Fausto Sessa

Il futuro della Anatomia Patologica

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Sometimes, Diagnosis Is in the Eye of the Beholder

HUFFPOST HEALTLY LIVING15/4/2015

Another star, Rita Wilson, has also made headlines recently with her own call to action about the need for second opinions in breast pathology if you have a biopsy. According to one pathology blog, Dr. Keith Kaplan mentions the need for some form of second opinion in questionable cases to ensure patient safety and quality. Pathologists have many quality assurance processes in place and collaborate with one another on challenging cases

According to the media report of Ms. Wilson's announcement, she was diagnosed with LCIS some time ago and was appropriately monitored. She then developed a lesion, which was biopsied and at first reported as LCIS. A second opinion reported PLCIS. On this basis, Ms. Wilson underwent bilateral mastectomies where they found area that indeed showed these abnormal appearing cells outside of a lobule, which was therefore termed invasive.

The takeaway message from Ms. Wilson's situation is this: Individuals read pathology slides. And the diagnosis is often in the eye of the beholder. We encourage second opinions about treatment, but most people don't realize that when they ask for a second opinion on the diagnosis, the opinion should be based on examination of the actual biopsy slides, not simply the original pathology report. Some cases are clear-cut but if there is any question, the more eyes looking at the tissue, the more accurate the diagnosis, and the more confident a woman can feel in the decisions she makes.

Pathologists are the most important doctors that patients

never meet. Their expertise is essential to help diagnose

disease, figure out how far it has spread, and determine

the best treatment options.

They huddle over microscopes much as they have for the

last 100 years, peering at slivers of human tissue, cells

and bodily fluids on glass slides to unlock the medical

mysteries in cells.

There can be significant differences in how pathologists

interpret what they see under the microscope or with the

naked eye, a growing number of studies show. That can

lead to serious consequences for patients if pathologists

miss cancer, or conversely, if they interpret a benign tumor

as malignant.

New Ways Doctors Reach Agreement

on Patient Diagnoses

Studies show many breast biopsies are misdiagnosed; some hospitals use digital images

THE WALL STREET

JOURNAL 9/6/2015

A panel of experts convened by the College of American

Pathologists and the Association of Directors of Anatomic

and Surgical Pathology issued new guidelines earlier this

year, citing studies that show disagreements among

pathologists and errors can happen in more than 10% of

cases. They ask pathology labs to develop standard

procedures to review cases and resolve disagreements,

ideally before sending results back to referring doctors.

UPMC and other medical centers around the country are

studying the use of new digital technology that scans

slides into a computer to create images that can be

shared and compared electronically. Software used by

such systems can help quantify biomarkers that are

important for diagnosing a tumor, such as the protein

HER2 in breast cancer, according to David Dabbs, chief of

the department of pathology at Magee-Womens Hospital.

THE WALL STREET

JOURNAL 9/6/2015

Currently, digital pathology is approved for primary and

secondary diagnosis in Europe, but not yet in the U.S.,

where the Food and Drug Administration is reviewing

whether the images are as good as physical slides of

pathology specimens. UPMC and GE Healthcare, which

have a joint venture called Omnyx, are currently cleared

by the FDA to use Omnyx’s digital pathology system to

review digital images of breast cancer tissue of patients

being considered for the treatment Herceptin.

THE WALL STREET

JOURNAL 9/6/2015

New Pan-European digital pathology network aims to

transform diagnosis and treatment of cancer and

other diseases

Previously pathologists would have to assess physical

slides under a microscope and post them by mail for a

second opinion. This could result in delays, risks slides

being lost or damaged and hindered collaboration efforts.

It could also delay the prescription of the most appropriate

course of care for patients.

The study supports the value of a second

opinion in cases of ambiguity. Indeed, it is axiomatic

that an abnormal breast biopsy is certainly a cause

for concern but does not constitute a medical

emergency. Extra time and care devoted to

confirmation of the histologic diagnosis and a

thoughtful discussion of the treatment options are

imperative. Importantly,

breast pathology is a biological continuum from

normal to invasive cancer whereas prescription of

treatment requires categorization into specific

diagnoses.

