CASE 1



CASE 1 - Extensive metastatic breast carcinoma within blood vessels

The most striking feature is extensive infiltration of small blood vessels by poorly differentiated carcinoma. This includes both arterioles and venules, although I think arterioles are predominantly involved. As well as metastatic carcinoma there is associated thrombosis and endothelial response to the intravascular tumour. Pulmonary blood vessels are also thickened suggesting pulmonary hypertension. Without elastin stains it is difficult to assist the architectural blood vessels in the lung. The general rule is that arteries follow bronchi and bronchioles up to alveolar capillaries. An elastin stain will show that muscular pulmonary arteries have two very distinct elastic lamina unlike systemic arteries. Pulmonary arteries are also thinner than systemic arteries for their external diameter. Pulmonary arteries should not have more than 20% of the total wall thickness as a proportion of the total external diameter. In normal individuals without pulmonary hypertension in vessels below 50 microns it is not possible to tell the difference between arterioles and venules without cutting serial sections. However the simple assessment is to count all vessels below 50 microns and normally very few of these vessels will have two elastic lamina, i.e. very few are muscularised arteries. Importantly in pulmonary, hypertension particularly hypoxic type, there will be an increased muscularisation of these vessels and may reach even 50% of vessels counted i.e. all arterioles below 50 microns are mascularised in severe hypoxic pulmonary hypertension.

In atrial septal defects a very striking feature will be intimal hyperplasia of medium sized pulmonary arteries which in a sense protects the smaller vessels. (see case 9). Immunochemistry showed strong oestrogen receptor positivity for the cells confirming the diagnosis of metastatic breast carcinoma. A point of interest is that the clinicians did not at all suspect that there was extensive metastatic disease and they thought this patient was having multiple pulmonary emboli. This shows the value of post mortem histology in such cases. The lungs themselves at post mortem showed oedema only and there was no suggestion that metastatic carcinoma was present at post mortem macroscopically.

Key points:

• It is always worth sampling tissues for possible metastatic carcinoma even if macroscopically they appear normal. Very frequently you will be surprised as in this case at the extent of the disease.

• Immunochemistry (and cytology) is often of value even in autolysed post mortem tissue.

• Elastic stains are extremely valuable in assessing pulmonary vessels (pulmonary veins follow the interlobular septa and are within the pleura).

CASE 2 - Tuberculosis

Sections show extensive necrotising granulomatous inflammation of the lymph nodes. Multiple multinucleated giant cells are seen. ZN stains were negative. However ZN staining is very insensitive and it has been quoted that you have to have at least 5-10,000 mycobacteria per cubic mm of tissue - the point being that perhaps only a proportion of tuberculosis bacilli stain ZN particularly if they are latent. A diagnostic point is that any necrotising granulomatous response is tuberculosis until proved otherwise. In AIDS of course you may have no granulomatous response and have overwhelming tuberculosis infection. The section of lung might just show foamy macrophages which until you do and ZN you then you realise they are actually stuffed full of the bacilli. This is so called anergic tuberculosis. However in this case there was good immunoresistance and therefore a striking necrotising response. Necrosis in tuberculosis is in fact a cytotoxic effect of the florid production of inflammatory mediators, particularly TNF-alpha.

CASE 3 - Cryptogenic fibrosing alveolitis (CFA, or Usual Interstitial Pneumonia).

The section of lung shows variable fibrosis although in places it is end-stage and therefore, as with the liver, end-stage pulmonary fibrosis loses some of it’s specific features as to the underlying cause. However the severity of the fibrosis with honeycomb change and subpleural fibrosis is rather striking and suggests CFA. This shows only subpleural fibrosis and not pleural fibrosis (the only process that usually causes visceral pleural fibrosis is asbestos-related disease). In this case there is variation of the fibrosis and of the inflammation and I think there are some so called active fibroblast lesions which are very specific for fibrosing alveolitis and indicate active lung disease even in a longstanding process. There are no granulomas or specific features. No asbestos bodies were found despite the clinical history of work with asbestos. (Generally you have to see at least two asbestos bodies per standard H/E section per slide to begin to attribute fibrosis to asbestos).

