Morphological Features and Mismatch Repair in Colorectal Tumors

Britta Halvarsson

Morphological Features and Mismatch Repair in Colorectal Tumors

Britta Halvarsson

Tumor microenvironment

Research output: Thesis › Doctoral Thesis (compilation)

Abstract

Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein.

The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V).

In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas.

Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.

Original language	English
Qualification	Doctor
Awarding Institution	Tumor microenvironment
Supervisors/Advisors	Nilbert, Mef, Supervisor Johansson, Leif, Supervisor Lindmark, Gudrun, Supervisor
Award date	2007 Jan 26
Publisher	Lund University, Faculty of Medicine Doctoral Dissertation
ISBN (Print)	91-85559-78-4
Publication status	Published - 2007

Bibliographical note

Defence details

Date: 2007-01-26
Time: 13:00
Place: Museum of Medical History in Helsingborg, Bergaliden 20

External reviewer(s)

Name: Palmqvist, Richard
Title: Associate professor
Affiliation: Department of Pathology, Umeå University

---

<div class="article_info">B Halvarsson, A Lindblom, E Rambech, K Lagerstedt and M Nilbert. <span class="article_issue_date">2004</span>. <span class="article_title">Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?</span> <span class="journal_series_title">Virchows Archiv</span>, <span class="journal_volume">vol 444</span> <span class="journal_pages">pp 135-141</span>.</div>
<div class="article_info">. <span class="article_issue_date">2006</span>. <span class="article_title">The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Fam Cancer</span>, (inpress)</div>
<div class="article_info">B Halvarsson, E Rambech, A Lindblom and M Nilbert. <span class="article_issue_date">2006</span>. <span class="article_title">The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Fam Cancer</span>, (inpress)</div>
<div class="article_info">B Halvarsson, A Lindblom, L Johansson, K Lagerstedt and M Nilbert. <span class="article_issue_date">2005</span>. <span class="article_title">Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Modern Pathol</span>, <span class="journal_volume">vol 18</span> <span class="journal_pages">pp 1095-1101</span>.</div>
<div class="article_info">B Halvarsson, W Muller, M Planck, AC Benoni, P Mangell, J Ottosson, M Hallén, A Isinger and M Nilbert. <span class="article_issue_date">2006</span>. <span class="article_title">Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.</span> <span class="journal_series_title">J Clin Pathol</span>, (inpress)</div>
<div class="article_info">B Halvarsson, H Anderson, K Domanska, G Lindmark and M Nilbert. <span class="article_issue_date"></span>. <span class="article_title">Tumor morphology for the identification of mismatch repair defective colon cancers.</span> (manuscript)</div>

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Pathology, (Lund) (013030000)

Subject classification (UKÄ)

Cancer and Oncology

Free keywords

Patologi (allmän)
patologisk anatomi
Lynch syndrome
Colorectal tumors
HNPCC
Mismatch repaire
pathological anatomy
General pathology
Genetik
cytogenetik
cytogenetics
Genetics
Medicin (människa och djur)
Medicine (human and vertebrates)
Immunohistochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@phdthesis{e8e4d4cc5bba431580f6051fd6ad2a16,

title = "Morphological Features and Mismatch Repair in Colorectal Tumors",

abstract = "Corlorectal cancer affects 5\% of individuals in the Western world and heredity is estimated to cause at least 10\% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15\% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein. The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V). In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92\% and a specificity of 100\%. When PMS2 immunostaining was added in study II the sensitivity raised to >95\%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66\%, although higher frequencies were found in larger and proximally located adenomas. Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23\% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.",

keywords = "Patologi (allm{\"a}n), patologisk anatomi, Lynch syndrome, Colorectal tumors, HNPCC, Mismatch repaire, pathological anatomy, General pathology, Genetik, cytogenetik, cytogenetics, Genetics, Medicin (m{\"a}nniska och djur), Medicine (human and vertebrates), Immunohistochemistry",

