The Role of Pathologist in Precision Medicine

Pathologist’s Role in Precision Medicine Hematopathology - March 2020

Perspective

The Role of Pathologist in Precision MedicineXianfeng Frank Zhao1,2

1Department of Pathology, University of Arizona College of Medicine Phoenix, Phoenix, AZ 85004; 2Phoenix VAHealth Care System, Phoenix, AZ 85004.

Abstract: Pathologists will play a key role in precision medicine for the follow reasons. Pathologistshave direct access to patient specimens, the most cutting-age diagnostic technologies, and integratedlaboratory data to design therapeutic plans. Pathologists also have the upper hand in carrying outtranslational research utilizing patient specimens. Owing to these advantages, the pathologists willplay an important part in future therapeutic target-based and individualized clinical trials, and theirrole will shift from that of a traditional diagnostician to that of a therapeutic consultant.

Keywords: decision making; pharmacomics; precision pathology; precision medicine; targeted ther-apy

The future of precision medicine will rely heavilyon the development of precision pathology, whichis further determined by the role of pathologists inprecision medicine.

Pathologists traditionally diagnose diseases fromspecimens harvested by clinicians. Clinicians collectspecimens from patients and send the specimens topathology laboratory. Pathologists in the laboratoryexamine the specimens first with naked eyes. Somepreliminary diagnoses can be made by an experi-enced pathologist in the grossing room based onthe observed color, shape, and texture of the lesions.The specimens are then submitted for histologicalexamination to confirm and fine tune the diagnoses.Diagnoses made by pathologists are very straightforward - they describe and classify what they see[1]. As a matter of fact, people often consider patho-logical diagnosis as the most objective because they

*Correspondence: X. Frank Zhao, 650 E Indian School Road,Main Bldg., Rm. 2131, Phoenix, AZ 85012. Office: 602-277-5551,x6346; Fax: 602-222-2669; Email: [email protected]

think pathologists make diagnoses based solely onwhat they see in tissues. On the contrary patholo-gists always integrate clinical information and radio-logic findings into their diagnoses. But afterwards,treatment options are largely left with the cliniciansand little roles for pathologists.

I used to explain to the general audience about thepathologist’s role in patient care by using an exampleof investigating a criminal case. Primary care physi-cian often gets the first report of the “crime” and ra-diologist helps to locate the “crime scene”. Surgeonsas “investigators” go to the “crime scene” to col-lect evidences. With all the collected evidences pre-sented to her/him, pathologist, being the “judge”,will analyze all the evidences (sometimes even con-flicting) to rule in or rule out the “criminal(s)”. Averdict (final diagnosis) will be made by the pathol-ogist and the “suspects” will be either ‘released’,‘sentenced’ or ‘executed’ by surgeons and/or hema-tologists/oncologists.

With development of various biological technolo-gies and artificial intelligence (AI), pathologistsknow patients much better from the laboratories,

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sometimes even better than seeing the patients bythemselves, since most of the genetic makeups andmetabolomics would not show at the patient’s inter-views and/or on physical examinations. With bigdata and machine learning, pathologists would beable to collect and process tons of information frompatients. The information will not only be relatedto the patient’s disease, but also about the patient’sphysiology, the interaction between the disease andthe patient, the interaction between the disease andtreatment, and the interaction between the treatmentand the patient. Since information can be accumu-lated with time all through the patient’s life, constantinteraction between the pathologist and the patientwill be the norm. With the first-hand material andthe resulted data, pathologists could guide clinicianswith treatment plans [2].

There may be disagreement among physiciansof different specialties as to their roles in precisionmedicine, but pathologists have the following majoradvantages:

1) Pathologists have direct access to patient speci-mens. Evidence-based medicine relies on objectivedata produced in the clinical laboratories. Whetherbeing surgical specimens, cytological specimens,body fluids, blood or patient’s normal or abnormaldischarges, they will be sent to the clinical laborato-ries and analyzed by various assays. Since pathol-ogists are well trained experts in analyzing thesedata, they have an advantage in using these patientspecimens in the diagnosis, treatment and prognosisof diseases and translational research.

2) Pathologists have access to the cutting-edgediagnostic technologies. Molecular profiling, nextgeneration sequencing, machine learning and AIare more and more widely used in clinical laborato-ries. Although these advanced technologies can beavailable in any laboratories, only the CLIA certifiedpathology laboratories can make clinical diagnosisand only pathologists have access to these diagnostictools.

3) Pathologists have the first-hand laboratory dataon therapeutic targets of disease and patients’ phar-

macogenomics, and pharmacometabolomics [3], andwith the help of AI analysis they can integrate allthese data and design therapeutic plans for manag-ing patients. Clinicians (and/or pharmacists) willmanage patients by following pathologists’ guid-ance.

4) With direct access to patient specimens, pathol-ogists have an advantage in carrying out trans-lational medical research, such as biomarker dis-covery, identification of novel therapeutic targets,and pharmacometabolomics-informed pharmacoge-nomics [4], etc. The research discoveries can betranslated directly into clinical practice.

5) Since precision medicine considers individualvariability, clinician-led population-based clinical tri-als to generalize a therapeutic regimen will eventu-ally give way to therapeutic target-based and indi-vidualized clinical trials designed by pathologists.

Owing to the above advantages inherited inpathologists, they will lead the advancement of pre-cision medicine, and thus precision pathology willnot only be the basis of precision medicine, but alsoguide the direction of precision medicine.

