Slide 1: Polyarteritis nodosa (PAN) Clinical History: Polyarteritis nodosa is a disease of small or medium sized muscular arteries.

The vascular involvement is widely scattered and therefore these patients may present with enormously varied clinical signs and symptoms. Non- specific symptoms such as weakness, malaise and low grade fever often dominate the clinical picture. Other common manifestations include haematuria, albuminuria, hypertension, abdominal pain, diffuse muscular aches and peripheral neuritis. Usually, a definite diagnosis can be established only by the identification of the vascular lesions. A biopsy of clinically involved tissue is best for this purpose. Microscopy: Polyarteritis nodosa is a multisystem disease. The slides in the class set are from the spleen. PAN affects arteries of medium or small size. Not every vessel of appropriate size will be affected so a thorough search of the slide will be necessary. Individual vessels will show different stages of the inflammatory process. The features to look for are: Fibrinoid necrosis of the vessel wall. This may be circumferential but is often localised to a single segment. Inflammation - characterised by neutrophils early in the disease and later by lymphocytes, plasma cells and macrophages. Intravascular thrombosis is a frequent sequel to the vasculitis leading to ischaemia and infarction in the areas supplied by these vessels. Necrosis of muscle in the vessel may lead to weakening of the vessel with focal aneurysm formation as a late complication. Such aneurysms are small (<1 cm) and can be demonstrated by arteriography in about 50% of cases. As the lesions heal fibroblastic proliferation occurs; the inflammatory cell infiltrate consists mainly of plasma cells and macrophages and thrombosis, if present, becomes organised. Healed lesions show only fibrotic thickening of the arterial wall and loss of fragmentation of the internal elastic lamina. Acute, healing and healed lesions usually co-exist in different loci. Notes: Slide 2: Temporal arteritis Clinical History:

Patients with temporal arteritis may present with headache, visual loss, facial pain and tenderness over the artery. The disease tends to affect older individuals and women are slightly more affected than men. About half of the patients with clinical manifestations of temporal arteritis will have systemic involvement. Biopsy of the temporal artery may be negative in up to 40% of patients with classical manifestations of this disease. Presumably the lesions are focal and may be missed on biopsy. Treatment should not be withheld on the basis of a negative biopsy if the clinical syndrome is otherwise characteristic. These patients are treated with steroids and the response is excellent. Microscopic Examination: Inspection of the slide shows three tiny rounded fragments of eosinophilic tissue. They are from a small muscular artery surrounded by connective tissue and a small amount of adipose tissue. They show varying degrees of change in the vessel wall, highlighting the segmental nature of the lesion. The vessel shows a narrowed lumen and the endothelial cells are sparse. The intima is expanded. A mononuclear inflammatory cells infiltrate including macrophages, lymphocytes, plasma cells and scattered multinucleated giant cells is present in the wall. If you rack down the condenser on your microscope the internal elastic lamina will show up as a wavy and glassy eosinophilic structure. This structure is fragmented and the macrophages are intimately associated with it. The cause of temporal arteritis has not been elucidated. The morphological changes suggest an immunological reaction against some component of the arterial wall, possibly the elastic tissue. Notes: Slide 3: Pericarditis, UP 820 [38T39M3610T31M4150] Clinical History: This 75 year old woman was admitted to hospital with a history of joint pains, breathlessness and swelling of the ankles. Examination revealed acute pulmonary oedema and congestive cardiac failure. She was treated with Digoxin, Lasix and morphine but failed to show much improvement. Two weeks after admission a chest x-ray revealed a left pleural effusion. Her condition deteriorated and she died one week later. Autopsy revealed bronchopneumonia with pleurisy and effusion, mitral and aortic stenosis, fibrinous pericarditis and polycystic kidneys. Gross:

The mounted specimen is a heart weighing 600 gm. The pericardial surface is covered by a thick fibrinous exudate which presents the typical bread and butter appearance of fibrinous pericarditis. The cusps of the aortic valve are thickened and the valve is stenosed. The mitral valve cusps are similarly thickened and rigid with the valve orifice being both incompetent and stenotic. Although there was no clinical history of rheumatic fever, these valvular lesions are almost certainly due to chronic rheumatic endocarditis. Microscopy: Grossly this is a block of pale pink tissue showing a blue pink layer along one margin. Microscopically this is the outer portion of the myocardium with epicardial adipose tissue and pericardium. The pericardium is obscured by a thick layer of adherent fibrin admixed with neutrophils. Organisation of this exudate has commenced as evidenced by the presence of granulation, including reactive fibroblasts, proliferating small blood vessels and a mixed inflammatory cell infiltrate (neutrohils, lymphocytes, plasma cells and macrophages). The myocardium shows fatty infiltration and moderate muscle fibre hypertrophy. This is a fibrinous pericarditis. Common causes include myocardial infarction, uraemia, and irradiation of the chest, rheumatic fever, SLE and trauma. Infectious agents may also produce this type of inflammation. The exudate may be phagocytosed, leading to resolution or organisation, the latter resulting in pericardial adhesions and ultimately fibrous obliteration of the pericardial sac. Notes: Slide 4: Myocarditis Clinical History: The deceased was sitting on the couch in his lounge room in the company of his son-in-law when he stiffened suddenly and lay back with his eyes rolling and biting hard on his tongue. Immediately, the son-in-law moved him to the floor and attempted resuscitation. Resuscitation was continued by an ambulance officer but there was no response. The deceased had been suffering from a viral illness for the previous 4 days. A doctor had seen him on the afternoon before he died with generalised aches and pains and a high temperature. The doctor had prescribed Panadeine Forte which apparently provided some relief. Gross: Cardiovascular system

At autopsy, there was intense congestion of the vessels in the neck and upper thorax. The heart weighed 350 gm. The pericardial cavity was normal. The ventricles were of normal volume and thickness. The basal thickness of the left ventricle was 17 mm and the right ventricle 6 mm. The atria were normal. The pulmonary valves were normal. The right coronary artery was dominant. Both left and right coronary arteries showed only minimal arteriosclerosis with no significant luminal narrowing. The pulmonary artery was normal. The thoracic aorta was normal. The abdominal aorta showed minimal atherosclerosis. Microscopy: Macroscopic examination of the slide shows an irregularly shaped portion of eosinophilic tissue. This is a section of the heart with the posterior left ventricular wall towards the label, the right ventricular wall towards the bottom of the slide with the interventricular septum in between the two and protruding to the right. Microscopic examination of the slide shows normal cardiac muscle fibres. A patchy interstitial inflammatory process is present, particularly in the posterior walls of the left and right ventricles. This inflammatory process is typified by intercellular oedema with a mixed inflammatory cell infiltrate. A few neutrophils, very occasional eosinophils and some macrophages can be identified within this infiltrate. There is associated vascular engorgement. There is only minimal muscle fibre necrosis. Notes: Slide 5: Endocarditis, UP 246 [39M4101A1341] Clinical History: This 71 year old woman, who had been previously well, had several rigors and was then admitted to hospital with a swinging temperature of up to 40C. She had a history of rheumatic fever as a girl. The week after admission she had an episode during which her right arm became cold and blue. Four days later she had a similar episode, apparently due to subclavian embolism. Blood culture was positive for E. coli. She died two weeks after admission. At autopsy she had a number of abscesses in the right kidney and an acute bacterial endocarditis. Gross: The mounted specimen shows a large bulky and friable vegetation on the right posterior cusp of the aortic valve. This vegetation has virtually

destroyed the valve cusp and has eroded into both left and right atria with encroachment on both the mitral and tricuspid valves respectively. Microscopy: Macroscopic examination of this slide shows a complex piece of eosinophilic tissue. This slide is taken from a mitral valve. The left ventricular myocardium is towards the label with the left atrial wall pointing away from the label like a small tail. The vegetation is situated at the junction of the ventricle and atrium, i.e. at the site of the valve cusp. The valve cusp has been destroyed by the vegetation which now forms an irregular mass towards the left hand side of the slide. Extension of the infective process has formed an oval shaped abscess in the pericardial fat. This can be seen macroscopically as an oval shaped bluish area. Microscopic examination of the vegetation shows an irregular mass of fibrin, red blood cells and inflammatory cells. The inflammatory cell infiltrate consists predominantly of neutrophils, however small numbers of macrophages are also present. Dystrophic calcification is seen within the vegetation. No organisms can be identified on the H & E stain. The valve leaflet has been completely destroyed by this inflammatory process. At the base of the leaflet oedematous granulation tissue can be seen. Beyond the granulation tissue and situated in the pericardial fat is a circumscribed abscess. This abscess consists of large numbers of both viable and degenerate neutrophils, red blood cells and fibrin. Abscess formation is one of the cardiac complications of infective endocarditis. Notes: Slide 6: Atherosclerosis, UP 386 [42M521E] Clinical History: This 57 year old man died with the diagnosis of ischaemic heart disease. Gross: The mounted specimen consists of the lower thoracic and abdominal aorta. It shows multiple variably sized atheromatous plaques which become confluent in the abdominal aorta. These plaques are well circumscribed, slightly raised and yellow/white in colour. A number of the larger plaques are complicated by superficial ulceration with adherent thrombus and focal dystrophic calcification. Microscopy: The slide shows the bifurcation of the carotid artery. Macroscopically a large pink mass can be seen protruding into, and partially occluding, the lumen of one of the branches. Under the microscope this slide shows

atheromatous plaques of varying ages. The large pink mass seen macroscopically represents the most developed plaque. This shows a fibrous cap with foam cells, proliferating smooth muscle cells, macrophages and collagen - seen particularly at one edge of the plaque. Beneath this is a large core of necrotic cell debris, haemorrhage, cholesterol clefts and foam cells. The underlying media is focally atrophic. Careful examination of the rest of the slide will show numerous foci of less well developed plaque formation. The combination of lipid deposition (atheroma) and superficial intimal fibrosis (sclerosis) is responsible for the term atherosclerosis. Atheromatous plaques may undergo a series of changes resulting in complicated plaques. These include calcification, ulceration, overlying thrombus formation, haemorrhage (as seen in this case) and aneurysmal dilatation of the vessel. It is these changes that usually account for the serious clinical consequences of this disease. Notes: Slide 7: Recent myocardial infarction, UP 1539 [33M5472M3703] Clinical History: This 61 year old hypertensive man complained of chest pain and dyspnoea on exertion for 2 years. He was admitted to hospital following the sudden onset of severe retrosternal chest pain. This pain radiated down the medial aspect of his right arm and was associated with dyspnoea and nausea. On examination he had a pulse rate of 100 and a blood pressure of 110/80. A pericardial friction rub was audible at the lower left sternal edge. ECG indicated anterior wall infarction with atrial extrasystoles. Two weeks after admission he had a cardiac arrest and died. Gross: The mounted specimen shows 2 transverse slices through the heart. There is an extensive anterior infarct (in the territory of the left anterior descending coronary artery). The infarcted cardiac muscle has a creamy yellow appearance. At the margins of the infarct there is a hyperaemic zone and careful inspection (particularly of the top slice) in this region reveals translucent grey tissue which corresponds to granulation tissue. The presence of this granulation tissue indicates that the infarct is at least 7 to 10 days old, which is consistent with the clinical history. A large apical mural thrombus is also present. Examination of the pericardium reveals a fibrinous pericarditis, again consistent with the clinical findings. Microscopy:

Macroscopic examination of this transverse section through the left ventricular myocardium shows well-defined focal eosinophilic areas in the subendocardial zone. These are surrounded by a basophilic rim of tissue similar to that seen in the renal infarct (slide 46). The blue appearance is due to the presence of numerous inflammatory cells. Microscopic examination of these eosinophilic areas shows extensive, confluent, coagulative necrosis. Here the myocardial fibre outlines can be recognised but only a few fibres lack nuclei. The transverse striations are still recognisable but appear fragmented and the cell cytoplasm of the necrotic cardiac fibres is more eosinophilic than the surviving fibres. If a field is selected in which necrotic fibres lie adjacent to viable periphery of the areas of infarction numerous viable and degenerate neutrophils are seen in the interstitial tissue between cardiac muscle fibres. Note that on microscopic examination the distribution of necrotic muscle fibres is more haphazard than apparent on macroscopic examination. These appearances are consistent with a myocardial infarct of approximately 2 to 7 days duration. Notes: Slide 8: Recent and healed myocardial infarction with hypertrophy, UP 2352 [33M5475B] Clinical History: This 65 year old man died as the result of a single vehicle accident. Forensic post-mortem revealed an extensive old antero-septal infarct and complete occlusion of the anterior descending branch of the left coronary artery. Gross: The mounted specimen consists of 5 transverse slices of the heart. There is an extensive old, antero-septal infarct as evidenced by fibrous scarring and thinning of the left ventricular wall in this region. The endocardium is also thickened and fibrotic. The patchy black discolouration of the tissue in this area is suggestive of vascular congestion or haemorrhage. This appearance should raise the possibility of superimposed recent ischaemic damage. In this particular case, there was no microscopic evidence of recent damage. However, an acute myocardial infarct was considered the most likely reason for the single vehicle accident because of the recent thrombus found in the left anterior descending coronary artery which is mounted in the specimen pot. This heart also shows striking left ventricular hypertrophy. Microscopy:

This is a transverse section of the heart taken from the posterior wall at the junction of left and right ventricles. The left ventricle wall is that part towards the label of the slide, the right ventricle is the thin part pointing away from the label and the interventricular septum is the portion in between pointing to the right. Macroscopically geographic areas of pale pink tissue can be seen towards the endocardial surface of the left ventricle and within the septum. The microscopic features include: 1. Irregular areas of virtually acellular, dense connective tissue (scar tissue). These are areas of previous myocardial infarction that have been organised. 2. Small foci of recent infarction (24 hours old) in the septum. These areas show coagulative necrosis of muscle fibres with increased eosinophilia, loss of nuclei and an associated neutrophilic infiltrate. Also present are groups of muscle fibres showing waviness suggestive of very recent ischaemia (1-2 hours old). 3. Scattered small areas of organising granulation tissue in the septum. These appear pale and oedematous with a light infiltrate of haemosiderin-laden macrophages and lymphocytes. 4. Diffuse hypertrophy of the surviving cardiac muscle fibres of the left ventricle. The histological appearances in cardiac hypertrophy are not specific and a diagnosis cannot be made on purely histological grounds. In order to confirm the histological impression, the heart weight must be shown and this should preferably be related to the patients weight. Features indicative of hypertrophy include enlargement of the cardiac muscle fibres and the rectangular or brick shape of the cardiac muscle fibre nuclei. This is seen in a large proportion of the cardiac muscle fibres in this heart. A non-specific feature, seen predominantly in hearts from elderly people, is the accumulation of brown granules at the nuclear poles of the cardiac muscle fibre cytoplasm. These granules are composed of lipofuscin and represent accumulation of lysosomal pigment as a result of degenerative changes occurring in the cardiac muscle fibre. 5. Evidence of atherosclerosis involving epicardial coronary vessels with luminal narrowing, fibrous intimal thickening and focal dystrophic calcification. 6. Fatty infiltration of the right ventricle. Mature adipose cells are seen extending as finger-like projections between the muscle bundles. Notes:

Slide 9: Helicobacter gastritis [photograph] Photograph Microscopy: Sections show a single biopsy fragment of acid producing gastric mucosa. There is no mucosal ulceration. The surface epithelium shows some mucin depletion and regenerative activity in the gland necks with increased nuclear size, prominent nucleoli, crowding of cells. Very careful examination (under high power) will reveal curved bacilli attached to the surface epithelial cells. These organisms are Helicobacter pylori. The lamina propria shows an infiltrate of lymphocytes, plasma cells and occasional neutrophils. This infiltrate does not extend down to the deep glands, hence the term superficial. Neutrophils also infiltrate the glandular epithelium. Importantly, there is no intestinal metaplasia, dysplasia or glandular atrophy in this biopsy. Helicobacter pylori was first isolated from the human stomach in 1983 and is now considered to have an aetiological role in Type B gastritis, most duodenal ulcers and some gastric ulcers. For the majority of people, infection with Helicobacter pylori is asymptomatic, despite histological evidence of inflammation. It is estimated that 50-90% of the Australian population over the age of 50 are infected - this may prove to be the commonest chronic human bacterial infection in the world! Much is still to be learned about the pathogenesis of H. pylori infection. The organism is highly adapted to survival at the tissue-mucus interface in the stomach, congregating at the intercellular junctions and attaching to the gastric epithelium via specific adhesions. What causes the cell damage and inflammation is as yet unknown. H. pylori infection can be diagnosed by culture, urease test, histology and serology (ELISA). Notes: Slide 10: Squamous cell carcinoma of the oesophagus, UP 2945 [62M8073D] Clinical History: No clinical notes are available for this specimen. The patient probably presented with dysphagia, oesophageal obstruction and cough due to the enlarged hilar lymph nodes. Patients with carcinoma of the oesophagus subconsciously tend to alter their diet from solid to semi-solid and liquid foods to accommodate their increasing dysphagia.

Gross: The specimen consists of a section of oesophagus with adjacent trachea, tracheal bifurcation and paratracheal and carinal lymph nodes. Examination of the oesophageal mucosa shows an oval shaped area of ulceration that has excavated deeply into the adherent lung tissue. As a result an irregular abscess cavity, surrounded by consolidated parenchyma, has formed in the lung. This ulcerated lesion consists of partly necrotic grey/white tumour tissue. Similar tissue is seen in enlarged and anthracotic lymph nodes representing metastatic spread. There also appears to be direct extension of tumour tissue to involve the tracheal mucosa. Microscopy: Macroscopic examination of this slide shows recognisable mucosa, submucosa and muscle coat at one end (away from the label) and loss of these layers at the other end. Here a variegated mass appears to be present. Under the microscope one can see an intact squamous mucosa with underlying lamina propria containing mononuclear inflammatory cells, muscularis mucosae and muscularis propria. The mucosa shows a very abrupt transition to severe dysplasia/carcinoma-in-situ. Here there is loss of the normal cell to cell relationships, crowding of the cells, nuclear hyperchromasia and greatly increased mitotic activity. This dysplastic focus rapidly evolves into a carcinoma with invasion by tumour cells of the lamina propria, submucosa and muscle coats. The tumour shows large, geographic islands of neoplastic squamous cells, accompanied by a desmoplastic stroma, invading the full thickness of the oesophageal wall. The surface of the tumour is ulcerated and covered with fibrin admixed with cellular debris. The tumour is moderately well differentiated with squamous pearl formation, individual cell keratinisation and intercellular bridges present. Notes: Slide 11: Gastric ulcer (chronic), UP3407 [63M4303C] Clinical History: This specimen is from a 68 year old lady who had a partial gastrectomy for chronic peptic ulcers. She would probably have presented with intermittent burning epigastric pain coming on shortly after meals and unrelieved by eating. She would have come to surgery following failure of medical treatment. Gross: The specimen consists of an irregular portion of gastric wall. The ulcer is oval in shape and deeply penetrating. Necrotic debris covers the base.

