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Case 1

  • Note: conjunctival pallor due to anaemia (caused by bleeding or dietary insufficiency).
  • Diffuse gastric adenocarcinoma is an especially aggressive cancer because it spreads quickly through the muscular layers of the stomach, causing “linitus plastica”, or a stiff, lead stomach. It is marked by genetic deletions in the carcinoma, resulting in the loss of e-cadherin, a molecule normally involved in “sticking” cells together.
  • Predisposing factors for gastric cancer: Helicobacter pylori infection and associated peptic ulcer disease, alcohol use, consumption of cured and salty meats.
  • DDx epigastric pain
    • Pancreatitis
    • Peptic ulcer
    • Gastric cancer
    • Reflux
  • Causes of anaemia - very common viva question
    • Decreased production - most common (75%)
      • Marrow damage
      • Decreased EPO
      • Decreased dietary intake of iron
      • Inflammatory states
    • Increased breakdown
    • Blood loss
    • Maturation defects
  • Histology of anaemia
    • Microcytic
      • hyperchromic (pale) and microcytic (small)
    • Normocytic
    • Macrocytic
  • Distinguish anaemia of chronic disease from anaemia of iron deficiency because ferritin low in iron deficiency and high in anaemia of chronic disease
    • Transferrin saturation is lower in anaemia of chronic disease (inflammatory cytokines decrease release of iron stores and uptake in gut)
    • Increase in hepcidin = decreased iron resorption from the gut --> decreased absorption of iron
    • IL1 and IL6 also affect the erythropoetin production
  • Peptic ulcer or gastric carcinoma
    • Both states may have a combination of blood loss and an anaemia of chronic disease (mixed picture)
  • Approach to pallor:
    • FBC
    • Blood smear
    • Iron studies (serum iron, ferritin, transferrin saturation)
  • FBC and blood smear
    • Morphology of the anaemia (MCV, reticulocytes, PLT and WBC count)
    • Complex blood disorder (neoplastic/aplastic) indicated by:
      • Nucleated cells
      • Blasts
      • Atypical mononuclear cells
      • Abnormalities in certain blood cells ESR/CRP
  • Signs of haemolytic anaemia
    • Unconjugated bilirubin o LDH
    • Low haptoglobin
  • LFTs
    • Liver disease
  • UEC
    • Renal disease

Slide 1

  • Look at epithelium left and right = cardiooesophageal junction
    • Oesophagus = left, stomach = right
  • This tissue shows the cardio-oesophageal junction. The oesophagus has stratified squamous epithelium, while the stomach contains glandular tissue. There is a focal area of ulceration, as well as grossly distorted, abnormal and irregular glands infiltrating through the muscularis propria of the stomach. These glands consist of pleomorphic, anaplastic cells with large nucleus to cytoplasm ratio, hyperchromic nuclei and mitotic figures. The presence of mucin in some cells have pushed the nucleus to one side (forming Signet cells), which may also be found in the oesophageal epithelium.
  • The wall of the stomach is thickened and cellular (purple, basophilic)
  • Ulcer at the cardiooesophageal junction
  • Muscle (pink streaks) are separated by cells
  • Architecture of the stomach is disrupted by infiltration of cells, which are some places making glands (adenocarcinoma)
    • Malignant cells -- infiltrating through the wall of the stomach
    • As it infiltrates, the cells produce mucus (because the cell used to be a mucus-producing glandular cell)
    • Malignant features of cells: pleomorphic, anaplastic, large N:C ratio, mitotic figure
  • Diagnosis: infiltrating adenocarcinoma of the stomach
    • Other type - intestinal (mainly form glands)
  • Sites of epithelium transition
    • Cardiooesophageal junction
    • Cervix
    • Anorectal junction
  • Layers in GIT
    • Mucosa, submucosa, muscularis externa, adventitia or serosa


Velan on gastric adenocarcinoma

  • Malignant ulcer
    • Commonly proximal rather than distal (which is common in benign ulcers)
    • Heaped up and beaded margins
    • Base contains necrotic slough (unlike benign ulcers)
    • Surface indurated
  • Omentum adheres to part of the stomach that has the ulcer - indicative of invasion
    • Tissue under ulcer is firm and hard to cut through
    • Whitish carcinoma infiltrates the wall and the superficial and deep margins are nodular due to invasion
  • Advanced gastric carcinoma = invasion into outer stomach wall
    • Dissect out perigastric lymph nodes
  • Intestinal type looks like glands, is more localised
  • Infiltrating type = diffuse, whole stomach is affected, no discrete area of disease
    • Called leather-bottle stomach

Slide 2

Six months after her initial presentation, the woman presented with a pathological fracture of the left hip. Despite surgical treatment, she became gradually more cachetic and died three months later.