Pathologists Remain Morphologists

Pathologists love their microscope because it pro-vides them the morphology of diseases. There werepredictions that pathologists and radiologists mightbe replaced in the future by AI and machine learning[5], which fortunately will not happen. Due to thelimitations of AI and complex scenarios in pathol-ogy, morphologic pattern recognition will still be anessential task of pathologists. However, in additionto making diagnosis on morphologic examination,pathologists will focus more on the extent of tumorinfiltration, recurrence, specimen acquisition and ad-equacy evaluation for molecular and other ancillarystudies. As long as surgery still exists, pathologistswill be required to evaluate surgical margins onfrozen sections. With the increasing popularity ofinterventional radiology, pathologists will be neededto evaluate adequacies and to distinguish a de novo

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from a recurrent disease. Due to the heterogeneityof tumors, results obtained from different parts of atumor can be significantly different. To acquire accu-rate information from the tumor, tumor specimenssampled for molecular and other ancillary studiesmust be from the most representative part of the tu-mor and only pathologists with excellent training ontumor morphology can take on this responsibility.

Pathologists and Radiologists

As both involved in diagnostic science, patholo-gist and radiologist play unique roles in precisionmedicine. As AI will be heavily employed in radi-ology, image interpretation will be accelerated andpromptly reported with almost no delays, whichmake it possible to skip image interpretation and toimmediately perform tissue biopsy if a malignancyis suspected. Perfect collaboration of radiologist andpathologists have already happened between inter-ventional radiologists and cytopathologists. Withvarious molecular tools available, limited amount oftumor cells/tissues obtained by fine-needle aspira-tion (FNA)/core needle biopsy (CNB) might be ableto provide therapeutic targets for treatment of pa-tients prior to a pathological diagnosis. To expeditediagnostic studies, radiology might be combinedwith pathology in providing diagnostic service toclinicians. A proposal to establish human diagnosticmedicine is currently under discussion and cross-disciplinary fellowships may be a daunting practicein the future.

Pathologists Assume Roles in Thera-peutic Decision Making

Pathologists traditionally diagnose diseases basedon pattern recognition. Since genotype determinesphenotype, abnormal phenotypic patterns are sur-rogates of diseases. Pathologists are experts in rec-ognizing abnormal patterns and thus diagnose dis-eases. Besides the morphologic patterns, includ-

Figure 1: Traditional modern medicine (upper) versusprecision medicine (lower).

ing cytological features, architectural changes, reac-tive backgrounds, and exotic visitors to the organsand tissues, they also evaluate cell types involvedin the pathological process by examining markersexpressed by the relevant cells, pattern of expres-sion (membranous, cytoplasmic, nuclear, Golgi), in-tensity of expression (strong, medium, weak), andexpression aberrancy (such as CD5 on B cells orCD19 on myeloids). Genetic abnormalities are animportant indication of malignancy and certain ge-netic patterns have been associated with certain dis-eases, sometimes making genetic abnormality as theonly evidence for confirming a disease (such as inmyelodysplastic syndrome). Once a final diagnosishas been made, how to manage the patient will bethe job of the clinicians and the pathologists will belargely “off the hook”.

In contrast, traditional diagnosis will be less im-portant in precision medicine since the diagnosis,surrogate of the disease, will be replaced by molec-ular data on genomics, proteomics, metabolomics,and transcriptomics, etc. and pathologists will pro-vide therapeutic strategies directly to the clinicians(Figure 1). For example, if Disease A occurs in pa-tient X it might be managed differently from a simi-lar disease (Disease A’) in patient Y because patientX is different from patient Y. You may argue thatpenicillin is effective against streptococcal infectionin both patient X and patient Y. Not necessary! Did

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Figure 2: Healthcare team on way to the precisionmedicine. Pathologist, radiologist and omicsist are inthe cockpit; whereas the clinicians are in the passengerseats.

you consider history of allergy in patient X and noallergy in patient Y and their possible drug resis-tance before you prescribe penicillin? Yes, you did,but because of the prevalence of drug resistance,physicians almost always prescribe Augmentin topatients with recurrent streptococcal infection. Weare currently using cytotoxic drugs (R-CHOP) totreat diffuse large B-cell lymphoma (DLBCL) basedon our experience with worldwide clinical trials, butsince using this therapeutic regimen is not consider-ing the differences in cytotoxicity and metabolismof the drugs in each individual patient, there is onlya 50% cure rate [6] and a 60-70% 5-year survival rate[7]. With precision pathology specific therapeutictargets will be identified for DLBCL of each patientwhose genetic makeup and metabolism will be wellunderstood. Therapeutic strategies will be tailoredto each patient with a regimen and dosage eventhough all the patients are inflicted with the sameDLBCL. This is the beauty of precision medicine.

Instead of looking for morphologic features, celltypes, architectural changes, and/or genetic abnor-malities like those of the past documented diseases,the precision pathologist will search for the ther-apeutic targets that are deemed responsive to theavailable drugs. The precision pathologist will alsoexamine the unique pharmacogenomics and phar-

macometabolomics of the patient. Based on thetherapeutic targets of the disease and the pharma-cogenomics and pharmacometabolomics of the pa-tient, the precision pathologist will design a ther-apeutic strategy with the clinicians who clinicallymanage the patient. The pathologist has never beenso involved before in managing patient and this isthe major role change for pathologist in precisionmedicine.

Driver versus Passenger in PatientCare Plane

Pathologists are typically consultants to cliniciansand passively providing advices and suggestions tothe clinicians who directly take care of the patients.This situation will change in the future precisionmedicine. According to one vision, healthcaresystem is like an airplane [8], and within thepatient care team pathologist will be the pilot withradiologist being the co-pilot and expert on “omics”as the flight engineer (Figure 2). With informationprovided by the “omics” expert, the pathologist willguide the treatment plans and the radiologist willidentify the accurate location of lesions. Althoughit remains controversial whether this metaphor isaccurate, this vision stresses the important role ofpathologist in the future precision medicine.

Acknowledgements

The author claims no conflict of interest.

Received: May 2, 2020 Published: October 18, 2020

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