The specimen has been cut to show you the submucosa, muscle coat and adventitial connective tissues in the region of the ulcer. Note that there is extensive fibrosis of the submucosa in this area and absence of the external muscle coat. Grey/white fibrous tissue can be seen extending beyond the muscle coat into the adventitial connective tissues. These are the features of a chronic ulcer. The uninvolved mucosa shows some tethering of the mucosal folds towards the ulcer but is otherwise unremarkable. Microscopy: Macroscopic examination of the tissue section shows a strip of stomach wall including mucosa, sub-mucosa, muscularis propria, and serosal connective tissue. At the top of the section there is an area of ulceration involving the surface mucosa, sub-mucosa and muscularis propria which extends down to involve the serosal tissues (the ulcer has been bisected to fit on the slide). Close examination shows that the muscularis propria is pulled up towards the ulcer base. The sub-mucosa appears thickened. Dark blue nodules representing lymphoid collections are seen immediately beneath the gastric mucosa and the ulcer. Microscopic examination shows the typical features of a chronic peptic ulcer. The ulcer is located in the antrum. At the ulcer base the 4 zones of Askanazy can be seen. The 4 zones, labelled 1 to 4, are numbered from the ulcer base. The most superficial zone is one of cellular debris where numerous viable and degenerate polymorphs can be seen. Beneath this there is a zone of fibrinoid necrosis of various types of cells including inflammatory cells and granulation tissue. Beneath this the third zone of Askanazy is one of granulation tissue and here variably sized capillary channels can be seen separated by fibroblastic connective tissue heavily infiltrated by a mixture of lymphocytes, neutrophils, and eosinophils. Beneath this there is a zone of mature fibrous scar tissue replacing the muscularis propria and entrapping large nerves and muscular arteries. Large aggregates of lymphocytes are present in this region. One of the arteries shows occlusion of its lumen by organised thrombus. Haemorrhage from these vessels in the base of gastric ulcers can be lifethreatening. The mucosa adjacent to an ulcer crater should always be examined carefully under the microscope to rule out the presence of dysplasia/carcinoma. In this case the mucosa shows prominent histological abnormalities. These include intestinal metaplasia with the presence of goblet cells in the surface epithelium and in the underlying

glands and a prominent active chronic gastritis with numerous inflammatory cells within the lamina propria. Notes: Slide 12: Gastrointestinal stromal tumour, UP 3242 [63M8890B] Clinical History: This 60 year old carpenter had some small bowel resected 12 months previously following a traumatic perforation caused by a motor vehicle accident. He complained of 3 months occasional postprandial vomiting, some nausea and weight loss initially thought to be related to the previous surgery. However, investigation revealed a tumour in the body of the stomach, along the greater curve. Gross: The mounted specimen shows a dome shaped tumour covered by flattened gastric mucosa. At the summit of the tumour there is an irregularly shaped area of mucosal ulceration. This peptic ulcer probably accounted for the patients symptoms. Sometimes these patients present with gastrointestinal haemorrhage from an area of ulceration such as in this specimen. Inspection of the cut surface of this tumour shows it to be well circumscribed and apparently encapsulated. There is a small central area of haemorrhage and the stroma shows some myxoid change Microscopy: Macroscopic examination of the slide shows a well circumscribed rounded mass covered on the one surface by mucosa. Microscopic examination reveals an intact acid-producing gastric mucosa. Close examination of this mucosa shows a moderate infiltrate of plasma cells, lymphocytes and occasional neutrophils within the lamina propria. Also present are small lymphoid aggregates. These features are consistent with a chronic gastritis. Deep to the muscularis mucosae and within the submucosa is a well-circumscribed neoplastic mass. This mass consists of interwoven fascicles of spindle shaped cells. The cells have plump cigar shaped nuclei and abundant eosinophilic cytoplasm. No mitoses are seen. This is a benign proliferation of smooth muscle cells presumably arising in the external muscle coat or from a blood vessel wall. Lesions such as this one were originally thought to be gastric leiomyomas, as they were believed to arise from gastric smooth muscle cells, most likely from the walls of small blood vessels. It is now recognised to be a member of a class of tumours, which arise from gastrointestal stromal cells. Malignant forms are occasionally encountered. Notes:

Slide 13: Gastric carcinoma, UP 2190 [63M8553] Clinical History: No clinical history is available on this 74-year-old man. However, he would probably have presented with weight loss, abdominal pain and anorexia. Gastric carcinoma is an insidious disease and patients are usually asymptomatic until late. Gross: The mounted specimen shows a protuberant and fungating tumour 5 cm in diameter arising on a broad base from the lesser curve of the stomach. There is superficial ulceration of the tumour mass centrally. The surrounding mucosa appears somewhat flattened, suggestive of a chronic gastritis or submucosal infiltration by tumour tissue. The serosa of the stomach appears normal and no lymph nodes can be identified. Histologically this tumour was a moderately well differentiated adenocarcinoma. The slide that you have to examine shows early gastric carcinoma. Early gastric carcinomas may appear as flat areas of mucosal thickening and induration. In some cases they may be protuberant, ulcerated or excavated. If you look carefully at the mucosa towards the right hand side of specimen UP 2190 you will see an oval shaped area approximately 2.5 cm across that appears slightly thickened and indurated. This appearance would be consistent with that of early or superficial gastric carcinoma. Microscopy: This slide shows early gastric carcinoma. The specimen you have examined in the museum shows a more advanced expanding carcinoma. Macroscopic examination of the slide shows muscularis propria (deep pink) submucosa and above this the mucosa (blue). The mucosa appears thickened. Under the microscope normal antral type gastric mucosa can be seen at each end of the tissue block. The muscularis mucosae, submucosa and muscularis propria appear normal. As one moves towards the centre of the slide the mucosa increases markedly in thickness. Here the glands show marked architectural distortion with crowding and back-to-back pattern. The epithelial cells show cytological evidence of malignancy with variation in nuclear size and shape, hyperchromasia, increased and abnormal mitoses. This is adenocarcinoma of the stomach. Most of the tumour is confined to the lamina propria but in one area invasion of the submucosa is seen.

The term superficial or early gastric carcinoma is reserved for those tumours that do not invade the muscularis propria (regardless of lymph node status). The 5 year survival rate is 80-95% and remains high even when lymph node metastases are present. This is in sharp contrast to the dismal prognosis for advanced gastric carcinoma. Notes: Slide 14: Giardiasis [photograph] Clinical History: Patients infected with Giardia lamblia may be asymptomatic. Other patients will present with copious watery diarrhoea associated with flatulence and cramps. This may last days to weeks and is then followed by bulky, semi solid malodorous stools. Chronic giardiasis may be associated with malabsorption, weight loss and growth retardation. Microscopy: Macroscopic examination of the slide shows a short strip of basophilic tissue. Microscopic examination reveals a small strip of small bowel type mucosa. Villous architecture is within normal limits. The tips of the villi show oedema involving the lamina propria. Also seen in the lamina propria is a moderate increase in chronic inflammatory cells, particularly plasma cells and also small numbers of neutrophils. Paneth cells can be clearly identified in the gland crypts. Carefully examine the space just above and around the intestinal villi and you will see the trophozoites of Giardia lamblia. In this section most of these organisms are seen in cross section and appear sickle shaped and grey/blue in colour. Occasional organisms can be seen enface and these are pear shaped and binucleate. The flagellae are not seen. Notes: Slide 15: Acute appendicitis, UP 938 [66M4171B] Clinical History: This 50 year old female presented with a 2 day history of constant right iliac fossa pain associated with nausea. On examination she had mild pyrexia (37.9C) and right iliac fossa tenderness with localised guarding and rebound. An appendicectomy was performed. Gross:

The mounted specimen consists of an 8 cm appendix with attached mesoappendix. The serosal surface shows multiple irregular areas of congestion and haemorrhage. A fibrino-purulent exudate is present covering the serosal surface onto the meso appendix. Microscopy: Macroscopic examination of the longitudinal section of the appendix shows diffuse thickening of the appendiceal wall with mucosal haemorrhage. Low power microscopic examination reveals central luminal purulent material and confluent mucosal ulceration with replacement of the mucosa by haemorrhagic purulent debris. There is a transmural inflammatory cell infiltrate separating the normal structures of the appendiceal wall such as vessels and smooth muscle. High power examination confirms the presence of a transmural acute inflammatory cell infiltrate consisting almost entirely of neutrophil polymorphs with some scattered eosinophils. There is oedema separating smooth muscle fibres of the appendiceal muscularis propria. The inflammatory process extends into the meso-appendiceal fat and a fibrino-purulent serosal exudate is present. Close examination of some of the small vessels within the appendiceal wall demonstrates margination of neutrophils along the endothelial surface. This is more prominent in earlier cases of appendicitis. Notes: Slide 16: Crohns Disease, UP 1462 [652M4455] Clinical History: This patient had a 4 year history of malaise, weight loss and diarrhoea with foul smelling stools. Barium meal, barium enema and sigmoidoscopy were normal on admission. But 3 weeks later the patient showed manifestations of subacute intestinal obstruction. Plain abdominal x-ray showed distended loops of small intestine with fluid levels. She had a large mass in the right iliac fossa and a laparotomy was performed. An area of regional ileitis with gross enlargement of mesenteric lymph nodes was found. A right hemicolectomy and resection of affected ileum with end-to-end anastomosis was carried out. Gross: The mounted specimen is a segment of ileum with some mesentery and a few mesenteric notes attached. The ileum has been opened to show thickening of the wall and narrowing of the lumen. In the part most affected, the mucosal surface is ulcerated and partially covered by a

necrotic slough. This grades through a characteristic cobblestone appearance to comparatively normal mucosa. The cut edge of the wall shows grey/white fibrous tissue expanding the submucosa and subserosal connective tissues. It is this thickening and fibrosis of the bowel wall that gives the inflexibility likened to a lead pipe or rubber hose. The serosal surface is roughened and has a granular appearance. The mesentery is thickened and oedematous. These features all indicate a transmural inflammatory process. A group of enlarged mesenteric lymph nodes is exposed and their cut surfaces show a homogenous greyish/white appearance. Microscopy: Macroscopic examination of the slide shows a section through the wall of the gastrointestinal tract. The muscle coat appears thickened and the submucosa is also expanded. Multiple tiny nodules of basophilic tissue (chronic inflammatory cells) are seen scattered through the full thickness of the bowel wall. Microscopic examination shows small bowel mucosa. There are two discrete areas of mucosal ulceration associated with non-specific inflammation. In these areas the mucosa has been lost and in its place is an exudate consisting of fibrin and neutrophils. At the base of the ulcer there is granulation tissue associated with a mixed inflammatory cell infiltrate. The surviving mucosa shows non-specific inflammation with large numbers of chronic inflammatory cells expanding and the lamina propria. Examination of the submucosa shows oedema and fibrosis. The lymphatic channels are dilated and multiple, variably sized aggregates of lymphoid cells are present. Careful examination of these lymphoid aggregates will reveal a number of central granulomata. These granulomata are similar to those seen in sarcoidosis. In addition to the lymphoid aggregates a diffuse moderate infiltrate of lymphocytes and plasma cells can be seen throughout the submucosa. Examination of the muscle coat shows thickening and also a light chronic inflammatory cell infiltrate. Beyond the muscle coat, in the subserosal connective tissues, lymphoid aggregates can also be seen, i.e. the inflammatory process is transmural. This is an important feature of Crohns disease. Granulomata are also an important feature of Crohns disease. However, in approximately 40% of cases they are absent or poorly developed. Notes: Slide 17: Diverticular disease, UP 387 [6770M3476A] Clinical History:

This 95 year old woman died of congestive cardiac failure. There was no history of any abdominal symptoms. In patients who are symptomatic (only about 20% of those affected) symptoms include intermittent cramping or sometimes continuous lower abdominal pain, constipation, distension and occasionally alternating constipation and diarrhoea. Diverticular disease may also cause bleeding. Gross: The specimen consists of a portion of colon in which multiple, small flask shaped outpouchings can be identified. These measure up to one (1) cm in diameter and have very delicate thin walls. Diverticula usually form along the margins of the taenia coli. Hypertrophy of the muscle coat is commonly seen but is not present in this particular specimen. Microscopy: Careful macroscopic examination of this slide clinches the diagnosis. The blue layer of the mucosa can be seen lining a small outpouching (diverticulum). The muscularis propria can be seen as a deep pink band either side of this diverticulum, but interrupted by the diverticulum. Under the microscope normal, intact colonic mucosa can be seen lining the bowel wall and the diverticulum. The surrounding connective tissues show evidence of an active, inflammatory process with oedema, vascular congestion, evidence of healing by fibrosis, lymphoid aggregates and infiltration by lymphocytes, plasma cells, eosinophils and neutrophils. Diverticulitis is a common complication of diverticular disease. Notes: Slide 18: Ulcerative colitis, UP 2304 [67M4103] Clinical History: This patient, a 56 year old male, was admitted to hospital because of severe diarrhoea of some 3 weeks duration associated with the development of dehydration. Sigmoidoscopy revealed a bleeding, ulcerated and granular mucosa. Biopsies and x-ray studies were suggestive of ulcerative colitis. He failed to respond to conservative treatment and a total colectomy with ileostomy and preservation of the rectal stump was performed. His post-operative course was stormy culminating in his death several days later. Gross: The mounted specimen consists of a 30 cm length of opened large bowel. Examination of the mucosal surface shows large irregular areas of mucosal ulceration. These appear darker and flatter than the surrounding preserved mucosa. Crypt abscesses produce small foci of ulceration

which coalesce giving rise to these large irregular areas of mucosal ulceration. The residual islands of mucosa become oedematous and hyperaemic as a result of the ongoing inflammatory process and this leads to the formation of pseudopolyps. Examination of the bowel wall shows that there is no expansion of the submucosa or subserosal connective tissues by fibrous tissue as seen in Crohns disease. The serosal surface of the bowel appears smooth and uninvolved. Microscopy: Macroscopic examination of this slide shows mucosa (blue), submucosa (pale pink) and muscularis propria (deep pink) at one end. The other end shows loss of the submucosa and mucosa - ulceration. A polypoid fragment of mucosa can be seen above the ulcer base - this is a pseudopolyp. Microscopically the mucosa shows increased numbers of inflammatory cells in the lamina propria, especially plasma cells. There is vascular engorgement and marked oedema of the submucosa, all indicators of an inflammatory process. Some gland crypts are distended by luminal neutrophils. These are crypt abscesses (but not all slides include a crypt abscess). Expansion and rupture of these abscesses undermines the mucosa leading to ulceration. The glandular epithelium shows mucus depletion, also an increase in mitotic activity and nuclear size, indicating regeneration. There is no dysplasia in this slide. The area of ulceration shows complete loss of mucosa with fibrin and cellular debris covering the heavily inflamed submucosa. There is extension of the inflammatory infiltrate, predominantly plasma cells, into the muscle coat. The serosa is oedematous and contains numerous engorged blood vessels. Above the zone of ulceration is a polypoid fragment of oedematous, heavily inflamed mucosa showing numerous crypt abscesses and striking vascular engorgement. This is a pseudopolyp Ulcerative colitis is typically a disease process confined to the mucosa (cf. Crohns disease which involves the entire bowel wall) but in very severe cases the inflammation can be more extensive. The mucosa in such cases needs to be carefully assessed for dysplastic change. The severity of the dysplasia and the risk of carcinoma are directly related to the extent and duration of the disease. Notes:

Slide 19: Pseudomembranous colitis, UP 2736 [67M4055] Clinical History: This male patient died as a result of multiple myeloma. Clinically, pseudomembranous colitis is typically associated with the use of broad-spectrum antibiotics, particularly Clindamycin and Lincomycin. But it has also been described occurring after surgery or superimposed on a chronic debilitating illness. This patient probably fits into the latter category. The toxin of Clostridium difficile, a normal gut commensal, is the usual cause of pseudomembranous colitis. Gross: The mounted specimen consists of two short lengths of opened large bowel. The mucosal surfaces of both segments are covered by small focal, grey/yellow plaques. These plaques protrude above the surface of the mucosa and have a stuck on appearance the intervening mucosa is somewhat flattened but otherwise unremarkable. These small plaque-like lesions constitute the pseudomembranes. At endoscopy if the pseudomembrane is pulled off, the underlying mucosa usually shows ulceration and will bleed. Microscopy: Macroscopic examination of this slide shows a deep pink band (muscularis propria) adjacent to a broad, pale pink zone (oedematous submucosa). This is covered by a thin undulating blue band (mucosa) which shows focal capping by bright pink material. Microscopic examination reveals this to be a portion of large bowel. This is autopsy material and the tissue is autolysed - hence the loss of most of the glandular epithelium. There is a patchy mucosal process characterised by caps of fibrin. The underlying glands are dilated. The fibrinous material appears to have erupted out of the glands. This material (the pseudomembrane) is usually admixed with recognisable cellular debris and neutrophils - not seen here because of the autolysis. Neutrophils are usually also present within the glands (crypt abscesses) and the lamina propria of the involved patches. The intervening mucosa is normal. The submucosa is very oedematous. Notes: Slide 20: Adenomatous polyp, UP 2498 [67M8220] Clinical History: This 47 year old man presented initially with a 2 year history of having passed small amounts of bright red blood intermixed with normal faeces

and a 6 month history of bloody diarrhoea. An operation at that time revealed an adenocarcinoma of the descending colon and multiple colonic polyps. The carcinoma was resected and a colostomy performed. He was readmitted several months later for the removal of the remainder of the colon with anastomosis of the ileum to the rectum. The present specimen is from the second operation. Gross: The mounted specimen consists of a 20 cm length of opened large bowel. Examination of the mucosal surface reveals multiple, pedunculated, colonic polyps. These polyps are red/brown in colour with a finely granular and lobulated surface. The uninvolved mucosal folds appear normal. At the top of the specimen fibrous scar tissue and black suture material can be identified. These features are related to his previous surgery. Microscopy: Macroscopic examination of the slide shows 2 oval-shaped portions of blue tissue. The upper portion has a short stalk of paler tissue. Microscopic examination of the slide shows two sections of an oedematous polyp. Look first at the stalk of the upper section. There is significant diathermy a in this region but one can still see normal colonic mucosa with its regular architecture and tall, mucus producing epithelium. There is an abrupt transition to the neoplastic epithelium and abnormal architecture of the polyp. The glands vary in size and shape (the tubular component). In a few areas there are finger-like projections at the surface of the polyp covered by neoplastic epithelium (the villous component). The neoplastic epithelium shows loss of mucin, nuclear hyperchromasia, increased mitotic activity and multi-layering of cells. There is no stromal invasion. This is moderate infiltrate of plasma cells, eosinophils and pigment-laden macrophages. The pigment-laden macrophages indicate that there has been previous haemorrhage into this polyp, probably as a result of torsion. All neoplastic polyps have malignant potential. The risk of carcinoma is related to: 1. The size of the polyp 2. The relative proportion of the villous component and 3. The degree of dysplasia. Obviously size is the only guide preoperatively to predicting the presence of cancer within a polyp.

Notes: Slide 21: Adenocarcinoma of colon, UP 843 [67M8143T0853M8016] Clinical History: This 60 year old woman presented with a history of anorexia, malaise and anaemia which had been present for 4 months. She had lost 14 pounds (approximately 6 kg) in weight during this time. Physical examination revealed a hard, non-tender mass in the right iliac fossa. At operation a large carcinoma of the caecum with lymph node metastases was found and a right hemicolectomy was performed. Gross: The mounted specimen consists of approximately 20 cm of opened large bowel. An 8 cm circumferential, polypoid and superficial ulcerated tumour mass is present centrally. The tumour tissue is tan in colour and shows extensive infiltration and expansion of the submucosa as well as infiltration into and beyond the muscle coat. Also included, on the posterior aspect of the specimen, are a number of significantly enlarged lymph nodes (microscopically the lymph nodes contained metastatic tumour, therefore this is a Dukes stage C carcinoma of the caecum). Microscopy: Macroscopically this slide shows a cellular blue mass in the region of the mucosa. A small oval blue nodule is seen in the muscularis propria (pink layer) Microscopic examination shows a small strip of normal large bowel mucosa at one edge. Follow this strip along and one finds an abrupt transition to a neoplastic process. The tumour cells show cytological features of neoplasia and form irregular gland-like structures arranged in a back-to-back fashion. These glands infiltrate the submucosa and are surrounded by a desmoplastic stroma. Within the muscularis propria lymphatic permeation and a lymph node metastasis can be seen. This is a moderately differentiated adenocarcinoma. Notes: Slide 22: Chronic cholecystitis, UP 763 [57M3100F] Clinical History:

This 46 year old woman gave a history of recurrent attacks of pain in the right hypochondrium. Following investigation a cholecystectomy was performed Gross: The specimen consists of a partially opened gallbladder. The gallbladder wall is mildly thickened and two large white mulberry gallstones are present within the lumen. Microscopy: Sections of the gall bladder wall show a focal flattening of the luminal, mucosal folds. There is no mucosal ulceration. The lamina propria is infiltrated by lymphocytes and plasma cells. Lymphoid follicle formation is seen both within the lamina propria and the serosal connective tissues. The muscle coat is hypertrophied and focally penetrated by RokitanskyAschoff sinuses. A chronic inflammatory cell infiltrate is also seen in the muscle coat. These are the features of chronic cholecystitis. Metaplasia and dysplasia and dysplasia of the surface epithelium may also be seen in some cases, but are not present here. Notes: Slide 23: Fatty Liver, UP 1735 [56M5521C] Clinical History: This 58 year old woman was admitted to hospital comatose following an intracerebral haemorrhage and died shortly afterwards. Steatosis of the liver was an incidental finding at autopsy. Gross: The mounted specimen consists of a slice of liver tissue. The hepatic parenchyma appears a rather peculiar bright orange colour, but if you turn the specimen around and look at the posterior aspect of this liver slice you will see that the parenchyma is a very pale yellow colour. This is what the tissue would have looked like in the fresh state at autopsy. This patient has significant steatosis. The pale colour is due to the presence of fat vacuoles within the hepatocytes. The liver in such a case is enlarged with a rounded inferior margin, a smooth capsule, and has a pale yellow brown greasy cut surface. Microscopy: Sections of liver show a normal hepatic architecture with no alteration in the relationship between central veins and portal tracts. The portal tracts are normal. The striking abnormality is a diffuse vacuolation of liver cells. In the majority of liver cells the vacuoles are small and numerous.

