CT scan, Blood testing for chromogranin A
Treatment: Octreotide, Surgical removal
Following a routine appendicectomy a patients pathology report states that a 1.5cm carcinoid tumour of the appendix tip is identified. How should this be managed?
It is important to establish that the tumour was completely removed and the case and histology images should be reviewed in an MDT meeting. However, the incidence of metastatic or recurrent disease in patients with such a small lesion is too low to justify any further interventions. Generally speaking further resectional surgery (right hemicolectomy) is reserved for those patients with tumours greater than 2cm in diameter or with involved margins.
Carcinoid tumours secrete serotonin. They originate in neuroendocrine cells mainly in the intestine (midgut-distal ileum/appendix), but can occur in the rectum, bronchi. Hormonal symptoms mainly occur when disease spreads outside the bowel
Clinical features
Onset: insidious over many years
Flushing face, Palpitations, Pulmonary valve stenosis and tricuspid regurgitation causing dyspnoea, Asthma, Severe diarrhoea (secretory, persists despite fasting)
Investigation: 5-HIAA in a 24-hour urine collection, Somatostatin receptor scintigraphy, CT scan, Blood testing for chromogranin A
Treatment: Octreotide, Surgical removal
What is carcinoid syndrome? What medical therapy is most useful for managing the symptoms of patients with carcinoid syndrome?
This occurs in the presence of metastatic disease where the vasoactive peptides that tumours produce enter the systemic circulation. The symptoms comprise flushing, diarrhoea, bronchoconstriction and heart failure. The cardiac complications arise primarily of fibrosis of the endocardium with constriction of the tricuspid and pulmonary valves.
Administration of octreotide is the usual practice. A longer acting version, lanreotide, is also commonly used. It is a somatostatin analogue. It therefore suppresses the release of some of the hormones implicated in carcinoid syndrome.
Carcinoid tumours secrete serotonin. They originate in neuroendocrine cells mainly in the intestine (midgut-distal ileum/appendix), but can occur in the rectum, bronchi. Hormonal symptoms mainly occur when disease spreads outside the bowel
Clinical features
Onset: insidious over many years
Flushing face, Palpitations, Pulmonary valve stenosis and tricuspid regurgitation causing dyspnoea, Asthma, Severe diarrhoea (secretory, persists despite fasting)
Investigation: 5-HIAA in a 24-hour urine collection, Somatostatin receptor scintigraphy, CT scan, Blood testing for chromogranin A
Treatment: Octreotide, Surgical removal
During a laparotomy for abdominal pain and intermittent small bowel obstruction the following lesion is identified. How would you manage it?
There is evidence of a lesion compressing the small bowel and there is a separate nodule visible on the small bowel mesentery. I would perform a full staging laparotomy and even if metastatic disease were present, I would usually manage this situation by performing a small bowel resection and primary anastomosis. Even where metastatic disease is present, resection of such lesions can relieve obstructive symptoms and produce good palliation. This case was subsequently demonstrated to be carcinoid tumour of the small bowel.
Carcinoid tumours secrete serotonin. They originate in neuroendocrine cells mainly in the intestine (midgut-distal ileum/appendix), but can occur in the rectum, bronchi. Hormonal symptoms mainly occur when disease spreads outside the bowel
Clinical features
Onset: insidious over many years
Flushing face, Palpitations, Pulmonary valve stenosis and tricuspid regurgitation causing dyspnoea, Asthma, Severe diarrhoea (secretory, persists despite fasting)
Investigation: 5-HIAA in a 24-hour urine collection, Somatostatin receptor scintigraphy, CT scan, Blood testing for chromogranin A
Treatment: Octreotide, Surgical removal
What are the typical macroscopic appearances of a gastro intestinal stromal tumour? Where are most gastrointestinal tumours located? From which cells do they originate? What are the main principles followed in treating GIST’s?
They typically appear as a smooth exophytic mass. More advanced lesions may develop mucosal ulceration and bleeding.
Around 70% of GIST’s are located in the stomach.
They originate from the interstitial pacemaker cells of Cajal.
Surgical resection is the main treatment modality. However, radical resection is not required as diffuse sub mucosal infiltration is not commonly found. Generally, margins of 2cm are considered potentially curative. It is therefore rare for radical gastrectomy (most lesions are gastric) to be necessary.
GIST’s are not common tumours (10 per million) and originate primarily from the interstitial pacemaker cells (of Cajal). Up to 70% occur in the stomach, the remainder occurring in the small intestine (20%) and the colon and rectum (5%). Up to 95% are solitary lesions and most are sporadic. The vast majority express CD117 which is a transmembrane tyrosine kinase receptor and in these there is a mutation of the c-KIT gene.