author = "Britta Halvarsson",

note = "Defence details Date: 2007-01-26 Time: 13:00 Place: Museum of Medical History in Helsingborg, Bergaliden 20 External reviewer(s) Name: Palmqvist, Richard Title: Associate professor Affiliation: Department of Pathology, Ume{\aa} University --- <div class={"}article\_info{"}>B Halvarsson, A Lindblom, E Rambech, K Lagerstedt and M Nilbert. <span class={"}article\_issue\_date{"}>2004</span>. <span class={"}article\_title{"}>Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?</span> <span class={"}journal\_series\_title{"}>Virchows Archiv</span>, <span class={"}journal\_volume{"}>vol 444</span> <span class={"}journal\_pages{"}>pp 135-141</span>.</div> <div class={"}article\_info{"}>. <span class={"}article\_issue\_date{"}>2006</span>. <span class={"}article\_title{"}>The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class={"}journal\_series\_title{"}>Fam Cancer</span>, (inpress)</div> <div class={"}article\_info{"}>B Halvarsson, E Rambech, A Lindblom and M Nilbert. <span class={"}article\_issue\_date{"}>2006</span>. <span class={"}article\_title{"}>The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class={"}journal\_series\_title{"}>Fam Cancer</span>, (inpress)</div> <div class={"}article\_info{"}>B Halvarsson, A Lindblom, L Johansson, K Lagerstedt and M Nilbert. <span class={"}article\_issue\_date{"}>2005</span>. <span class={"}article\_title{"}>Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.</span> <span class={"}journal\_series\_title{"}>Modern Pathol</span>, <span class={"}journal\_volume{"}>vol 18</span> <span class={"}journal\_pages{"}>pp 1095-1101</span>.</div> <div class={"}article\_info{"}>B Halvarsson, W Muller, M Planck, AC Benoni, P Mangell, J Ottosson, M Hall{\'e}n, A Isinger and M Nilbert. <span class={"}article\_issue\_date{"}>2006</span>. <span class={"}article\_title{"}>Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.</span> <span class={"}journal\_series\_title{"}>J Clin Pathol</span>, (inpress)</div> <div class={"}article\_info{"}>B Halvarsson, H Anderson, K Domanska, G Lindmark and M Nilbert. <span class={"}article\_issue\_date{"}></span>. <span class={"}article\_title{"}>Tumor morphology for the identification of mismatch repair defective colon cancers.</span> (manuscript)</div> The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Pathology, (Lund) (013030000)",

year = "2007",

language = "English",

isbn = "91-85559-78-4",

series = "2007:9",

publisher = "Lund University, Faculty of Medicine Doctoral Dissertation",

type = "Doctoral Thesis (compilation)",

school = "Tumor microenvironment",

}

TY - THES

T1 - Morphological Features and Mismatch Repair in Colorectal Tumors

AU - Halvarsson, Britta

N1 - Defence details Date: 2007-01-26 Time: 13:00 Place: Museum of Medical History in Helsingborg, Bergaliden 20 External reviewer(s) Name: Palmqvist, Richard Title: Associate professor Affiliation: Department of Pathology, Umeå University --- <div class="article_info">B Halvarsson, A Lindblom, E Rambech, K Lagerstedt and M Nilbert. <span class="article_issue_date">2004</span>. <span class="article_title">Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?</span> <span class="journal_series_title">Virchows Archiv</span>, <span class="journal_volume">vol 444</span> <span class="journal_pages">pp 135-141</span>.</div> <div class="article_info">. <span class="article_issue_date">2006</span>. <span class="article_title">The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Fam Cancer</span>, (inpress)</div> <div class="article_info">B Halvarsson, E Rambech, A Lindblom and M Nilbert. <span class="article_issue_date">2006</span>. <span class="article_title">The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Fam Cancer</span>, (inpress)</div> <div class="article_info">B Halvarsson, A Lindblom, L Johansson, K Lagerstedt and M Nilbert. <span class="article_issue_date">2005</span>. <span class="article_title">Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.</span> <span class="journal_series_title">Modern Pathol</span>, <span class="journal_volume">vol 18</span> <span class="journal_pages">pp 1095-1101</span>.</div> <div class="article_info">B Halvarsson, W Muller, M Planck, AC Benoni, P Mangell, J Ottosson, M Hallén, A Isinger and M Nilbert. <span class="article_issue_date">2006</span>. <span class="article_title">Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.</span> <span class="journal_series_title">J Clin Pathol</span>, (inpress)</div> <div class="article_info">B Halvarsson, H Anderson, K Domanska, G Lindmark and M Nilbert. <span class="article_issue_date"></span>. <span class="article_title">Tumor morphology for the identification of mismatch repair defective colon cancers.</span> (manuscript)</div> The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Pathology, (Lund) (013030000)

PY - 2007

Y1 - 2007

N2 - Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein. The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V). In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas. Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.

AB - Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein. The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V). In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas. Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.

KW - Patologi (allmän)

KW - patologisk anatomi

KW - Lynch syndrome

KW - Colorectal tumors

KW - HNPCC

KW - Mismatch repaire

KW - pathological anatomy

KW - General pathology

KW - Genetik

KW - cytogenetik

KW - cytogenetics

KW - Genetics

KW - Medicin (människa och djur)

KW - Medicine (human and vertebrates)

KW - Immunohistochemistry

M3 - Doctoral Thesis (compilation)

SN - 91-85559-78-4

T3 - 2007:9

PB - Lund University, Faculty of Medicine Doctoral Dissertation

ER -

Morphological Features and Mismatch Repair in Colorectal Tumors

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Fingerprint

Cite this