pathology

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What You Really Need To Know About Dense Breasts

From left: 1) a breast of normal density showing fat (white), fibrous tissue (pink) and glands within the rectangle, while a cancer is present (circle). This illustrates the fact that cancer can occur in breasts of any density; 2) an extremely dense benign breast without any fat, composed of pink fibrous tissue and minimal amounts of glands; 3) an extremely dense breast involved by cancer (infiltrating haphazard small glands), in contrast to Fig 2, but very similar in appearance, demonstrating the subtle similarities. (Courtesy Michael Misialek)

From left: 1) a breast of normal density showing fat (white), fibrous tissue (pink) and glands within the rectangle, while a cancer is present (circle). This illustrates the fact that cancer can occur in breasts of any density; 2) an extremely dense benign breast without any fat, composed of pink fibrous tissue and minimal amounts of glands; 3) an extremely dense breast involved by cancer (infiltrating haphazard small glands), in contrast to Fig 2, but very similar in appearance, demonstrating the subtle similarities. (Courtesy Michael Misialek)

By Michael Misialek, M.D.
Guest Contributor

Reading the pathology request on my next patient, I saw she was a 55-year-old with an abnormality on her mammogram. Upon further investigation I discovered she had dense breasts and a concerning “radiographic opacity.” The suspicion of cancer was high based on these findings and so, a breast biopsy had been recommended. As I placed the slide on my microscope and brought the tissues into focus, I immediately recognized the patterns of an invasive cancer. Unfortunately the suspicion had proven correct.

Just a few patients earlier, an almost identical history had prompted another breast biopsy. This time the results were far different, a benign finding and obviously a sense of relief for the woman. Every day these stories unfold; the never ending workup of abnormal mammogram findings. Both radiographically and microscopically, it can be challenging at times sorting out these diagnoses, particularly in the face of dense breasts.

But what, exactly, are dense breasts and why are they suddenly in the news?

Breast Tissue 101

Breast tissue is actually made up of three tissue types when viewed under the microscope. The percentage of each varies between patients. There is fat, fibrous tissue (the supporting framework) and glandular tissue (the functional component). This is what I actually see under the microscope. Cancer can occur in fatty or dense breasts. It can be toughest to assess when the background is dense.

Biopsy, considered the gold standard in diagnosis, may even prove difficult to interpret when in the background of dense breasts. Dense breasts can hide a cancer, making it more difficult to detect both by mammogram and under the microscope.

Breast density has taken a lot of heat recently. A new study published in the Annals of Internal Medicine found that not all women with dense breasts and a normal mammogram warranted additional screening, as was previously thought. Understandably this report has received much attention. The authors found nearly half of all women had dense breasts. This alone should not be the sole criterion by which additional imaging tests are ordered since these women do not all go on to have a cancer. Clearly other risk factors are at play.

Confusion All Around

This is confusing for patients and doctors alike, especially when it seems as if screening guidelines are a moving target. Recently, the American College of Physicians issued new cancer screening guidelines: among these was mammograms, being recommended every two years. This too is getting a lot of press.

The American College of Radiology, American Cancer Society, Society of Breast Imaging and American College of Obstetricians and Gynecologists recommend yearly mammograms beginning at age 40. Continue reading

Cancer Haves And Have-Nots: Care And Treatment In 2 Different Worlds

By Michael J. Misialek, M.D.
Guest Contributor

Imagine feeling a lump on your body, visiting a doctor, and then waiting seven months (if you’re lucky) to find out whether it is cancer.

This has been the reality for the vast majority of patients in two of the world’s most impoverished nations, Rwanda and Haiti — both emerging from different but unthinkably grim histories of structural violence.

But since 2012, more patients are getting the care that everyone deserves, no matter what country they live in. A medical partnership between several Boston-based hospitals has radically reduced turnaround time for cancer diagnosis, and shrunk the number of people who fall through the cracks.