The goal of surgery is resection of the tumour with a 1-2cm margin of normal tissue. As a result extensive resections are not required. Unfortunately there is a high local recurrence rate, the risk of which is related to site, incomplete resections and high mitotic count. Salvage surgery for recurrent disease is associated with a median survival of 15 months.
The prognosis in high risk patients is greatly improved through the use of imatinib, which in the ACOSOG trial (imatinib vs placebo) improved relapse rates from 17% to 2%.
In the UK it is advocated by NICE for use in patients with metastatic disease or locally unresectable disease.
What is meant by the term HER status as applied to breast cancer pathology?
The term HER status refers to human epidermal growth factor receptor. In the context of breast cancer this refers to the HER 2 sub unit. The epidermal growth factor receptor is a member of the tyrosine kinase class of cellular receptor. These play a role in cellular growth and differentiation. Up to 25% of breast cancers demonstrate HER-2 over expression. HER-2 over expression is associated with an aggressive clinical pheno-type that includes high-grade tumors, increased growth rates, early systemic metastasis, and decreased rates of disease-free and overall survival.
Risk factors for development of breast cancer: Female gender, Family history (see below), Nulliparity, Early menarche, Late menopause, Current or previous lobular or ductal carcinoma in situ, Previous atypical ductal hyperplasia, Exposure of the chest area to ionising radiation (e.g. CT scanning)
Genetic risk factors: Two high risk pre-disposing genes BRCA 1 and 2 are thought to account for over 80% of highly penetrant inherited breast cancer (population frequency of 0.2%). The vast majority of familial breast and ovarian cancer are linked to BRCA 1 and 2. In patients with a BRCA 1 genetic mutation, the lifetime risk of breast cancer is of the order of 60-80% and the risk of ovarian cancer is 40-60%. For those with BRCA 2 mutations, the risks are 50-85% for breast cancer and 10-30% for ovarian cancer. Overall, approximately 5%of all breast cancers are linked to a genetic predisposition. Genetic transmission typically follows an autosomal dominant pattern (but with limited penetrance). Lower risk genetic abnormalities are more prevalent but can be difficult to characterise. They may, however, be a factor in many other sporadic breast cancers.
The risk of developing breast cancer doubles if a first degree relative has been affected with the condition and triples if two relatives have. The risk is higher if the cancer was diagnosed at a young age. The risk increases four to six fold if two first degree relatives have developed the disease.
Criteria for identifying women at increased risk of breast cancer:
- One first degree relative (mother, sister or daughter) with bilateral breast cancer or breast cancer AND ovarian cancer
- One first degree relative with breast cancer diagnosed under the age of 40
- Two first or second degree relatives with breast cancer (grandmother, granddaughter, aunt or niece) with breast cancer diagnosed under the age of 60 or ovarian cancer at any age on the same side of the family
- Three first or second degree relatives with breast and ovarian cancer on the same side of the family; if no first degree relatives then the second degree relatives have to be on the paternal side
Individuals who are deemed likely to have a genetic predisposition for breast cancer can be considered for genetic testing. If a major mutation (e.g. BRCA 1) is identified then other members of the family can be considered for testing (should they so wish). Scoring systems are available to predict the likelihood of identifying BRCA 1 and 2 mutations, ovarian cancer diagnosed under the age of 60 and breast cancer diagnosed under the age of 30 years confer the greatest likelihood and these together with other factors formed the basis of the Manchester manual model for predicting the likelihood of identifying BRCA 1 and 2 mutations.
Pathology of BRCA 1 tumours: Often medullary type, High grade, High mitotic rate, Increased lymphocytic infiltration, Lower oestrogen and progesterone receptor positivity
The prognosis of breast cancer is related to a number of factors, these include tumour type, size of the lesion, tumour grade, degree of lymph node involvement, vascular invasion and hormone receptor status. Tumours of special type generally have a more favourable prognosis than conventional tumours.
Invasive ductal and invasive lobular carcinoma typically spread via the lymphatics. There is an increased risk of haematogenous metastasis in those patients who display evidence of vascular invasion. Prognosis for both ductal and lobular cancers is similar. However, lobular cancers are far more likely to be multifocal and may also metastasise to the contralateral breast.
Breast cancer that has yet to invade the basement membrane is referred to as in situ disease. Both ductal and lobular in situ variants are recognised.
Ductal carcinoma in situ
Sub types include; comedo, cribriform, micropapillary and solid
Comdeo DCIS is most likely to form microcalcifications
Cribriform and micropapillary are most likely to be multifocal
Most lesions are mixed (composed of multiple subtypes)
High nuclear grade DCIS is associated with more malignant characteristics (loss of p53, increased erbB2 expression)
Local excision of low nuclear grade DCIS will usually produce satisfactory outcomes.