In other cells they are larger and is some a single vacuole replaces much of the cell cytoplasm and compresses the hepatocyte nucleus to one side. The fatty change is particularly prominent at the periphery of the lobules around the portal tracts. There is no evidence of sinusoidal dilatation or centrilobular hepatocyte atrophy which would be expected if the fatty change were due to chronic venous congestion. This diffuse type of fatty change is a rather non-specific manifestation of impaired hepatic metabolism of fat or excessive fat mobilisation. It is seen commonly in chronic alcoholism, diabetes mellitus, obesity, starvation and jejuno-ileal bypass. Notes: Slide 24: Viral hepatitis Clinical History: No history is available for this case. Acute viral hepatitis can be divided into 4 phases: 1. An incubation period, which varies depending on the causative agent. 2. A symptomatic pre-icteric phase which is usually marked by nonspecific constitutional symptoms. 3. A symptomatic icteric phase during which the patient has dark urine, pale stools and itching. 4. Convalescence. Gross: The liver is slightly enlarged and variably green depending on the phase of the acute disease and the level of the jaundice. Microscopy: Macroscopically this is a thin core of blue-pink tissue. Microscopic examination shows this to be liver tissue. The overall architecture appears to be normal. The portal tracts are slightly expanded and contain a lymphocytic infiltrate. The lobules appear normal but there is some variation in hepatocytic nuclear size and occasional tri- and bi-nucleate cells are seen. This indicates regeneration and, combined with the fact that no necrosis is seen, suggests that this patient is in the recovery phase of their illness. In the acute stage one sees coagulative necrosis of individual cells and also lysis of small groups of cells. Kupffer cells undergo hypertrophy and hyperplasia as they phagocytose cellular debris these cells are elegantly demonstrated with a PAS stain but difficult to discern on an H & E. Remember that the diagnosis of acute viral hepatitis does not usually require a liver biopsy.

Most cases of acute viral hepatitis resolve. Approximately 5-10% of patients develop chronic disease (except those caused by HAV) and in 1% of patients the infection is fatal. Notes: Slide 25: Haemochromatosis, UP 2496 [56M5741A] Clinical History: This 40 year old man first presented in 1967 with a 9 month history of polyuria and polydipsia. Examination revealed glycosuria, elevated blood sugar (44 mg per 100 ml) and hepatosplenomegaly. A needle biopsy of the liver showed haemochromatosis. The serum iron was 198 mg per 100 ml. His diabetes mellitus was controlled with daily insulin. He was readmitted to hospital in 1971 complaining of a distended abdomen. Examination revealed a slate coloured skin, spider naevi, ascites and hepatosplenomegaly. A barium swallow showed large oesophageal varices. Splenectomy was undertaken because of hypersplenism with thrombocytopenia. Post operatively the patient developed an intraperitoneal haemorrhage which required a further laparotomy and multiple blood transfusions. He died 2 days later in acute hepatic failure. An autopsy revealed haemochromatosis and massive pulmonary oedema. The pancreas was fibrotic. This patients pancreas and kidneys are also present in the museum. Gross: The mounted specimen consists of a slice of liver, the lower half of which has been stained with Perls stain to demonstrate the intense deposition of iron. A well-developed micronodular cirrhosis is present throughout the liver section. Small, variably sized nodules of tan coloured liver tissue are separated from one another by delicate grey fibrous septae. At autopsy the liver would have appeared slightly larger than normal, dense and chocolate brown in colour. Microscopy: Macroscopically this slide shows a rectangular piece of deep blue tissue. This is a Perls stain for iron. Perl devised this stain in 1867. Ferric iron salts stain blue. Under the microscope one can identify liver tissue. The architecture is distorted. There is expansion of the portal tracts and fibrous bridging between portal tracts. Regenerative nodules can also be seen. This is micronodular cirrhosis.

The Perls stain demonstrates the presence of iron in most of the cells. Primary haemochromatosis is characterised by the deposition of iron in parenchymal cells - liver, pancreas, myocardium, skin, joint linings and endocrine glands - with sparing of phagocytes (? genetic inability to take up iron). Systemic siderosis refers to the deposition of iron in the cells of the mononuclear-phagocyte system and occurs as a normal response to iron overload. It is not associated with organ dysfunction. Secondary haemochromatosis is seen when the mononuclear-phagocyte system is overwhelmed and deposition of iron then occurs in parenchymal cells. In this slide very heavily stained cells are present in the portal tracts and scattered through the lobules - these are cells of the mononuclearphagocyte system (macrophages and Kupffer cells) that contain large deposits of iron derived from the phagocytosis of necrotic hepatocytes. An autosomal recessive gene transmits primary haemochromatosis. Early diagnosis is important if the damaging effects of iron overload are to be avoided. Careful screening of family members should be done. This involves measurement of serum iron, ferritin and transferrin saturation. Treatment involved removal of iron from the body using phlebotomy and iron chelators. Patients with pigment cirrhosis are a risk of developing hepatocellular carcinoma. Notes: Slide 26: Alcoholic hepatitis & Cirrhosis, UP 701 [56M4851B] Clinical History: This 49 year old man was a very heavy drinker. He was admitted to hospital 4 years prior to his death with a history of dyspepsia and abdominal pain, usually occurring about 1 1/2 hours after meals. On examination at that time he had some tenderness in the epigastrium and a palpable liver. A barium meal showed a gastric ulcer and he was given medical treatment. A liver biopsy showed hepatic cirrhosis with steatosis. 18 months later he had an episode of haematemesis and melaena. Oesophageal varices were identified endoscopically and also on a barium meal. His final admission to hospital was precipitated by vomiting of appreciable amounts of bright red blood. Investigations revealed that he was bleeding from his oesophageal varices and attempts were made to stop the bleeding using surgical method but he died 2 days later. At autopsy extensive oesophageal varices were identified, the previous gastric ulcer had healed and the liver was obviously cirrhotic and weighed 2050 grams. Gross:

The mounted specimen is a slice of liver. Multiple variably sized small nodules of grey/brown tissue distort the normal hepatic parenchyma. These nodules are separated from one another by grey/white bands of fibrous connective tissue. The capsular surface of the liver shows an irregular nodularity. Microscopy: Sections of liver tissue show an abnormal liver architecture. Macroscopic examination of the slide demonstrates numerous pale eosinophilic nodules of hepatocellular tissue separated by darkened pink fibrous septa. The nodules vary in size and shape. Microscopic examination shows that within the lobules there is loss of the normal sinusoidal architecture. In some of the larger nodules central veins and portal tracts are present but in many small nodules there is no central vein. There is moderate steatosis with large fat vacuoles distorting some cells. Occasional necrotic hepatocytes are present with an accompanying focal infiltrate of neutral polymorphs. The portal tracts are expanded and distorted by a proliferation of fibrous tissue. There is also a mononuclear (lymphocytic) cellular infiltrate in the fibrous stroma and proliferation of small bile ductules. These appearances are suggestive of alcoholic cirrhosis with associated alcoholic hepatitis (necrosis of hepatocytes and neutrophilic infiltrate). In order to make a diagnosis of cirrhosis both fibrosis and regenerative nodules must be present. Notes: Slide 27: Hepatocellular carcinoma, UP 4876 [56M4851M8173] Clinical History: This 71 year old man had a long past history of chronic obstructive airways disease and ischaemic heart disease. He also had a history of alcohol abuse and liver disease and had been a recent in-patient in a private hospital because of varicose ulcers of the lower leg. He was admitted to the Royal Hobart Hospital after collapsing suddenly at home. There was a recent history of diarrhoea. On examination his speech was slurred though he was conscious and orientated. Ascites was present and there were signs of chronic obstructive airways disease. Investigations revealed mild impairment of liver function (albumin 28, ALP 148, Gamma GT 73) and abdominal ultrasound showed the presence of a large mass in the right lobe of the liver. While investigations were continuing the patient suffered a large malaena and haematemesis and died.

Other findings at post mortem included solitary deposit of metastatic tumour in the base of the right lung, oesophageal varices with mucosal erosions and recent gastro-intestinal haemorrhage, portal vein thrombosis, massive ascites, testicular atrophy and gynaecomastia Gross: The mounted specimen shows a slice taken from the right lobe of the liver. The background liver parenchyma appears abnormal and shows the pattern of well-developed micronodular cirrhosis. In addition there is a large mass of pale tumour tissue measuring 10 cm in maximum diameter. The tumour appears multinodular and shows extensive areas of haemorrhage with smaller foci of necrosis. A few small nodules of tumour tissue are seen outside the main tumour mass. Microscopy: Macroscopic examination of the slide shows an irregularly shaped portion of variegated tissue with foci of haemorrhage (red) and necrosis (pale pink). Microscopic examination shows lobules of tumour tissue separated by fibrous connective tissue. Many of these tumour lobules show central tumour necrosis. The tumour cells are variably differentiated. In some areas the cells are well differentiated and show a trabecular architecture resembling the normal sinusoids of the liver. These cells have central round nuclei, eosinophilic cytoplasm and many show steatosis. Brown bile pigment can be identified in these foci. In other areas the tumour is very poorly differentiated and the cells show all the features of highly malignant cells - extreme variation in size and shape nuclear hyperchromasia, bizarre mitoses and tumour giant cells. The intervening stroma is oedematous and heavily infiltrated by chronic inflammatory cells. Hepatocellular carcinoma has a propensity to invade veins and if you look carefully at some of the rounded deposits of tumour you will see that the tumour cells actually lie within an endothelial-lined space (i.e. a blood vessel/lymphatic channel). This is a variably differentiated hepatocellular carcinoma with vascular invasion. Notes: Slide 28: Acute haemorrhagic pancreatitis, UP 4173 [59M4160M5441B] Clinical History: No notes are available for this particular patient. However, most patients with acute haemorrhagic pancreatitis present with a sudden onset of an

acute abdomen. Their pain is usually constant, intense and referred to the upper back. Most patients show peripheral vascular collapse or shock. The onset of the pain may be related to a large meal or an alcoholic binge. Gross: The mounted specimen consists of a portion of pancreas and below that, a portion of mesenteric fat. Examination of the pancreas shows the organ to be swollen and to contain multiple focal areas of haemorrhage (the dark black areas). Also present within the peripancreatic fat and the mesenteric fat are multiple discrete chalky/white foci. This appearance is typical of fat necrosis. Lipase released by he damaged pancreatic acinar cells attacks the fat cells releasing free fatty acids. The free fatty acids saponify with calcium salts to form soaps. As a result of this reaction, the patients serum calcium drops significantly and the characteristic lesions of fat necrosis appear. The peritoneal cavity usually contains a slightly turbid brown fluid in which globules of fat can be identified (chicken broth fluid). Microscopy: The slid shows pancreatic tissue with large areas of necrosis and haemorrhage. The necrosis involves both the adipose tissue and the parenchyma. In the adipose tissue the ghost outlines of individual fat cells can still just be made out and around the edges of the zones of necrosis there is an accumulation of amorphous grey-blue material. This represents the calcium soaps that form when calcium complexes with the free fatty acids released by the action of lipase. An intense neutrophilic infiltrate usually accumulates rapidly around the areas of necrosis. This is not present in this slide - the patient was severely debilitated and presumably unable to mount an appropriate immune response. Notes: Slide 29: Islet cell tumour of pancreas [photograph] Clinical History: B Cell tumours (insulinomas) are the most common of the islet cell tumours. These tumours may elaborate enough insulin to induce clinical hypoglycaemia. The patients typically suffer hypoglycaemic attacks related to fasting or exercise and promptly relieved by the administration of glucose. The hypoglycaemic attacks usually manifest as confusion, stupor or loss of consciousness. Gross:

About 90% are solitary and approximately 10% are multiple. They vary in size but are usually quite small and may be difficult to find surgically. Microscopy: Macroscopic examination of the slide shows tiny islands of blue-pink tissue separated by irregular clear spaces. A single more solid nodule of tissue is seen at one end. Microscopic examination shows a discrete, encapsulated neoplasm within autolysd pancreatic tissue. The pancreas autolysis rapidly following death due to the release of powerful proteases from the acini. The tumour shows a gyriform pattern of cell ribbons. The tumour cells are relatively uniform in size, cuboidal in shape with central round nuclei and pale, eosinophilic cytoplasm. A delicate highly vascular stroma is present. Immunocytochemistry plays a key role in further classifying these lesions by identifying the hormone/s being produces. The most common islet cell tumour is the Beta cell tumour (insulinoma) - 90% of these are solitary and benign. Most of these tumours are small, less than 15 mm. Other islet cell tumours include Alpha cell (glucagonoma) and G cell (Gastrinoma) and these are usually malignant. The correlation between morphology, as seen under the microscope, and clinical behaviour (benign vs malignant) is poor in ALL endocrine tumours. Nuclear pleomorphism is particularly unreliable and mitotic activity not much better. Notes: Slide 30: Carcinoma of pancreas [photograph] Clinical History: Carcinoma of the pancreas is an insidious lesion that does not usually present until late. The major symptoms include weight loss, abdominal pain and back pain. Jaundice is present in about 90% of lesions involving the head of the pancreas and in 10 to 40% of patients with carcinoma of the body or tail. Gross: The tumours show a typical appearance for carcinoma, i.e. grey/white tumour tissue, infiltrating and replacing the normal pancreas. The tumours are usually poorly defined and have obviously invasive margins. Carcinomas of the body and tail tend to be larger than those of the head because of later presentation. Microscopy:

Unfortunately this slide shows no residual normal pancreatic tissue. There is extensive infiltration of adipose tissue and connective tissue by neoplastic, mucin-producing gland-like structures. These glands vary in size and shape and in some areas there is a back-to-back configuration. A desmoplastic stroma is present between the glands. The tumour cells show nuclear pleomorphism and occasional mitoses. A mixed population of inflammatory cells is present throughout the lesion and there are also extensive areas of necrosis. The smaller piece of tissue also shows metastatic tumour in a local lymph node and perineural infiltration. This is a moderately differentiated, adenocarcinoma that arises from the ductal epithelium of the pancreas. Notes: Slide 31: Pulmonary oedema Gross: The lungs are heavy and on slicing exude a watery and sometimes frothy fluid. Microscopy: Sections show a piece of architecturally normal lung tissue. There is intense vascular congestion and most of the alveolar spaces contain pale pink, slightly granular material. This is oedema fluid. Pulmonary oedema may be due to cardiogenic or non-cardiogenic causes. As a result pulmonary oedema may be seen in a variety of clinical settings. Cardiogenic pulmonary oedema occurs because of an increase in hydrostatic pressure; non-cardiogenic pulmonary oedema occurs because of a change in alveolar capillary permeability. Common causes of cardiogenic pulmonary oedema include myocardial infarction, arrhythmias and severe congestive heart failure. Notes: Slide 32: Chronic venous congestion of lung. Gross: The lungs are usually slightly heavy and deep red brown in colour. Microscopy: Macroscopic examination of the slide shows a slice of lung tissue in which much of the air containing tissue has been replaced by pink material. Examination under the microscope shows dilatation and tortuosity of the alveolar capillaries. Normal alveolar capillaries only permit the passage of one red cell at a time; some of these vessels are wide enough to take

two or three cells at a time. The alveolar walls are thickened, predominantly due to the capillary dilatation, but in some areas due to increased interstitial connective tissue. The second most prominent feature is the presence of numerous haemosiderin-laden macrophages within the alveolar lumen. These cells are large, usually with an eccentric nucleus and have an orange-brown cytoplasm. The pigmentation is due to the presence of breakdown products of haemoglobin derived from small intra-alveolar haemorrhages. These can be seen in some areas in this section and arise as a result of rupture of the dilated alveolar capillaries. A third feature in this slide is thickening of vessel walls. In the larger arteries this is seen as intimal thickening but in smaller vessels there is diffuse thickening of the wall due to proliferation of smooth muscle fibres. The atrial wall thickening is an indication of pulmonary hypertension ad suggests the presence of a cardiac valvular lesion such as mitral stenosis. In one area of the slide a collection of polymorphs is seen within alveolar spaces and represents early bronchopneumonia. Notes: Slide 33: Pulmonary emboli and infarction, UP 12 [28M3710M5470B] Clinical History: This 46 year old woman had been ill for some months with leukaemia. Some 3 days before death she developed pain in the lower chest and a right middle lobe consolidation was noted radiologically. She also had a watery haemoptysis. She died suddenly from a massive pulmonary embolus. Gross: The mounted specimen shows a parasagital slice of the right lung. Most of the pulmonary artery branches contain emboli. The apical segment of the lower lobe and most of the middle lobe show evidence of pulmonary infarction. These infarcts are haemorrhagic (dark brown to black in colour) and the surrounding pulmonary parenchyma is consolidated. Compare this parenchyma with that of the upper lobe which is normal. This consolidation will be as a result of the inflammatory response to the infarcts. In areas of consolidation the alveolar air spaces appear more prominent because they are clearly outlined by oedematous interalveolar septae. Microscopy:

Macroscopically this is a rectangular piece of pink tissue. At one edge the pale, lacy pattern of pulmonary parenchyma can be recognised. Red-pink material (embolus) is visible occluding a pulmonary artery. The opposite edge is deep pink in colour with loss of the lacy pattern. In this area a small, slightly paler triangular-shaped zone is visible, with its base orientated towards the edge of the tissue block. This is the zone of infarction. A hyperaemic margin is present around the infarct. Microscopic examination shows the pulmonary artery to be occluded by thromboembolus. It has the same internal structure as seen in recent thrombus. The pulmonary parenchyma is intensely congested with intraalveolar oedema and haemorrhage. An infiltrate of neutrophils is seen focally. The zone of infarction shows well-developed coagulative necrosis. It is important to remember that following a pulmonary embolus a series of changes may be seen. These range from no macroscopic abnormality through intra-alveolar haemorrhage to true necrosis of alveolar tissue. In this section we see a focus of true necrosis but in many areas the predominant change is intra-alveolar haemorrhage. If no necrosis occurs then the intra-alveolar haemorrhage can be cleared by macrophages with return to normal lung histology but if necrosis occurs then healing by organisation of granulation tissue ensues, resulting in fibrous scar formation. Notes: Slide 34: Lobar Pneumonia, UP 11 [28M4002A] Clinical History: This 61 year old man was admitted to hospital severely ill, mentally confused, cyanosed and hypotensive with a blood pressure recorded as 56/30. He had had a recent respiratory infection with vomiting and chest pain. Gross: The specimen consists of a slice of the left lung. The upper lobe shows diffuse consolidation with sparing of a small part of the anterior segment. The consolidated tissue is grey/brown in colour. The underlying pulmonary architecture can still be discerned. Careful examination of the upper lobe will show tiny areas of abscess formation. Examination of the lower lobe shows consolidation and congestion accounting for the red/brown colour and also patchy areas of grey/white consolidation. The appearances in the upper lobe are typical of the grey hepatisation stage of lobar pneumonia. The lower lobes show red hepatisation. In the early

stages the lung consolidation appears red (due to vascular engorgement and leakage of red blood cells into alveolar spaces) and later grey (following the lysis and removal of red cells and the influx of fibrin). The pleural surface of the lung is also inflamed and may be covered by a fibrino-purulent exudate. Microscopy: Macroscopically this is a rectangular piece of partly solid material. Microscopic examination shows this to be lung tissue the alveolar architecture is recognisable, macrophages laden with carbon pigment are present and a small bronchus is seen. A diffuse pathological process is evident. All the alveolar air spaces are distended by a cellular infiltrate. Careful examination of this infiltrate shows it to consist of neutrophils. Oedema fluid (granular, pale pink material) and fibrin (stringy deeper pink material) are also present. The alveolar septae are widened and also show infiltration by neutrophils. Despite the rather dramatic appearance of this inflammatory process, complete resolution is possible as long as the architectural framework of the pulmonary parenchyma is not destroyed. The intra-alveolar exudate is removed by macrophages. Most cases of lobar pneumonia occur in healthy young adults and are caused by Streptococcus pneumonia Types 1,2,3, and 7. Mortality is low and with modern antibiotic treatment complications few. Notes: Slide 35: Bronchopneumonia, UP 639 [2850M4021D] Clinical History: This 56 year old man became semi-comatose and a cerebral tumour was suspected. A craniotomy was performed and an inoperable astrocytoma found. He died 2 months later. At autopsy both lungs were heavy and showed widespread patchy consolidation. Gross: The mounted specimen is a slice of the left lung. Examination of the pulmonary parenchyma shows multiple tiny grey/white foci of consolidation centred on small bronchi and bronchioles. In some areas these small foci have become confluent. This patchy and focal distribution of consolidation is typical of bronchopneumonia. Microscopy: Macroscopic examination of this slide shows a square shaped piece of lung tissue. The majority of the lung tissue is air containing and is transparent. However, there are scattered areas of dense blue tissue which represent patchy areas of inflammation. Several large tubular structures