Expertise vs Evidence in Assessment of Breast Biopsies: An Atypical Science

Diagnostic Concordance Among Pathologists Interpreting Breast Biopsy Specimens

Jama March 2015

Digital pathology: Attitudes and practices in the

Canadian pathology community, J Path Inf 2013

The applications of telepathology in Canadian institutions

The use of digital images as an educational tool among Canadian

pathologists

In his State of the Union Address, president Obama announced a new initiative on personalized medicine. The Precision Medicine Initiative will be launched with a $215 million investment in the President’s 2016 budget and will pioneer a new model of patient-powered research. It promises to accelerate biomedical discoveries and provide clinicians with new tools and knowledge for patient management, including personalized treatment of cancer. Next generation sequencing (NGS) becomes the cornerstone of personalized medicine by providing a comprehensive analysis of human genome.

Association for Molecular Pathology Companion Symposium Syllabus

Future of Pathology in the Era of Personalized Medicine

Historically, pathology has served a central role in diagnosis and classification of human diseases. Pathologists provide interpretation of cellular, biochemical, molecular and microbiological markers and guide treating physician in the management of patients. Now, it is critically important that pathologists claim ownership of the genome sequencing and lead on genetic data interpretation for prediction of disease risk and therapy response.

Developing and expanding expertise in NGS testing, pathologists need to be involved in specimen selection, NGS data interpretation, integration of sequencing results with other clinicopathological data, generation of a comprehensive reports, and communication of the NGS results to the treating physician. Pathologists as laboratory physicians have to provide an expertise on high quality of NGS testing and ensure that oversight of genome-based laboratory testing falls under the jurisdiction of pathologists and our national organizations. These goals require changes in the approaches to practicing pathology and education of pathology residents and fellows.

The New Paradigm in Cancer Treatment

Molecular Markers and Targeted Therapy

EGFR: Erlotinib/ Gefitinib20% Lung adenocarcinomas

KRAS: Cetuximab resistance36-50% Colon adenocarcinoma

BRAF V600E: PLX403260% Melanoma

ALK: Crizotinib3-5% Lung adenocarcinoma

ALK IHC in LUNG CANCER

ALK positive with translocation

Caso positivo delezione regione 3’ ALK (segnale verde)

Kelly L et al, PNAS 2015

Kelly L et al, PNAS 2015

More accurately establish cancer risk in thyroid nodules with

indeterminate cytology to minimize unnecessary surgeries

Provide accurate prediction of risk of recurrence and tumor-

related mortality to individualize RAI therapy

Detect therapeutic targeted for aggressive types of thyroid

cancer

Molecular markers, detected using NGS panels and other

techniques, will help the pathologist to:

Evolution of Pathology Practice

Immunostains for Identification,

Treatment and Prognostication of

Gastrointestinal Tumors

• HER2/neu staining as a target for therapy in gastric

and esophageal adenocarcinomas.

• Assessment of Ki-67 proliferation index as a

prognostic factor in neuroendocrine tumors.

• HER2/neu staining as a target for therapy in gastric

and esophageal adenocarcinomas

Gastric and Esophageal Adenocarcinoma

• The low 5-year survival is largely due to a high

proportion of patients presenting with locally

unresectable disease or distant metastases

• Target therapies have emerged as promising

treatment options: Human epidermal growth factor-2 (HER2)

• HER2 is overexpression in a subset of gastric and

esophageal adenocarcinoma (20-30%)

HER2 and Trastuzumab

HER2 and Trastuzumab

Assessment of HER2 (IHC)

Score Criteria for Resections Criteria for Biopsies Mag

3+

2+ basolateral or lateral

1+ membranous staining in ≥10% of

0

Strong complete, basolateral or

lateral membranous staining in≥10% of tumor cells

Weak-to-moderate complete,

membranous staining in ≥10% oftumor cells

Faint or barely perceptible

tumor cells; staining only in partof their membrane

No staining or membranous

staining in <10% of tumor cells

No staining or membranous

staining in clusters of <5 tumor cells

No staining or membranous

staining in clusters of <5 tumor

Weak-to-moderate complete,

basolateral or lateral membranousstaining in cluster(s) of ≥5 cohesive

tumor cells

Faint or barely perceptible

membranous staining in cluster(s) 400Xof ≥5 cohesive tumor cells

100-

200X

N/A

Strong complete, basolateral or

lateral membranous staining incluster(s) of ≥5 cohesive tumor

cells

20-40X

HER2 3+ GASTRIC CANCER

HER2 GASTRIC CANCER

Assessment of Ki-67 proliferation index as a

prognostic factor in neuroendocrine tumors.