  • Bone metastasis; pathological # of left hip
  • Note cartilage and intervening
  • Specimen two (bony metastases): This is a specimen of bone and cartilage with widespread metastases, associated connective tissue with glandular structures lined by malignant cells. These malignant cells are less differentiated than the primary

tumour and have caused a pathological fracture in the woman.

  • Primary malignancies that metastasise to bone: prostate, lung, breast, thyroid, renal.
    • Cause dull, constant ache with periodic spikes in pain and pathological fractures.
    • Glandular structures have appeared in marrow spaces (abnormal), and destroying the bone (lytic)
  • Youngsters get bone primaries, not old people
  • Common causes of mets to bone: breast, lung, prostate, renal, thyroid
    • The majority of pathological fractures occur in patients with metastatic breast cancer (53%); other tumour types associated with fracture include the kidney (11%), lung (8%), thyroid (5%), lymphoma (5%) and prostate (3%).
  • Types of bone met: sclerotic (blastic) = white; lytic = grey/black

Case 2

A previously healthy 62 year old man presented following a single episode of bright red bleeding per rectum. Over the preceding month he had noted increasing constipation. He had not had any other problems with his health.

  • Note: bright rectal bleeding (haematochezia) suggests left-sided colon involvement.
  • Differentials for this case (colonic bleeding) include:
    • Haemorrhoids (varicosities in the rectum), anal fissuring due to constipation (and low fibre), diverticular disease (low fibre, causing chronic constipation and formation of mucosal/submucosal pouches through the muscular wall), large adenomas (causing small amounts of bleeding) and colorectal adenocarcinoma. Inflammatory bowel disease (more consistent with ulcerative colitis causing explosive diarrhoea). Ischaemic colitis (due to cardiovascular disease - bleeding + diarrhoea)
  • Colorectal cancer (left sided) = change in bowel habit (patients commonly say constipation incorrectly)
    • Lt cancers tend to be apple-core or napkin-ring constriction, faeces more solid. On the right, faeces are much more fluid and the presentation is more likely to be anaemia due to occult bleeding (anaemia in this age = colorectal unless proved otherwise).
  • Risk factors: family history (e.g. FAP, HPCC), previous polyps removed

Slide

This is a specimen showing a moderately well- differentiated colorectal adenocarcinoma. There is some normal glandular colonic epithelium with goblet cells , but to the right there is a large malignancy penetrating the muscularis propria of the colon. It has abnormal, irregular glands with some mucin (lost goblet cells), showing the cytological features of malignancy and a desmoplastic response by fibroblasts which produce a collagenous stroma.

  • 80-85% of colorectal adenocarcinomas occur from the adenoma to adenocarcinoma sequence, due to mutations in the APC gene (tumour suppressor).
  • Useful investigations on this man: per-rectal examination, sigmoidoscopy, colonoscopy, FBC (microlytic, hypochromic anaemia), increased platelets, EUC, LFT (typically obstructive pattern – raised ILP, GGT, Br). Raised AST and ALT typically mean hepatocyte necrosis.
    • Also check for hepatomegaly (for metastases)
    • CEA for monitoring therapy (not good for diagnosis; notspecific or sensitive); CA-125 (ovarian); CA-15.3 (breast); CA-19 (pancreatic)
    • CT scan for staging (won't pick up intestine)
    • CT enterography/MRI enterography - fill the bowel with water and sorbitol/osmotic material, use T2 weighted sequences to look at mucosa; can do "virtual colonoscopy"; used for IBD (not colon cancer)
    • Capsule endography - swallow camera and you can watch the video

Slide

  • This is a specimen showing a moderately well- differentiated colorectal adenocarcinoma. There is some normal glandular colonic epithelium with goblet cells , but to the right there is a large malignancy penetrating the muscularis propria of the colon. It has abnormal, irregular glands with some mucin (lost goblet cells), showing the cytological features of malignancy and a desmoplastic response by fibroblasts which produce a collagenous stroma.
    • 80-85% of colorectal adenocarcinomas occur from the adenoma to adenocarcinoma sequence, due to mutations in the APC gene (tumour suppressor).
    • Probably started with a polyp
    • Note loss of differentiation
    • Goes right through the muscularis propria
    • Lymphocytes: reaction to try to get rid of the cancer (vane attempt)
  • Pathologist's report to surgeon
    • T:State layer the adenocarcinoma has reached in the colon (submucosa, muscularis propria, serosa, or out). Also the size and the differentiation (grade).
    • N: Next step is nodes
    • M: Malignancy
    • Positive margins?
  • Staging (TNM)
  • Know the colorectal staging off by heart
    • It's in Robbins
  • Stages:
    • 0 - Tis, N0, M0
    • 1 - T1;T2, N0, M0
    • 2a - T3, N0, M0
    • 2b - T4, N0, M0
    • 3a - T1/T2, N1, M0
    • 3b - T3/T4, N1, M0
    • 4 - any T, any N, M1

Case 3

Dr. Armand Trousseau’s pancreatic cancer, a diagnosis which he deduced from epigastric pains that radiated to his back, weight loss, insidious and progressive jaundice, pallor in his stools, darkening of urine, extreme lethargy and irritability.

