Administrative Office
St. Joseph's Hospital Site, L301
50 Charlton Avenue East
HAMILTON, Ontario, CANADA L8N 4A6
PHONE: (905) 521-6141
FAX: (905) 521-6142
Issue No. 91
QUARTERLY NEWSLETTER
June 2007
Molecular Pathology of Cancer: A Pathology Perspective
The Anatomic Pathology sections of the Hamilton Regional Laboratory Medicine Program receive a
wide variety of tumors from different organ sites. The molecular pathology and genetic events in cancer are
becoming increasingly important in our understanding of tumor genesis and are key for the development of
targeted therapies. An overview of recent advances in molecular pathology as they pertain to diagnostic
pathology is presented.
Lung Cancer
Lung cancer is the leading cause of cancer deaths worldwide, largely due to the fact that most are
diagnosed at an advanced stage. Diagnosis of precancerous conditions would contribute to lowering mortality.
Carcinogenesis occurs through progressive alterations in the structure and function of critical genes involved in
cell proliferation and differentiation. Early important work as well as recent advances in research using largescale, high throughput genomic scanning, gene expression profiling and translational research have identified
major markers of carcinogenesis and potential therapeutic targets.
In the Pathology laboratory, diagnosis of malignancy or early neoplastic lesions in the lung by routine
histologic examination of biopsy material and/or cytologic screening remains the current gold standard. A few
immunohistochemical tests have been proposed to help in diagnosis but this is generally less robust than
morphologic evaluation. In the research setting, a number of ancillary tests that could be used by pathologists
have been developed recently, but await large-scale application and validation. Preliminary studies indicate that
the overall sensitivity and specificity of detecting lung cancer can be increased when combining newer methods
with conventional ones. One promising method which could be applicable to the most non-invasive approach of
screening is detection of specific, but common chromosomal abnormalities present in cells from early, preinvasive or malignant lesions using fluorescence in situ hybridization (FISH) performed on cytologic material
such as sputum or bronchial washings. Given the high volume of patients screened for lung cancer at the
Center for Respiratory Health at St Joseph's Healthcare, further validation of this test could easily take place.
Another area of particular interest to pathologists is identification of prognostic or predictive markers
within a given tumor specimen. An important marker which has emerged for lung cancer patients is epidermal
growth factor receptor (EGFR). Similar to Her2/neu in breast cancer, subsets of lung cancer patients whose
tumors express this receptor protein may respond to targeted therapy using tyrosine kinase inhibitor drugs.
EGFR protein can be detected immunohistochemically and gene copy number assessed by FISH. In the near
future, these tests may become routine in the pathology laboratory.
Breast Cancer
Breast cancer is the most common malignancy in women in the Western World. Traditionally, the
diagnosis and treatment relied on the evaluation of tumor histology, grade, stage and hormone receptor status.
In the last 10 years, testing for additional abnormalities such as Her2/neu gene over-expression and BRCA1
and 2 gene mutation have been used in clinical practice.
- 2 During this time, research providing gene expression profiling of breast cancers has revealed additional
discriminating molecular features between estrogen receptor (ER)-positive, ER-negative and Her2/neu-amplified
cancers. As such, it has become more appropriate to think of breast cancer as distinct cancer sub-types or
families rather than as a single disease. The number of subtypes that exist and how best to assign a given case
is currently unknown and standard methods for molecular classification are still in development. It is
hypothesized that multigene signatures can be used to help guide therapy and predict prognosis and response
to preoperative chemotherapy in an improved manner compared to current strategies. The extent to which such
signature-driven approaches improve patient outcome would still need to be determined in prospective clinical
trials.
Currently at the HRLMP, breast cancers are routinely tested for ER, progesterone receptor (PR) and
Her2/neu protein expression by immunohistochemistry. In some cases, specific immunohistochemical tests can
help discriminate between in situ and early invasive breast cancers and different breast cancer histological
subtypes. HRLMP has also recently received approval from the Cancer Care Ontario Advisory Committee to
routinely implement fluorescent in situ hybridization (FISH) testing for Her2/neu gene copy number in cases with
indeterminate immunohistochemical results.
Renal Cell (Kidney) Cancer
Within the group of renal cell carcinoma (RCC), distinct histological subtypes can be identified: clear
cell (75%), papillary (10-15%), chromophobe (5-10%), collecting duct and medullary (approx. 1%). Specific
genetic alterations have been associated with different subtypes. Insights into molecular pathways affected by
these alterations have lead to recent advances in targeted therapies for patients with metastatic RCC.
In approximately 60% of clear cell RCCs, the von Hippau Lindau (VHL) tumor suppressor gene is
inactivated. Cells which are deficient in VHL accumulate hypoxia inducible factor (HIF) and have increased
expression of HIF inducible genes some of which are angiogenic factors such as vascular endothelial growth
factor (VEGF), platelet derived growth factorβ (PDGF β) and transforming growth factor α (TGFα). New
therapies have been developed which can interrupt these pathways. For example, Bevacizumab is a
recombinant human monoclonal antibody against VEGF which has been shown to a have a 10% partial
response rate in patients with metastatic clear cell RCC compared to placebo. Other new therapies include
Sunitinib and Sorafenib which inhibit the VEGF and PDGFβ pathways by acting on VEGF and PDGFβ
receptors. The mammalian target of rapamycin complex 1 kinase (referred to as mTOR) has regulatory effects
on HIF and is inhibited by Temsirolimus. Use of this drug has been shown to have a survival benefit in patients
with advanced RCC.
The development of such targeted therapies has come from the understanding of molecular events in
these tumors; however, complete and durable responses with these agents have not been achieved in the
majority of patients. Therefore further work is required with close correlation of clinical, histological and
molecular events to achieve success in the treatment of RCC.
1. Tsao MS, Sakurada A, Cutz JC et al., Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J
Med. 2005 Jul 14;353(2):133-44.
2. Savic S, Glatz K, Schoenegg R et al. Multitarget fluorescence in situ hybridization elucidates equivocal lung cytology.
Chest. 2006 Jun;129(6):1629-35.
3. Annuska et al. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics
2006; 7:278.
4. Wolff et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Arch Pathol Lab Med. 2007; Jan 131(1):18.
5. Brugarolus J. Renal Cell Carcinoma – Molecular Pathways and Therapies. NEJM 2007; Jan. 11: 185-187.
6. Vira MA, Novakovac KR et al. Genetic Basis of Kidney Cancer. Br J Urology. 2007; 99: 1223-1229.
Dr. J.-C. Cutz is a staff pathologist at St Joseph's Healthcare Hamilton with expertise in Lung and Molecular
Pathology and is the newly appointed supervisor of the Diagnostic AP Molecular Lab. Dr. G. Gohla is a staff
pathologist at St Joseph's Healthcare Hamilton and member of the Breast Disease Site Team for the Juravinski
Cancer Center. Dr. K. Chorneyko is a staff pathologist at St Joseph's Healthcare Hamilton and is a member of
the Renal Pathology Service at HRLMP and Medical Director of the Diagnostic Electron Microscopy Unit at
McMaster Medical Center.
Dr. J.-C. Cutz, Dr. G. Gohla, Dr. K. Chorneyko
Discipline of Anatomic Pathology
Hamilton Regional Laboratory Medicine Program
St. Joseph’s Healthcare Hamilton