GI and Liver Flashcards
Pink Inclusions in Hepatocytes
Non-neoplastic:
Apoptotic bodies
Mallory hyaline
Fibrinogen
Megamitochondria
Congenital:
Alpha 1 antitrypsin
Glycogen storage disorder
Neoplastic: HCC, embryonal sarcoma
Neutrophils in Liver
Non - Neoplastic:
“surgical hepatitis”
CMV
Ascending cholangitis
NASH / ASH
Neoplastic: in association with malignant tumours, both primary and secondary
Liver Special Stains
Reticulin: Architecture, plate thickness
Trichrome: Staging of fibrosis
PAS: BM, AIAT globules, storage disorders
PERLS: presence, site, grading of iron
Rhodanine: Copper deposition (Wilson, cholestasis)
Orcein: elastic fibres, Cu associated binding protein, Hep B surface antigen
Subtypes of HCA
1) HNF1A inactivated (loss of LFABP)
2) Inflammatory adenoma (express CRP / SAA in 50%)
3) Beta catenin activated. (nuclear BCat of diffuse GS)
4) SHH activated (ASS1 +, increased risk of bleeding)
5) Unclassified
IPX for Primary Liver Carcinoma
HCC: HepPar1, arginase +, CK 7 / CK 20 -
CC: CK7 / CK 19 +, albumin RNA ISH +
HCA versus Well Diff HCC
HCA:
Younger, female, hormones, non cirrhotic
Bland cytology, no reticulin loss, low Ki67
Glypican and HSP70 negative
HCC:
Older, cirrhotic or chronic liver disease
Glandular / acinar formation, loss of reticulin network
Increased atypia and mitoses
Ki67 increased c.f. background
Glypican 3 and HSP70 positive
DDx Granulomas in the Liver
PBC
Sarcoidosis
Infection (Hep C, Tb, atypical Mb)
Drugs
Paraneoplastic syndrome
Idiopathic
MMR / BRAF in GI Cancers
Loss of MLH1 / PMS2
= promoter hypermethylation
or germline mutation (Lynch)
BRAF V600E positive = most likely promoter hypermethylation (sporadic)
Isolated loss of PMS2
Loss of MSH2 / MSH6
= most likely to be germline mutation
Synoptic Report Malignant Polyps
Site and size of polyps, pedunculated or sessile
Precursor polyp type
Histologic type of cancer
Histologic grade
Size of invasive carcinoma
LVI
PNI
Tumour budding score
Margin status
MMR / BRAF
Other: NE markers, Ki67 as needed
Haggitt versus Kikuchi
Haggitt =
Adenocarcinoma in a pedunculated polyp
Four levels: depth of invasion from head of stalk to submucosa (level 4)
Kikuchi =
Adenocarcinoma in a sessile polyp
Three levels: depth of invasion within submucosa (sm1 - 3)
Explain how to Cut Up This Specimen
- PPE, 3 points of ID, orient and photograph
- Review MDM and imaging (where is tumour located, size)
- Measure stomach, duodenum, pancreas, ducts, gallbladder, fat. Open stomach / duodenum and fix.
- Ink pancreatic margin, SMV / vascular groove, uncinate (SMA)
- Take margins: stomach, duodenum, bile duct and pancreatic margin
- Section superior to inferior, lay out slices and photograph
- Describe tumour - border, size, cut surface distance to margins
- Block tumour to closest margins and anatomy documenting this on photo blocking diagram
- Look for lymph nodes
Explain how to cut up this Specimen
- PPE, 3 points of ID, orient and photograph
- Review MDM notes / imaging ? site, size of tumour, relationship to structures, prior NAT
- Measure length and diameter of specimen, width of mesocolon to apical tie, measure distance of PPR and APR to distal margin. Comment on completeness of mesorectum and ink mesorectum. Open and fix.
- Margins from proximal, distal and apical tie including apical lymph node.
- Look for polyps, diverticulae / other pathology.
- Measure tumour, distance to proximal and distal margins and relationship to anterior peritoneal reflection.
- Slice from superior to inferior, lay out slices of tumour and photograph. Describe depth of invasion and closest CRM.
