Upper GI Histopathology Update

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Upper GI Histopathology Update

• Dr David Cundell
• ST4 Histopathology, BRI

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Acknowledgement

• Dr Newton Wong, Consultant Histopathologist at
  BRI and regional network lead for Upper GI
  Histopathology.

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Outline

• Specimens request forms

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Outline

• Specimens request forms
• Staging

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Outline

• Specimens request forms
• Staging
• Molecular biology / personalised medicine

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Outline

• Specimens request forms
• Staging
• Molecular biology / personalised medicine
• Carter report future of path services

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• Specimens
• Please resist any temptation to open surgical
  specimens. Slicing through tumours can compromise
  accurate staging assessment
• Pathologist should be left to open them after
  inking any non-peritonealised CRM

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• Clinical information for the request form useful
  at the time of cut up
• Previous investigation findings
• Operation undertaken, not just the name of the
  organ removed
• Any margin that may be at particular risk
• Significant co-existant pathology does patient
  have another malignancy?
• Treatment has patient been given
  chemo/radiotherapy? Including the use of any
  monoclonal antibody therapy

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• Staging
• Anatomical definitions in oesophageal anatomy
• Junctional neoplasms
• TNM 7 update for oesophagus and stomach cancer

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• Cervical Oesophagus
• From the lower border of the cricoid cartilage to
  the thoracic inlet, about 18 cm from the
  incisors.

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• Intrathoracic (including abdominal oesophagus)
• Upper thoracic portion From the thoracic inlet
  to the level of the tracheal bifurcation (18-24
  cm).
• Mid-thoracic portion From the tracheal
  bifurcation midway to the gastroesophageal (GE)
  junction (24-32 cm).
• Lower thoracic portion From midway between the
  tracheal bifurcation and the gastroesophageal
  junction to the GE junction, including the
  abdominal esophagus between 32-40 cm.

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Classification of Gastroesophageal Junction
Adenocarcinoma, Siewert I-III

• Type I tumour of distal oesophagus, infiltrates
  the oesophagogastric junction from above
• Type II true carcinoma of the cardia arising
  immediately at the oesophagogastric junction
• Type III subcardial gastric carcinoma that
  infiltrates the oesophagogastric junction and
  distal oesophagus from below.
• Siewart JR et al. Adenocarcinoma of the
  Esophagogastric Junction Results of Surgical
  Therapy Based on Anatomical/Topographic
  Classification in 1,002 Consecutive Patients.
  Ann Surg. 2000 September 232(3) 353361.

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TNM 6 to 7

• Tumours of gastric cardia / OGJ to be harmonised
  with distal oesophagus as bulky tumours at
  diagnosis that straddled the junction introduced
  different stage groupings depending on
  designation
• Simplify T categories across the tubular GIT to
  aid conceptualisation
• Gastric carcinoma may have LN metastases when
  still confined to lamina propria due to abundant
  lymphatics in gastric mucosa (cf. colorectal)
• Reference
• Washington, K. 7th Edition of the AJCC Cancer
  Staging Manual Stomach. Ann Surg Oncol (2010)
  173077-3079

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TNM 7Oesophagus
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TNM 7 changes

• Tumors arising at the OGJ, or in the cardia of
  the stomach within 5 cm of the OGJ and cross the
  OGJ, are staged using the TNM system for
  oesophageal rather than stomach cancer.

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TNM 7 changes

• Tumors arising at the OGJ, or in the cardia of
  the stomach within 5 cm of the OGJ and cross the
  OGJ, are staged using the TNM system for
  oesophageal rather than stomach cancer.
• All other cancers with a midpoint in the stomach
  lying more than 5 cm distal to the OGJ, or those
  within 5 cm of the OGJ but not extending into the
  OGJ or esophagus, are staged using the stomach
  TNM

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TNM 7 Oesophageal Cancer
Depth of invasion pT Stage
In situ, intraepithelial, noninvasive high grade dysplasia Tis
Invasive tumor confined to mucosa (LP, MM) T1a
Invades submucosa T1b
Muscularis propria invaded T2
Adventitia and/or soft tissue invaded T3
At serosal surface T4a
Invades adjacent organ T4b
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Layers of the oesophageal wall
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TNM 7 Oesophagus - validated through
retrospective re-staging

• Reid TD, Sanyaolu LN, Chan D, Williams GT, Lewis
  WG. Relative prognostic value of TNM7 vs TNM6 in
  staging oesophageal cancer. Br J Cancer 2011 Sep
  6105(6)842-6. Department of Surgery, South East
  Wales Cancer Network, University Hospital of
  Wales, Cardiff, UK. (n200)
• Zhonghua Zhong Liu Za Zhi. 2012 Jun34(6)461-4.
  Preliminary experience of clinical applications
  of the 7th UICC-AJCC TNM staging system of
  esophageal carcinoma. Lu et al. Source Department
  of Thoracic Surgical Oncology, Cancer Hospital
  (Institute), Chinese Academy of Medical Sciences
  and Peking Union Medical College, Beijing 100021,
  China. (n1397)
• Both studies drew the conclusion that TNM7
  provides superior prognostic information.

