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Getting to the Heart of a Diagnosis

  • From Paths of Progress Spring/Summer 2014

    How Pathology Directs Cancer Patients

    by Naomi Funkhouser

    woman at a microscopeAccuracy matters, particularly when it comes to a cancer diagnosis. How a sample of tissue or blood is characterized — which is necessary to make a diagnosis — can make an enormous impact. It can determine whether a patient has cancer, influence treatment options and prognosis, and color many decisions for the patient and care provider.

    But diagnosing cancer is not always black and white. It can be nuanced. Within the broad brush of a cancer are subtle subtypes of disease.

    As our knowledge of the many different cancer types grows exponentially, understanding that complexity becomes even more important. Sometimes test results can be inconclusive or give ambiguous results. And while some cancers are more straightforward, others can be notoriously difficult to diagnose correctly. Understanding the landscape of a disease can suggest new directions.

    The specialized expertise of pathologists, diagnostic radiologists, surgical oncology specialists, and medical oncologists can offer a critical second opinion — whether it is from reviewing pathology samples or reinterpreting imaging results in a clinical context — because in a lifetime of practice, general oncologists may not see the number of specific subtypes of uncommon cancers a specialist treats each year at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). Specialists can fine-tune a diagnosis, reclassifying a cancer into an important subtype or re-categorizing the grade or stage, and, in the process, changing the course of treatment.

    And, in a few cases, an oncologist might be able to tell a patient that the revised diagnosis is something that looks like cancer, but is not.

    Expert Pathology

    Christopher Fletcher, MD, FRCPath, chief of onco-pathology at DF/BWCC and vice chair for anatomic pathology at Brigham and Women's Hospital, is an international expert in sarcoma pathology.

    At the heart of any cancer diagnosis is pathology. Every year, pathologists at Brigham and Women's Hospital (BWH) peer under microscopes to analyze the biopsies of more than 20,000 DF/BWCC patients.

    "The vast majority of cancer diagnoses are still made down a microscope," says Christopher Fletcher, MD, FRCPath, chief of onco-pathology at DF/BWCC, vice chair for anatomic pathology at BWH, and an international expert in sarcoma pathology. Aided by special tests like immunohistochemistry (which stains specific proteins in tissue cells) and molecular genetics (which can detect distinctive changes in specific chromosomes or genes), a pathologist determines many things: whether a breast cancer tumor is invasive, the type and grade of the tumor, the presence or absence of lymph node involvement, whether the edges ("margins") of a specimen removed by surgery are positive or negative for any residual tumor, whether the tumor expresses estrogen receptors, and possibly other prognostic factors. The same process applies to cancers of almost any organ system — ovarian cancer, lymphoma, sarcoma, and colon cancer, for example. This expert analysis produces a robust diagnosis, the starting point that guides all future treatment decisions.

    Specialized expertise is critical. "For the overwhelming majority of cancers, the correct diagnosis, upon which treatment decisions are made, is made by a pathologist — who also adds nuances concerning identification of possible therapeutic targets and status of surgical margins," says Fletcher. "At major cancer centers like DF/BWCC, there is access not only to the most up-to-date technologies for pathologic diagnosis, but also to a group of subspecialized, highly experienced faculty pathologists, many of whom are nationally or internationally recognized experts in their field. Their skilled pathology review may lead to significant changes or refinements in diagnosis in as many as 15 percent of cases, depending on the type, or rarity, of the cancer."

    Ultimately, the frequency with which a diagnosis is changed depends on how common the disease is, says Fletcher. The rarer the cancer — some types of lymphoma or sarcoma, for example — the more likely the diagnosis may change. In some cases, the diagnosis can change from cancer to a non-malignant result, a scenario that George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at DF/BWCC and senior vice president for experimental therapeutics, says he sees about twice a year.

    Demetri credits Fletcher's pathology team with being among "the best in the world," he says. "We live off the quality of their pathology."

    A Diagnostic Revolution

    An accurate diagnosis opens up new treatment options. Demetri estimates that in up to 20 percent of sarcoma cases, "there are significant changes in a diagnosis that make a meaningful difference in how patients are managed."

    "We are in the early stages of a diagnostic revolution in cancer," Demetri says. Once there is an accurate tissue diagnosis from a pathologist, patients often receive a qualified diagnosis. For example, a patient may learn not just that he has non-small cell lung cancer (NSCLC) but a new genetic subtype of NSCLC for which there are targeted therapies. These critical details drive how patients are treated in an increasing number of cancer types, across lung cancer, colorectal cancer, sarcoma, lung cancer, melanoma, and several others.

    Understanding the different genetic subtypes and the molecular underpinnings driving them is at the heart of Profile, a comprehensive research study launched by scientists at Dana-Farber and BWH, and now including Boston Children's Hospital. Since the project began in 2011, Profile scientists have analyzed the DNA in tumor tissue from more than 6,000 patients, studying the genetic makeup of tumors for variations in the more than 300 genes that scientists believe are most likely to be involved in cancer.

    And while this molecular profiling rarely overturns a diagnosis, it can identify treatable targets, provide a more comprehensive picture of disease, and lead to research options and potential drug targets, according to Demetri. "We have a broad spectrum of clinical research trials, often based on precise identification of specific molecular targets, which is especially important for those with advanced cancers with no known curative options," Demetri says.

    Why a Second Opinion Matters

    Paulina Thompson (left, with her husband, Jeff) traveled to Boston after a breast cancer diagnosis at age 50. Pathology here confirmed the initial diagnosis and molecular analysis further classified Thompson's oncotype and directed a treatment plan.

    Often, a second opinion serves to confirm a particular diagnosis, and, in the process, identify treatment options, including clinical trials. That was the case for Paulina Thompson, who traveled to DF/BWCC from Virginia Beach after a breast cancer diagnosis at age 50.

    Thompson and her husband, Jeff, arrived in Boston "in a fog," with seven pages of questions, she says. "When you are told you have cancer, the first thing you realize is that you don't know what you don't know."

    She met with breast surgeon Laura Dominici, MD, and medical oncologist Sara Tolaney, MD, both with the Susan F. Smith Center for Women's Cancers at Dana-Farber.

    Dominici recommended a mastectomy because of the number of tumors and the distance between them, which would have required the removal of a third to half of Thompson's breast. "She thought it was unlikely that I'd be happy with the cosmetic outcome if I didn't opt for a mastectomy," Thompson says.

    Tolaney helped the Thompsons understand their options after surgery much of which would be determined by the pathology from the mastectomy.

    Pathology confirmed the initial diagnosis of invasive ductal carcinoma. Molecular analysis further classified Thompson's oncotype and directed a treatment plan. Thompson was eligible for a clinical trial called the Tamoxifen and Exemestane Trial (TEXT), which is designed to determine whether there is a role of aromatase inhibitors for women whose ovarian function is suppressed.

    Thompson and her husband moved temporarily to Boston for surgery and follow-up care.

    For Thompson, a cancer diagnosis from expert subspecialists working in coordination led to individualized treatment. Having the most accurate diagnosis from the start meant tailored treatment options, an intimate understanding of disease, and the tools and team to put a plan in place.

    Today, Thompson is back in Virginia and in her third year of taking tamoxifen. For the first two years, she also received monthly hormone suppression shots. Last year, she opted to end the monthly shots and had her ovaries removed. She continues to visit DF/BWCC every six months and "will most likely make an annual pilgrimage there for the rest of my life," she says. "It's a small price to pay for saving my life."

    Learn more about Profile.

    Paths of Progress Spring/Summer 2014 Table of Contents 

Posted on April 09, 2014

  • Precision Cancer Medicine
  • Sarcoma
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