A “Whole Person” Approach to Histology

Pathologist and assistant professor Rebecca Waters, DO, on finding “zebras” and her osteopathic medicine background

María Carla Rosales Gerpe, MSc, PhD

María Rosales Gerpe, MSc, PhD, is a freelance scientific writer with more than a decade of research experience in molecular biology and gene therapy. She's also a reporter for Metroland...

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Published:Oct 03, 2023
|5 min read
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Photo portrait of Rebecca Waters, DO
Rebecca Waters, DO, is a doctor of osteopathic medicine and a board-certified pathologist and assistant professor at the University of Texas MD Anderson Cancer Center’s Department of Pathology.

Rebecca Waters, DO (doctor of osteopathic medicine), is a board-certified pathologist and assistant professor at the University of Texas MD Anderson Cancer Center’s Department of Pathology. 

At this year’s American Society for Clinical Pathology (ASCP) annual meeting from October 18 to 20, 2023, in Long Beach, CA, Waters and her colleague professor Melissa Taggart, MD, will be presenting findings from their histological assessments of colorectal cancer in their session titled, Accurate Assessment for Colorectal Cancer Diagnosis and Staging: Challenging and Emerging Concepts.

Ahead of her talk, Today’s Clinical Lab spoke with Waters to discuss the importance of pathology in cancer diagnosis, as well as how her career path has influenced the way she approaches her work.

Spotting zebras: The importance of pathology in cancer diagnosis

A recent review by University of Texas MD Anderson Cancer Center clinicians, including Waters, found that approximately 40 percent of newly diagnosed gastroesophageal cancers had distant metastatic spread. Unfortunately, this prevalence of metastasis is not unique to gastroesophageal cancer, and for many cancers that spread through the body, metastasis can yield symptoms that can confound a clear diagnosis, hindering effective treatment.

This is a significant reason why “it’s fairly common at a large cancer center to see things that clinicians consider ‘zebras’ or surprises,” says Waters, referring to a saying coined by Dr. Theodore Woodward in the 1940s, “when you hear hoofbeats, think horses, not zebras,” which alludes to the simplest explanation.

The phrase was further popularized by Lisa Sanders, MD, in her “Diagnosis” column for The New York Times and a Netflix documentary series by the same name, where she crowdsources information for rare and hard-to-diagnose diseases. 

In some ways, a pathologist’s job is similar, though instead of crowdsourcing clues, pathologists interrogate a sample via biomarkers and/or histological stains to ascertain the origin of a condition or disease. 

“A good example would be a patient who had a liver mass,” says Waters, with a remote history of melanoma, which the patient’s doctors suspected had metastasized to the liver. Immunohistochemistry screening showed the liver biopsy was positive for GATA-3, a known marker of metastatic breast cancer. Thanks to pathology, the patient’s diagnostic path now includes an additional clue that may lead to a more targeted treatment for breast cancer, rather the initially suspected melanoma metastasis.

“We’re really fortunate when we know the patient’s past medical history, but sometimes we don’t,” says Waters about how critical pathology can be for finding the right diagnosis. Even with a complete medical history, like the patient with a GATA-3–positive liver biopsy, Waters and her team still found a “zebra.”

The importance of biomarkers for histological assessment

According to a 2021 article published in Advanced Drug Delivery Reviews, histopathological findings aided by tumor protein biomarkers remain a critical step in tumor diagnosis and staging to inform conventional anticancer therapy. The importance of biomarkers for histological assessment is one of Waters’s research interests at MD Anderson, and one which she is passionate about. 

Cancer-specific stains and biomarkers yield more accurate diagnoses with the potential for better prognoses for patients, but “histology work can yield nonspecific results,” she says. Currently, the field lacks predictive biomarkers for some cancers and needs more standardization across protocols and biomarker validation studies.

“Whoever finds an immunostain to differentiate pancreatic adenocarcinomas from upper gastrointestinal carcinomas has the golden ticket,” Waters often jokes with her trainees. Her co-led educational session at ASCP 2023 aims to help clinicians address challenges in interpreting and reporting immunohistochemical prognostic/predictive studies.

“It's a marathon, not a race”: A journey to pathology

The ongoing challenges of the discipline do not deter Waters; rather, the inherent troubleshooting in histology, and profound impact of its data, are what led Waters to pursue pathology after completing her DO degree.

Waters described learning about pathology during residency rounds as a key moment. Being able to dig deeper into the issue and zoom in on the biological cause of disease really appealed to her.

Prior to pursuing her clinical residency in anatomic/clinical pathology, and further specializing with back-to-back clinical fellowships at Mayo Clinic and the Cleveland Clinic, Waters trained as a doctor of osteopathic medicine (DO). 

“It’s a marathon, not a race,” says Waters of her long journey to pathology, for which she heeds the following advice: “it’s going to be a long journey, but it should be an enjoyable one.”

Doctor of Osteopathic Medicine Training Snapshot




2007Bachelor of Science, Texas A&M University, College StationNutrition
2013Doctor of Osteopathic Medicine, University of North Texas Health Science Center–Texas College of Osteopathic MedicineOsteopathic medicine
Pathology Training Snapshot




Clinical residency at University of Texas Medical Branch
Anatomic/clinical pathology
Clinical fellowship at Mayo Clinic
Surgical pathology
American Board of Pathology
Clinical fellowship at the Cleveland Clinic 
Gastrointestinal, hepatic, and pancreaticobiliary pathology

What is osteopathic medicine?

According to the American Osteopathic Association, just over a tenth of all physicians in the US are DOs, making it one of the fastest-growing healthcare professions in the country. Although US university-accredited and board-certified DOs can practice in Canada, no Canadian university offers a degree in osteopathic medicine, which takes a whole-person approach to health care.

The DO designation is not as commonly known as the ubiquitous “MD,” though osteopathic medicine has been practiced in the US since the first DO school was founded in the late 1890s. DOs undergo the same training as their MD counterparts, and like MDs, must also pass a medical board exam to practice medicine. DOs also pursue fellowships alongside MDs at hospitals, medical centers, and other medical institutions around the world. 

Toward preventive, whole-person approaches to medicine

“DOs examine patients not just for their symptoms, but as the whole person,” says Waters. When a patient is examined by a DO, they can expect questions beyond the routine physical exam. 

“DOs ask how the patient is doing in their personal lives, what kind of stressors they encounter, etcetera,” she says. This information is often difficult to obtain as primary care physicians often see patients back-to-back with little time and an ever-increasing amount of paperwork.

But by making it a requirement, DOs first focus on preventive ways to manage their patient’s health. This approach is also being considered more and more by MDs, who can specialize in preventive medicine. Managing an aging population with preexisting conditions that increase vulnerability to emerging pathogens and environmental threats like air pollution can overwhelm an already overburdened healthcare system.

“In the laboratory, I don’t see patients in the traditional sense,” says Waters. But, “having pursued DO education allows me to have an open mind when examining cases.” Using a whole-person approach to medicine has allowed her to appreciate the interconnectedness of human biological processes, which have many overlapping pathways, especially as it relates to cancer metastasis.

Waters will be presenting at ASCP 2023 Annual Meeting on Wednesday, October 18 at 1:30 PM to 2:30 PM PDT.

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Using a whole-person approach to medicine has allowed pathologist Rebecca Waters, DO, to appreciate the interconnectedness of human biological processes.
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