- Block 6 - 8 blocks of tumour - background polyp, depth of invasion and closest CRM. Document on photo blocking diagram.
- Look for lymph nodes.
Explain how to cut up this Specimen
- PPE, 3 points of ID, orient specimen.
- Review MDM notes and imaging - ?size / site of tumour, relationship to adjacent structures, NAT
- Measure lesser curve, greater curve, width, proximal and distal resection margins, omentum in 3 dimensions. Inspect serosal surface.
- Ink circumferential resection margin. Open along greater curve and pin out on board to fix.
- Photograph specimen. Describe gastric mucosa including site, size, appearance of tumour. Measure tumour to proximal and distal margins. Take shave margins to prox and distal.
- Section stomach through tumour. Lay out slices and photograph. Describe deepest point of invasion and distance to circumferential resection margin.
- Block tumour to closest margins and anatomy. Block background mucosa. Record on photo diagram.
- Look for lymph nodes.
Syndromes Associated with GI Polyps and Tumours
1. Lynch: AD, MMR proteins
- colorectum, stomach, small bowel, pancreaticobiliary, endometrial, ovary, upper urothelial tract
2. Muir-Torre: AD, MSH2, MLH1
- phenotypic variant of Lynch, sebaceous adenomas and carcinomas and keratoacanthomas
3. FAP: AD, APC
- Small and large intestine, periampullary adenocarcinoma, fundic gland polyps with dysplasia in stomach. Cribiform morular thyroid neoplasms. Nasopharyngeal angiofibromas in males.
Gardner - variant of FAP, adenomas plus: soft tissue and ovarian fibromas, fibromatosis, osteomas, supernumerary teeth
4. Turcot: variant of FAP or Lynch. Either:
Medulloblastoma plus FAP or
GBM and Lynch.
Other:
Serrated polyposis syndrome
Peutz Jegher syndrome
Juvenile polyposis syndrome
Cowden (PTEN hamartoma) syndrome
Cronkhite-Canade syndrome
Herediatry diffuse gastric cancer syndrome
Syndromes Associated with GIST
1. Carney - Stratakis syndrome (AD, SDH genes)
- SDH deficient GIST
- Paragangliomas
- SDH deficient RCC
2. Carney Triad (SDHC hypermethylation)
- SDH deficient GIST
- Paragangliomas
- Pumonary chondromas
3. NF1
4. KIT and PDGRFA mutated syndromic GIST’s
Genes involved in development of GIST
C-KIT (imatinib)
PDGFRA
SDH
NF1
Synoptic Reporting of GIST
- Focality (uni / multi), site, size
- Histologic subtype (spindled, epithelioid, mixed)
-
Mitotic count per 5 mm2 to determine grade
- < 5 per 5 = low grade, > 5 per 5 = high grade - Necrosis
- Pre- resection therapy / treatment effect
- Risk assessment: based on size, site and mitotic count
- Margins status, nodes, distant metastases
Ancillary tests: CKIT, DOG1, SDH, PDGFA, NF1
pT Stage based on size: cutoffs 2, 5, 10 cm
Explain Principles of EMR
EMR (endomucosal resection) is a technique for the treatment and staging of superficial neoplasms of the GIT
Most commonly used for Barrett’s oesophagus, early gastric cancers and colon polyps.
Techinque performed under endoscopy and involves injecting a lifting agent under the lesion followed by ligation. Specimen should be retireved, oriented and pinned flat to board before fixation.
Synoptic Report EMR / ESD Oesophagus
- Procedure type, specimen size and location (upper, mid, lower, GOJ), tissue layers included
- Tumour focality (uni, multi), histologic type, histologic grade, size of invasive tumour, depth of invasion, LVI
- BE and dysplasia (LGD, HGD) present
- Margins to invasive carcinoma and dysplasia
Criteria for Sessile Serrated Polyposis Syndrome
- Presence of 20 or more serrated polyps anywhere in colon
- Presence of 5 or more serrated polyps proximal to sigmoid colon at least two of which are >1cm in size
- Any serrated polyp in a person who has a family history of SPS
Explain Criteria for Tumour Budding
Tumour budding = presence of single cells or small clusters of less than five cells at the advancing edge of the tumour.