Neuroendocrine Tumors/Carcinomas

Neuroendocrine Tumors/Carcinomas

• Prognostic markers:

o Ki-67

Differentiation

Well-differentiated

Grade Ki-67 Index Mitotic Count

Low-grade (G1)

Well-differentiated

Poorly-

differentiated

Intermediate-grade

High-grade (G3)

(G2)

< 3%

3 - 20%

> 20%

< 2 / 10 HPF

2 - 20 / 10 HPF

> 20 / 10 HPF

G1

G2

G3

Proliferation fraction

What is the percentage of positive cells?

Ki-67 - NordiQC20 cases scored by 126 pathologists

Automatic and Manual Proliferation RateEstimation from Digital Pathology Images

Digital pathology is a major revolution in pathology and is changing the clinical routine for pathologists.We work on providing a computer aided diagnosis system that automatically and robustly provides the pathologist with a second opinion for many diagnosis tasks. However, interobservervariability prevents thorough validation of any proposed technique for any specific problems. In this work, we study the variability and reliability of proliferation rate estimation from digital pathology images for breast cancer proliferation rate estimation. We also study the robustness of our recently proposed method CAD system for PRE estimation. Three statistical significance tests showed that our automated CAD system was as reliable as the expert pathologist in both brown and blue nuclei estimation on a dataset of 100 images.

Digital Pathology Market by Slide Scanners (Whole

Slide Imaging), Analytics (Image Analysis Software),

Delivery Modes (Web Based/Cloud Based) & by Whole

Slide Image Storage - Global Forecasts & Trends to

2018The global digital pathology market was valued at an

estimated $250.2 million in 2013 and is expected to grow

at a CAGR of 11.8%, to reach an estimated $437 million

by 2018.

The demand for digital pathology is growing and is

expected to continue to rise in the coming years as well.

The use of scanners and image analysis software enable

pathologists to be efficient and this leads to improved

quality care for patients.

The high growth for the market can be attributed to the

favorable reimbursement scenario in U.S. and the use of

digital pathology to improve the quality of cancer

diagnosis in Canada in North America. The high growth in

the Asian region can be attributed to the rise in awareness

of digital pathology and its benefits, collaborative efforts

by players, and federal health departments encouraging

the uses to improve the quality of cancer diagnosis.

Market Research Reports

Based on geographies, the market is segmented into

North America, Europe, Asia, and the Rest of the World

(RoW). Each geography further includes country-wise

markets for North America (U.S. and Canada), Europe

(Germany, U.K, France, Italy, Spain, and Rest of Europe),

and Asia (Japan, China, India, and Rest of Asia). North

America is the largest market, followed by Europe and

Asia. However, the Asian market is slated to grow at the

highest rate over the next five years.

The major players in the digital pathology market include

3DHistech (Hungary), Leica Biosystems (Germany),

Ventana Medical Systems (U.S.), Hamamatsu Photonics

K.K. (Japan), Mikroscan Technologies (U.S.), Definiens

AG (Germany), Visiopharm (Denmark), and Indica Labs

(U.S.).

The report categorizes overall digital pathology market on

the basis of products, applications, and geographies.

Based on products, the market comprises of scanners,

analytics, storage, and communication. Based on

applications, the market is categorized into human and

animal pathology. Human pathology is segmented into

pharmaceutical and biotechnology companies, hospitals

and reference laboratories, and training and education

centers, while animal pathology is segmented into

pharmaceutical and biotechnology companies, contract

research organizations, and academic and government

research institutes.

This report broadly categorizes the global digital pathology

market into different products and applications. Scanners

accounted for the largest share of the digital pathology

products market, followed by analytics. The analytics

market is expected to grow at the highest CAGR of 12.4%

from 2013 to 2018. The high growth can be attributed to

the growing importance of image analysis software that is

increasingly being used to understand cancer complexity

and the drive for personalized medicine, among others.

This report covers the definition, description, and forecast

of the global market in terms of products, applications,

and geographies.

The global digital pathology market was valued at an

estimated $250.2 million in 2013 and is expected to grow

at a CAGR of 11.8%, to reach an estimated $437 million

by 2018. The market is dominated by North America,

followed by Europe, Asia, and the Rest of the World

(RoW). The dominance of the North American market can

be attributed to reasons such as the favorable

reimbursement scenario in the U.S. and the use of digital

pathology to improve the quality of cancer diagnosis in

Canada. However, the Asian market is expected to

experience the highest growth in the market. The high

growth in the Asian region can be attributed to the rise in

awareness of digital pathology and its benefits,

collaborative efforts by players, and federal health

departments encouraging the uses to improve the quality

of cancer diagnosis.

Source: MarketsandMarkets Analysis

The Pathologist does not meet the expectations