In summary, cryptogenic fibrosing alveolitis, although is of unknown cause is a very defined clinical entity. It is often associated with autoimmune disease such as rheumatoid arthritis or scleroderma and asbestos-related industry exposure may blur the situation and there may be an attempt to attribute asbestos to the development of CFA. The absence of asbestos bodies, pleural plaques, visceral pleural fibrosis, is usually the most helpful feature together with the typical features of CFA. These are particularly naked eye, posterior-basal cobblestone type fibrosis which is subpleural when the lungs are looked at macroscopically. It is very rapidly advancing in late-middle age and in many ways has a prognosis of that of lung cancer with a rather low five year survival. This is in contrast to NSIP (non-specific interstitial pulmonary fibrosis) which has a much better prognosis).

The difference with NSIP is that CFA has a patchy distribution with what is called temporal and spacial variation or heterogeneity. In places you may have absolutely normal lung right next door to very severe fibrosis. NSIP in contrast is a much more diffuse process both with cellular information and fibrosis, more evenly distributed. Of course there should not be any specific features such as granulomas, centrilobular distribution etc.

KEY POINTS:

• It can be difficult sometimes to resist a claim that this CFA is not secondary to asbestos-related disease. This is why it is always valuable to keep lung tissue for asbestos counts, particularly wet formalin-fixed tissue which is most valuable for such asbestos counts.

CASE 4 - Fatty Change of the Liver

The most striking feature in this section is of macrovascular fatty change or fatty liver disease. In this case there was exposure to acute alcohol but can be seen in many other diseases influence fat metabolism. It is a reversible condition where large vacuoles of triglyceride fat accumulate in the liver cells. Although having multiple causes, it is a single process and is particularly associated with acute alcohol and obesity and other disease of fat metabolism. In this case there was no evidence of chronic liver disease in the background. There may be hepatitis (steatohepatits). I often prefer the term ‘alcohol dependency syndrome’ rather than alcoholism or alcohol liver disease but this is just a personal choice. There are many causes of fatty liver and these are as follows (copied straight from Wikipedia!)

Metabolic causes include abetalipoproteinemia, glycogen storage diseases, acute fatty liver of pregnancy, lipodystrophy and a rare disease Weber-Christian disease.

Nutritional causes particularly malnutrition, intravenous nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, and bacterial overgrowth in small bowel diverticular disease.

Drugs are well known to cause fatty liver including alcohol are: Amiodarone, Methotrexate, Tetracycline which is out of date, some retroviral drugs, steroids, Tamoxifen and some environmental toxins such as phosphorous and mushroom poisoning.

Fatty changes are also seen in inflammatory bowel disease, HIV, Hepatitis C and

alpha -1-antitrypsin deficiency.

Fatty change is an accumulation of lipid which is initially seen by the nucleus and then fuses to cause vacuolation which resembles signet rings. Of course they appear empty in tissue sections because the fat is dissolved during the tissue processing.

Essentially fatty change is an imbalance between the storage and use of lipid by the cells. For example, peripheral insulin resistance inhibits the transport of fatty acid from the adipose tissue to the liver. Problems with receptor molecules that control enzymes which are responsible for the oxidation of synthesis of fatty acids can also contribute to fatty change. Alcohol damage, mitochondria and other cellular structures impairing lipoprotein production and export of fats. Progression to cirrhosis is of course is dependent on the underlying chronicity of the cause.

No single pathway of cause of fatty liver has been found but in summary there are three major mechanisms.

• Decreased fatty acid oxidation by mitochondria

• Increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver

• Deficient incorporation or export of triglycerides as very-low density lipoprotein (VLDL).

CASE 5 - Bronchopneumonia

I found the most helpful way of classifying pneumonia is a clinical-microbiological way rather than anatomical. The usual description of anatomical description pneumonia is of lobar versus broncho-pneumonia. It is useful to point out that the clinical definition of pneumonia is rather different than the way pathologists define pneumonia. Clinicians define pneumonia as evidence of lower respiratory tract infection with new chest x-ray changes.

