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From Turning Point 2019

By Robert Levy

As a pathologist-in-training in the early 1990s, Deborah Dillon, MD, remembers viewing a sample of lymphoma tissue under a microscope and thinking, "'I know that every one of the tumor cells has a particular chromosomal abnormality, but I can't see it.' It was frustrating – would there ever be a way to peer into the genetic makeup of cells?"

Wish granted. DNA sequencing is extending the reach of pathology into regions of the cell that once seemed impossibly remote. A field once defined by what could be seen with the naked eye or under a microscope has embraced technology for probing specific genetic errors within tumor cells – to the point where molecular pathology is now a field unto itself. It's a mark of how far the field has advanced over the past 25 years that, today, Dr. Dillon – a specialist in breast cancer pathology at the Susan F. Smith Center for Women's Cancers – is herself a molecular pathologist.

As the treatment of women's cancers becomes increasingly personalized – keyed to the specific characteristics of each patient and each patient's cancer – the field of pathology has more than kept pace. It might even be said that pathology invented personalized medicine: its concern with individual differences has become the model for cancer care as a whole.

Pathology's Part

At the most basic level, pathology is the branch of medicine concerned with diagnosing disease based on an examination of organs, tissues, and fluids from the body. In oncology, pathologists are the physicians who examine tissue to evaluate, first, if a patient has cancer or related disease and, if so, what type, whether and how far it has spread, how aggressive it is, and other information that will guide treatment. In women's cancers, for example, pathologists determine whether a breast tumor is hormone receptor-positive (meaning its growth is fueled by estrogen or progesterone), and whether ovarian cancer has metastasized or remains within the ovaries.

Pathologists describe their role as providing the starting point for therapy. "A pathology exam is fundamental to a patient's care," says Susan Lester, MD, PhD, a breast cancer pathologist in the Susan F. Smith Center. "Treatment can't begin until a diagnosis is made. In breast cancer, for example, we're looking at slides to determine if the cancer is noninvasive or invasive and if it expresses hormone receptors or is positive for the HER2 protein. These are the major determinants of how a patient is treated."

Although pathologists are not clinicians, in that they usually don't see patients, they are very much part of the clinical team, working closely with oncologists and others directly involved in treatment. "The pathologic diagnosis is the hub around which the treatment of patients rotates," says breast pathologist Stuart Schnitt, MD, chief of breast oncologic pathology, Dana-Farber/Brigham and Women's Cancer Center. "If you don't have the right diagnosis, patients can't possibly receive the right treatment."

"'If you know pathology, you will be a better physician' – My father, an orthopedic surgeon, told me this before I began clinical rotations as a medical student," says Marisa Nucci, MD, director of gynecologic pathology at the Susan F. Smith Center. "What I came to realize is that pathology is at the core of care. To quote [Canadian physician] Sir William Osler, 'as is our pathology so is our practice.'"

Means of Interrogation

Pathologists' means for making a diagnosis are many and varied. Like a stubborn defendant on a witness stand, tumor cells do not always yield their secrets easily. Pathologists, in the role of cross-examiner, subject tumor tissue to a variety of tests to wrest as much information as they can from each specimen.

They examine the tissue without the aid of a microscope to note its shape, size, color, and weight. They view it under a microscope to ascertain what the cancer cells look like, how they compare to normal cells (the closer the resemblance, the better the prognosis, in general), and whether they've spread to nearby tissue and lymph nodes. They use immunohistochemical studies on glass slides to identify specific proteins in cancer cells. They run cytogenetic tests to find chromosomal abnormalities. And, as part of the Profile program at Dana-Farber and Brigham and Women's Hospital, women with metastatic breast cancer and many patients with gynecologic cancers have the opportunity to have their tumor tissue analyzed for genetic abnormalities that may be susceptible to drugs being tested in clinical trials.

Molecular analysis of tumor tissue allows for more deeply informed decisions on treatment but can't replace traditional microscope-based techniques. "The approaches complement each other," Dr. Lester remarks. "They provide fundamentally different pieces of information; it's when you put them together that they become very powerful."

"For example, we now use special techniques such as immunohistochemistry to evaluate whether a tumor has a defect in mismatch repair and is more likely to respond to immunotherapy," Dr. Nucci observes. "In addition, we are beginning to use molecular sequencing to help uncover targetable mutations for individualized treatment."

The more information pathologists can coax or coerce from tumor cells, the better they can pin down the precise nature of the cancer and treat it accordingly. "We now have the opportunity to refine our system for classifying tumors by factoring in molecular data," Dr. Dillon says. "In the end, that should lead to better treatment."

The Collaborative Approach

The classic image of a pathologist may be of a white-coated physician working alone at a microscope, but pathologists routinely collaborate with other pathologists and clinicians, particularly in difficult cases where a second – or third, or fourth – set of eyes can be helpful. "Subtleties within a tumor sample can make diagnosis challenging," Dr. Schnitt states. "It can be a question of, 'Is this breast cancer HER2-positive or not; is it really a grade 3 cancer; are there signs that blood or lymph vessels have been invaded by the tumor?'" Multiheaded microscopes that enable multiple pathologists to view a specimen simultaneously allow for a sharing of expertise. Difficult cases are also presented at tumor boards, periodic meetings at which pathologists and clinicians from several disciplines review and discuss diagnoses and treatment options of specific patients.

It is at these meetings, and in their daily interactions with physicians and other clinicians, that pathologists are most fully in their element. "I'm a gynecologic pathologist, but in many ways my intellectual orientation and the colleagues I work most closely with are clinicians," says George Mutter, MD. "We're not here just to make diagnoses. We want to make patients' lives better, and we do that by being part of a team that manages patient care."

Practice and Prevention

Making accurate diagnoses begins, but doesn't exhaust, pathology's place in personalized cancer medicine. Pathologists allied with the Susan F. Smith Center have, for example, made important advances in women's cancers prevention. Dr. Mutter and his colleagues identified a condition known as endometrial intraepithelial neoplasia (EIN), which places women at greatly heightened risk of developing endometrial cancer. Patients with the condition can choose to be closely monitored for signs of endometrial cancer or undergo a procedure to prevent the cancer from occurring. The discovery by gynecologic pathologist Christopher Crum, MD, that many ovarian cancers originate in the fallopian tubes may lead to new approaches for preventing this cancer as well.

Other Susan F. Smith Center pathologists are exploring whether genomic alterations in cancer cells track with changes in tumor behavior. Breast cancer pathologist Beth Harrison, MD, and her colleagues have collected tissue samples of rare breast cancers and are utilizing Oncopanel – the DNA-sequencing technology used in the Profile program – to identify genomic changes within them. "We've found some interesting molecular changes that suggest tumors with certain pathologic features may be more aggressive than we would have expected based on their traditional pathologic classification," she explains.

In other research, Dr. Harrison, with Tari King, MD, FACS, chief of breast surgery at Dana-Farber/Brigham and Women's Cancer Center, and breast surgeon Faina Nakhlis, MD, genomically profiled samples of high-grade lobular carcinoma in situ (LCIS) – areas of abnormal breast cell growth that significantly raise a woman's risk of breast cancer. "We found highly prevalent alterations in the gene for HER2, which could serve as a molecular marker for this type of LCIS," she relates. Although there currently is no clinical test for this alteration, the discovery raises the possibility of a new way to identify women with this condition.

These research efforts and others suggest that pathology's future is as wide-open as the one Dr. Dillon imagined at the start of her career.