PATHOLOGY 101 BLADDER CANCER ADVOCACY NETWORK SEPTEMBER 24 TH, 2001

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1 PATHOLOGY 101 BLADDER CANCER ADVOCACY NETWORK SEPTEMBER 24 TH, 2001 Dara L. Aisner, M.D., Ph.D. Assistant Professor, Pathology Co-Director, Colorado Molecular Correlates Laboratory

2 Pathology Myths & Truths Myth: Pathology is about performing autopsies Truth: Pathologists are trained to perform autopsies during residency, but it is not a large part of practice for most pathologists All medical examiners are pathologists (coroner s aren t), but only a small fraction of pathologists are medical examiners

3 Pathology Myths & Truths Myth: Pathology all happens after-the-fact Truth For many disease types, especially cancer, treatment decisions are dependent on the findings from pathology You usually don t get to meet your pathologist, but they are very much an active part of your clinical care team

4 Pathology Myths & Truths Myth: Pathologists describe everything like food Truth: Pathologists describe ALMOST everything like food Warning: Food analogies will crop up!

5 What is Pathology? 1. The branch of medicine concerned with the cause, origin, and nature of disease, including the changes occurring as a result of disease 2. The manifestations of disease, esp changes occurring in tissues or organs

6 What is Pathology REALLY? Anytime any tissue gets taken out of anybody, it gets sent to pathology for evaluation Pathologist s job is to: Characterize the nature of the lesion Essentially normal? Inflammatory? Infectious? Pre-cancerous? Cancerous? Cancerous with invasion? Classify the lesion into discrete groups to aid in treatment Ex: cancer subtypes, identification of specific infectious agents Characterize the aggressiveness and extent of the lesion GRADING & STAGING

7 How Does Pathology Work? Specimen arrives in pathology Microscopic evaluation The glass slides are stained to be able to see different features of the tissue Specimen is evaluated grossly Size and type of specimen Grossly visible abnormalities described Cut into small pieces to allow microscopic evaluation Fixation in formalin Food Analogy #3: Think of a deli-slicer on a small scale The paraffin block is sliced very thinly and the slices are put onto glass slides Food Analogy #1: Examined like a loaf of bread we even call slicing a specimen up breadloafing Food Analogy #2: This is like pickling The specimen is processed Series of chemical exposures that dehydrates, hardens and rehydrates the tissue takes from 6 12 hours The specimen is embedded in a mold of paraffin wax Allows the specimen to be cut very thinly The paraffin mold with tissue in it is called a block

8 Pathology Processing: Tissue Cutting the tissue Fixation & Processing Tissue embedding in paraffin Microscopic evaluation Slide staining Block cut to make slides

9 Pathology & Cancer: Type and Stage are the Keys Treatment in cancer is often determined by cancer type & grade Can frequently be determined on a biopsy or other minimally invasive method Sometimes requires the pathologist to use special stains and is heavily influenced by cancer stage Stage indicates the extent (or spread) of disease Defined differently in every organ system These definitions are determined by rigorous science which determines correlations between certain findings and prognosis Staging can be approximated using imaging techniques Pathology evaluation is gold standard

10 Pathology & Bladder Cancer Three major types of bladder cancer: Transitional cell carcinoma Squamous cell carcinoma Adenocarcinoma Major specimen types in the evaluation of bladder cancer: Voided urine Bladder washing Bladder biopsy Transurethral resection of bladder tumor Cystectomy removal of bladder Lymph nodes near the bladder

11 Bladder Cancer Diagnosis Specimen types: Voided urine looking for shed cancer cells Bladder washing looking for cancer cells removed by the washing Bladder biopsy looking for cancer cells in the tissue Cancer types & subtypes: Lots of different sub-types Grading Usually at diagnosis, pathologist will classify the lesion as high-grade or low-grade Two major systems for this, but a single standard is nearly universally adopted

12 Bladder Cancer: Staging Major issue in staging bladder cancer is whether the tumor invades the muscle of the bladder Hammersen, F. (1980) Histology, A Color Atlas of Cytology, Histology and Microscopic Anatomy 2nd Ed

13 Bladder Cancer: Therapy & Staging Transurethral resection of bladder tumor Can be used as initial therapy in bladder cancer Also used to diagnose muscle invasion Specimen arrives in lots of little pieces For tumors without muscle invasion, this may be the definitive procedure For tumors shown to HAVE muscle invasion, more treatment is needed

14 Bladder Cancer: Therapy & Staging Muscle invasive lesions that go on to cystectomy: The bladder is intact when it arrives in pathology Can evaluate ALL the layers of the bladder Lymph nodes are often evaluated to determine if there is local spread

15 Reading a Pathology Report Major sections of a pathology report: Diagnosis Comment Microscopic Description Gross Description

16 Reading a Pathology Report Key terms in a bladder cancer report: Carcinoma = cancer Dysplasia = pre-cancer Muscularis = muscle Serosa/perivesical adipose = deepest layer WHO = World Health Organization ISUP = International Society for Urologic Pathology AJCC TNM = Staging system T indicates muscle invasive or no N involvement of lymph nodes M distant metastases Immunohistochemistry a special technique that helps pathologists classify lesions

17 Molecular Pathology The Next Wave Traditional pathology has been nearly the same for over 100 years A few major developments Automatic methods, some improvements in processing Special stains help with classification Better optics in microscopes Last 10(ish) years development of Molecular Pathology Molecular Pathology is one of the major driving forces behind Personalized Medicine

18 What is Molecular Pathology? Evaluation of the genes and changes in genes in individual patients tumor cells to: Help with diagnosis Predict disease course Predict response to therapy = Personalized Medicine

19 How does Molecular Pathology work? Individual tumor cells from patient specimens are isolated from tissue DNA (or RNA) is extracted from the tumor cells Testing is designed to look for changes in DNA/RNA that are NOT present in the non-tumor cells Tumor cells are evaluated on the slide for changes in DNA Fluorescence In Situ Hybridization (FISH)

20 Personalized Medicine & Molecular Pathology it works! In several cancer types, molecular pathology testing is standard practice to determine if a patient is likely to respond to specific drugs Lung cancer Colon cancer Melanoma What about bladder cancer?

21 Diagnosis of Bladder Cancer - UroVysion FISH test looking at cells in urine Can tell if cells are cancerous based on DNA changes Used for diagnosis and surveillance after treatment

22 Personalized Medicine & Bladder Cancer Two genes (TP53 and FGFR3) commonly have mutations in bladder cancer Mutation in TP53 associated with aggressive lesions Mutation in FGFR3 associated with lower agressiveness Does this tell us anything that looking at the slide doesn t? Does this tell us anything about what therapy to use?

23 Personalized Medicine & Bladder Cancer What if we could use a test to predict who would have Aggressiveness & spread of disease Responsiveness to specific chemotherapy agents Responsiveness to targeted therapy agents A new study aims to do exactly that

24 Personalized Medicine & Bladder Cancer pn0 Laval Cohort ROC Curve In process: development of a test which can be done on a biopsy specimen which tests many genes at the same time (Theodorescu lab) Can predict which patients will have lymph node metastases pn1-3 Max AUC=0.72 P=0.004 Top 21 Probes Can predict which patients will respond to standard chemotherapy Smith et. al, Lancet Oncology 2011

25 Personalized Medicine Many new targeted therapy agents being tested in many tumor types Will be most effective with combined with testing for biomarkers Deciding who to treat with what therapy at what point in time Research dollars support discoveries in bladder cancer biology and treatment Funding is also needed to develop the predictive tests

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