Evaluating post-treatment breast specimens

That includes difficulty finding the tumor—there’s no good correlation between imaging findings and pathology findings. Imaging may be negative with a lot of residual disease on pathologic evaluation, or imaging may still see a lesion but there is no residual viable carcinoma microscopically.

Once the correct area is identified and sampled, “the second step is identifying tumor,” Dr. Bossuyt says. That’s easy enough if a lot of tumor remains. But in most cases, breast cancer is not a ball of tumor that shrinks. Instead, the cancer will often percolate, so to speak, through normal tissue, she says. Areas with relatively normal-looking breast tissue can alternate with areas containing tumor. If there are few tumor cells left, it can be hard to identify them.

And often there are multiple areas of concern and the specimens are extremely complex. “So these are not easy specimens for the pathologist to handle,” Dr. Bossuyt says.

“But it’s also an opportunity where we add a lot of value.”

Hence the need for two Big C’s: clips and communication.

The first may be more straightforward. When neoadjuvant treatment leads to pCR—which happens in most HER2-positive breast cancers, says Dr. Krishnamurti—it can be difficult to find the tumor bed. A biopsy clip can help direct pathologists to the right spot. At Yale, she says, the radiologists put a clip in the breast biopsy site, even in cases not involving neoadjuvant therapy.

Placing a clip in the biopsied lymph node is equally important. Following neoadjuvant therapy, the tumor can completely resolve, but the lymphatic channels may become fibrotic from the treatment, preventing the sentinel node dye or radioisotope from reaching its mark.

The clip ensures that surgeons have the right node. “When we give the frozen section report, in addition to telling them whether there is tumor in the lymph node, we also tell them that a clip was found,” says Dr. Krishnamurti. That can extend to complicated cases involving multiple tumors, she adds, a not infrequent topic of discussion at tumor boards.

When UT Southwestern began doing more neoadjuvant chemotherapy, Dr. Sahoo recalls, the subject of lymph nodes began to dominate tumor board discussions. One case still stands out for her, involving a patient who had a positive lymph node before therapy; during the surgery, the surgeon removed sentinel lymph nodes. The pathology revealed residual tumor in the breast, while the sentinel lymph nodes that were removed were all negative.

“So my question was, ‘Where is that lymph node that was positive? How do we know that the biopsied node was removed?’” The surgeon’s response: Anything highlighted by the blue dye or hot (radioisotopes) was removed. But as Dr. Sahoo pointed out, she wasn’t certain which node was biopsied without seeing changes of a clip site. “So that’s when we started putting a biopsy clip marker in the lymph nodes if we know somebody’s going to receive neoadjuvant chemotherapy.”

“In order to do those things you have to work as a team,” Dr. Sahoo says. She can tell her surgeon colleagues that even though she’s reporting that all the nodes are negative, it doesn’t mean the positive node is accounted for. At the same time, she says, they realize, I can’t rely on blue dye—I have to specifically remove that positive lymph node. “Unless you do that, you can’t tell if the patient has complete pathologic response.” Her surgeon colleagues got ahead of the game, she says, and started to localize the biopsied node prior to surgery with radioactive seed to ensure removal of the node at surgery, instead of relying on tracers (blue dye or radioisotope).

Enter that other C, communication.

While wider adoption of EHRs has made things easier for pathologists, Dr. Sahoo says, that’s not the end of the discussion. Surgeons and oncologists might ask why the pathology report lacks the “y” for treatment in the staging, for example, or ask pathologists to repeat a marker. Surgeons and oncologists are clearly “keeping us on our toes,” she says. “We are constantly making sure everything is addressed in the pathology report.”

But EHRs don’t automatically dispense information, either. As Dr. Bossuyt notes, neoadjuvant specimens aren’t always labeled as such. For all breast specimens, “It’s really important to figure out why we have these specimens.”

At tumor board meetings, Dr. Krishnamurti says conversations often revolve around multiple tumors. Another challenge involves receptor profiles.

At Yale, “We routinely repeat the ER, PR, and HER2 on all neoadjuvant-treated specimens,” she says, “but by the international consensus you’re not required to repeat predictive markers unless the patient is in a trial or the oncologist requests it.”

Sometimes the tumor profile changes after treatment, however. Most often, receptors may be lost or decrease, she says. Sometimes a new receptor, which was not expressed before, now is, possibly due to tumor heterogeneity.

Dr. Esserman has her own spin on the importance of communication, and she doesn’t absolve her surgeon colleagues of responsibility.

“We use pathology tracking sheets,” she says. “We’ve been doing this for years to make sure the pathologist knows: Here’s where the tumor is located; what treatment the patient had ahead of time; were they on I-SPY; treatment specifics; making sure the pathologist knows to look for the clip in the tumor bed and where.

“It’s essential to communicate that to pathologists,” she says. “They can’t do their job unless you do that.” She developed the worksheet after talking with pathologists about what they needed. That also led to more standardization among her surgeon colleagues as far as marking specimens. “The more we can standardize what we do, the easier it is for them.”

Likewise, the surgeons asked the pathologists to have a standard way of grossing specimens. “That lets me look down and say, OK, they went from medial to lateral, and I know where the margins are,” says Dr. Esserman. “You’re trying to figure out, if you have to go back, where you have to go back.”

Now that pathologists no longer come to the OR regularly, she says, “I ink my own specimens. I do it in six colors because I want to make sure I know the orientation. There’s no way for a pathologist to know that unless they come to the OR. And if you’re not set up at your institution to do that, the surgeons can be taught to ink the specimens.”

For the most complicated cases, she continues, “I’ve actually asked the pathologist to make a map of the specimen—where it’s positive, where it’s not. On these complex cases, if you sit down and talk to someone about it, and you sort it out, you can figure out who really needs to go back to the OR and who can avoid an unnecessary procedure.”