It is difficult to quantify the exact numbers here, since record keeping in the past has been poor. One data point: In Rwanda, where these interventions are in place, far fewer patients are lost to follow-up after they’ve been treated compared to patients in other poor countries, according to Dr. Larry Shulman, senior vice president for medical affairs at Dana-Farber Cancer Institute, and leader of the medical partnership.

As a pathologist at of one of these partner institutions — Newton-Wellesley Hospital — I can’t help but think about the patient behind the slides under the microscope. Here’s one: Tushime, an 11-year-old Rwandan girl, who had a large tumor protruding from her jaw.

The tissue sample from Tushime’s tumor arrived in Boston in a suitcase carried by an employee of Partners in Health, the global nonprofit. Like all other specimens, hers was processed into a slide by the pathology department of Brigham and Women’s Hospital and read by Harvard faculty.

Tushime’s tumor turned out to be a rhabdomyosarcoma, a common childhood sarcoma. After 48 weeks of chemotherapy and surgery in Rwanda, she is now healthy and free of disease. Doctors there used standard chemotherapy for a cost of about $300 (which was covered by Partners in Health, Dana Farber and the Rwandan government). They relied on age-old, tried and true chemotherapy drugs; in comparison, the newer chemotherapy agents in the U.S. often cost several thousands of dollars.

Even though access to care has improved dramatically in the developing world there is so much work to be done. There are patients who still present with tumors at an advanced stage, many being neglected for months or even years because of barriers to care. There’s often a lack of access to facilities for both diagnosis and treatment, and funding for cancer care is limited. As a result, ordinary diagnoses become extraordinary.

This is an image of a less aggressive (low grade) breast cancer, something that is fairly common among patients in the U.S. You can see the well formed tubules and glands of cancer, but fewer tumor cells growing in a more organized fashion -- only about 30 percent of the image is tumor. (Courtesy of Michael J. Misialek)

This is an image of a less aggressive (low grade) breast cancer, something that is fairly common among patients in the U.S. You can see the well formed tubules and glands of cancer, but fewer tumor cells growing in a more organized fashion — only about 30 percent of the image is tumor. (Courtesy of Michael J. Misialek)

This is an image of an aggressive (high grade) breast cancer not uncommonly diagnosed among patients in countries where access to medical care is limited, such as Haiti. You can see a solid mass of cancer -- the photo is 100 percent tumor. (Courtesy of Michael J. Misialek)

This is an image of an aggressive (high grade) breast cancer not uncommonly diagnosed among patients in countries where access to medical care is limited, such as Haiti. You can see a solid mass of cancer — the photo is 100 percent tumor. (Courtesy of Michael J. Misialek)

Under my microscope, I’ve seen some of the most aggressive appearing tumors from patients in these countries. What are typically rare cancers here in the U.S., such as sarcomas or unusual variants of breast cancers, are all too common in developing nations. Continue reading

Pathologist: What Women Need To Know About Breast Biopsy Accuracy

A breast biopsy which illustrates the grey zone of pre-cancer (Courtesy of Dr. Michael J. Misialek)

A breast biopsy which illustrates the grey zone of pre-cancer (Courtesy of Dr. Michael J. Misialek)

By Michael J. Misialek, MD

If you’re a woman who has ever had a breast biopsy, you may be asking yourself a few serious questions:

“How do I know if my breast biopsy is completely accurate?” And, “Who is the pathologist reading the biopsy, and what is their level of training?”

Many more patients are asking these and similar questions following widespread media coverage on a Journal of the American Medical Association (JAMA) study, which casts doubt about the accuracy of interpreting these biopsies.

Let’s break the study down and ease some anxiety. Perhaps most importantly, this provides a great opportunity to learn about one of the lesser know medical specialties, pathology…which is what I do.

The JAMA study, “Diagnostic Concordance Among Pathologists Interpreting Breast Biopsy Specimens,” revealed the following key finding:

• Overall agreement between individual pathologists’ interpretations and that of an expert consensus panel was 75 percent, with the highest agreement on invasive breast cancer and lower levels of agreement for ductal carcinoma in situ (DCIS) and atypical hyperplasia.