can be recognised and these contain bluish debris within their lumina. These are peripheral bronchi and bronchioles. Close examination both macroscopically and under the microscope reveals that the areas of consolidation are related to the air passages. Microscopic examination of the consolidated areas shows alveolar spaces filled with viable and degenerate polymorphs. Occasional macrophages are present. The inflammatory cells are predominantly within alveolar spaces but some are present within the alveolar walls. The bronchial lumina are filled with a similar inflammatory cell infiltrate. There is extensive desquamation of the surface epithelial lining of the bronchioles but much of this is post mortem artifact. The patchy nature of the acute inflammatory infiltrate and its relationship to acute purulent bronchitis and bronchiolitis is typical of bronchopneumonia. Notes: Slide 36: Tuberculosis of lung, UP 1086 [28M4470M4620B] Clinical History: This 50 year old Chinese man had a cough, fever and loss of weight for almost 1 year before admission to hospital. Just prior to admission he coughed up about 300 ml of blood and became extremely breathless. An x-ray of his chest revealed apical cavitation in both lungs and evidence of basal consolidation. He was commenced on antituberculous therapy but had another haemoptysis and died soon afterwards. Gross: The mounted specimen consists of a parasagital slice of the left lung. The upper lobe shows 2 cavities both containing adherent caseous material. The larger irregular cavity has probably formed as a result of coalescence of a number of smaller cavities. The parenchyma surrounding these cavities is consolidated and shows grey/white caseous material. The visceral pleura related to the apex of the lung is thickened and fibrotic. The lower lobe of the lung shows multiple, small, patchy grey/white foci which are focally confluent. This appearance is typical for a confluent bronchopneumonia. Tuberculous bronchopneumonia follows aspiration of caseous material within bronchi. This material usually comes from apical cavities. Microscopy: Macroscopic examination of the slide shows lung tissue with a central abnormal area where there is dense fibrosis with areas of basophilic material showing central degeneration. Examination under the microscope

shows that these three areas represent caseous foci and here the typical features of caseous necrosis and fibrocaseous tuberculosis are seen. The central caseous material is made up of necrotic inflammatory cellular debris which appears as amorphous structureless eosinohilic material. At the periphery of the necrotic tissue a prominent zone of palisaded epithelioid macrophages is seen. These cells are elongated with spindle shaped eosinophilic cytoplasm and elongated vesicular basophilic nuclei. Scattered Langhans type giant cells are seen in this layer. External to the palisaded epithelioid cells there is a diffuse infiltrate of lymphocytes and some plasma cells within collagenous fibrous tissue. In order to confirm the diagnosis of tuberculosis pieces of lung tissue should be cultured and sections stained with the Ziehl-Nielsen stain for acid-fast bacilli. Notes: Slide 37: Miliary tuberculosis of lung, [photograph] Clinical History: Miliary tuberculosis may follow a primary infection, particularly in adults who are immunodeficient, infants and children. It may also complicate secondary (reactivation) tuberculosis. Gross: The individual lesions of miliary tuberculosis are tiny (1 to several mm in size). They are usually well-circumscribed, yellow to white colour and firm. Central necrosis or cavitation is usually not present. Microscopy: Macroscopic examination of the slide shows multiple, discrete eosinophilic nodules surrounded by thin basophilic rims scattered through a lace-like tissue. Microscopic examination of the slide shows pulmonary parenchyma with focal granulomata. These granulomata show central caseous necrosis with a peripheral rim of palisading histiocytes and occasional giant cells. A moderate infiltrate of lymphocytes is present around the periphery of each lesion. In a number of areas the granulomata have coalesced to form large complex structures. The uninvolved pulmonary parenchyma shows vascular congestion and moderate anthracosis. A fibrinous exudate is present covering the pleural surfaces. Notes: Slide 38: Cytomegalovirus infection of the lung

Clinical History: There is a high frequency of cytomegalovirus infection amongst adults. Between 50 and 80% of adults will show evidence of exposure to CMV in the form of complement fixing antibodies. CMV infection in adults is almost invariably latent and virtually asymptomatic unless a patient is immunocompromised. Microscopy: Macroscopic examination of the slide shows a small rectangular piece of tissue with a delicate lace-like pattern. Microscopic examination reveals a portion of lung tissue. The overlying pleura is oedematous and shows a proliferation of small blood vessels. A fibrinous exudate covers the pleural surface. Examination of the pulmonary parenchyma shows evidence of intra-alveolar haemorrhage and hyaline membrane formation. The hyaline membranes are most clearly seen just beneath the pleura. In addition, many of the alveoli contain oedematous fibrous tissue, indicative of organisation of an inflammatory exudate. Scattered throughout the pulmonary parenchyma are numerous large cells showing oval basophilic intranuclear inclusions with a surrounding clear halo. A few cells also contain basophilic cytoplasmic inclusions. These inclusions and the enlargement of the cells are typical of cytomegalovirus. The inclusions seen in this particular case are most often seen in alveolar macrophages but can also occur in the alveolar lining cells and in the endothelial cells of septal capillaries. CMV infection usually incites an interstitial pneumonitis. In this patient there is very little evidence of an interstitial inflammatory cell infiltrate indicative of the patients immunocompromised status. In summary, this is CMV pneumonia in an immunocompromised patient showing some evidence of organisation. Notes: Slide 39: Adult Respiratory Distress Syndrome Clinical History: No clinical history is available for this case. Adult Respiratory Distress Syndrome (ARDS) may be seen in many different clinical situations. The causes of ARDS include the following: 1. Infectious agents, particularly viruses. 2. Inhalants, such as oxygen or smoke. 3. Drugs, including chemotherapeutic agents and heroin. 4. Ingestants, e.g. Kerosene and paraquot.

5. Shock, which may be traumatic, haemorrhagic, neurogenic or cardiogenic. 6. Sepsis. 7. Radiation. 8. Miscellaneous this category includes acute pancreatitis, burns, cardiopulmonary bypass, near drowning and many other conditions. The onset of ARDS is associated with dyspnoea and tachypnoea. Initially the chest x-ray is normal. As the disease progresses there is increasing cyanosis, hypoxaemia and respiratory failure, associated with diffuse bilateral infiltrates on chest x-ray. These patients have stiff (non compliant) lungs and are difficult to ventilate. The hypoxaemia becomes progressively worse and respiratory acidosis develops. The mortality rate is high. Gross: The lungs are usually heavy and firm with intense congestion imparting a red colour. In fatal cases a superimposed bronchopneumonia is quite common. Microscopy: Macroscopic examination of the slide shows a triangular shaped portion of tissue. This tissue is lobulated and appears fairly solid. Microscopic examination of the slide shows pulmonary parenchyma. There is interstitial and intra-alveolar oedema. Brightly eosinophilic hyaline membranes are seen lining a number of the alveolar air spaces. These membranes consist of protein rich oedema fluid mixed with the remnants of necrotic epithelial cells. The presence of hyaline membranes always indicates significant epithelial damage. There is regenerative hyperplasia of Type 2 pneumocytes. These cells are seen lining the alveolar spaces and are increased in size with prominent nucleoli. A light inflammatory cell infiltrate is seen in the parenchyma. It is not hard to see why these patients should be so difficult to ventilate. Notes: Slide 40: Squamous cell carcinoma of the bronchus, UP 1117 [26M8043B] Clinical History: No clinical notes are available for this particular patient. However, most patients with carcinoma of the lung are between the ages of 40 and 70. The presenting symptoms include cough, weight loss, chest pain and dyspnoea. Not infrequently patients will present with symptoms related to

metastases. Carcinoma of the bronchus may also present as a paraneoplastic syndrome. Gross: The mounted specimen consists of a slice of lung showing a large grey/brown tumour mass, arising in a main bronchus. The tumour protrudes into and occludes the lumen of the bronchus. There is also significant extension by grey/brown tumour tissue into the surrounding pulmonary parenchyma. The bronchi peripheral to the tumour mass are dilated and filled with mucus. Also present are at least 3 lymph nodes containing metastatic tumour. The uninvolved lung parenchyma shows mild to moderate anthracosis. Microscopy: There are a number of different tissue blocks for this slide; on most of them one should be able to identify macroscopically some bronchial cartilage (pale blue) surrounded by cellular (blue) tissue. Under the microscope a transition from normal respiratory epithelium to metaplastic squamous mucosa is seen on some slides. The tumour itself consists of geographic islands and trabeculae of cohesive cells which show cytological features of malignancy: hyperchromasia, increased and bizarre mitoses, variation in size and shape, loss of normal cell-to-cell relationships. Areas of necrosis are present. The tumour cells show an infiltrative growth pattern with invasion of peribronchial tissues and pulmonary parenchyma. A desmoplastic stroma surrounds the tumour islands. Careful examination of the cells reveals squamous type differentiation look for intercellular bridges, individual cell keratinisation and squamous pearl formation. Squamous cell carcinomas tend to occur in segmental bronchi and are therefore situated centrally. Patients usually present with signs of bronchial obstruction. Central necrosis with cavitation occurs in these tumours and can be visualised on the chest X-ray. There is a strong aetiological association with smoking. The prognosis for lung carcinoma is poor. Notes: Slide 41: Small cell carcinoma of the lung, UP 183 [2670M8043] Clinical History: This asymptomatic 44 year old man had a routine chest x-ray which showed a shadow in the left lower lobe. A lobectomy was carried out. No enlarged lymph nodes were found.

Gross: The specimen consists of the lower lobe of the lung sliced to show an apparently well demarcated tumour mass that appears to have arisen from a bronchus. The tumour is grey/brown in colour and shows no evidence of haemorrhage or necrosis. No enlarged lymph nodes can be identified. The surrounding lung parenchyma shows mild to moderate anthracosis. Microscopy: Macroscopic examination of this slide shows a highly cellular (dark blue) nodule of tissue. Microscopic examination reveals fragments of cartilage, compressed bronchi, blood vessels and a small amount of pulmonary parenchyma. These tissues have been distorted and invaded by neoplastic cells. The tumour cells have round to oval, hyperchromatic nuclei and scant cytoplasm. They are about 1.5 times the size of a lymphocyte and are arranged in a packeted fashion with a delicate fibrovascular stroma. Foci of necrosis are scattered throughout the tumour. Lymphatic permeation by tumour cells is present. Oat cell carcinoma is the most common type of small cell carcinoma of the lung (the other type is called intermediate). It probably originates in primitive cells of the basal bronchial epithelium which, in the process of neoplastic change, undergo partial differentiation toward neuroendocrine cells. Ultrastructurally a few dense core neurosecretory granules are seen in some cells. Paraneoplastic syndromes are particularly associated with small cell carcinomas. The long-term outlook for patients with small cell carcinoma is bleak. The presence of distant metastases at diagnosis is particularly common. Chemotherapy may produce a short-term improvement. Notes: Slide 42: Metastatic adenocarcinoma of the liver, UP 899 [56M8146A] Clinical History: This 80 year old man had a history of perforated gastric ulcer and peritonitis approximately 30 years ago. On admission he gave a 5-day history of constant nagging epigastric pain. On examination he had a firm, tender irreducible right epigastric hernia. A clinical diagnosis of carcinoma of the stomach was made. The patient had severe ischaemic heart disease associated with congestive cardiac failure and was not considered an operative candidate. He died 12 days after admission.

At autopsy the liver weighed 3950 grams and was studded with large soft white lobulated tumour masses. Metastatic tumour was also present in the head of the pancreas and in para-aortic nodes. The primary site of the tumour was a small adenocarcinoma in the prepyloric region of the stomach. Gross: The mounted specimen consists of a slice of liver tissue showing multiple, well demarcated deposits of grey/brown tumour tissue. Focal areas of central necrosis and haemorrhage are seen within these deposits. The intervening liver tissue shows a nutmeg pattern consistent with chronic venous congestion. Microscopy: Macroscopic examination of the slide shows 4 separate fragments of tissue. Each of the central 2 fragments contains a small rounded nodule of basophilic tissue. Microscopic examination reveals from the label downwards: adrenal tissue, hepatic tissue, splenic tissue and a lymph node completely replaced by tumour tissue. The tumour cells show nuclear pleomorphism and increased mitotic activity. They are arranged in irregular back-to-back gland-like structures. A prominent desmoplastic stromal response is seen in the replaced lymph node. The lymph node contains carbon pigment suggesting that it comes from the mediastinum. The primary tumour in this case was an adenocarcinoma of the lung. Notes: Slide 43: Acute pyelonephritis, UP 1662 [71M4102B] Clinical History: This 43 year old man was admitted to hospital because of increasing tiredness and dyspnoea. He was found to be severely anaemic. Investigations showed this was caused by carcinoma of the caecum. Following blood transfusions his caecal tumour was resected. One week post-operatively he developed pneumonia followed by a subphrenic abscess. There was cellulitis around the site of an intravenous infusion line and a gram-negative septicaemia was diagnosed. In spite of a wide range of antibiotics his condition continued to deteriorate and he died 2 months later. At autopsy had acute bacterial endocarditis and acute pyelonephritis. Gross: The mounted specimen consists of part of 1 kidney. The kidney weighed 460 grams. The capsular surface is smooth and shows minute areas of

hyperaemia. The cut surface shows widening and pallor of the cortex with hyperaemia of the medulla. These features are due to a marked acute inflammatory response associated with oedema and hyperaemia. Microscopy: Macroscopic examination of the tissue section shows a wedge shaped piece of renal tissue including cortex and medulla. Bluish linear streaks arranged at right angles to the surface capsule are seen within the renal parenchyma. If these are examined under the microscope the blue appearance is seen to be due to large numbers of neutrophil polymorphs expanding the renal interstitial tissue. Neutrophils also extend into tubular epithelium and many tubules are dilated with neutrophils within the lumen. The glomeruli appear relatively spared. In the medulla neutrophils are seen within the interstitium but appear more prominent within dilated collecting tubules. The appearances are those of acute pyelonephritis. In the majority of cases infection arrives at the kidney via the urinary tract. In many cases acute pyelonephritis is associated with obstructive lesions in the urinary tract but in other cases may be related to vesico-ureteric reflux in the absence of obstruction. In the renal papillae intrarenal reflux occurs and infected urine extends into the large collecting ducts. From there the infecting organisms can spread directly into the renal parenchyma. The inflammatory process may resolve with little tissue damage or progress to chronic pyelonephritis (slide 44). Notes: Slide 44: Chronic pyelonephritis, UP 3127 [71M3520M4302C] Clinical History: This 26 year old woman had frequent urinary tract infections. Clinical and x-ray investigations suggested that she had unilateral hydronephrosis, possibly associated with pyonephrosis. A nephrectomy was performed. Gross: The mounted specimen consists of a small kidney (70 gm) showing multiple coarse, discrete and irregular scars involving the capsular surface. The cut surface of the kidney shows hydronephrosis with moderate dilatation of the pelvi-calyceal system. There is focal congestion and possible haemorrhage of the mucosa. There was congenital pelvi-ureteric stenosis causing the hydronephrosis. In this situation recurrent infections and possibly the effects of obstruction alone contribute to the scarring in the renal parenchyma. The more common form of chronic pyelonephritic scarring is that associated with chronic reflux. In this condition the scars

tend to be situated at either pole and have a similar appearance with discrete irregular scars overlying blunted or deformed calyces. Microscopy: Macroscopic examination of the slide shows an abnormal wedge-shaped area towards the top of the larger piece of tissue. The clear areas in this wedge consist of two zones of fat separated by a dilated space which represents a dilated branch of one of the minor calyces. The renal parenchyma immediately adjacent to this area appears relatively normal. Microscopic examination of the abnormal area reveals features characteristic of chronic pyelonephritis. The most characteristic feature is the localised nature of the abnormality which is often related to a single calyx. The infective process reaches the kidney via the urinary tract and refluxing papillae. The features to note are the extensive interstitial fibrosis, marked decrease in the number of glomeruli present, dilatation of renal tubules which contain eosinophilic hyaline casts, and prominent medial hypertrophy within interlobular vessels. The prominent dilatation of renal tubules together with accumulation of eosinophilic luminal material is referred to as thyroidisation. Scattered inflammatory cells are present in the interstitial tissue between the atrophic and dilated tubules. The predominant inflammatory cell is the lymphocyte. The smaller piece of tissue shows similar features. Notes: Slide 45: Glomerulonephritis Clinical History: No history is available for this case. The clinical history will vary depending on the type of glomerulonephritis present. Patients will present with one of 5 major glomerular syndromes. These syndromes include: Acute nephritis Rapidly progressive glomerulonephritis Nephrotic syndrome Chronic renal failure Asymptomatic haematuria or proteinuria. In the case of this particular type of glomerulonephritis (Type 1, membrano-proliferative) patients may present with haematuria, proteinuria (in the non-nephrotic range) or a combined nephrotic-nephritic picture. Gross:

The gross morphology of glomerulonephritis is rarely seen as this disease is diagnosed on renal biopsy. However, in acute cases the cortical surface usually appears red brown and smooth and is dotted by fine punctate petechiae. Microscopy: Macroscopic examination of this slide shows 2 rectangular blocks of pink tissue. Microscopic examination shows renal tissue. Both portions of tissue show similar features. The important pathological changes are confined to the glomeruli. All the glomeruli present are involved (diffuse) and each in its entirety (global). Inspection of the glomeruli shows them to be enlarged and hypercellular, indicating that this is a proliferative type of glomerulonephritis. The hypercellularity is due to mesangial cell proliferation and an increase in mesangial matrix material. This proliferation of mesangial cells accentuates the normal lobularity of the glomerulus. There is also focal proliferation of parietal epithelial cells resulting in the formation of crescents. There is some thickening of the glomerular basement membrane, most obvious in the peripheral capillary loops. Silver staining shows reduplication of the basement membrane (tram-track appearance) as a result of mesangial cell interposition. Occasional sub-endothelial deposits were seen under the electron microscope. Immunofluorescence showed C3 deposited in a granular pattern and also IgG, C1q and C4 suggesting an immune complex pathogenesis. This type of glomerulonephritis may occur as a primary glomerulonephritis or in association with SLE, hepatitis B antigenaemia, infected ventriculo-atrial shunts, schistosomiasis, liver disease and certain malignancies. It typically has a chronic progressive course with 50% of patients developing renal failure within ten years. Notes: Slide 46 Renal infarct, UP 4892 Clinical History: This 55 year old man had a 2 month history of increasing confusion and loss of weight. He also complained of a 1 day history of left arm weakness. He was a smoker and had a past history of alcohol abuse. In hospital he developed increasing coma with no evidence of infection or CNS abnormality on CT scan. He was treated with antibiotics and steroids with dramatic improvement in his conscious state, but persistence

of his left arm weakness. Six days after admission he suffered a grand mal seizure in the morning and later that day collapsed suddenly. He was shocked and his haemoglobin was noted to have dropped. He was treated with fluid replacement unsuccessfully. At autopsy he was found to have a massive primary retroperitoneal haemorrhage, primary carcinoma of the lung with metastases to local lymph nodes and the cerebellum, multiple pulmonary emboli with associated infarction and vegetations on both the aortic and mitral valves with multiple focal infarcts in the brain and both kidneys. In addition, there was an organising inferior myocardial infarct associated with subendocardial foci of more recent ischaemic damage which may have an embolic aetiology. Gross: The mounted specimen consists of a bisected kidney showing 2 areas of recent renal infarction. The capsular surface of the kidney is relatively smooth and shows a number of small simple renal cysts. At the upper pole there is a well-circumscribed geographic area of hyperaemia admixed with creamy yellow tissue. The cut surface shows a necrotic tissue with a focally hyperaemic border. An impacted embolus is visible in a branch of the renal artery supplying this area. In the lower pole there is a small triangular shaped area of medullary congestion probably related to ischaemic damage. The uninvolved cortex and medulla appears relatively normal. Microscopy: Macroscopic examination of the section of kidney tissue shows two well demarcated areas which are paler that the surrounding tissue. At the margin of these pale areas a bluish line is seen. Closer examination under the microscope reveals that these blue areas contain large numbers of viable and degenerate neutrophil polymorphs. In the pale areas ghost outlines of tubules and glomeruli are recognised. The cell outlines are preserved but the cytoplasm is a diffuse pink colour and most of the nuclei have disappeared. Some pyknotic nuclei remain within the glomeruli. In infarction nuclear changes due to necrosis include disappearance of nuclei (karyolysis), nuclear condensation and reduction in size (pyknosis) and nuclear fragmentation (karyorrhexis). This form of necrosis in which cell outlines are preserved is called coagulative necrosis. The peripheral neutrophilic infiltration is an early response on the part of the body to an area of tissue damage. In time granulation tissue and subsequently mature fibrous tissue will replace the infarcted tissue.