  • Differentials for his case: pancreas-related (pancreatitis, carcinoma of the head of the pancreas) and biliary-tree related (cholangitis, gall stones, cholangiocarcinoma, PSC, PBC).
  • His LFTs show extrahepatic obstruction of the bile duct (increased Br, ALP, GGT).
  • Three useful tests for him would be: ERCP and biopsy, US and abdominal CT. Trousseau developed migratory thrombophlebitis, which confirmed his diagnosis.
  • Trousseau’s sign of malignancy (Trousseau syndrome)
    • Found in certain cancers, such as pancreas and lung, characterised by hypercoagulability and venous thrombosis formation caused by pro-thrombotic (procoagulant; NB all cancers cause you to be hypercoagulable) agents released by the cancer and the body’s response.
    • Causes thrombosis in the portal circulation, lower extremities, in deep and superficial veins (causing vasculitis).
    • Clots forming, resolving, then appearing again elsewhere is called thrombophlebitis migrans or migratory thrombophlebitis.
    • Signs: pain in the body part affected; skin redness or inflammation and swelling (oedema) of the extremities.; Tender nodules under the skin
      • Characterised by recurrent episodes of localised thrombosis of superficial veins in limbs and trunk.
    • Trousseau’s sign of malignancy is not due to hypocalcaemia. There is another sign, called Trousseau’s sign of latent tetany which occurs due to hypocalcaemia. It is when you occlude the brachial artery for 3 minutes, and wait to see if carpal spasm occurs (flexion at the wrist and metacarpophalangeal joints, extension of the distal and proximal interphalangeal joints, and adduction of the thumb and fingers.
  • Pale stools and dark urine tells us the cause of the jaundice is the bile duct - bilirubin, when excreted into bowel, is converted to bilinogen, which makes poop brown. If this process is obstructed, the bilirubin builds up in the blood and is excreted in the urine --> dark urine.
  • ASH and ALT (transaminase) are normal
  • Bilirubin elevated
  • ALP and GGT elevated --> cholestatic/obstructive pattern
    • ALP and GGT reside on canalicular membrane
  • Should have ordered the fractionated bilirubin (conjugated and unconjugated)
  • Investigations: lipase, amylase (pancreatitis), abdominal U/S (dilatation of bile duct), endoscopic retrograde cholangiopancreatography (ERCP); abdominal CT (looking for ducts or masses)
    • Abdo U/S - can't see tail (most pancreatic cancers arise in the head); bowel loops can get in the way
    • ERCP is invasive, can cause pancreatitis; MRCP less invasive
  • Classification of jaundice (affects water solubility; conjugation with glucuronate)
    • Prehepatic
      • Haemolysis
    • Intrahepatic
      • Cirrhosis/cancer (hepatocellular death)
    • Posthepatic
      • Obstruction

Slide

  • Pancreas = exocrine + endocrine
  • Note ducts and acini, and the islets of langerhans (IoLs are endocrine, most of pancreas is exocrine with a few endocrine islands)
  • Specimen Four (pancreatic carcinoma): This is a slide showing the pancreas, with areas of normal pancreatic tissue and grossly abnormal malignant portions. The malignant portion of the pancreas contains mitotic figures, complete destruction of normal pancreatic architecture, pleomorphism, infilitrating glandular structures and a desmoplastic stroma.
    • Pancreatic adenocarcinomas (infiltration) have a terrible prognosis due to late diagnosis. It is also highly infiltrative and metastasises easily, and may show perineural invasion along nerves.
  • We have pleomorphic glandular structures that are infiltrating throughout the parenchyma
  • Glandular cells: pleomorphic, basophilic, highly irregular, large N:C ratio
  • Stroma - desmplasia: fibroblastic reaction to tumour. Desmoplasia is classic in pancreatic cancer
  • Malignant cells invade as solitary malignant cells as well
  • Note nerve: there are malignant cells hugging the nerve - perineural invasion (a classic feature of pancreatic carcinoma)
  • People can survive pancreatic cancer - only if it's insulinoma or somatostatin secreting cells (endocrine malignancies are less nasty)
  • Look up paraneoplastic syndromes in Goljan