What is the role of the pathologist in clinical

pathology?

Anjen Chenn, MD-PhDDirector, Clinical Pathology

University of Illinois at Chicago

Clinical Pathology is laboratory medicine.

i.e., Laboratory testing in patient care.

The diagnosis of disease and information relevant to the treatment and prognosis of

disease is based on laboratory testing of patient

mateirals.

Typical Hospital Budget

LabOther

Clin Chem. 1996 May;42(5):813-6.Why is the laboratory an afterthought for managed care organizations?Forsman RW.

Medical Decisions Impacted*

LabOther

Clin Chem. 1996 May;42(5):813-6.Why is the laboratory an afterthought for managed care organizations?Forsman RW.

e.g. admission, discharge, drug therapy

Chart Title

CPAPcytopathology

Clinical revenue

Clinical Pathology oversees all of the laboratory “testing

cycle.”

Lab Medicine. 2009 40, 105-113.Clinical Laboratory Tests: Which, Why, and What Do The Results Mean? Wians, FH,.

Most of CP training focuses on the analytic phase of

testing.

Where can the Pathologist uniquely contribute?

1) Clinicians need guidance on test selection.

Over 2000 tests on test menu

Example

MD: “My name is xxx.  I am faculty in the Department of yyy.  I am working with the ID department here and looking at ways we can strategize increasing routine HIV screening.”

Example

AC- “Love to help out. What are you looking for?  Would you like to meet?”

Example

MD- “thanks for your quick response.  What I wanted to see is what lab uses for HIV testing currently?”

Example

AC: “molecular or serological, and which would be best for your purposes?”

Example

MD- “I am not sure.  What is typically done for screening, molecular or serological?  I am unfortunately not that familiar with which one is the more routine test for HIV screening vs confirmatory testing.”

2) Pathologists guide appropriate testing.

Risk of false positive increases as testing

increases.

Specificity = true negatives/(true negatives + false positives)= probability of a negative test given no diseaseFalse-positive rate = 1 - Specificity

If a diagnostic test has 5% chance of “abnormal” value (given normal distribution),

P(single test) = 0.95P(2 normal) = 0.95^2 = 0.9P(10 normal) = 0.95^10 = 0.6P(20 normal) = 0.95^20 = 0.36

Risk of false positive increases as testing

increases.

1 2 10 200

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Where can the Pathologist uniquely contribute?

Primary data is uninformative.

Clinical context is essential

Tumor

Normal

This is a V600E mutation in the BRAF gene.The frequency of BRAF mutation in melanoma is ~50%The frequency of the V600E mutation is ~90% (among BRAF mutant melanomas).Having this mutation confers increased sensitivity to BRAF inhibitors (e.g. vemurafinib).

In Colorectal cancer:Approximately 8–15% of colorectal cancer (CRC) tumors harbor BRAF mutations. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. Several studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab in the chemotherapy-refractory setting. Based on these findings, BRAF mutations were suggested to be a negative predictor of response to anti-EGFR therapy.

While BRAF V600-mutated melanomas are sensitive to vemurafenib, BRAF V600-mutated CRCs may not be as sensitive. Activation of EGFR in colorectal cancer could explain why colorectal cancers generally have a lower response to BRAF inhibitors.

In Colorectal cancer:Approximately 8–15% of colorectal cancer (CRC) tumors harbor BRAF mutations. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. Several studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab (may benefit KRAS WT tumors) in the chemotherapy-refractory setting. Based on these findings, BRAF mutations were suggested to be a negative predictor of response to anti-EGFR therapy.

In Colorectal cancer:Approximately 8–15% of colorectal cancer (CRC) tumors harbor BRAF mutations. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. Several studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab (may benefit KRAS WT tumors) in the chemotherapy-refractory setting. Based on these findings, BRAF mutations were suggested to be a negative predictor of response to anti-EGFR therapy.

there is a benefit for BRAF testing in conjunction to KRAS testing in colorectal cancer.

In Colorectal cancer:

While BRAF V600-mutated melanomas are sensitive to vemurafenib, BRAF V600-mutated CRCs may not be as sensitive. Activation of EGFR in colorectal cancer could explain why colorectal cancers generally have a lower response to BRAF inhibitors.

BRAF mutational status is marginally helpful in CRC for guiding use of BRAF inhibitors. With limited specimen, need to prioritize testing performed.

In Lung cancer:Somatic mutations in BRAF have been found in 1–3% of all NSCLC), most of which are adenocarcinomas. 

In contrast to melanoma where the majority of BRAF mutations occur at valine 600 (V600) within exon 15 of the kinase domain, BRAF mutations in lung cancer also occur at other positions within the kinase domain.

The clinical significance of BRAF mutations in lung cancer is unclear (some case reports).

Where can the Pathologist uniquely contribute?

How will this result change your behavior?

• Could change treatment course

e.g. Presence of BRAF mutation in metastatic melanoma suggests treatment with vemurafenib

• Could influence inclusion in trials

e.g. Inclusion Criteria for NCT01340846 Pharmacokinetics Study of the Effects of GSK2118436

Include: “BRAF V600 mutation-positive tumor as determined in a CLIA-approved laboratory”

• Could change subsequent testing

e.g. Absence of KRAS mutation in CRC suggests testing for BRAF mutation

• Could impact future disease monitoring

e.g. Blood. 2012 Mar 29;119(13):3151-4. Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia.Schnittger S et al.

“confirmed BRAFmut as a useful marker in HCL, its absence in HCL variant, and developed an RT-PCR-based assay to monitor minimal residual disease in HCL.”

How does the pathologist make a difference?

“Lead, follow, or get out of the way.”

Thomas Paine (not a pathologist)

Pathologists should play an essential part in developing practice

guidelines.

This means: work with the leaders in

relevant disciplines at your institution.

Leadership at the institution need to

understand the value of Pathology.

This means: show the value of Pathology!

Internal studies may be needed.

Some of the places CP interfaces to add value

• Laboratory Utilization & Practices Committee

• Transfusion Practices Committee• Anticoagulation Taskforce Committee• Infection Control• New and developing programs• Clinical Trials

“What is my unique contribution?”

Where can the Pathologist uniquely contribute?