The definition of lower respiratory tract is rather difficult to pin down. Some people say the inlet of the larynx is the point of entry of the lower respiratory tract, other people say the cricoid or the inlet to the thorax. I guess clinically we really mean infection or inflammation of the alveolar spaces and this is where we and clinicians agree. I think the most useful way of classifying pneumonia is of four types.

• Community-acquired

• Hospital acquired or nosocomial, perhaps better termed Gram- negative opportunistic

• Aspiration pneumonia

• Pneumonia in the immunocompromised host

You can see that the community-acquired and the aspiration pneumonia tend to have a lobar distribution and therefore by fit into lobar pneumonia. The bronchopneumonia and the pneumonia in the immunocompromised host tend to fit bronchopneumonic process. It is worth noting that in a single section like this it is difficult to classify this pneumonia. This section is being given just to stimulate some discussion as how you would classify pneumonia. In this particular case I think this is pneumonia on the background of other underlying disease such as debility, old age, post operative cases and cancer.

Example.

In summary the different types of pneumonia are as follows:-

• Community acquired pneumonia – the things in common with this microbiologically are very virulent bugs such as Pneumococcus, Legionella, Influenza virus, Haemophilus, Staphylococcus aureus for example. Tend to be a lobar pneumonia as mentioned above. Often acquired in the community hence the name of the disease and generally has a good prognosis unless it becomes bacteremic when there is at least 40% mortality no matter what the age of the patient.

• Hospital-acquired pneumonia is badly named. It really means that the patient has become colonized and infected by their own Gram negative bacteria following debility. Of course you can catch bugs in the environment too. Therefore bronchopneumonia always has to have a “due to” such as old age, fractured neck of femur, colonic cancer with operation and so on. The prognosis of bronchopneumonia of this type usually relates to the underlying process. In other words if somebody has advanced untreatable colon cancer their prognosis of bronchopneumonia is extremely poor.

• Aspiration pneumonia. As it names suggests is usually associated with inhalation of infected material, particularly gastric or oral contents. It usually has a lobar distribution because for example if you are sitting up it tends to go into your intermediate bronchus of your right lower lobe. Usually caused by anaerobes.

• Pneumonia in the immunocomprised host is caused by very odd bugs such as viruses, fungi and pneumocystis.

•

CASE 6 - Deep Vein Thrombosis with organization with association with road traffic accident

The section show organizing thrombus in this deep leg vein. There was recent pulmonary embolus in the lungs. There was evidence that this thrombus had been there at least two or three weeks. It is difficult to date thrombi but some key points that endothelial response to the thrombus occurs in a few days. Iron deposition occurs at one week. Elastic tissue deposition in the thrombus occurs at 21 days. Fibrosis occurs afterwards as in this case. It can be very important to date thrombi as in this case where there was a question if the road traffic accident was related to the death. Therefore histology is always very important to take in such cases. The burden of proof at an inquest is ‘balance of probablilities’, or ‘is it more likely than not’, or ‘probable’ (not ‘possible’).

CASE 7 - Myocardial Infarction

Changes in myocardial infarction are not really fully formed naked eye in to at least 24 to 48 hours. It has been said that you can see histological changes earlier than that, probably 6 to 8 hours but is often very difficult. People have attempted to date infarcts by using enzyme-leaching techniques but these have really no practical use. The first changes are eosinophilic or hyaline change of the myocytes with loss of nuclear staining. You get fibrillation and breaking up of the myocytes at about a day. Inflammation only begins to occur after 3 to 5 days. I think this case is just at the limit of 24-48 hours, although it is always difficult to date. Inflammation is most severe at about a week to 10 days at about the same time infarcts are likely to rupture. Fibrosis occurs about 21 days to 6 weeks at least.

CASE 8 - Malignant mesothelioma

It could be argued that why do a post mortem in malignant mesothelioma with a good occupational history? However one argument is that you always need to check exactly what the tumor is and there are sometimes surprises where somebody has been attributed malignant mesothelioma and it turns out to be another type of tumour. I always take background lung as well as tumour for assessment of asbestos load, although in many cases in view of a very strong clinical history this is often not needed. It is always useful to remember that the burden of proof in coroner’s inquest is balance of probabilities ie, is it more likely than not that such a feature such as asbestos is associated with a particular entity. Immunochemistry that was used for as this case confirming mesothelioma was CK5-6, calretinin, WT1. CAM 5.2 can be used for desmoplastic malignant mesothelioma. In contrast a simple PAS-D stain can be useful for excluding adenocarcinoma. We sometimes forget to do this simple straight forward stain but in my opinion if you have epithelial mucin which is positive for PAS-D then it cannot be malignant mesothelioma.

CEA and AEU-1 are useful and TTF are useful pointers towards adenocarcinoma.

CASE 9 - Atrial septal defect with severe pulmonary hypertension

This was an untreated atrial septal defect of a man who was just about to have it repaired when he came into hospital. He suddenly died. He had features of severe pulmonary hypertension. The atrial septal defect was of interest in that it was more of a very prominent Eustacian valve bridging across the atrium and this was diverting blood through the atrial septal defect, so blood was being pushed in the opposite direction than it would normally flow and causing cyanosis. It had reached a point where he was reaching severe pulmonary hypertension. In a sense blood flow was beginning to reverse and he was getting a form of Eisenmenger’s syndrome. It is unusual to see such severe untreated pulmonary hypertension these days. The old Heath & Edwards classification was based on congenital heart disease in children. Type 1 would be simple muscular hypertrophy, Type 2 would be loose mucinous intimal hyperplasia, Type 3 was fibrous intimal hyperplasia, Type 4 as in this case was so-called angiomatoid and plexiform lesions and Type 5 would be severe fibrinoid necrosis seen in malignant hypertension in the kidney. One thought is that in fact 4 and 5 are in the wrong order and that fibrinoid necrosis and thrombosis happens and then you get organization of thrombus giving the plexiform lesions and post-stenotic dilatation, giving the so called angiomatoid lesions. Nevertheless there were striking features of pulmonary hypertension in his lung and an elastin stain is extremely useful to delineate the process. You would never get such severe vascular changes in really any other type of pulmonary hypertension other than severe congenital heart disease. Hypoxic lung disease would never reach this severity. Primary pulmonary hypertension I suppose could be of similar severity but this is usually a very distinct clinical entity with young and middle-aged females developing pulmonary hypertension of unknown cause or secondary to appetite-suppressant type drugs.

CASE 10 - Sarcoid of the heart

This man had an unknown and untreated sarcoidosis of the heart. As you can see there are numerous granulomas which may be showing some forms of fibrinoid necrosis, but this can be seen in severe sarcoid. There is an extraordinary amount of destruction of the myocardium. There was also background hypertrophy which perhaps may be of a response to the myocarditis. Giant cell myocarditis is a differential but granulomas are actually not a feature in this disease and it is also a disease primarily of children. The sarcoid granulomas will also involve in a conducting system and the death is probably due to abnormal rhythm of the heart. He only had granulomas in his liver, although the definition of sarcoid is a multisystem granulomatous disorder of unknown cause. Sarcoid is a very well recognized cause of sudden death in the heart.

CASE 11 - Asbestosis

The incidence of asbestosis has dramatically dropped and I personally only see at most one case every two years. This is due to the dramatic reduction in severe asbestos exposure in the latent time we are talking about which is around about 20 years. It is usually defined as at least two asbestos bodies in standard sections of lung associated with pulmonary fibrosis. Pulmonary fibrosis is often associated with pleural plaques and visceral pleural fibrosis. Nothing much else gives you visceral pleural fibrosis other than asbestos-related disease. Asbestos begins as a centrilobular distribution and it extends to completely take over secondary lobules. There is often very little in the way of inflammation. As in this case asbestos bodies can be extremely easy to find. Thick-unstained sections or Perl’s stains can help find asbestos bodies. Thicker sections I suppose alter the two-fibres per section definition a bit. Counts are in the millions per gram of lung tissue.

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