The role of the pathologist in clinical pathology is to oversee the laboratory testing cycle and provide guidance to clinicians. Pathologists can uniquely contribute by: 1) Guiding clinicians on appropriate test selection from the large test menu. 2) Guiding appropriate testing to avoid unnecessary tests that increase the risk of false positives. 3) Interpreting laboratory results in the proper clinical context since primary data can be uninformative without considering the clinical scenario.

1. What is the role of the
pathologist in clinical
pathology?
Anjen Chenn, MD-PhD
Director, Clinical Pathology
University of Illinois at Chicago

2. Clinical Pathology is laboratory
medicine.

3. 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.

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

5. Medical Decisions Impacted*
Lab
Other
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

6. Clinical revenue

7. 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,.

8. Most of CP training focuses on
the analytic phase of testing.

9. Where can the Pathologist
uniquely contribute?

10. 1) Clinicians need guidance on
test selection.
Over 2000 tests on test menu

11. 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.”

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

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

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

15. 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.”

16. 2) Pathologists guide
appropriate testing.

17. Risk of false positive increases
as testing increases.
Specificity = true negatives/(true negatives + false positives)
= probability of a negative test given no disease
False-positive rate = 1 - Specificity

18. If a diagnostic test has 5% chance of
“abnormal” value (given normal
distribution),
P(single test) = 0.95
P(2 normal) = 0.95^2 = 0.9
P(10 normal) = 0.95^10 = 0.6
P(20 normal) = 0.95^20 = 0.36

19. Risk of false positive increases
as testing increases.
Number of tests performed
Probabilityofan‘abnormal’result

20. Where can the Pathologist
uniquely contribute?

21. Primary data is uninformative.
Clinical context is essential
Tumor
Normal

22. 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).

23. 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.​

24. 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.

25. 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.

26. 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.

27. 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).

28. Where can the Pathologist
uniquely contribute?

29. How will this result change
your behavior?

30. • Could change treatment course
e.g. Presence of BRAF mutation in
metastatic melanoma suggests
treatment with vemurafenib

31. • 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”

32. • Could change subsequent testing
e.g. Absence of KRAS mutation in
CRC suggests testing for BRAF
mutation

33. • 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.”

34. How does the pathologist
make a difference?

35. “Lead, follow, or get out of the
way.”
Thomas Paine (not a pathologist)

36. Pathologists should play an
essential part in developing
practice guidelines.
This means:
work with the leaders in relevant
disciplines at your institution.

37. Leadership at the institution
need to understand the value
of Pathology.
This means:
show the value of Pathology!
Internal studies may be needed.

38. 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

39. “What is my unique
contribution?”

40. Where can the Pathologist
uniquely contribute?