Some of the glomerular capillaries adjacent to the area of infarction appear congested. This is a common finding in recent infarcts and macroscopically can give a hyperaemic border to the pale area of infarction. Notes: Slide 47: Amyloid kidney Clinical History: No clinical history is available for this particular patient. The symptoms of amyloidosis depend on the size of the deposits and their location. Renal involvement is the dominating feature of reactive systemic or secondary amyloidosis. Patients present with proteinuria and casts. Renal amyloidosis is an important cause of the nephrotic syndrome and may be severe enough to induce hypoalbuminemia. Progressive damage to the renal parenchyma leads to renal failure and uraemia. Hypertension is usually not a component of the renal failure secondary to amyloidosis. Renal involvement is the major cause of death in patients with amyloidosis. Gross: The kidneys may be normal in size or slightly enlarged. They appear pale grey in colour and have a waxy, firm consistency. Microscopy: Macroscopically this is a pale grey rectangular block of tissue. The histological section shows renal tissue with bright orange colouration of the cortical glomeruli. Also staining orange are tubular basement membranes in the medulla and many of the arterial vessels. The stain is Congo Red, giving a positive reaction for amyloid. Other stains also capable of defining amyloid including iodine and thioflavine-T. Notes: Slide 48: Renal cell carcinoma, UP 281 [71M8313A] Clinical History: This 45 year old man had a history of haematuria for some weeks. An intravenous pyelogram showed evidence of calyceal distortion. A nephrectomy was carried out. Gross: The mounted specimen shows a bisected kidney containing a fairly well demarcated rounded tumour mass. The cut surface of the tumour shows geographic areas of creamy yellow tissue, small areas of cystic

degeneration and haemorrhage. There is no extension by tumour tissue into the pelvi-calyceal system or renal vein. The external surface of the kidney shows distortion by the tumour mass but there is no obvious capsular invasion. The uninvolved capsular surface is smooth and shows persistent foetal lobulation. Microscopy: Macroscopic examination of this slide shows a large irregularly shaped block of tissue with variably sized and shaped areas of blue grey tissue in which small cystic spaces and foci of haemorrhage are visible. A small wedge-shaped area of solid tissue is present at one end of the section. Microscopic examination of this wedge-shaped area shows normal renal tissue. Arising in this tissue is a large tumour mass. The tumour has a lobulated appearance and is comprised of polygonal shaped cells with distinct cell borders, clear cytoplasm and central, hyperchromatic nuclei. These cells are arranged in solid nests and gland-like structures. Some of the gland-like structures are cystically dilated and contain granular pink material. A very delicate fibrovascular stroma is present and there are numerous foci of haemorrhage. Also present is an area of old tumour necrosis showing hyalinisation and dystrophic calcification. This is a typical appearance for renal cell carcinoma (clear cell carcinoma) - in a minority of cases the tumour cells have granular eosinophilic cytoplasm rather than clear cytoplasm and careful examination of this slide will reveal small numbers of this cell type. The clear cells contain glycogen and lipid in their cytoplasm - hence the yellow colour of the tumour macroscopically. The cell of origin for these tumours is the tubular epithelium; they are therefore adenocarcinomas. Notes: Slide 49: Transitional cell carcinoma of the bladder, UP 945 [74M8133B] Clinical History: No clinical notes are available for this particular patient. However, all bladder tumours produce painless haematuria. Occasionally, there is also a history of dysuria, frequency and urgency. Urinary cytology may be very helpful in making a diagnosis and in the follow up of patients after treatment. Gross: The specimen consists of a portion of bladder wall. There is an exophytic tumour mass measuring up to 2 cm across showing a delicate papillary surface.

Microscopy: Macroscopically the slide shows a large block of tissue which is partly pink and partly grey-blue. The grey-blue tissue shows a papillary pattern and represents the tumour. The pink tissue is the underlying connective tissue and smooth muscle of the bladder wall. Under the microscope the section shows a highly complex, papillary epithelial tumour replacing the normal bladder mucosa and invading the muscle coat of the wall. Each papilla has a fibrovascular connective tissue core attached to which is a multilayered transitional-type epithelium. This epithelium is up to 10 cells thick in some areas. As the tumour invades the wall the cells form solid nests, ribbons and gland-like structures. Nuclear pleomorphism and occasional mitoses are seen. This is a Grade 11 transitional carcinoma of the bladder. Notes: Slide 50: Hyperplasia of the prostate, UP 822 [7710M7300C] Clinical History: This 70 year old man was admitted to hospital with acute urinary retention. In hospital he became confused, semi-conscious and died 4 days later. At autopsy he had pulmonary oedema, hepatic congestion and a scarred myocardium. Both kidneys showed scarring with bilateral hydronephrosis and hydroureter. Gross: The mounted specimen consists of an opened bladder with a grossly enlarged prostate gland. The enlargement of the prostate gland narrows the urethra to a slit. Nodular enlargement of the middle lobe of the prostate is present. This can act as a ball valve-like obstruction at the mouth of the urethra. Examination of the cut surface of the prostate gland on the left hand side shows the nodularity that is typical of this disease. Each of these nodules is made up of hyperplastic glandular tissue separated by fibrous connective tissue stroma. The bladder is dilated and shows marked thickening of the wall with striking trabeculation of the mucosa. Microscopy: Examination of the tissue under the microscope shows numerous glandular structures lined by tall columnar epithelium separated by a stroma in which fibroblasts and smooth muscle cells can be recognised. Proliferation of both glandular and stromal elements is seen but in this particular example glandular proliferation is more evident.

The glands appear closely packed and many show infolding of the lining epithelium. The cells are tall columnar in shape with eosinophilic cytoplasm and basally placed small round basophilic nuclei. Close examination of the stroma shows greater prominence of the smooth muscle cells than is seen in the normal prostate. In most cases of hyperplasia of the prostate there is an increase in the number of both smooth muscle and glandular epithelial cells. In selected areas within the prostate, however, the proliferation of one element may predominate. Thus one can find nodules composed completely of glandular tissue and others composed completely of smooth muscle. Hyperplasia of the prostate is a very common finding in elderly men at post mortem. Notes: Slide 51: Carcinoma of the prostate Clinical History: Prostatic carcinomas tend to arise in the subcapsular region of the gland. This is in direct contrast to nodular hyperplasia which arises in the inner periurethral portion of the middle and lateral lobes. As a result nodular hyperplasia presents with urinary symptoms relatively early, while these are late findings in prostatic carcinoma. These tumours can be diagnosed early using careful rectal digital examination followed by transperineal or transrectal biopsies for the confirmation of the diagnosis. Gross: The tumour tissue is firm and gritty and slightly yellower than normal prostatic parenchyma. Microscopy: Macroscopic examination of this slide shows a large oval-shaped portion of eosinophilic tissue with geographic areas of basophilia and numerous tiny cystic spaces. Microscopic examination reveals that the tissue is extensively infiltrated by tumour. These cells have round nuclei, small but prominent nucleoli and clear cytoplasm. They form gland-like structures arranged in a backto-back fashion. The intervening stroma is desmoplastic. Scattered through the tissue are larger gland-like structures bearing a resemblance to the hyperplastic prostatic glands seen in Slide 50, some of these contain corpora amylacea. Careful inspection of the epithelial cells lining these hyperplastic glands reveals that many of them contain nucleoli - a feature suggestive of dysplasia. Mitoses are usually hard to find in prostatic carcinomas and in some tumours even nucleoli are not prominent. In

these cases the pathologist relies on the pattern of gland arrangement (crowding, back-to-back and cribriform patterns) and signs of invasion (desmoplastic stroma, peri-neural and lymphatic permeation). Perineural invasion is well demonstrated in your slide - look carefully around the periphery of the nodule. Notes: Slide 52: Seminoma of the testis, UP 1468 [78M9063E] Clinical History: This 51 year old man had noticed a painless swelling of his right testis for 8 weeks. He gave no history of trauma or previous venereal disease. The testis, epididymis and 6 cm of spermatic cord were removed. Gross: The mounted specimen shows complete replacement of the testis by homogenous pale grey/white tumour tissue. There is no evidence of haemorrhage or necrosis and the tunica albuginea appears to be intact. There is some haemorrhage in the soft tissues of the spermatic cord, presumably related to the surgery. Microscopy: Macroscopic examination of the slide shows a roughly semicircular portion of tissue with a central oval-shaped basophilic mass. A pale eosinophilic capsule can be seen along the curved aspect of the tissue section. Microscopic examination of the slide reveals testicular tissue. The tunica albuginea is present and beneath this seminiferous tubules lined by spermatogenic cells and Sertoli cells are seen. Some contain sperm. Interstitial Leydig cells are also present - these cells have round nuclei, prominent eccentric nucleoli and abundant, granular cytoplasm that stains brightly eosinophilic. They are arranged in small clusters of 3-5 cells and are the source of testosterone. A chronic inflammatory cell infiltrate plasma cells and lymphocytes - with accompanying fibrosis is present. The tumour mass appears fairly well circumscribed with a surrounding zone of compressed and fibrotic testicular parenchyma. It consists of irregular sheets of large cells with watery cytoplasm, hyperchromatic nuclei and one or more prominent nucleoli. Occasional mitoses are seen. Compare these cells with the spermatogenic cells lining the seminiferous tubules. Fibrous septae, heavily infiltrated by lymphocytes, divide the sheets of tumour cells into irregular lobules. Pure seminoma is extremely radiosensitive and more than 90% of patients with Stage I and II disease can be cured.

Notes: Slide 53: Squamous metaplasia of the cervix [photograph] Microscopy: The tissue section is taken from the cervix. At the ectocervical end the covering epithelium is squamous and at the other end the covering epithelium is columnar in type and there are underlying endocervical glands. In the intervening zone squamous metaplasia is present. In fact much of the squamous epithelium recognised in the section is mature metaplastic squamous epithelium as endocervical glands can be recognised beneath the squamous epithelium. In the area where active squamous metaplasia is taking place the native columnar epithelium appears elevated by basal metaplastic cells resembling squamous epithelium. Squamous metaplasia in the cervix occurs when the endocervical epithelium is exposed to the acidic environment of the vagina during cervical mucosal eversion. The endocervical epithelium is not sufficiently resistant to this environment and gradually changes from a simple columnar epithelium to a squamous epithelium. This process is brought about through transformation of subcolumnar reserve cells into cells showing light microscopic and ultrastructural characteristics of squamous cells. The undifferentiated reserve cell can differentiate into either simple columnar epithelium or squamous epithelium depending upon the environment. Gradually the reserve cells proliferate as squamous cells elevating the overlying endocervical epithelium. In time the columnar cells are shed from the surface and one is left with maturing squamous epithelium. Notes: Slide 54: Wart virus infection with cervical intraepithelial neoplasia (CIN) Clinical History: Macroscopic examination of the slide shows two irregular fragments of pink tissue. Microscopic examination shows endocervical tissue with a tall, columnar mucus-producing epithelium lining the glands and partly covering the surface of the biopsy fragment. Metaplastic squamous mucosa replaces a significant proportion of the normal endocervical mucosa. Look carefully at this metaplastic epithelium. The basal cell layers show vertical nuclear polarity, nuclear hyperchromasia, increased nuclear size and mitotic

activity - this change involves approximately 1/3 of the thickness of the mucosa of one of the fragments and 2/3 of the mucosal thickness of the other fragment. These are the features of cervical dysplasia - mild (1/3) and moderate (1/3-2/3). Importantly, surface maturation of the squamous cells is still present in both biopsies. Both these biopsies show evidence of wart virus infection - the changes are best seen in the mildly dysplastic lesion. The cells show irregular nuclei (crumpled paper bag), bi-and multinucleate forms and koilocytosis (clearing of the cytoplasm). Immunoperoxidase techniques can be used to identify viral antigens in the cells. The virus involved is the Human Papilloma Virus (HPV) of which there are many types. Types 16, 18 and 31 (high risk types) are usually associated with carcinoma and Types 6 and 11 (low risk types) are most often found in condylomas. HPV DNA is detected by hybridisation techniques in 75-100% of patients with cervical condylomas, cervical dysplasia and invasive carcinoma. This is strong evidence for HPV involvement in cervical cancer. Viral DNA of the high-risk types is thought to become integrated with host DNA, possibly near a protooncogene and acts as a promoter, in concert with other co-carcinogens (initiators). There is now general agreement that most squamous cell carcinomas of the cervix are preceded by the sequence squamous metaplasia - dysplasia carcinoma in situ. (The pre-malignant potential of squamous metaplasia can be totally disregarded). The precancerous lesions of the cervix are classified in two ways: Dysplasia Cervical Intraepithelial Neoplasia (CIN) Mild 1 Moderate 2 Severe 3 Carcinoma-in-situ The CIN approach emphasis that the dysplastic changes represent a spectrum of the same basic change. It does not distinguish between severe dysplasia and carcinoma in situ. This is the preferred approach at this hospital. Notes: Slide 55: Carcinoma in situ (CIN III) of cervix [photograph] Clinical History: Cervical intraepithelial neoplasia typically evolves over a long period and produces no clinical manifestations. Occasionally, patients may complain

of an increased vaginal discharge. For this reason routine screening of all sexually active women using the Papanicolaou smear is recommended. Gross: No recognisable abnormality of the cervix is seen with the naked eye. Areas of carcinoma in situ (which are depleted of glycogen) will not stain when the cervix is painted with a solution of iodine and potassium iodide (the Schiller test). At colposcopy, areas of white epithelium and abnormal patterns referred to as mosaic or punctuation patterns may be observed. Microscopy: Macroscopic examination of this slide shows two irregular eosinophilic pieces of tissue, each with a mucosal surface (basophilic band) along one edge. Microscopic examination reveals them to be sections from the cervix. Normal squamous epithelium lines the surface at the end of the section. Normal endocervical glands lined by tall columnar mucus-producing epithelium are present at the opposite end of the section surrounded by connective tissue. The surface epithelium, which should be endocervical in type, has been replaced by a squamous mucosa that shows features of CIN 3. These include an increase in nuclear size and mitotic activity, vertical polarity and greatly reduced surface maturation of the cells through the full thickness of the epithelium. There is no invasion of the stroma by atypical cells so this is CIN 3 (carcinoma-in-situ or severe dysplasia. A predominantly chronic inflammatory cell infiltrate is present in the surrounding stroma. CIN 3 is clearly a precursor of invasive carcinoma. With appropriate therapy 100% cure should be achieved in these patients. Notes: Slide 56: Squamous cell carcinoma of the cervix, UP 4880 [83M8073B] [photograph] Clinical History: No clinical notes are available for this patient. However, many cervical cancers are asymptomatic. Once they become clinically overt, patients usually present with irregular vaginal bleeding, leukorrhoea, pain on coitus and dysuria. Gross: The specimen consists of a uterus, cervix and attached adnexal structures. Close inspection of the cervix shows distortion of the tissue by a fairly well demarcated lobulated mass that is grey/yellow in colour. This mass

appears to have arisen in the region of the transformation zone of the cervix and is extending upwards and laterally as well as downwards and laterally. There is evidence of central cavitation and haemorrhage. A number of small mucous retention cysts can be identified in the endocervical canal. The endometrium appears thin. The myometrium is normal. Both ovaries and fallopian tubes are unremarkable. Microscopy: Macroscopic examination of this slide shows an irregular shaped piece of tissue with a well-defined lining along one edge. Under the microscope examine the pale pink area away from the label first. This is ectocervical tissue covered by an intact squamous mucosa. The underlying stroma contains a number of dilated lymphatic channels. Follow this normal mucosa along and you suddenly come to a focus of mucosal loss with an adherent fibrinous exudate. Immediately adjacent to this area is a large tumour mass showing focal superficial ulceration and deep invasion of the cervical connective tissues. The tumour cells form large sheets and broad trabeculae. They have ovalshaped nuclei with small nucleoli and show numerous mitoses. There is significant variation in nuclear size and shape. Cell outlines are fairly distinct in some areas. Obvious squamous cell differentiation is not seen here - this is a large cell, non-keratinising SCC of the cervix (the most common variant). Large cell keratinising SCC shows the typical features of squamous type differentiation: squamous pearls, individual cell keratinisation and intercellular bridges. A mixed inflammatory cell infiltrate is present at the deep margin of the infiltrating tumour. There is no vascular or lymphatic invasion by tumour cells. Notes: Slide 57: Endometrial polyp + leiomyoma + adenomyosis, UP 494 [82M8890T84M7381] Clinical History: This 53 year old woman presented with a history of menorrhagia of unknown duration. A total hysterectomy was performed. Gross: The mounted specimen consists of a bisected uterus, including the cervix and right fallopian tube and ovary. The cervix appears within normal limits. The uterus is enlarged and significantly distorted by a number of well-circumscribed rounded lesions of variable size. The cut surface of these lesions shows whorled white tissue with no evidence of

haemorrhage or necrosis. These are fibroids, situated subserosally and intramurally. The endometrial cavity contains a polypoid mass with a smooth surface and multiple tiny cysts on the cut surface. Some of these cysts appear to contain mucoid material. This is a fairly typical appearance of a benign endometrial polyp. The endometrial lining can also be discerned on careful inspection. It is approximately 2-3 mm in thickness and has a slightly furry appearance. Microscopy: Macroscopic examination of the slide shows a rectangular portion of basophilic tissue in which a well-circumscribed oval shaped pink nodule is identified. Attached to this rectangle of tissue and apparently arising from it, is a wedged shaped area of tissue showing multiple small cystic spaces. Microscopic examination of this slide reveals 3 distinct areas of pathological change! The myometrial tissue is unremarkable but within it is a small fibroid (Leiomyoma). This corresponds to the pink nodule seen macroscopically. Examination of the leiomyoma will show interwoven fascicles of plump spindle cells with cigar shaped nuclei. The cell population is uniform and there is no mitotic activity. This lesion is undergoing hyalinisation, a degenerative change, which can be seen as fairly bright eosinophilic intercellular material. Examination of the multicystic lesion identified macroscopically shows it to consist of multiple variably sized cystic spaces lined by inactive endometrial type epithelium. Careful inspection will reveal foci of metaplasia including mucus producing cells (endocervical canal) and squamous cells. The glandular epithelium shows no dysplastic features and there is abundant intervening stroma. This is a benign endometrial polyp. A tiny amount of inactive endometrium is present. Examination of the serosal surface of the myometrium will show a tiny collection of gland-like structures. These glands are lined by endometrial epithelium and surrounded by a small amount of endometrial stroma. This is a focus of adenomyosis. Notes: Slide 58: Endometriosis of the ovary, UP 1241 [87M3857] Clinical History: No clinical notes are available for this particular patient. However, most patients present with severe dysmenorrhoea and pelvic pain. Menstrual irregularities are common and infertility is the presenting complaint in 30 to 40% of women.