Handling these specimens is “a team sport,” Dr. Esserman says. “First of all, it’s fun to work with your colleagues if you know them and everybody knows what their jobs are. There’s no substitute for talking to each other. And having some camaraderie and saying, How can I make your job easier so you can make my job easier?”

Talking to clinical colleagues “actually makes it more pleasant and more rewarding for the pathologist,” says Dr. Bossuyt. “Because you’re working closely with your colleagues, and you know what’s happening to the patient.”

If it’s not clear by now, the complexities of these specimens can make pathology reports more byzantine as well.

Say, for example, a pathologist gets a request for Ki-67 analysis to see if a patient would benefit from abemaciclib. The interpretation of the Ki-67 result is dependent on whether the specimen has been pretreated, which may not be immediately clear from the report, Dr. Bossuyt says. “You can look at the ypT stage, but that’s all the way at the end of the report.” And while elements in current reporting try to address the neoadjuvant setting, things can still be confusing, she says.

Among her concerns: If there is no residual tumor because it was removed in the core biopsy, “then information from the original biopsy is added in the synoptic report. In the neoadjuvant setting, that’s not appropriate because the report for that surgical specimen needs to have the information at that point in time.” Dr. Bossuyt would like more clarity: “This is the information post-treatment.”

She’d also like to make it easier for clinicians to identify in the report whether there’s been a pCR. They might read, for example, that there’s no residual invasive carcinoma, then encounter a note referring to, say, lymphovascular invasion. “You’ll stage it as ypT0, and that’s prominent in the report,” Dr. Bossuyt says, “but buried somewhere else is that it’s not a pCR. It can be very confusing.”

Just as important is response in the lymph nodes. It’s been an area of longstanding confusion, she says. A report that indicates no residual tumor, but that there is carcinoma in the lymph nodes, is not a pCR—and it portends a worse prognosis. “We need to clearly identify those patients.” Moreover, she says, “In untreated specimens, isolated tumor cells are less important. They’re not going to affect prognosis or treatment in a big way. But in the neoadjuvant setting, any disease in the lymph nodes is important.”

Cellularity also plays a key role, says Dr. Esserman. “It can make the difference between more chemotherapy or not.” But sampling and location challenges muddy the picture for everyone.

Dr. Sahoo still encounters questions from her colleagues on this, even after two decades of experience, tumor board discussions, and consistent use of the RCB in addition to AJCC stage in their reports.

She gives one example of how complicated these cases can be. “Let’s say a case was reported out as pT1a by AJCC staging criteria,” indicating a tumor that is greater than 1 mm but less than or equal to 5 mm post-therapy. The pathologist had measured the largest contiguous focus in the tumor bed, which was 4 mm. But what if there are 10 or 20 foci (“Who’s counting?” she asks), some of them with single cells; what does that mean? “The surgeon asks, ‘You say the tumor bed is 20 mm, but then you say it’s pT1a. Which one is it?’”

With RCB in the report, pathologists can explain that even though the tumor bed is 20 mm, the scattered tumor cells only constitute 10 percent of tumor cellularity (compared with 100 percent before treatment). “Versus if I say, ‘It’s a 20-mm area of residual tumor but the cellularity is 80 percent.’” Which, Dr. Sahoo says, indicates the neoadjuvant treatment had minimal impact; on the other hand, reporting a cellularity of one, five, or 10 percent suggests a strong response, with only a few scattered tumor cells remaining.

The current AJCC recommendation for doing T stage is based on the largest contiguous focus, but that can be hard to pin down. “How much stroma do you need in between tumor clusters to call it contiguous or noncontiguous?” Dr. Sahoo asks.

“Nobody counts the number of foci,” she points out. “After five or six sections, each slide could have, say, five or 10 foci.” Totting them up “is not practical,” nor would it be easy to explain their size. “It is difficult for the oncologists to picture in their mind what the residual tumor looks like from reading a report, unless I am able to translate what I see under the microscope in a standardized manner.”

This is true of any organ system where the tumor has been treated neoadjuvantly, she adds. When the goal is to reduce the tumor volume, and ideally make it disappear, pathologists can be left with the equivalent of a locked-room mystery: “When you get the specimen, you are trying to make sense of what little is left—and how to tell the surgeon and the oncologist what is left, given the entirety of what you see.” Easier, perhaps, for poets to figure out how to capture the sensation of moonlight on a river.

Dr. Sahoo is sympathetic to the demands placed on each group of specialists. “You have three different people—oncologist, pathologist, surgeon—doing three different things.” Of the three, the pathologist is probably best positioned—like a baseball catcher—to see everything that’s happening with the patient and to talk to everyone involved.

Dr. Sahoo reports that the volume of these samples has increased to the point where, “believe it or not, some weeks our first-year residents will say, ‘I have not grossed or seen a breast cancer that hasn’t been treated with neoadjuvant chemotherapy yet.’” With untreated tumors fast disappearing, so are the old ways of looking at things.

If that’s astounding for pathologists, it’s even more so for patients. But this approach is demanding for them as well, Dr. Bossuyt says.

“Instead of going to the surgeon and having the tumor taken out, we’re asking patients to not do that immediately,” she says. “And they get treatment that is very difficult to tolerate. Patients have to live with this tumor for six months. Then they want to know: ‘Was it helpful? How did the tumor do?’” And when pathologists can then offer a detailed, quantitative response assessment, “Patients can do something with that number.”

It’s true, agrees Dr. Esserman. Ultimately, refining and standardizing the approach will only make things better. As she puts it, “That will let us get the right drugs to the right people at the right time.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.