"'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.
Ovarian cancer cell
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.