Gross: The mounted specimen consists of an open unilocular cystic structure. This cyst measures approximately 9 x 6 cm in size and contains blood. The lining of the cyst appears smooth. The wall of the cyst is relatively thin except towards the top of the specimen where a nodule of connective tissue is identified. Careful examination of this tissue reveals a number of tiny cystic spaces just beneath the capsule, these probably represent functional ovarian cysts. This is the residual ovarian tissue. Microscopy: Macroscopic examination of the slide shows an irregular piece of tissue. The fallopian tube lies towards the label. This can be recognised by the very delicate and complex blue folds of the fimbriae lining the lumen. Below the fallopian tube is ovarian tissue. Within the ovarian tissue two irregularly shaped blood filled cysts can be seen. Microscopic examination of this slide confirms the presence of the fallopian tube. Complex fimbrial folds are lined by a tall columnar ciliated epithelium. There is no evidence of chronic inflammation. The tube is bound to the ovary by oedematous fibrous adhesions. Careful examination of the two blood-filled cystic lesions within the ovary reveals the microscopic features of endometriosis. The cyst closest to the label of the slide is lined by tall columnar endometrial cells and associated with these cells is a small amount of endometrial stroma. A mixed inflammatory cell infiltrate is present within the stroma. Beyond the endometrial stroma is a broad band of oedematous fibrous connective tissue. Pigment laden macrophages are a feature both within this connective tissue and just beyond it. The other cystic lesion shows destruction of the endometrial lining and stroma. To make a definite histological diagnosis of endometriosis, one needs to identify at least 2 of the 3 diagnostic features (endometrial glands, endometrial stroma and pigment laden macrophages). Also present in this ovary are two developing follicles. Notes: Slide 59: Tubal ectopic pregnancy, UP 271 [8610M2624] Clinical History: This woman had 3 normal confinements, 2 premature stillbirths and one neonatal death. For 3 months after ceasing the oral contraceptive pill, she had suffered from irregular periods and menorrhagia. She was examined at home where she felt faint and had a tender abdomen suggestive e of an ectopic pregnancy. She was admitted to hospital and found on vaginal

examination to be tender in the right fornix. At operation a right tubal ectopic pregnancy was found and a right salpingectomy was performed. Gross: The mounted specimen consists of the right uterine tube with a large amount of blood clot extruding from the fimbriated end. Within the blood clot, a foetus measuring 10 mm in length can be seen. Beneath the fallopian tube there is an ovarian cyst measuring 3 cm in diameter and containing translucent gelatinous material. Also attached to the fimbriated end of the fallopian tube are 3 thin walled parovarian cysts. Microscopy: Macroscopic examination of the slide shows a rounded collection of material with a variegated appearance. There is an intimate admixture of pink and red tissue. Examination of this material under the microscope shows blood (red) and fibrin (pink) admixed with white blood cells and platelets. Scattered through this blood clot are small numbers of immature chorionic villi. These villi are rounded structures covered by two layers of cells. The inner cuboidal layer is the cytotrophoblast and the outer syncitial layer is the syncitiotrophoblast. No foetal tissue is seen on this slide. Notes: Slide 60: Mature cystic teratoma of the ovary, UP 473 [87M9080D] Clinical History: No clinical details are available for this particular patient. However, cystic teratomas are usually found in young women during their reproductive years. The patients may present with abdominal pain or a mass. Menstrual irregularities and torsion of the tumour may also occur. Gross: The mounted specimen shows a hydrosalpinx and an ovary containing a cystic tumour. The cyst would have contained greasy sebum and hair. The lining of the cyst is essentially smooth with a number of nodules of more solid tissue. Protruding from these nodules are black hairs and wellformed teeth. The cyst wall consists of fibrous connective tissue measuring up to 1 cm in thickness. Microscopy: Macroscopic examination of this slide shows an oval shaped portion of tissue that contains a number of variably sized and shaped cystic structures. Close inspection of the solid component shows a variegated appearance.

Microscopic examination of this slide shows a range of mature tissues. These tissues may arise from any of the 3 germ layers, although those of ectodermal origin are usually the best represented. See if you can identify the following: Ectoderm: epidermis sebaceous glands Mesoderm: smooth muscle connective tissues blood vessels Endoderm: respiratory epithelium mucin-producing glands squamous mucosa thyroid A small amount of oedematous ovarian stroma is present along one edge of the tissue and this contains a follicular cyst. Foreign body type giant cells and numerous foamy macrophages are present. The cystic spaces in these tumours usually contain sebum and hair. If the cyst ruptures this material incites a strong foreign body type inflammatory response. In assessing these tumours it is important that all the tissue elements present are mature. The presence of immature (embryonic) tissue elements indicates malignancy. Notes: Slide 61: Mucinous cystadenoma of the ovary Clinical History: This 34 year old woman noticed a lump in her abdomen. Her doctor thought it was similar in size to a 16-week pregnancy but her periods were regular and her pregnancy test was negative. A laparotomy was performed and an ovarian cyst was removed. Gross: The mounted specimen consists of an open bilocular ovarian cyst. Part of the fallopian tube is stretched across the serosal surface of the cyst. The cyst contained clear, watery fluid (this would suggest a serous type lining however, the lining type and nature of the fluid within the cyst do not always correlate). The lining of the cyst cavities is smooth with no evidence of papillary projections or solid nodules of tissue. The cyst wall

is thin and composed of fibrous tissue. There is no macroscopic evidence of malignancy. Microscopy: The section consists of a portion of the cyst wall and shows it to be lined by a simple columnar mucus-secreting epithelium. The cells are tall and columnar with abundant eosinophilic cytoplasm and apical intracytoplasmic mucin. The nuclei are round or oval, basophilic, and vesicular. The epithelium is completely regular and there are no cytological features to indicate malignancy. The mucinous epithelium of this tumour is believed result from metaplasia of the surface germinal epithelium of the ovary. Thus the normally flat mesothelial cells of the ovarian surface initially undergo invagination and then metaplasia to form cysts lined by a columnar mucus-secreting epithelium. This epithelium then undergoes further neoplastic change resulting in the development of numerous cysts of varying sizes lined by identical epithelium. A cystadenoma is basically an adenomatous grouping of glands in which the glandular acini have undergone cystic dilatation. The cysts can be unilocular or multilocular. Notes: Slide 62: Fibrocystic disease of the breast Clinical History: Fibrocystic changes in the breast may produce a palpable breast lump. This disease is important as all lumps in the breast require differentiation from carcinoma and some of the elements of fibrocystic disease may predispose to the subsequent development of carcinoma. Gross: The breast tissue may have a firm, rubbery consistency and if cystic change is a significant component, variably sized cysts may be identified macroscopically. These cysts may be as large as 5 cm in diameter and they contain semitranslucent, turbid fluid. Microscopy: Macroscopic examination of the slide shows a small irregularly shaped fragment of predominantly eosinophilic tissue with multiple tiny cystic spaces and small foci of basophilia. Microscopic examination of this slide shows breast tissue. The following features are present: 1) Interstitial fibrosis 2) Cystic dilatation of ducts

3) Apocrine metaplasia of ductal epithelium 4) Adenosis - hyperplasia of the glandular component of the breast 5) Sclerosing adenosis - intralobular fibrosis with proliferation of small ductules and acini. There is one small focus of this change. 6) Epithelial hyperplasia (epitheliosis), which is a benign proliferation of epithelial cells. There is no epithelial hyperplasia (epitheliosis) in this case, but epitheliosis is part of the spectrum of fibrocystic disease. The association between fibrocystic disease and cancer is proportional to the degree of epithelial hyperplasia and atypia seen; there is no increased risk of breast carcinoma with any of the other components (see above list). Notes: Slide 63: Fibroadenoma of the breast Clinical History: This young woman had a mobile, firm breast lump. It was surgically removed and shelled out readily from the surrounding breast tissue. Gross: The mounted specimen shows a well-circumscribed, rounded tumour mass measuring 2.5 cm in diameter. The cut surface is greyish/white in colour. These lesions have a firm, rubbery consistency. Microscopy: Macroscopic examination of the tissue section shows a rounded nodule of tissue with an internal lobulated structure. The lobules appear pale and are separated by dense strands of eosinophilic material. Examination under the microscope shows that the pale foci consist of loose connective tissue containing glandular structures and the individual foci are separated by dense eosinophilic collagenous fibrous tissue. Within the lobules the proliferation of loose connective tissue has compressed some glandular acini and ducts to form elongated thin tubules. In some areas the tubular lumen has disappeared and simple cords of epithelial cells are seen. This pattern of fibroadenoma is known as an intracanalicular fibroadenoma. In other areas the proliferation of loose connective tissue has not compressed the glandular acini or ducts. This pattern is known as pericanalicular fibroadenoma. It is not unusual for both patterns to be seen together in the one lesion. Fibroadenoma of the breast is a benign tumour in which the entire lobular tissue proliferates. Thus there is proliferation of both glandular elements and the normal loose connective tissue stroma of the lobule. In cases such as this the proliferation of the lobular connective tissue is predominant and

has caused compression of the proliferating glandular elements. In some areas of the section the proliferating glandular elements are more obvious. There are no cytological features to suggest malignancy and thus this is a benign tumour in which there is proliferation of both epithelial and stromal elements. This is not completely unexpected, as we know there is cooperation between epithelium and stroma in the normal functioning breast. Notes: Slide 64: Invasive duct carcinoma of the breast Clinical History: No clinical notes are available for this particular patient. Most patients will present with a breast lump. Gross: The specimen consists of a right breast and a portion of the right axillary tail. A hard tumour mass approximately 2 cm in diameter is present in the upper, outer quadrant of the breast. Associated with this mass is ulceration of the overlying skin. The nipple appears macroscopically normal. Examination of the cut surface of the specimen shows that a large amount of tumour tissue has been removed for histological examination and assessment of oestrogen receptors. One can see the grey/white fibrous connective tissue that constitutes the desmoplastic stroma surrounding the tumour cells, radiating out from the centre of the lesion. Also present within the breast tissue are two small lymph nodes. These are rounded in shape and pale brown in colour. Microscopy: Sections show benign fibrocystic disease in the surrounding breast tissue. Most of the tissue however appears abnormal and strands of tumour cells are seen separated by connective tissue. The tumour cells on high power examination show a moderate variation in cell size and shape together with variation in nuclear characteristics. Some nuclei possess small fairly inconspicuous nucleoli. Characteristically, it is difficult to detect mitotic figures in this type of carcinoma and the major clue to the diagnosis is the architectural disarray. At the periphery of the tumour, malignant cells can be seen distending ducts - this represents intraduct breast carcinoma. Scirrhous carcinoma is a poorly differentiated adenocarcinoma which excites a prominent desmoplastic stromal reaction. Because of the marked desmoplasia the tumour feels firm and cuts with a gritty sensation. Notes:

Slide 65: Healing fracture Microscopy: Macroscopic examination of the slide shows a longitudinal section through a long bone fracture. The fractured ends of the long bone are separated transversely but are united by a fusiform mass of pale pink tissue which, under the microscope, proves to be a mixture of fibrous tissue, cartilage and woven bone. This mass of fibrocartilaginous and bony tissue uniting the two ends of the fractured long bone is known as fibrocartilaginous callus. In some areas within the callus granulation tissue can be recognised. Close examination of the fractured ends of the long bone show numerous empty lacunae indicating that some of the bone fragments are necrotic due to interruption of blood supply at the time of fracture. At the fracture site the periosteum can be seen to be elevated and cartilage is extending down the periosteum into the fracture space. Although in the centre of the fracture the predominant tissue is cartilage at the margins where the periosteum has been elevated from the underlying bone shaft the process is more advanced and the predominant tissue is woven bone. Healing of a fracture is a continuous process but can be divided easily into three stages. The first stage is the development of a haematoma at the fracture site and organisation of this haematoma to form granulation tissue known as procallus. In the second stage (fibrocartilaginous callus) cells from the displaced periosteum and the endosteum overlying the bone fragments proliferate to form cartilage, fibrous tissue, and woven bone. In the third stage the fibrocartilaginous callus is steadily replaced by woven bone to form bony provisional callus. In time this bony callus is remodelled along the lines of weight bearing to complete the fracture repair. Notes:

Slide 66: Rheumatoid arthritis Clinical History: This 62 year old female was admitted to hospital with severe shortness of breath and died several hours later. An autopsy revealed a recent myocardial infarct, massive pulmonary embolism and rheumatoid arthritis which was most marked in the fingers of the right hand. Gross:

The mounted specimen consists of the right ring finger which is grossly swollen and erythematous in the region of the proximal interphalangeal joint. Rheumatoid arthritis is essentially a severe form of chronic synovitis, but as the disease progresses, periarticular soft tissue oedema and inflammation may occur and this causes the fusiform swelling around the joint. Microscopy: Macroscopic examination of this slide shows an irregular arrangement of eosinophilic papillary structures with a thin covering of basophilic tissue. Microscopic examination of the slide shows finger-like protrusions of inflamed and oedematous fibrovascular stroma covered by plump epithelial cells that are focally multilayered. Fragments of fibrin are also present. This synovial tissue shows all the salient features of rheumatoid arthritis: 1) Villous hypertrophy of synovium 2) Hyperplasia of synoviocytes 3) Chronic inflammation: plasma cells, lymphocytes, and lymphoid follicles. This exuberant inflammatory tissue is known as pannus. The pannus eventually covers the articular surfaces of the joints involved and, by release of enzymes and mediators, destroys the underlying bone and cartilage. Notes: Slide 67: Rheumatoid nodule Clinical History: Rheumatoid nodules usually occur in the subcutaneous connective tissues and may appear in up to 25% of patients with rheumatoid arthritis. They are also described in the lungs, spleen, pericardium, myocardium, heart valves, aorta and many other internal organs. Gross: Rheumatoid nodules in the skin typically occur in relation to pressure points, e.g. elbows, back of forearms and the occiput. They are typically non-tender, firm rounded masses, measuring up to 2 cm in size. Microscopy: Macroscopic examination of the slide shows a wedge-shaped portion of pink tissue with a thin, blue surface covering along one side. Microscopic examination of the slide shows non-hair-bearing skin with a thickened epidermis showing hyperkeratosis. These features suggest that the biopsy may have been taken from the palm of the hand or the heel. In

the deep dermis, a number of variably sized and shaped lesions can be identified. These lesions show a central area of brightly eosinophilic, fibrinoid necrosis. Surrounding this zone of necrosis is a layer of palisading epithelioid cells. Beyond the layer of epithelioid cells is dense fibrous connective tissue. In some cases numerous lymphocytes and plasma cells are seen in this connective tissue, but this inflammatory infiltrate is not present in this particular case. Notes: Slide 68: Gout Clinical History: No clinical notes are available for this particular patient. Soft tissue tophi usually appear in association with chronic gouty arthritis. Patients with chronic arthritis will have suffered multiple episodes of acute arthritis. These episodes are usually of increasing severity and progress to involve more and more joints. Soft tissue tophi are usually non-tender. Gross: The mounted specimen consists of part of a para articular nodule. Tendinous connective tissue can be identified related to the surface of this nodule. The cut surface shows a fairly well circumscribed lesion comprised of multiple deposits of creamy, yellow material. Microscopy: Macroscopic examination of the slide shows a wedge shaped portion of tissue with a variegated appearance. A large amount of pale pink material is present, separated by delicate septa that appear dark pink to blue. Microscopic examination of the slide shows the lesion to be partly encapsulated. The capsule consists of dense fibrous connective tissue in which small blood vessels, nerves and adipose tissue are clearly identified. Thin fibrous septa extend from the capsule into the bulk of the lesion. Large numbers of foreign-body type giant cells are intimately associated with these fibrous septa and appear to be attempting to engulf the pale eosinophilic material that fills the spaces between the septa. The nature of this pale eosinophilic material is impossible to determine accurately using the light microscope. If this slide were viewed with polarised light, the urate crystals would show up as birefringent and needle-like in shape. If one suspects gout clinically any tissue removed for histology needs to be fixed in absolute alcohol not formalin, as the urate crystals are soluble in formalin and will dissolve. Notes:

Slide 69: Osteoarthritis Clinical History: No clinical notes are available for this particular patient. Patients with osteoarthritis usually have stiffness and pain first thing in the morning which subsides once they start moving about but then recurs later in the day as the result of undue activity. The hips, knees and back are the joints most often involved. Gross: The mounted specimen consists of a surgically resected femoral head. The articular surface over half of the femoral head is denuded of cartilage with the exposure of underlying smooth bone (eburnation). The remaining cartilage shows fissuring and flaking. The margins of the articular surface are extremely irregular. This irregularity is due to the formation of multiple small osteophytes, most of which are covered by cartilage. Microscopy: Macroscopic examination of the slide shows a rectangular portion of tissue. The interwoven trabeculae of cortical bone can be clearly identified. The pale pink tissue along the upper surface of the tissue block represents the articular cartilage. Under the microscope look first at the articular cartilage. The loss of proteoglycans results in decreased metachromasia of the cartilage. This accounts for the eosinophilic as opposed to basophilic staining. The surface of the articular cartilage should be smooth - in this case fissuring, pitting and flaking are clearly seen. In some areas the articular cartilage has disappeared altogether exposing subchondral bone. This exposure of subchondral bone may lead to increased vascularity and thickening of the bony trabeculae. These changes are clearly seen in a number of areas on this slide. In other areas death of osteocytes or increased osteoclastic activity has led to thinning of the bony trabeculae with microcyst formation. As a result of all these changes, deformation of the articular ends of the bone may occur. Notes: Slide 70: Osteochondroma Clinical History: No notes are available for this particular patient. Gross: The mounted specimen contains a fragment of bone including cortex and trabecular marrow. Protruding from the external surface of this bone is a lesion approximately 1 cm in length covered by a smooth cartilaginous cap.

Microscopy: Each lesion consists of a bony outgrowth covered by a cartilaginous cap and the lesion grows by a process of endochondral ossification from the base of the cartilaginous cap. As the lesion matures the cartilaginous cap disappears and the bony outgrowth ceases to increase in size. Exostoses present as single or multiple bony outgrowths from the metaphyseal shafts of long bones near the epiphysial plate. As each lesion develops it increases in size and increases its distance from the epiphysial plate. They are best regarded as hamartomas and may result from displacement of epiphysial cartilage which retains its ability to produce bone via endochondral ossification. The lesions usually present in late childhood or adolescence. They appear most frequently on the long bones of the extremities and are usually asymptomatic and come to attention as a chance radiographic finding. In some cases they present as obvious deformities or may impinge on a nerve or blood vessel. Notes: Slide 71: Osteosarcoma Clinical History: This 9 year old boy was admitted to hospital with an indurated swelling below and lateral to the knee which was thought to be a deep-seated abscess, possibly related to osteomyelitis. X-Ray however, showed a tumour in the upper end of the fibula in which there was extensive bone formation, suggesting an osteosarcoma. At operation the fibula was excised preserving the lateral popliteal nerve. Postoperative radiotherapy was given. Gross: The mounted specimen consists of the upper end of the fibula. A large fusiform tumour is present. This tumour shows extensive bone and cartilage formation with multiple areas of haemorrhage. The cortex of the original bone has been partly destroyed by tumour tissue. Microscopy: Macroscopic examination of the slide shows a variegated portion of tissue. In the top left hand corner a small amount of residual cortical bone can be seen - the rest of the tissue is tumour. The bright pink zone is an area of necrosis. Examination of the tissue section under low power magnification shows a variety of tissues present. The tumour shows areas of malignant cartilage,

bone formation, tumour cells forming pink acellular osteoid, and cellular areas resembling fibrosarcoma. The tumour is infiltrating skeletal muscle and a few residual densely eosinophilic skeletal muscle fibres can be recognised at one edge of the tumour. There is also a large area of tumour necrosis. Any tumour in which the tumour cells can be seen to be forming osteoid or bone is by definition an osteosarcoma. The tumour cells can also form cellular areas which are identical to fibrosarcoma, malignant fibrous histiocytoma or chondrosarcoma. Thus an osteosarcoma can show predominantly fibrosarcomatous or chondrosarcomatous differentiation. The tumour cells in this case are irregular in shape but are basically spindle shaped and have a moderate amount of eosinophilic cytoplasm. They vary considerably in shape, size and staining characteristics. Scattered mitotic figures are present. Osteoid is recognised as amorphous, rather hyaline, eosinophilic material lying between tumour cells and within which tumour cells lie within a small space or lacuna. In some areas the osteoid is seen to be calcified and resembles woven bone. Osteosarcoma is a highly malignant tumour of osteoblasts and has a very poor prognosis. Notes: Slide 72: Myeloma. Clinical History: No clinical notes are available for this particular patient. The clinical features of myeloma stem from the effects of 1) infiltration of organs, particularly bones, by the neoplastic plasma cells and 2) the production of abnormal excessive immunoglobulins. Patients therefore present with bone pain, pathological fractures, hypercalcaemia and recurrent infections. Gross: The mounted specimen consists of a narrow slice of sternum. The normal marrow space has been obliterated by tumour tissue. These deposits usually appear as soft, red gelatinous tissue. Radiographically the lesions have a distinctive, sharply punched out appearance. Microscopy: Macroscopic examination of the slide shows multiple irregular fragments of tissue. These fragments are variegated in appearance with red, pink and blue areas. Microscopic examination of the slide shows blood (red), coagulative necrosis of tumour tissue (pink) and viable tumour tissue (blue). Close

examination of the viable tumour tissue shows sheets of non-cohesive cells with ill-defined eosinophilic cytoplasm and round to oval nuclei. The nuclei show a characteristic clumping of nuclear chromatin. These nuclear features indicate plasmacytic differentiation. Multiple myeloma is a multifocal plasma cell neoplasm. Notes: Slide 73: Reactive lymphoid hyperplasia Clinical History: This 73 year old man present with an enlarged lymph node in the left submandibular region. Involvement of the node by metastatic carcinoma or lymphoma was considered the most likely possibility clinically and a lymph node biopsy was performed. Lymph node biopsies should be sent urgently and fresh to the Pathology Laboratory in a sterile container. On arrival in the laboratory a pathologist will examine the removed node. Depending on the clinical setting and the macroscopic appearance of the node, tissue will be submitted for microbiological culture, cell marker studies, electron microscopy and routine processing. Gross: The biopsy specimen from this patient consisted of a lymph node measuring 1.6 cm in maximum dimension. Microscopy: Macroscopic examination of the slide shows 3 rounded portions of deep blue tissue. Close inspection reveals numerous paler grey-blue zones 1-2 mm in diameter. Examination under the microscope shows preservation of the normal nodal architecture. The cortex has been significantly expanded by numerous, variably sized reactive germinal centres. A mantle of small lymphocytes surrounds each germinal centre. The paracortex is compressed and contains predominantly small lymphocytes. This is an example of the follicular type of reactive lymphoid hyperplasia. This is indicative of a B cell response to an immune stimulus. In many cases the features are non-specific (as in this case) and the aetiology is obscure. Notes: Slide 74: Sarcoid Clinical History:

Sarcoidosis is a multisystem disease characterised by non-caseating granulomata. As a result it is a protean clinical disease. However, most patients present with shortness of breath, cough, chest pain or haemoptysis associated with constitutional signs and symptoms. Gross: The lymph nodes are usually large and discrete. Early on in the disease the nodes are soft but as the disease progresses and becomes more chronic, the nodes may become fibrotic. Microscopy: Macroscopic examination of the slide shows an irregularly shaped block of eosinophilic tissue with a delicate, lace-like pattern of basophilic tissue throughout. Microscopic examination shows numerous rounded and coalescing eosinophilic areas separated by lymphocytes and occasional germinal centres. The eosinophilic lesions consist of focal aggregates of epithelioid macrophages with pale oval nuclei, prominent nucleoli and plentiful foamy eosinophilic cytoplasm, i.e. granulomata. There is no evidence of central necrosis in any of the many granulomata seen. Fibrous tissue is present within and around these lesions. The histological appearance of these granulomata is typical for sarcoidosis but special stains should always be done to exclude tuberculosis, atypical mycobacterial and fungal infections. Similar lesions can also be seen in Hodgkins disease, Crohns disease and in nodes draining a carcinoma the diagnosis of sarcoidosis is therefore one of exclusion. Langhans or foreign-body type giant cells may also be present and may contain Schaumann bodies (laminated concretions of calcium and proteins) and asteroid bodies (criss-crossing bundles of collagen). Sarcoidosis is a systemic disease and granulomata may occur virtually anywhere. It follows a rather unpredictable course - progressive pulmonary fibrosis with cor pulmonale is the mode of death for most of the patients who die of the disease (~10%). Notes: Slide 75: Nodular/follicular lymphoma Clinical History: Follicular lymphomas tend to occur in older patients and present with generalised painless lymphadenopathy. In about 85% of patients the tumour cells show a characteristic translocation t(14;18). These tumours have a long indolent natural history and appear to be unaffected by treatment.