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TNM 7Stomach
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TNM 7 Tumour changes, stomach
Tis Intraepithelial tumor without invasion of the lamina propria (including high grade dysplasia)
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades the muscularis propria (NB. previously pT2a was MP invasion pT2b subserosal invasion)
T3 Tumor penetrates the subserosa (NB. Previously pT3 included serosal invasion)
T4a Tumor invades serosa
T4b Tumor invades adjacent stuctures
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TNM 7 Tumour changes, stomachIncidence of
nodal metastasis is a good predictor of prognosis
justifying new subclassification of pT1 (NB.
Previously pT1 encompassed invasion of LP, MM
SM)
Tis Intraepithelial tumor without invasion of the lamina propria (including high grade dysplasia)
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades the muscularis propria (NB. previously pT2a was MP invasion pT2b subserosal invasion)
T3 Tumor penetrates the subserosa (NB. Previously pT3 included serosal invasion)
T4a Tumor invades serosa
T4b Tumor invades adjacent stuctures
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TNM 7 Tumour changes, stomach
Tis Intraepithelial tumor without invasion of the lamina propria (including high grade dysplasia)
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades the muscularis propria (NB. previously pT2a was MP invasion pT2b subserosal invasion)
T3 Tumor penetrates the subserosa (NB. Previously pT3 included serosal invasion)
T4a Tumor invades serosa
T4b Tumor invades adjacent stuctures
A. Marchet et al. Validation of the new AJCC TNM
staging system for gastric cancer in a large
cohort of patients (n2,155) focus on the T
category European Journal of Surgical Oncology
2011. (T2/3 cases n686). Retrospective review of
686 patients previously classified as having T2
tumors, using new TNM staging gt T2 and T3
disease were 270 (39.4) and 416 (60.6),
respectively. After a median follow-up of 55
months, the 5-year overall survival rates were
67.3 and 52.3 for patients with T2 and T3
tumors, respectively (Plt0.001). Prognostic
difference significant
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TNM 7 Node changes, stomach
Nx Regional LN cannot be assessed
N0 No regional LN mets
N1 Mets in 1-2 regional LN (pN1 previously 1-6)
N2 Mets in 3-6 regional LN (pN2 previously 7-15)
N3a Mets in 7-15 regional LN (pN3 previously gt 15)
N3b Mets in 16 regional LN
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TNM7 Metastasis changes, stomach

• Mx - deleted
• Clinical M staging until biopsy proven metastasis
• M0 No distant mets
• M1 Distant mets
• Positive peritoneal cytology
• Non regional or distant LN
• Peritoneal surfaces
• Other organs
• Therefore only pM1 exists, used following tissue
  diagnosis of distant metastasis or positive
• peritoneal cytology

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Outline

• Molecular pathology / personalised medicine
• Her-2 analysis in gastric cancers
• Mutational analysis in GISTs
• NICE K-RAS analysis re cetuximab for liver
  metastases

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• Molecular pathology All carried out locally
• HER-2 testing for gastric adenocarcinomas
• Mutational analysis for gastrointestinal stromal
  tumours (GISTs)
• K-Ras analysis
• As cetuximab can be prescribed for some patients
  with wild type K-Ras liver metastases from
  colorectal adenocarcinoma.

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• HER2 (Human Epidermal Growth Factor Receptor 2,
  Neu, ErbB-2)
• A protein encoded by ERBB2 gene on chromosome
  17q12
• NB. HER2 similar structure to human epidermal
  growth factor receptor. Neu derived from a
  rodent glioblastoma neural tumor. ErbB-2
  similarity to protein product of avian
  erythroblastosis oncogene B. Gene cloning showed
  that HER2, Neu, and ErbB-2 proteins are all
  encoded by the same gene.
• Amplification of ERBB2 linked to pathogenesis
  progression of certain aggressive types of breast
  cancer but also gastric cancer
• References
• Xie SD et al. HER 2/neu protein expression in
  gastric cancer is associated with poor survival.
  Mol Med Rep. 20092(6)943-6. Forty-one out of
  218 (18.8) gastric cancer specimens showed HER
  2/neu-positive expression. In multivariate
  analysis, HER 2/neu expression was a significant
  independent prognostic predictor of gastric
  cancer (plt0.001), and was associated with poor
  survival in gastric cancer patients.
• Park DI et. HER-2/neu amplification is an
  independent prognostic factor in gastric cancer.
  Dig Dis Sci 2006 Aug51(8)1371-9. Epub 2006 Jul
  26. Twenty-nine (15.9) of 182 patients expressed
  the HER-2/neu protein by immunohistochemistry.
  Tumors with HER-2/neu amplification were
  associated with poor mean survival rates (922 vs
  3243 days) and 5-year survival rates (21.4 vs
  63.0 P lt 0.05).
• 2008 Gastrointestinal Cancers Symposium overall
  HER2 expression (IHC 3 and/or FISH ) of 22 in
  2168 patients tested and confirmed a higher rate
  of HER2 positivity in GEJ tumors than in gastric
  cancer samples (34 vs 20).