What this means is that the agreement between a general pathologist and an expert was excellent for breast cancer (those with the ability for metastasis), but varied significantly for early cancers and high-risk pre-cancers.

While the study’s findings may not be surprising to physicians who understand the challenges of diagnosing complex breast cases, news of the article could lead to unnecessarily heightened anxiety for patients and the public as breast cancer is a highly publicized and pervasive disease.

The study confirmed that the majority of breast pathology diagnoses, especially at either end of the spectrum (benign disease and invasive breast cancer) are accurately made by practicing pathologists regardless of practice setting. The overall rate of agreement for invasive breast cancer cases was 96 percent.

Issues with diagnostic disagreement mainly center on the borderline cases, between atypical hyperplasia, that is, pre-cancer, and DCIS, early cancer.

Why does this matter? Overdiagnosis can lead to unnecessary surgery, treatment and anxiety. Underdiagnois can lead to a delay in treatment. The bottom line is that experience matters.

Factors that contributed to greater disagreement included: a low case volume, small practice size, nonacademic practice and high breast density.

The study has many weaknesses. Chief among them was that only a single slide per case was given to each pathologist. As a practicing pathologist, this never happens. I will review multiple slides, often ordering several additional deeper sections and ancillary special stains, studying each carefully. This practice was prohibited in the study.

Additionally, the study cases were a mixture of core biopsy and excision specimens. A core biopsy is obtained using a needle, often by a radiologist, in which a small core of tissue is removed. An excision is a “lumpectomy” which is done in the operating room where a large section of breast tissue is removed. Diagnostic criteria vary between a needle core and excision. Often times it is not necessary to render an exact diagnosis on the core biopsy, but rather recognize an abnormality and recommend an excision for which additional tissue will clarify the diagnosis.

Even the experts disagreed in the study (75 percent initial agreement then 90 percent after discussion).

This illustrates the fact that pathology is both a science and art. Experts may stress slightly different criteria in their pathology training programs. The “eye of a pathologist” is a difficult measure to quantify and is dependent on multiple factors that best function in real time, not an artificial study.

Another weakness is that there is no evidence that the experts were more accurate in predicting outcomes than test subjects. Perhaps most importantly, a second opinion was not allowed in the study, even when study participants indicated uncertainty. These are in fact the very cases that would most likely have been shown around, sent out for consult and further worked up.

It is not realistic to introduce such a large caseload of breast biopsies that are heavily weighted towards atypical hyperplasia and DCIS. Since these borderline cases represent only a small fraction of breast biopsies in actual practice, diagnostic agreement in routine practice is higher than that reported in this study. No clinical information other than patient’s age was given to the study pathologists, and no imaging findings were included. In actual practice, integration of the clinical setting and imaging findings is routinely used in making a diagnosis.

The findings are not unique to pathology. All of medicine has grey zones, where controversy often exists. The study does have an important message for pathologists. As noted in the accompanying editorial, it should serve as a “call to action.” A better, more reproducible definition of atypical hyperplasia is needed.

The article highlights the need for an active quality management program in surgical pathology that includes targeted review of difficult or high risk cases. The College of American Pathologists (CAP) and the Association of Directors of Anatomic and Surgical Pathology have been developing an evidence-based guideline expected to be released in May to provide recommendations to reduce interpretive diagnostic errors in anatomic pathology.

The CAP is proactively addressing educational opportunities through advanced breast pathology training programs designed to provide a route for pathologists to demonstrate their expertise regardless of the setting in which they practice.

Patients can take steps to help ensure their breast biopsy is read accurately:

o Inquire about the pathology laboratory that will examine your tissue sample. Is the laboratory accredited? The CAP accredits more than 7,600 laboratories worldwide and provides an online directory for patients. Continue reading

Pathologist’s View On Prostate Cancer Grey Zone: ‘What Do My Numbers Mean?’