Multifocal lesions, large and high nuclear grade lesions will usually require mastectomy
Whole breast irradiation improves locoregional control when breast conserving surgery is performed
Lobular carcinoma in situ
Much rarer than DCIS
Does not form microcalcifications
Usually single growth pattern
When an invasive component is found it is less likely to be associated with axillary nodal metastasis than with DCIS
Low grade LCIS is usually treated by monitoring rather than excision
Nottingham Prognostic Index
The Nottingham Prognostic Index can be used to give an indication of survival following breast cancer surgery. In this system the tumour size is weighted less heavily than other major prognostic parameters.
Calculation of NPI: Tumour Size x 0.2 + Lymph node score+Grade score
George, a 59 year old miner is brought to the clinic with a painful foot. This is the examination finding: Describe how you would proceed.
His ABPI measures 1.2. In the context of the examination findings above, what does this suggest?
I would undertake a full examination of the patients vascular system. I would assess for signs of hypercholesterolaemia, check the blood pressure and examine all pulses. I would take an ankle brachial pressure index measurement.
In order to determine the management I would need to know the aetiology of the condition. However, it is evident that there is dry gangrene of the first three toes with gangrene developing in the fourth toe.
ABPI of 1.2 suggests that the patient may have underlying diabetes. Patients with diabetes can develop calcification in the vessel walls with false elevation of the ABPI measurements due to incompressible vessels. To determine the nature of the underlying arterial disease I would arrange a duplex scan.
Gangrene occurs when a tissue is deprived of its blood supply and dies. Cells die by necrosis. The underlying pathophysiology is that a tissue region is deprived of its blood supply. Two main types of gangrene are recognised, wet and dry gangrene.
Dry gangrene essentially represents mummification of a tissue area. The tissues themselves have died. However, there is no surrounding infection and the gangrenous process is typically clearly demarcated. Over time, the tissue will separate and the gangrenous area will fall off.
Wet gangrene refers to the state where the tissues themselves have become gangrenous but occurs in moist tissues such as the bowel or in areas where there is surrounding infection. The demarcation in wet gangrene is not clear and the process of infection will often allow the gangrene to spread to surrounding areas. In contrast to dry gangrene, patients with wet gangrene will often show signs of systemic disturbance.
Gas gangrene occurs when an area of devitalised flesh becomes colonised with gas forming organisms such as clostridium perfringens. The infection progresses rapidly with marked destruction of healthy tissue.
Management
Dry gangrene with no systemic disturbance requires no specific management other that focus on the underlying cause. Gangrene in patients with underlying peripheral vascular disease (even if it is dry) is an absolute indication for revascularisation.
Wet gangrene is managed by administration of broad spectrum intravenous antibiotics, optimising blood flow and surgically resecting the affected tissue.
Gas gangrene is usually treated with broad spectrum intravenous antibiotics and wide surgical debridement.
How does this condition develop? What organism is the typical cause ? How is it treated?
There is widespread necrosis and discoloration of the limb with spreading gangrene. There is evidence of gas formation implying synergistic infection with gas forming organisms. - Infection with clostridium perfringens.
Gas gangrene is a surgical emergency. Treatment involves the administration of intravenous broad spectrum antibiotics and prompt surgical debridement of the affected tissues. Debridement should continue until viable tissues with no stigmata of infection are reached.
Gangrene occurs when a tissue is deprived of its blood supply and dies. Cells die by necrosis. The underlying pathophysiology is that a tissue region is deprived of its blood supply. Two main types of gangrene are recognised, wet and dry gangrene.
Dry gangrene essentially represents mummification of a tissue area. The tissues themselves have died. However, there is no surrounding infection and the gangrenous process is typically clearly demarcated. Over time, the tissue will separate and the gangrenous area will fall off.
Wet gangrene refers to the state where the tissues themselves have become gangrenous but occurs in moist tissues such as the bowel or in areas where there is surrounding infection. The demarcation in wet gangrene is not clear and the process of infection will often allow the gangrene to spread to surrounding areas. In contrast to dry gangrene, patients with wet gangrene will often show signs of systemic disturbance.
Gas gangrene occurs when an area of devitalised flesh becomes colonised with gas forming organisms such as clostridium perfringens. The infection progresses rapidly with marked destruction of healthy tissue.
Management
Dry gangrene with no systemic disturbance requires no specific management other that focus on the underlying cause. Gangrene in patients with underlying peripheral vascular disease (even if it is dry) is an absolute indication for revascularisation.
Wet gangrene is managed by administration of broad spectrum intravenous antibiotics, optimising blood flow and surgically resecting the affected tissue.
Gas gangrene is usually treated with broad spectrum intravenous antibiotics and wide surgical debridement.