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• EGFRs have plasma membrane-bound receptor
  tyrosine kinases.
• extracellular ligand binding domain,
  transmembrane domain, intracellular domain gt
  second messenger signalling
• HER2 heterodimerisation gt autophosphorylation of
  tyrosine residues within the cytoplasmic domain
  of the receptors
• Initiates a variety of signalling pathways
• promotes cell proliferation
• opposes apoptosis
• NICE guidance Nov 2010
• Herceptin / Trastuzumab as part of combination
  chemotherapy for patients with metastatic
  gastric or junctional carcinomas that
  overexpress HER2
• Analyse either
• The amount of HER2 protein that has been
  translated (IHC)
• Examine the nucleus to see if there is
  amplification of the gene (ISH)
• Reference

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• GIST
• Most (50-80) GISTs arise because of a mutation
  in c-kit, a gene encoding a receptor for a growth
  factor called stem cell factor (CD117)
• Mutation of gene gt activation of the KIT
  receptor tyrosine kinase gt downstream
  phosphorylation in the signal transduction
  pathway gt increased cellular proliferation.
• In a minority of cases, GISTs result from
  mutational activation of the closely related
  tyrosine kinase PDGF receptor a (PDGFRA).
• Molecular analysis involves assessment of
• KIT exons 9 and 11, 13 17
• PDGFRA exons 12 and 18
• The tyrosine kinase inhibitor imatinib / Glivec
  represents a major breakthrough in the treatment
  of GISTs, which are generally resistant to
  cytotoxic chemotherapy.
• Additional cytogenetics
• Low risk noncomplex or even normal karyotypes,
  with deletion of chromosome 14 often being the
  only observable cytogenetic aberration.
• Moderate-risk as for low risk plus deletions of
  chromosomes 1p, 9p, 11p, or 22q

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• KRAS
• Kirsten rat sarcoma protein encoded by KRAS
  gene. KRAS protein is a GTPase tethered to cell
  membranes. Involved in signal transduction
  pathways, acting as a molecular on/off switch.
• A single amino acid substitution, and in
  particular a single nucleotide substitution, is
  responsible for an activating mutation. The
  transforming protein that results is implicated
  in various malignancies, including colorectal
  carcinoma
• KRAS mutation is predictive of a very poor
  response to cetuximab therapy in colorectal
  cancer (40 cases), as the mAb targets the EGFR
  upstream of the mutant protein.
• NICE Cetuximab in combination chemotherapy is
  recommended for the first-line treatment of
  metastatic colorectal cancer only when all of the
  following criteria are met
• The primary colorectal tumour has been resected
  or is potentially operable.
• The metastatic disease is confined to the liver
  and is unresectable.
• The patient is fit enough to undergo surgery to
  resect the primary colorectal tumour and/or to
  undergo liver surgery if the metastases become
  resectable after treatment
• Reference
• Leivre,A et al. KRAS Mutation Status Is
  Predictive of Response to Cetuximab Therapy in
  Colorectal Cancer Cancer Res 200666 (8). April
  15, 2006

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Outline

• Specimens request forms
• Staging
• Molecular biology / personalised medicine
• Carter report future of path services

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Consequences of the Carter report Modernisation
of Pathology Services published in December
2008

• Recommendations on the centralisation of service
  provision into networks
• Satellite centres provide frozen section / MDT
  cover
• Logistical problems with specimen handling eg.
  the opening of specimens for adequate fixation to
  prevent autolysis
• Histopath costs are staff heavy but grouped with
  blood sciences, inappropriate as different
  pattern of work less automation
• Changes underway in this region
• Southmead, UHB Weston may merge at NBT
• http//www.pathologists.org.uk/publications-page/C
  arter20Report-The20Report.pdf

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• Thank you