High tumour budding associated with:
- increased risk of LN metastases in polypectomy specimen - need resection
- increased risk of LN metastases in stage II resection patients - need CTX
Tumour budding counts:
- should be done on H&E in a hot spot area
- count total number of buds in an area 0.785mm2 (20x on some microscopes but need to check normalisation table in CAP protocol)
- report both total number of tumour buds and three tier score (low 0-4, intermediate 5 -9 and high 10 +)
Issues:
- don’t count in post NAT specimens (no data)
- difficult subtypes e.g micropapillary, mucinous (don’t count groups suspened in mucin) and medullary (obscured by TIL’s, can us CK to identify but count on H&E)
Risk Factors for Cholangiocarcinoma
Congenital:
Choledochal cysts, multiple VMC, congenital hepatic fibrosis
Infectious:
Liver flukes, HCV and HBV
Inflammatory / Other:
Hepatolithiasis, PSC
Risk Factors for HCC
Majority of the risk factors for HCC result in cirrhosis.
Hepatotropic viruses
Alcohol Use
NAFLD
Metabolic / Hereditary disorders: A1AT, tyrosinemia, glycogen storage disease, hereditary haemochromotosis
Drugs and toxins: thorotrast, anabolic steroids, Aspergillus flavus
Definition of Barretts Oesophagus
Definition of BE depends on geography. In USA, Australia and NZ:
- Replacement of oesophageal squamous mucosa with metaplastic columnar epithelium which includes goblet cells and…
- ..in an area of endoscopically abnormal mucosa (salmon pink)..
- …>1cm above GOJ
Should receive four quadrant biopsies at 2 cm intervals along the entire length of altered mucosa for assessment.
Assess for presence of BE and the negative for dysplasia, indeterminate for dysplasia, LGD, HGD.
After diagnosis patients receive anti-reflux medication and regular surveillance (interval depends on RF e.g. length, dysplasia)
HGD can be treated with endoscopic ablative therapy or EMR
Interpretation of HER2 in GOJ / Gastric Adenocarcinoma
HER2 is a receptor tyrosine kinase present on the surface of cells.
Member of the epidermal growth factor receptor EGFR, family and is encoded by the HER2/neu oncogene.
Amplification or overexpression of this oncogene is associated with the development and progression of certain breast and gastric carcinoma types.
HER2 receptor can be targeted by monoclonal antibodies (e.g. trastuzumab) for therapy.
In GOJ / gastric adenocarcinomas: HER2 amplification can be assessed by IPX or ISH studies.
With IPX assessment is based on basolateral staining, intensity of the staining and the number of cells staining (biopsy 5 cells or more, resection >10% of tumour cells)
Grading of NET’s
NET’s and NEC’s are graded on the basis of mitotic count per 2mm2 / 10 HPF and Ki67 proliferation index.
Ki67 counted in a hot spot area.
Count at least 500 cells.
“eyeball” / manual count / or digital image analysis
Mitoses count in ~50 HPF and report average per 10 HPF
Cut offs:
Ki67 < > 3%
Mitoses < > 2 / 10 HPF
IPX for Metastatic NET
SATB2: rectum / appendix
CDX2: small intestine
PAX8 / IL1: pancreas
TTF1: lung
Coeliac Serology
Tissue transglutaminase antibody
Deamidated gliadin eptide
IgA levels
HLA-DQ2/DQ8 typing for people at risk of CD (first degree relatives, T1DM, IgA deficiency, other autoimmune disease, Trisomy 21)
Refractory Coeliac Disease
Persistent villous blunting, LP inflammation and IEL despite 6 - 12 months of strict gluten free diet
_Consider and exclud_e: collagenous sprue, tropical sprue, autoimmune enteropathy and immune deficiency eg CVID.
Type 1 RCD:
IEL phenotype identical to usual Coeliac disease i.e. CD8=CD3+ IEL’s. TCR gene rearrangement polyclonal.
Can use immunosuppression. No increased risk of EATL.
Type 2 RCD:
CD8 lost in >50% of CD3+ IEL’s. Loss of surface CD3, CD7, CD8. TCR gene studies oligo/monoclonal.
Increased risk of EATL.
Pigment in Liver
Bile
Iron (PERLS +)
Copper (Rhodanine +)
Lipofuscin (Fontana-Masson +)
Reporting Elements Metastatic CRC to Liver
Number of tumours, size of each, distance to margins
Histologic type and grade of tumour
Treatment response to NAT - tumour regression score (Rubrei and Grant, only fibrosis counts, presence and %)
MMR / BRAF
Background liver: including sinusoidal obstruction syndrome due to oxiplatin and any concurrent disorder
Defining Steatosis in Liver (& Causes)
Steatosis = Abnormal accumulation of fat within hepatocytes
Steatohepatitis = Fat + Injury (balloon cells and lobular inflammation)
These are part of the same disease process, and both lead to fibrosis, but steatohepatitis leads to fibrosis faster
Changes usually seen in Zone 3 first. Portal infiltrates may be present, but are usually mild. If they are severe, consider additional Dx’s
Macrovesicular steatosis: Change in lipid metabolism. Nucleus pushed to the side by usually a single medium to large sized droplet. Causes: metabolic disease, obesity, TPN, PEM, steroid therapy.
Microvesicular steatosis: Usually represents mitochondrial injury. Nucleus remains central with innumerable, fine fat droplets. Only use this term if it is a diffuse change. Causes: Acute fatty liver of pregnancy, Reye syndrome, in born errors of fatty acid metabolism, alcohol.
Quantifying Fat
< 5% Normal
5 - 33% Mild
33-66% Moderate
>66% Severe
Grading and Staging of Steatohepatitis
Grading:
% of fat (mild, moderate, severe)
Lobular inflammation
Hepatocyte Ballooning
Staging:
Fibrosis
Systems: SAF, NASH-CRN score
Causes of Excess Iron in Liver
Haemochromatosis
Thalassemia
Excess RBC transfusions
Small amounts of iron also seen in many chronic liver diseases e.g. NAFLD, ALD, Hep B / C, cirrhosis
Grading of Iron in Liver Biopsy
Modified Scheurer
Grade 0 - discrete granules not visible or barely discernible at 400x
Grade 1 - discrete granules barely discernible at 250x, easily seen at 100x
Grade 2 - discrete granules resolved at 100x
Grade 3 - discrete granules resolved at 25x
Grade 4 - masses visible with naked eye or at 10x
Classification of Gastric Cancer
Lauren Classification: Diffuse, Intestinal or Mixed
WHO Classification: Tubular, Poorly cohesive (includes signet ring cell carcinoma), Mixed, Mucinous, Papillary, Micropapillary, Hepatoid, Adenosquamous, SCC, Undifferentiatiated / Anaplastic, Gastroblastoma, SCNEC, LCNEC, MANEC
Appendiceal Mucinous Neoplasms
In appendix: LAMN and HAMN
In peritoneum:
WHO 5th edition:
G1: Low grade peritoneal mucinous neoplasia
G2: High grade peritoneal mucinous neoplasia
G3: High grade peritoneal mucinous neoplasia with signet ring cells
PSOG:
Low grade mucinous carcinoma peritonei
High grade mucinous carcinoma peritonei
High grade mucinous carcinoma peritonei with signet ring cells
* submit 1 / cm of mucinous deposits
* search for and sample solid areas
Tumour Regression Score in GIT
Modified Ryan Scheme
Score 0: No viable cancer cells (complete response)
Score 1: Single cells or rare groups of cells (near-complete response)
Score 2: Residual cancer with evident regrssion but more than single cells or rare groups of cells (partial response)
Score 3: Extensive residual cancer without evidence of tumour regression (poor or no response)
Causes of Copper Deposition in Liver
Wilson’s diseae
Chronic cholestatic liver disease PBC, PSC (periportal hepatocytes)
Indian childhood cirrhosis
PFIC