Prostate cancer, circled. (Photo courtesy Dr. Michael Misialek)

Prostate cancer, circled. (Photo courtesy Dr. Michael Misialek)

By Dr. Michael Misialek
Guest Contributor

We don’t like to admit it but cancer is rarely black and white. Increasingly a cancer diagnosis means living in a murky morass of constantly reassessing risk.

Here’s one man’s story of living on that precarious line. His saga, seen through a pathologist’s filter, illustrates the uncertainties surrounding prostate cancer. And, as the number one cancer in men, it is increasingly becoming a familiar story for many. Questions like, ‘What do my numbers mean?’ ‘Should we treat or not?’ and if so, ‘Which treatment is best for me?’ inevitably arise.

Mr. B. is a 64-year-old man who was found to have an elevated PSA four years ago on his routine physical exam. Obviously, prostate cancer was the first thought that came to mind, particularly since his father had the disease. What he soon learned is that prostate cancer is a complex diagnosis — one that requires the careful integration of the physical exam, biopsy results, radiographic studies and lab results.

And, of course, it’s a diagnosis that comes with many decisions and choices; choices that depend upon understanding the grey zone of medicine. Prostate cancer is rarely clear cut. As much as numbers like the PSA and Gleason score (the sum of the two most predominant grades in a patient’s tumor) guide diagnosis and treatment, they also contribute to the uncertainties on the best course of action.

When Mr. B’s elevated PSA was first detected, his primary care physician referred him to a urologist at Newton-Wellesley Hospital. His prostate was normal on physical exam and they elected no biopsy at the time. Over the next couple of years the PSA slowly continued to rise, still with no change in his physical exam. Last year a biopsy was done and was negative. No cancer, a relief. What was found was some inflammation. Could this have contributed to the rise in PSA? It certainly could have, but a negative biopsy did not rule out cancer. The journey of watching numbers continued.

This year Mr. B.’s PSA rose yet again, and his urologist ordered an MRI which was negative. Mr. B. underwent another biopsy. (Not an easy process since he takes the blood thinner Coumadin and any invasive procedure needs to be carefully coordinated with stopping and restarting this medication.) The biopsy is also uncomfortable: his first biopsy involved six needles, but this time it was twelve.

The slides came to me. I put them on my microscope and carefully studied each of them. As I scanned at low magnification I found two tiny foci of abnormal glands which qualified for a diagnosis of cancer. Continue reading

Boston Pathologist Hears From Colleagues: How Nigeria Prepares For Ebola

 Ministry of Health workers burying one of the first Ebola dead outside Monrovia. (Photo courtesy  Rodney Sieh, editor of FrontPageAfrica, Liberia’s leading investigative online news magazine.)

Ministry of Health workers burying one of the first Ebola dead outside Monrovia. (Photo courtesy Rodney Sieh, editor of FrontPageAfrica, Liberia’s leading investigative online news magazine.)

The Ebola outbreak in Western Africa has now claimed more than 1,000 lives. Here, Dr. Michael Misialek, associate chair of pathology at Newton-Wellesley Hospital and assistant clinical professor of anatomic and clinical pathology at Tufts University School of Medicine, shares what he’s hearing from his Nigerian pathology colleagues.

By Dr. Michael Misialek
Guest contributor

As I sat in the meeting on Monday, helping plan our hospital’s response to a hypothetical suspected Ebola case, it seemed surreal.

Just a few days previously, I bet most Americans would have had trouble finding Liberia, Sierra Leone or Guinea on a map, and Ebola was most certainly not a household name. What a difference a few days can make.

Could Ebola come to Boston? It  could, theoretically. Many other local hospitals are having similar meetings to plan for that contingency. The World Health Organization recently stated that the Ebola outbreak is moving faster than it can control, and thus labeled it an international health emergency. The countries of Liberia, Sierra Leone and Guinea have been hardest hit. Nigeria recently reported two deaths with 10 confirmed cases.

When asked if they are ready, Dr. Ogunbiyi says, ‘No, there is work to be done.’

Nigeria, the most populous country in Africa, is understandably worried. To find out how it is preparing itself and use some of that knowledge for our own preparations, I recently spoke with two colleagues there: Dr. Yawale Iliyasu, an attending pathologist at Ahmadu Bello University in Zaria, Nigeria, and president of the West African Division of the International Academy of Pathologists; and Dr. J.O. Ogunbiyi, a pathologist at the University College Hospital in Ibadan, Nigeria, and former president of the same division.

As pathologists trained in the study of disease, we may often be the first to recognize and report on new and emerging illnesses. Continue reading

Pathologist: Legacy Of A 31-Year-Old Lung Cancer Patient

Microscopic image of the lung cancer that killed Kevin, a non-smoker, at just 31. (Courtesy M. Misialek, with family permission.)

Microscopic image of the lung cancer that killed Kevin, a non-smoker, at just 31. (Courtesy M. Misialek, with family permission.)

He was only 31 years old, the autopsy paperwork said.

What could have taken the life of someone just a few years younger than me? Stage 4 lung cancer, the chart said. And Kevin wasn’t a smoker.

I made the first incision. As I worked, it became clear that cancer had overtaken Kevin’s body. Tumor had encased his lungs, growing into the rib cage and heart, blurring the normal anatomical landmarks.

As a pathologist, I have learned that cancer knows no boundaries. It can strike anyone regardless of age, sex, race or class. I’ve also witnessed a disheartening trend over the past few years: many of the patients I see with cancer are younger and younger.

When I began my training, it was eye-opening to diagnose breast cancer in a 40-year-old. Over time, that yardstick has dropped a decade, then more. Once, my colleagues and I would stand in amazement having diagnosed the disease in 30-year-old patients. Now, unfortunately, that bar is set at more like age 20.

Kevin (Courtesy M. Misialek, courtesy of the family.)

Kevin (via M. Misialek, courtesy of the family.)

What is cancer? Cancer can be microscopic, only a few cells under my microscope, or it can be large and disfiguring. It can be indolent or aggressive. Some cancers may never cause harm while others will be relentless and deadly. This is something I have yet to understand. Many pathologists and other researchers are working on this exact question.

To me, everyone who battles cancer is a hero. Each patient is unique. It might be tumor characteristics seen on a pathologist’s slide or data collected from a clinical trial, but all patients teach us important lessons. They add to our growing understanding of cancer and search for a cure.

Kevin’s oncologist, Dr. Daniel Costa of Beth Israel Deaconess Medical Center, came over to collect some tumor tissue. It turned out that Kevin was one special patient. His tumor harbored a rare mutation in the ALK gene which made him eligible for the then still-experimental inhibitor PF-02341066. Being one of the first patients treated with the drug, he was a pioneer, blazing a path where no one had been before.

Kevin was also an outspoken advocate for lung cancer, working to erase the stigma that it is a patient’s fault because they smoked. Continue reading

Under The Microscope, A Pathologist Sees Beauty — And Danger

A pap smear shows cervical cells infected by human papilloma virus (Michael Misialek)

A pap smear shows cervical cells infected by human papilloma virus (Michael Misialek)

By Dr. Michael Misialek
Guest contributor

It was a typical busy morning. A flurry of people in and out of my office along with a growing stack of slides. I picked up the next slide, a pap smear.

The requisition stated “24 yo, routine pap.” She had no prior history of any abnormalities. As I studied the slide, the normal cervical cells sparkled in shades of blue and pink. Together with their small uniform nuclei, this created an evenness to the slide, like a calm pond.

But off to one side, a cluster of dark and enlarged cells floated like sinister water lilies. I diagnosed “low grade squamous intraepithelial lesion,” a precursor to cervical cancer and a result of HPV, human papillomavirus.