Microscopy: Macroscopic examination of the slide shows two rounded fragments of basophilic tissue. Close inspection reveals small nodules of slightly paler tissue scattered throughout. Microscopic examination shows complete effacement of the normal nodal architecture by a nodular proliferation of neoplastic lymphoid cells. This is therefore a nodular/follicular lymphoma. Careful examination of the cells forming these nodules shows them to be a mixture of small cleaved and large cells. This patient has a malignant nodular lymphoma of mixed cell type (low grade). Nodular lymphomas have a better prognosis than diffuse lymphomas of the same cytological subtype. Notes: Slide 76: Hodgkin disease (nodular sclerosing) Clinical History: This 41 year old woman presented with lymphadenopathy for investigation. CT scan revealed mediastinal enlargement and biopsy showed Hodgkin lymphoma. She was treated with chemotherapy over the next 4 years. She then felt increasingly unwell and medical examination revealed a large left sided cervical mass. This was demonstrated in a CT scan which also showed considerable superior mediastinal shadowing. The cervical mass subsequently enlarged; fine needle aspiration (FNA) was performed but the results were not diagnostic. An abscess developed at the FNA site and she was admitted to hospital one month later for treatment. It was decided to perform a left cervical lymph node biopsy at this time since the previous biopsy was unavailable and the current status of the disease needed to be established. The biopsy was duly performed and she continued on chemotherapy. She was discharged home a few days later, to continue chemotherapy as an outpatient. Gross: This is a photograph of the lymph node mass received in the laboratory. It has been cut in half for sectioning and the 2 halves displayed. Note the faint outlines of several apparently discrete nodes on the cut faces. The mounted museum specimen gives an idea of the possible appearance of the mediastinal lymph node mass. It shows a portion of the abdominal aorta. The aorta shows moderately severe atherosclerosis with numerous atheromatous plaques, some of which are complicated by superficial ulceration. A matted mass of enlarged lymph nodes surrounds the aorta.

These nodes measure up to 3 cm in size and their cut surfaces show homogenous grey/pink tissue with numerous geographic areas of creamy, yellow necrosis. Microscopy: Macroscopic examination of the slide shows a roughly circular piece of tissue. Microscopic examination reveals a lymph node showing complete effacement of its normal architecture. The diagnostic features of Hodgkin disease include Reed-Sternberg cells, mononuclear variants of the R-S cell (Hodgkin cells) and a mixed background population of non-neoplastic inflammatory cells including eosinophils, lymphocytes and plasma cells. Two additional features distinguish the nodular sclerosing type of Hodgkin disease. Fibrosis: dense bands of collagenous fibrous tissue separate the cellular areas producing a lobular pattern. Lacunar cells: these are variants of Reed Sternberg cells. The lacunar cell variant has a folded or multilobulated nucleus lying within a clear space with fine pink bands radiating outwards from the nucleus; the latter are artifacts caused by shrinkage of the cell during processing in the laboratory The Reed-Sternberg cells (and variants) are large cells with very striking inclusion-like eosinophilic nucleoli. Try and identify them using the following diagram:

Classic Reed-Sternberg Cell

Hodgkin Cell (mononuclear variant) There are 3 major subtypes of Hodgkin disease: 1. Nodular sclerosis 2. Mixed cellularity 3. Lymphocyte predominance and a less common subtype, lymphocyte depletion. Nodular sclerosing is the commonest type and has a good prognosis.

The Reed Sternberg cell and its variants are the transformed neoplastic cells of this disease and typically account for 1 to 5% of the total tumour mass. Notes: Slide 77: Multinodular goitre Clinical History: This 47 year old man had a goitre for 30 years which recently caused marked dyspnoea. A partial thyroidectomy was carried out. Gross: The mounted specimen shows the thyroid gland viewed from behind. The specimen weighs 670 gm. The capsular surface of the gland is distorted by a number of variably sized nodules and shows prominent blood vessels. The cut surface of the gland confirms the presence of multiple variably sized and shaped nodules. These nodules are separated by delicate grey/white fibrous septa. A number of foci of haemorrhage are apparent within some of the nodules. One nodule is surrounded by a thick, white fibrous capsule and shows macroscopic evidence of dystrophic calcification both within the wall of the capsule and centrally within the nodule. Microscopy: Macroscopic examination of the slide shows an irregular fragment of eosinophilic tissue that is divided into lobules. Within each lobule rounded nodules of bright eosinophilic material are seen. Microscopic examination shows thyroid tissue. Collections of variably sized and shaped follicles are present grouped together to form irregular lobules. The follicles are distended with colloid material and lined by a single layer of cuboidal cells with regular nuclei. There is no peripheral scalloping. Other features to look for are haemosiderin-laden macrophages and fibrosis. Dystrophic calcification may also occur but is not present in this slide. Multinodular goitres are important because of: 1) size and location 2) possible abnormal function (thyrotoxicosis) 3) confusion with malignancy. Notes: Slide 78: Hyperplastic goitre Clinical History:

No clinical notes are available for this particular patient. However, these patients usually present with signs and symptoms of hyperthyroidism. Most of the patients are under 40 years of age and usually female. Gross: The mounted specimen consists of a subtotal thyroidectomy. The thyroid gland is enlarged and has a fleshy appearance with little obvious colloid. No thyroid nodules are present. These patients are usually treated medically prior to surgery and as a result there is some shrinkage of the thyroid gland and diminished vascularity. Microscopy: Macroscopic examination of the slide shows fairly cellular tissue in which small pink foci of thyroid colloid can be recognised. In a hyperplastic gland there is a relative increase in the number of cells at the expense of colloid and macroscopically because of the increased numbers of nuclei the tissue section appears more basophilic than normal thyroid. Examination under the microscope reveals the changes associated with thyroid hyperplasia. It is important to remember however that some of the most obvious changes will not be seen as these patients are treated prior to surgical intervention. The features to note are: (a) Numerous small follicles containing little pale colloid. (b) Larger follicles showing active scalloping of colloid at the follicle margin. This peripheral vacuolation of colloid is an artifact occurring during tissue processing but is a reliable artifact in that it is only seen in hyperplastic glands. (c) The cells lining the larger follicles appear low columnar or cuboidal in shape with basal basophilic nuclei. (d) Some of the larger follicles show slight papillary infolding of the lining epithelium. In the resting thyroid the thyroid epithelial cells appear flat and the follicles are distended with colloid. As activity of the follicle increases the nucleus increases in size and becomes basal, the follicle-lining cell becomes columnar and there is papillary infolding of epithelium. Colloid is removed and the follicles decrease in size eventually containing little or no colloid. Thyroid tissue responds to TSH-like substances to a varying degree in different areas and therefore examination of a section such as this shows varying stages of the hyperplastic process in different areas. In hyperplasia of the thyroid there is an increase in both the number of cells and the size of individual epithelial cells. Notes: Slide 79: Hashimotos thyroiditis + follicular adenoma

Clinical History: This 66 year old woman had complained of progressive enlargement of the thyroid gland over about a year. There was no clinical evidence of thyrotoxicosis or myxoedema. A partial thyroidectomy was carried out. Gross: The mounted specimen shows part of the thyroid gland. The capsule is intact. The cut surface shows grey/brown fleshy tissue with accentuation of the normal lobulations. This process symmetrically involves the gland. (The adenoma that is present on the microscopic slide is not seen in the specimen - the slide comes from a different patient. The photograph shows a follicular adenoma). Microscopy: Macroscopic examination of the slide shows an irregular fragment of tissue with a lobular pattern. The lobules vary in size and shape and contain numerous small round basophilic areas many of which have pale centres. Also present are two distinct areas - one is round and brightly eosinophilic, the other is slightly larger, oval and faintly basophilic (adenoma). Microscopic examination of the slide shows thyroid tissue. The follicles are small and many appear atrophic. The striking feature is the very intense chronic inflammatory cell infiltrate including plasma cells, lymphocytes and active germinal centres. This infiltrate extensively replaces the gland. Small groups of Hrthle cells can be seen - these are follicular epithelial cells with abundant, brightly eosinophilic, granular cytoplasm. They are virtually non-functional. As a bonus, this slide also shows a circumscribed encapsulated proliferation of benign follicular epithelial cells - an adenoma. The cells show regular, round nuclei and granular cytoplasm. No mitoses are seen. A follicular pattern is present. This is therefore a follicular adenoma. Adenomata are usually fairly small (<4 cm), well-circumscribed, soft lesions that vary in colour from tan to grey-white. Notes: Slide 80: Papillary carcinoma of the thyroid Clinical History: Papillary carcinoma of the thyroid accounts for the majority of thyroid cancers in people under the age of 40. These lesions usually present as incidental painless neck lumps. In a number of patients the first sign of disease is metastatic enlargement of a cervical lymph node. Gross:

These tumours are usually grey-white in colour and range in size from microscopic foci up to nodules of 10 cm in diameter. In the larger lesions the cut surface of the tumour may have a furry appearance. Some tumours are associated with dense fibrous sclerosis and some may even be encapsulated (see photograph). Microscopy: Macroscopic examination of the slide shows an irregularly shaped fragment of eosinophilic tissue with an ill-defined oval lesion containing geographic areas of basophilia. Microscopic examination shows normal thyroid tissue that is partly replaced by a non-encapsulated tumour mass. This tumour consists of delicate papillary formations of tumour cells separated by fibrous stroma. The papillary structures show a complex branching pattern. Characteristic optically clear/ground-glass nuclei are usually found in this disease but are not seen in this case although psammoma bodies are numerous. Infiltrating nests of tumour cells, surrounded by desmoplastic stroma, are clearly seen. This disease has an indolent course - 70-80% of patients survive at least 10 years. Notes: Slide 81: Meningitis Clinical History: This 33 year old man had 10 days of malaise with rather vague aches and pains and 2 days of pain in his chest. He behaved as if inebriated but complained of a very severe headache. He collapsed on the day before admission. When admitted to hospital his temperature was 39 oC, pulse 80 and he had Cheyne-Stokes respiration. There was neck stiffness with a positive Kernig sign. He had papilloedema and decreased power in the right leg. There were bilateral ankle clonus and extensor plantar reflexes. The cerebro-spinal fluid was purulent and pneumococci were cultured from it. He died 2 days after admission. Gross: The mounted specimen shows an extensive purulent exudate in the subarachnoid space but chiefly around the brain stem, in the interpeduncular fossa, extending into the Sylvian fissures and spreading over the frontal, and to a lesser extent, the parietal lobes. The cut surface of the brain shows a purulent ependymitis involving the ventricles. Microscopy:

Macroscopic examination of the slide shows cerebral cortex and overlying this the subarachnoid space. Normally the subarachnoid space contains only fluid and a few cells but in this case it appears to be more cellular than the underlying brain tissue. Examination under the microscope reveals the presence of numerous viable and degenerate polymorphs filling the subarachnoid space. A few scattered mononuclear macrophages are present but these are insignificant compared to the numbers of neutrophils present. This acute inflammatory exudate extends down into the brain sulci and to a limited extent along the Virchow-Robin spaces which are in fact continuations of the subarachnoid space around penetrating blood vessels. There is virtually no extension of the inflammatory process into the cerebral parenchyma. The appearances in this section are typical of bacterial meningitis. Notes: Slide 82: Cerebral abscess Clinical History: Patients usually present with progressive focal and general signs of raised intracranial pressure. A systemic or local source of infection can usually be identified. Gross: These lesions appear similar to abscesses elsewhere in the body. There is a central area of necrotic brain tissue and purulent exudate surrounded by a fibrous capsule. Microscopy: Macroscopic examination of the section of brain tissue shows a central small cavity surrounded by haemorrhagic tissue. Examination of the central cavity shows it to consist of degenerate cellular debris and scattered viable and degenerate polymorphs. This is the histological appearance of pus. Surrounding this central purulent material is a broad zone of haemorrhagic granulation tissue. Some glial cells are present within the granulation tissue and this process is known as a gliomesodermal reaction because both glial cells producing gliosis and mesenchymal cells producing granulation tissue participate. The usual components of granulation tissue are seen and a prominent feature is the presence of perivascular collections of plasma cells. There is extensive interstitial haemorrhage in the region of this gliomesodermal reaction. The surrounding brain tissue shows a minor degree of interstitial oedema and perivascular collections of lymphocytes and plasma cells are noted.

The normal response to damage in the brain is colliquative (liquefactive) necrosis followed by reparative gliosis. If the tissue damage involves the meninges, a structure of mesodermal origin, or if a brain abscess forms then a gliomesodermal reaction develops and ultimately results in an area of fibrous scarring together with gliosis. In this section the typical layers of an abscess are not well demonstrated. The two internal layers are present, a zone of liquefied pus enclosed by granulation tissue, but the peripheral mature fibrosis tissue is not present in this case. Notes: Slide 83: Spinal muscular atrophy Microscopy: Macroscopically this slide shows two irregular fragments of eosinophilic tissue. Microscopic examination reveals skeletal muscle cut in both transverse and longitudinal sections. Look first at the transverse section. Here, one sees groups of small atrophic fibres and groups of persisting normal muscle fibres. The atrophic fibres are small, angulated and brightly eosinophilic. There is considerable apparent increase in the number of nuclei. Normal structural features such as cross striations are retained. The grouped nature of the atrophy suggests that this lesion is neurogenic in origin. Peripheral nerves supply groups of muscle fibres (motor units) so that damage to the nerve results in atrophy of the whole motor unit. Neurogenic atrophy can be secondary to diseases of the spinal cord (involving anterior horn cells); motor nerve roots and peripheral nerves. This case shows neurogenic muscular atrophy in a child with WerdnigHoffman disease (infantile spinal muscular atrophy). Diagnostic muscle biopsies are most helpful in the differential diagnosis of progressive muscle wasting. This is a highly specialised area of surgical pathology - success depends on a careful clinical history, examination, laboratory investigations, meticulous biopsy technique and the performance of a battery of sophisticated tests on the processed tissue (including histochemistry, immunofluorescence, electron microscopy). The muscle chosen for biopsy should be one that is moderately affected by the disease. Close liaison with the pathologist is important - he is able to advise the clinician on the best biopsy site and whether any other tissue, e.g. skin/nerve would be diagnostically helpful. Special muscle biopsy kits are available at the Royal Hobart Hospital Notes:

Slide 84: Multiple sclerosis Clinical History: This 58 year old woman first complained of difficulty in walking some 17 years before death. When admitted to hospital 4 years before she died, she was unable to walk and had urinary incontinence with a chronic renal infection. When examined she could move her arms with marked ataxia and had exaggerated reflexes in the right arm and left knee with bilateral extensor plantar responses. Her speech was normal and she had no nystagmus. In the last 2 years of her life, muscular spasms were frequent and she often complained of pain. Two days before her death she developed a cough and subsequently died with respiratory distress. At autopsy she had right lower lobe lipoid pneumonia, active chronic pyelonephritis and multiple sclerosis plaques in the cerebral hemispheres, brain stem and spinal cord (particularly the cervical region). Gross: The mounted specimen shows 2 coronal slices of the cerebral hemispheres in which there are many paraventricular plaques. These plaques are irregularly shaped, sharply demarcated and translucent grey in colour. Initially, plaques appear pink in colour and swollen. They may occur in grey and white matter and although the angles of the cerebral ventricles are favoured sites, plaques be identified anywhere in the CNS. They range in size from barely visible up to several centimeters. Microscopy: Macroscopically this slide shows a cross-section of the spinal cord stained by the Solochrome Cyanin method to demonstrate myelin. Zones of demyelination can be identified involving several areas of the cord - these are plaques. Microscopic examination of the slide confirms demyelination. Notes: Slide 85: Cerebral infarct Clinical History: This 70 year old woman was admitted to hospital for repair of an inguinal hernia. She had congestive cardiac failure and atrial fibrillation but these improved with medical treatment. Four days after her operation she was found collapsed and on examination had a right hemiparesis of both upper and lower limbs with a right extensor plantar response. She developed a right hemiplegia, became unable to talk and was incontinent. She died 10 hours later.