Monet water lilies (WikiPaintings)

Monet water lilies (WikiPaintings)

Have you ever studied one of Monet’s masterpieces? The flowing movement of the lines, the broad pastel brushstrokes in the early evening sky, all drawing the viewer into a world of serenity.

Looking at this painting with a more critical eye, you can pick out the faint lemony yellow dots on the floating water lilies creating that effect of  illumination. You notice the different colors of blues and greens that were used to create the depth of the water. All of these fine details emerge only upon closer examination, not upon first glance.

In my work as a pathologist, I frequently think about the beauty under my microscope, never failing to be amazed by the seemingly endless combinations of colors and cells that define my diagnoses.

We pathologists might be considered Monets in our own right. We are connoisseurs of the fine art that is your living tissue on our slides. Under our microscopes, the cells burst into vibrant hues of red, blue, yellow and pink, producing a rainbow of colors.

On initial examination, this is the impression that is created, but as we study the cells further, a new piece of artwork with much finer detail is revealed. The cells can gel together like the desert sands or flow in harmony like a running river. What lurks beneath that art can sometimes be a beautiful disaster, like a Jackson Pollock drip painting.

Art and science, typically on different sides of the brain, have never fit together so well, I think. A pathologist combines these two worlds — the visual aesthetic, and the hard medical information it denotes. I was taught in medical school to think of horses when hearing hoof beats — the simplest diagnoses will probably prove correct — but not to forget the zebras. As a pathologist, I look for the zebras in the herd. Among thousands of cells we are trained to find the one abnormal.

On that 24-year-old’s pap smear sample, I homed in on that group of big dark cells. As I focused in, I quickly recognized this painting: these were koilocytes, the diagnostic cells of an HPV infected cervical cell. Continue reading

The Unseen Pathologist: Why You Might Want To Meet Yours

The right smaller circle is normal breast tissue. The left are the donut-shaped glands, with white centers, that are the telltale signs of an invasive breast cancer. (Image courtesy Michael Misialek)

The smaller circle on the right is normal breast tissue. The bigger circle on the left contains the donut-shaped glands, with white centers, that are the telltale signs of an invasive breast cancer. (Image courtesy Michael Misialek)

By Dr. Michael Misialek
Guest contributor

“How much time do I have?” was the first question Mrs. C asked.

She had called me in a panic. Earlier in the week, I had diagnosed her with breast cancer. She called me after learning the bad news from her radiologist. A whirlwind of appointments with oncology, surgery and radiation oncology ensued, overwhelming her with information.

I knew her case — these cells and her pathology — well, having just presented the pathology at our weekly breast cancer conference.

I struggled to reassure her, telling her that treatment has advanced and catching it early was very encouraging.

But there was silence. I envisioned her on the other end of the line, nervous fingers playing with the phone cord. Finally she said, “It would give me great comfort to meet with you since you are a pathologist. I would like to review my slides along with you.”

Dr. Michael Misialek (Courtesy)

Dr. Michael Misialek (Courtesy)

It was an exceedingly rare request by a patient, but one I deeply welcomed.

I am a pathologist. I spend more time studying your cells and developing a diagnosis then your other doctors spend with you. For particularly tough cases, I ask my partners for help, even send images for another opinion to my academic specialist colleagues, who may in turn show them to still more pathologists.

Many eyes have likely seen your cells. Yet, I am often unseen by you, maybe even unknown. But it doesn’t have to be that way. You can request a meeting with me, you can ask — as Mrs. C did — to review your pathology, whatever the diagnosis, benign or malignant. No request is too small.

Will the health care system allow for this? Won’t it resist? My colleagues from other specialties have embraced it. But currently we cannot bill for these patient consults. That’s part of my reason for writing this: We pathologists are advocating to make our consultations with patients billable, like a patient’s consultations with any other specialists. Pathologists are taking on new roles, and the system needs to change to reflect the value of pathology.
Continue reading