At autopsy the left internal carotid artery was occluded by thrombus and there was recent cerebral infarction involving the territory of the left anterior and middle cerebral arteries. Gross: The mounted specimen of the brain shows marked swelling of the left cerebral hemisphere associated with left uncal and left sub-falcine herniation. Thrombus can be seen occluding the left internal carotid artery. Examination of the cut surface of the brain also shows marked swelling of the left cerebral hemisphere in the anterior and middle cerebral artery territories. Macroscopically, apart from the swelling, there is not a lot to see, but the Pathologist performing the autopsy would have found this portion of the brain to be extremely soft and friable. This appearance is consistent with that of an extremely recent (10 hours) cerebral infarct. The microscopic slide is taken from an old cerebral infarct in which most of the necrotic cerebral tissue has already been removed. Microscopy: Macroscopic examination of the slide shows a rectangular piece of pink tissue. There is a wedge-shaped zone which is paler than the surrounding tissue - this is the zone of infarction. The pial surface of the brain is still recognised as a thin pink ribbon overlying part of the infarcted tissue. This preservation of the most superficial parts of the cerebral cortex is typical in cortical infarcts. Examination of the infarcted tissue under the microscope reveals amorphous, granular, pink material in which the ghost outlines of some necrotic neurones can be identified. The other dominant cell seen predominantly at the edges of the infarct is the compound granular corpuscle. This cell is a modified microglial cell and appears large and round with a small usually eccentric basophilic nucleus. The cytoplasm is granular and brown in colour due to the presence of lipid and haemosiderin derived from the necrotic brain tissue. . Deep to the area of infarction numerous reactive astrocytes are seen. Their cytoplasm is prominent and densely eosinophilic with processes extending out into the neuropil. The nucleus is large, slightly vesicular and usually compressed to one side. These reactive astrocytes are called gemistocytes. In brain tissue the different cellular components have a different susceptibility to hypoxia. The most sensitive cell is the neurone followed by the astrocyte, oligodendrocyte, microglial cell, and least susceptible is

the endothelial cell. Thus in the centre of an area of infarction where there is complete loss of blood supply, all cellular components other than endothelial cells and microglial cells disappear. The necrotic cellular debris is ingested by activated microglial cells which remove the cellular debris, pass into perivascular spaces, and ultimately enter the blood stream. In the area adjacent to the centre of the infarct neurones are lost but astrocytes persist and become reactive. They develop the histological features characteristic of gemistocytic astrocytes and produce neuroglial fibres. In the early stages the astrocytes are plump with abundant cytoplasm and are known as protoplasmic astrocytes. In time the amount of cytoplasm disappears, there are more neuroglial processes and the astrocytes are then termed fibrous astrocytes. Eventually all that is left is a cystic cavity containing a few small blood vessels surrounded by a zone of gliosis. In this slide we are looking at an intermediate stage in the process of organisation of a cerebral infarct. Notes: Slide 86: Meningioma Clinical History: No clinical notes are available for this particular patient. The clinical signs and symptoms caused by meningiomas depend upon their location. They grow slowly and so the onset of signs and symptoms may be insidious. Gross: The mounted specimen consists of a rectangular fragment of dura mater measuring 5 x 3 cm in size. Arising from the cerebral surface of the dura mater is a lobulated tumour mass measuring 3 cm in maximum dimension. The external surface of the mass appears bosselated and almost papillary. The cut surface shows expansion of the dura mater with most of the tumour bulging into the subarachnoid space. The tumour tissue is pale grey in colour and homogenous. There is no evidence of necrosis or haemorrhage. Microscopy: Sections show a cellular mass of tumour tissue. No recognisable normal tissue is present. Scattered nodules of calcified material, psammoma bodies are present. The tumour consists of small whorls of tumour cells which are indistinctly separate from one another. The individual tumour cells, which are derived from the arachnoid cells of the subarachnoid space and arachnoid granulations, have indistinct eosinophilic cytoplasm and vesicular pale basophilic round to oval nuclei. Psammoma bodies are

often seen at the centre of the tumour cell whorls. No mitoses are present and there is no evidence of cellular pleomorphism or necrosis. Meningiomas behave as benign tumours and cause clinical symptoms by forming space-occupying lesions within the rigid cranial cavity. There are several different microscopic variants some of which have a greater tendency to progress to malignant behaviour. The lesion in this example is completely benign and was cured by surgical excision. Notes: Slide 87: Astrocytoma Clinical History: This 54 year old man had several episodes of limb weakness associated with slurring of his speech in the several weeks before he was admitted to hospital. A carotid angiogram demonstrated a shift of the anterior cerebral artery to the left. Pneumoencephalogram showed gross ventricular distortion, apparently due to a right fronto-parietal tumour but this could not be localised on needling of the brain. He died several months later. Gross: The mounted specimen is a coronal slice of the cerebral hemispheres which shows marked right cerebral swelling with subfalcine herniation and uncal grooving. The gyri are markedly flattened. The tumour is most obvious in the right superior frontal gyrus where it replaces both grey and white matter. It is also apparent in the white matter of the right centrum semiovale and in the corpus collosum which is markedly thickened. This rather nondescript macroscopic appearance is a feature of welldifferentiated astrocytomas. Microscopy: Macroscopically this slide shows a rectangular portion of tissue with two small blood vessels recognisable towards the top. Beside the blood vessels are smaller pieces of more darkly staining tissue. Microscopic examination shows the two blood vessels to be lying in a distorted sulcus. The darkly stained tissue identified macroscopically is near normal grey matter. The rest of the slide is tumour tissue. The neoplastic cells are astrocytes - they show quite marked variation in nuclear size but mitotic figures are not seen. The cytoplasm is fibrillary in appearance. There is no tumour necrosis and no vascular proliferation, indicating that this is a low-grade tumour. This is a fibrillary astrocytoma. Astrocytomas are most common in late middle age. They are solid poorly defined tumours with a grey-white colour that show a tendency to become

more anaplastic with time, frequently progressing to glioblastoma multiforme. Notes: Slide 88: Glioblastoma multiforme Clinical History: This 42 year old man had a history of an epileptic fit following an accident 8 months prior to his death. During the subsequent 5 months he had several further major epileptic fits but detailed neurological investigations were negative. About this time however, he began to show a gradual mental deterioration with loss of memory, altered speech and inaccurate writing. He was lethargic and apathetic when readmitted to hospital 2 months before death. He had bilateral papilloedema and brisk reflexes on the right side. A left carotid arteriogram showed a vascular tumour approximately 7 cm in diameter in the left frontal lobe and a biopsy showed glioblastoma multiforme. He died weeks later. Gross: The mounted specimen shows the brain after horizontal slicing. Externally, there is gross swelling of the left frontal lobe with marked subfalcine herniation and uncal grooving on the left side. A large tumour is present in the left frontal lobe which extends to involve the meninges. This tumour measures 8 cm in diameter and is partly cystic and partly solid with numerous foci of haemorrhage and tumour necrosis. Macroscopically, the lesion appears fairly well demarcated from the surrounding brain tissue. Microscopy: Macroscopic examination of the slide shows a rectangular portion of tissue. There is a U-shaped portion of pale eosinophilic tissue related to one edge - this represents near normal grey matter with a central sulcus containing small blood vessels. To one side of the U is a zone of variegated tissue. Here, irregular areas of brightly eosinophilic tissue are interspersed with basophilic zones - this is the tumour. The more homogenous tissue on the other side of the U is near normal white matter. Microscopic examination of the tumour shows very extensive tumour necrosis. Tumour necrosis in a primary glial tumour equates with a highgrade lesions, i.e. glioblastoma. (This patient had also received radiotherapy prior to his death and this would have contributed to the degree of necrosis seen). Other important features to note are the vascular proliferation at the margin of the lesion and the greatly increased

cellularity compared to the surrounding brain tissue. Many of these tumours show striking cellular pleomorphism, tumour giant cells and bizarre mitoses - these features are not present in this case. Glioblastoma multiforme is an anaplastic tumour of astrocytes. The prognosis for patients with these tumours is very poor. Mean survival is only 8-10 months. Notes: Slide 89: Neurofibroma Clinical History: This English born 73 year old man had severe bronchitis, deafness and obvious neurofibromatosis. He was also extremely short. He had apparently been reasonably well until the night before his admission to hospital when he was found collapsed. At autopsy he was a dwarfed elderly man, a mere 150 cm in length and most of his body was covered with skin lumps ranging in size from a few mm to large pedunculated lesions 5 cm in diameter. These neurofibromata were most numerous on the abdomen. He had chronic bronchitis and emphysema with cor pulmonale, ischaemic heart disease with a left ventricular scar and an old left cerebral infarct in the white matter lateral to the left caudate nucleus. In the stomach there were several leiomyomata. In addition to the cutaneous neurofibromata there were many neurofibromata affecting the cervical nerves, the sympathetic chain, the spinal ganglia and chorda equina. Gross: The mounted specimen shows 2 slices of the neurofibromata involving the abdominal sympathetic chain adjacent to the adrenal glands. The tumours are well circumscribed and show a fairly homogenous grey/white cut surface. Also included is a rectangular portion of abdominal skin bearing numerous cutaneous neurofibromata. These range in size from a few mm up to 4 cm and a number of the larger lesions are pedunculated. Many of these lesions also show superficial ulceration. Microscopy: The slide is made from a neurofibroma of the dermis. Macroscopic examination shows an ovoid, eosinophilic mass lined by epidermis at the edges with ulceration of the tip. Microscopic examination shows a diffuse proliferation of spindle cells with wavy nuclei.

The intervening stroma has a fibrillary appearance. Numerous small blood vessels are seen. The lesion is non-encapsulated and there are no features of malignancy. Neurofibromas are formed by the combined proliferation of all the elements of a peripheral nerve - axons, Schwann cells and fibroblasts. Grossly, they tend to be fusiform in shape, involving the whole nerve, or may result in diffuse tortuous enlargement of the nerve (plexiform neurofibroma). Superficial neurofibromas may present as small soft pedunculated skin lesions - as in this case. The presence of multiple neurofibromas suggests a diagnosis of von Recklinghausens disease, the most common autosomal dominant condition in humans. Notes: Slide 90: Molluscum contagiosum Clinical History: No clinical notes are available for this particular patient other than that the lesion was removed from the knuckle of the 5th finger. Molluscum contagiosum is a common and self-limiting viral disease. Infection is usually spread by direct contact, particularly among children and young adults. The causative agent is a pox virus. The lesions are firm and often itchy. Gross: The mounted specimen consists of an ellipse of skin and underlying connective tissue bearing a round, raised pale lesion with a small central umbilication. The lesion measures approximately 8 mm across (quite large for molluscum contagiosum). Microscopy: Macroscopically, this slide shows a strip of skin bearing a cup-shaped basophilic lesion. Microscopic examination reveals hair-bearing skin. The lesion identified macroscopically shows verrucous epidermal hyperplasia with acanthosis (thickening of the epidermis) and hyperkeratosis. Large cytoplasmic inclusions are present in the epidermis. These appear eosinophilic in the stratum granulosum and become more basophilic towards the epidermal surface. These are the pathognomonic molluscum bodies and contain numerous virions. Notes: Slide 91: Verruca vulgaris

Verrucae are common lesions of young children and adolescents. They are caused by papilloma viruses (DNA-containing papova viruses). HPV2 is usually associated with verruca vulgaris. The most common type of wart is verruca vulgaris and these lesions typically occur on the backs of the hands. The lesions consist of small grey/white to tan papules that have a rough surface. Microscopy: Macroscopically, this slide shows a small fragment of tissue half of which is basophilic and the other half eosinophilic. Microscopic examination shows a strip of epidermis - very little dermal tissue is present. There is hyperkeratosis (increased keratin on the skin surface), parakeratosis (incomplete keratinisation - as evidenced by persistence of nuclei in surface keratin) and epidermal hyperplasia. Careful examination of the epidermal cells reveals zones of perinuclear cytoplasmic clearing (koilocytosis). The viral nuclear inclusions are basophilic on H + E staining and can be specifically identified by the immuno-peroxidase technique. Infected cells show two types of cytoplasmic inclusions - eosinophilic accumulations of tonofilaments and condensed basophilic keratohyaline granules. These are the result of the viral cytopathic effect. Notes: Slide 92: Foreign body suture granuloma Microscopy: Macroscopic examination of the slide shows a piece of skin with a central, bluish nodule. Microscopically, this is hair-bearing, solar-damaged skin with a central superficially ulcerated lesion. The lesion consists of a large number of inflammatory cells related to refractile fragments of suture material. Foreign body giant cells are well seen with multiple, vesicular nuclei and abundant, well defined cytoplasm. Engulfed fragments of suture material can be seen within cytoplasmic vacuoles. Macrophages, plasma cells and lymphocytes are also present infiltrating a well vascularised, oedematous stroma. This is a foreign body granulomatous reaction. Non-absorbable suture material persists in the body indefinitely and acts as a foreign body becoming walled off by a granulomatous inflammatory process. Notes: Slide 93: Healing wound

Microscopy: Macroscopic examination of the tissue section shows skin and underlying subcutaneous fat. In the centre of the section haemorrhage and strands of pink tissue can be seen in the subcutaneous fat. The epidermis above this is slightly raised. Under the microscope this area of the epidermis shows an overlying crust composed of degenerate neutrophils and fibrin. Two small foci of ulceration are seen and these represent the entry/exit points of the surgical sutures. Between these, small islands of squamous epithelium can be seen extending into granulation tissue - this is the actual site of the incision. The subcutaneous fat shows foci of haemorrhage with granulation tissue and early scar tissue. Necrotic, basophilic cellular debris is seen in the suture tracks. The appearances are typical of a healing recent surgical wound. At the time of surgery sectioning through the tissue produces tissue damage and interstitial haemorrhage. Subsequently, there is repair of the damaged tissue and organisation of the interstitial haemorrhage by granulation tissue. Ultimately, the granulation tissue will disappear and be replaced by mature fibrous tissue. Notes: Slide 94: Compound naevus Clinical History: No clinical notes are available for this particular patient. Gross: The mounted specimen is an oval shaped portion of skin and underlying connective tissue showing a similarly shaped pigmented lesion. This lesion is sharply defined from the surrounding skin and has a slightly papillary surface with numerous fine hairs protruding from it. The pigmentation, although quite dark, is even in distribution. This appearance (the large size and hairiness of the lesion) is typical of a congenital naevocellular naevus. The common acquired naevus is usually dark brown in colour and slightly smaller in size and tends not be as hairy. Microscopy: The section shows a strip of skin and underlying subcutaneous tissue. Clusters (nests) of naevus cells are seen at the dermo-epidermal junction and in the underlying papillary dermis. Within the papillary dermis the cells are more scattered and not collected into tight clusters as they are at the dermo-epidermal junction. The naevus cells have a small amount of fairly indistinct eosinophilic cytoplasm and medium sized, round to oval, vesicular nuclei with a small prominent central nucleolus. Many contain fine granular brown pigment.

Naevus cells are believed to be of neural crest origin. During the evolution of a naevus junctional nests of cells proliferate then become separated from the epidermis and enter the papillary dermis. When naevus cells are present both at the dermo-epidermal interface and within the papillary dermis (as in this case) the lesion is known as a compound naevus. If the cells are restricted to the dermo-epidermal junction the lesion is a junctional naevus and when they are completely within the dermis the lesion is called an intradermal naevus. A naevus is generally regarded as a hamartomatous lesion in which there is an abnormal local collection of naevus cells. Notes: Slide 95: Intradermal naevus Gross: Intradermal naevi tend to be elevated and lightly pigmented. The degree of pigmentation in naevo-cellular naevi usually corresponds to the magnitude of the junctional component, since there is no junctional activity in an intradermal naevus, these lesions tend to be lightly pigmented and eventually non-pigmented. Quite often a few hairs will be seen growing out of an intradermal naevus. Microscopy: Macroscopically, this slide shows an eosinophilic piece of tissue with multiple small foci of basophilia, a focus of haemorrhage and a very thin basophilic covering. Microscopic examination shows hair-bearing skin with underlying subcutaneous adipose tissue and skeletal muscle. There is a central nodular lesion that is covered by normal epidermis. No junctional nests of naevus cells are present. The dermis is expanded by groups and nests of naevus cells. These cells have oval nuclei with pale cytoplasm. There is no cellular atypia or mitotic activity. Notes: Slide 96: Malignant melanoma Clinical History: This 56 year old man had a dark growth on the left thigh. It was not known how long the tumour had been present as the patient was mentally deficient. On examination enlarged inguinal lymph nodes were palpable. Gross:

The mounted specimen shows a rectangular portion of skin and underlying connective tissue. Centrally, there is a rounded nodular lesion measuring 1.5 cm in diameter. This lesion is darkly pigmented and shows extensive superficial ulceration. It is not sharply demarcated from the surrounding normal skin. Also included in the specimen is a portion of fibro-fatty connective tissue in which 3 small lymph nodes can be identified. Microscopy: Macroscopic examination of the slide shows a strip of skin and underlying subcutaneous connective tissue with a central lobulated tumour extending down into the dermis. Microscopically, this lesion consists of sheets of large pleomorphic melanocytes with very distinctive nucleoli and pale cytoplasm. Mitoses are frequent and many are bizarre. Towards the skin surface some of these cells show fine granules of brown cytoplasmic pigment. The overlying epidermis is ulcerated and covered by a crust. At the edges of the main tumour mass an intra-epidermal component of superficial spreading melanoma can be seen in some sections. The diagnosis of malignant melanoma may be a subtle and difficult one. Notes: Slide 97: Solar keratosis Clinical History: Solar or actinic keratoses typically occur on sun-exposed skin (face, arms, dorsum of hands). The lesions are small (less than 1 cm in size) and vary from tan brown to flesh coloured. They typically have a rough sandpaper like surface. Occasionally, these lesions are so hyperkeratotic as to produce a cutaneous horn. These are premalignant lesions and should therefore be treated. Microscopy: Macroscopically, this slide shows a portion of pale eosinophilic tissue covered by a thin basophilic layer (epidermis) and bearing a central small keratotic lesion. Microscopic examination shows hair-bearing skin with marked dermal elastosis. Elastosis consists of matted aggregates of thickened elastic fibres that stain a blue-grey colour. This is probably the result of abnormal elastic synthesis by sun-damaged fibroblasts. Centrally, the epidermis shows marked hyperkeratosis with parakeratosis. Look carefully at the basal layers of the epidermis in this region and you will see hyperplasia of the basal cells and cytological atypia. The basal cells

are increased in number and show nuclear hyperchromasia. There is no invasion of the dermis. Notes: Slide 98: Squamous cell carcinoma of the skin Clinical History: This 82 year old man had a lesion on his ear treated with X-Ray therapy. Gross: The mounted specimen is part of the pinna. There is a large destructive and ulcerative lesion measuring 3.5 cm across which has a rolled circinate edge. The tumour tissue is grey/white in colour. Microscopy: Macroscopic examination of the slide shows a section of skin and underlying subcutaneous connective tissue. In the centre there is an elevated cellular lesion. Microscopic examination shows focal ulceration at the surface of the lesion and tongues of tumour cells extending from the epidermis down into the underlying dermal connective tissue. Separate nests of tumour cells are completely surrounded by dermal connective tissue. Close examination of the tumour cells shows the characteristic cytological features of malignancy. These include considerable variation in nuclear size, shape, and staining characteristics together with frequent individually necrotic cells, and normal and abnormal mitotic figures. There is also definite evidence of squamous differentiation with intercellular prickles between tumour cells and foci of keratin pearl formation. Here, tumour cells are arranged in a whorl-like structure with central keratin formation. The adjacent dermal connective tissue shows the floccular appearance characteristic of prolonged solar damage (elastosis). Squamous cell carcinoma of the skin is most commonly associated with solar damage. Squamous cell carcinomas arising in areas of solar degeneration rarely metastasise. Notes: Slide 99: Basal cell carcinoma of the skin Clinical History: This 48 year old man had a slowly enlarging lesion on the right upper eyelid for 3 years which was surgically removed. Gross:

The mounted specimen consists of a rounded portion of hair-bearing skin and underlying connective tissue. Centrally, there is an ulcerated lesion 7 mm in diameter, which shows a thickened and rolled edge. Microscopy: Macroscopic examination of the slide shows a section of skin and underlying subcutaneous tissue. Immediately beneath and elevating the epidermis is a blue, cellular tumour. The margins of the tumour appear smooth and rounded. Examination under the microscope shows nodular masses of tumour cells extending from the epidermis into the underlying dermal connective tissue and elevating the overlying focally ulcerated epidermis. The tumour cells have a fairly uniform monotonous appearance - they are spindle in shape with indistinct eosinophilic cytoplasm and oval basophilic nuclei with indistinct nucleoli. A characteristic feature of basal cell carcinoma is the tendency of the cells at the periphery of the tumour nests to become vertically orientated and form a palisaded layer. Frequent mitotic figures are seen and this is also a feature of basal cell carcinoma. Basal cell carcinomas are believed to arise from a pluripotential cell in the basal layer of the epidermis which has the capacity to differentiate into epidermis and any of its adnexal structures. Thus in basal cell carcinomas one may see evidence of keratinisation, hair follicle formation, or sebaceous differentiation. These tumours tend to locally infiltrate and ulcerate but rarely metastasise. Notes: Slide 100: Capillary haemangioma Clinical History: This 38 year old man had a small reddish lesion on the right upper arm for as long as he could remember. In the last few years it had bled after trauma on several occasions and also became slightly larger. Gross: The mounted specimen consists of an ellipse of skin and underlying connective tissue. Centrally, there is a well-circumscribed raised dark lesion measuring 1 cm in diameter. Microscopy: Examination of the section macroscopically reveals a rectangular piece of tissue covered on one of the short sides by epidermis. Most of the tissue appears lobulated and basophilic. Examination under the microscope shows that the lobules are composed of numerous intertwining small

blood vessels which vary in size and shape. In the deeper parts of the section the proliferated vessels are separated by mature adipose tissue. Scattered larger arterial vessels and larger veins can be recognised. The majority of vessels are lined by endothelial cells and contain a few smooth muscle cells within their walls and therefore, probably correspond best to venules. Other vessels are smaller and are of capillary size. In some areas the lobules of tissue are more cellular due to the proliferation of pericytic cells. The proliferation of blood vessels seen in a haemangioma is thought to arise as an abnormality of development and is therefore regarded as a hamartoma. The natural history of these lesions is that they present at birth, may grow for a couple of years, then progressively involute and eventually disappear. In this way the lesion does not behave as a benign neoplasm of blood vessels which would be expected to continue to grow until surgically removed. Notes: