Breast Cancer Staging After the Z11 Trial: Is Axillary Ultrasound Necessary? - HD

Introduction

Hi, I am Gary Whitman.

I'm a professor of radiology
and radiation oncology at the University
of Texas MD Anderson Cancer Center in Houston, Texas.

Today we're gonna talk about axillary staging
with ultrasound after the Z 11 trial.

I have no disclosures
and no disclosures from my immediate family members.

Objectives

Our objectives are to understand the role
of ultrasound in staging the regional lymph nodes
to appreciate the value of percutaneous biopsy
and sampling the regional lymph nodes
to review the advantages
and disadvantages of axial lymph node dissection
and to consider axial staging following the Azo Z 11 trial.

Staging Overview

When we think of staging, we think of the breast,
the regional lymph nodes, and distant sites.

In this talk, we're gonna focus specifically on the regional
lymph nodes with emphasis on the axial lymph nodes.

For example, when we look here, we can see that
the hilum is displaced and flattened,
and the cortex is somewhat expanded in this
metastatic axial lymph node.

When we think of staging, we use the TNM system,
which involves looking at the tumor,
the nodes in the metastases for the tumor.

The T score is based on the size,
and as you can see, as the size of the tumor increases, the
t goes from T two to T four.

With nodes, we look at the nodal distribution.

For example, if we look at N two,
that would be metastasis
to four or more ipsilateral axial lymph nodes.

N three, for example, would be involvement
of infraclavicular and supraclavicular lymph nodes.

And for metastasis, M zero is no distant metastasis,
and M1 is distant metastatic disease.

For the staging, we take the TNM together to come up with
the appropriate stage.

So if we looked at two B, the tumor would be T two
N one for the nodes and no distant metastatic disease.

And you can see, for example,
if we had N three infraclavicular supraclavicular disease,
that would make it stage three c.

Focus on Axillary Lymph Nodes

In this presentation, we're gonna focus exclusively on the
axillary lymph nodes.

As you know, axial lymph node status is associated
with relapse-free survival
and is also associated with overall survival.

The involvement
of axillary lymph nodes affects local therapy,
specifically the use of chemotherapy,
which may be preoperatively,
what we call neoadjuvant chemotherapy or adjuvant
after surgery.

And also, when we look at the therapy involved,
we will talk about axillary dissection
and sentinel lymph node biopsy.

This is a case where there are small
calcifications in this lymph node.

This was a case of metastatic disease involving
this axial lymph node.

In a patient with invasive ductal carcinoma,
sometimes we can see metastatic lymph nodes on MRI.

As you note here, sometimes the lymph nodes may be difficult
to see due to the field of view or field in homogeneity.

As you can see here, there are a couple
of axial lymph nodes that were involved by tumor.

On this MRI with sentinel lymph node mapping,
we see a few lymph nodes here in the axilla.

Now this indicates that this was uptake
of the technetium 99 M sulfur colloid does not necessarily mean
that these were metastatic disease,
but just that these were active lymph nodes,
as you can see here, is the injection site in the breast.

Here are the lymph nodes taken up
by the radiopharmaceutical.

When we look at metastatic disease involving the lymph node,
the metastatic disease comes in
through the afferent lymphatic
and expands the cortical component of the lymph node
and compresses the hilar part, as you see here.

So on this schematic, we have the rim,
thin hypoechoic cortex and the echogenic hyperechoic hilum.

And here we see it in real life,
the echogenic hilum and the thin peripheral cortex.

When the node becomes metastatic,
you can see on this side that the
the hilum is very thin.

The cortex is expanded compared to the normal size with,
with a larger hilum in a very thin cortex.

Again, the normal side
with a very large hilum metastatic side here
with the hilum compressed and thin and cortical prominence.

Here, just another example of a metastatic lymph node,
and we can see that the hilum is markedly compressed
and very expanded cortex.

As we note here. As the lymph node becomes malignant, it tends
to become more rounded in shape.

And these are both metastatic lymph nodes.

No evidence of a discernible hilum here.

Sometimes with the malignancy,
there may be hilar compression as we see here
with this straight line that there's metastatic disease in
this cortical area here resulting in hilar compression.

And here's just an example of an expanded cortex.

The hilum is displaced and compressed right here.

Ultrasound in Determining Benign or Malignant Nodes

Hilar compression ultrasound can help us in
determining if the lymph node is benign or malignant.

And then we can use ultrasound guidance for guiding FNA
or core biopsy to sample axillary lymph nodes.

In this particular case, we would sample the bulging area
as we see here, the cortical bump to show
that this is evidence of metastatic disease.

And when we think of palpable breast tumors, about half
of them are associated with axial nodal involvement.

Nodal involvement tends to correlate with tumor size.

In other words, as the tumor gets larger, it's more likely
that there will be nodal involvement.

So if there's a palpable suspicious lymph node,
about seven out of 10 of those are metastatic.

However, about in about three out of 10,
cases of non palpable lymph nodes can be metastatic
and ultrasound can help us define those.

There are some limitations with sonography.

The sensitivity is 56 to 73%.

The specificity is about 70 to 90%.

However, lymph node sonography is
more sensitive than palpation.

And it can help us
to identify suspicious non palpable lymph nodes,
which can be, and it can be used
to help guide biopsy FNA if you have cytology
support or core biopsy.

This would be just an example here.

We're doing the FNA in the expanded cortical component here.

This was showing evidence of metastatic disease.

We could take it to our cytologist
for an immediate preliminary read,
and look at the sample and that'll determine
that we have adequacy
and we've diagnosed evidence of metastatic disease.

Here there can be limitations.

This was a small invasive ductal carcinoma
in the right breast, 10 o'clock region.

Notice the cortical bulge here on this lymph node.

We sampled it, it was negative at FNA,
however, at sentinel lymph node biopsy, there was evidence
of micrometastatic disease.

So our ultrasound guided FNA will show macro metastatic
disease where sentinel lymph node biopsy may show evidence
of micrometastatic disease.

So ultrasound is helpful in determining if the patient
undergoes sentinel lymph node biopsy.

If there's a negative ultrasound and
or a negative biopsy, the patient would undergo sentinel
lymph node biopsy, a positive ultrasound
or a positive needle biopsy,
then the patient would undergo axillary lymph node dissection.

Sentinel Lymph Node Biopsy

In the clinically node negative patient sentinel lymph node
dissection has been the standard for axillary evaluation.

This has been shown in single center trials,
multi-center trials
and prospective randomized trials
with sentinel lymph node evaluation.

Radiopharmaceutical technetium 99,
m sulfur colloid and blue dye would be injected in the region of the tumor.

Oftentimes peritumoral, sometimes subdermal,
this could be done by palpation, it could be done subdermal,
it could be done under ultrasound guidance.

It could be done under mammographic guidance
to deliver the radiopharmaceutical
and the blue dye around the tumor.

Then we have the here we have the injection site.

This is the radiopharmaceutical injected
into by the tumor.

Here we see a sentinel lymph node.

That just means that as a sentinel node does not necessarily
mean that it's benign or malignant,
but this approach with sentinel lymph node biopsy has
allowed us to do accurate assessment
of the axillary lymph nodes without the complications
of axillary lymph node dissection.

So this is decreased potential morbidity
and improved our sampling area as well.

And furthermore, we
can hopefully avoid complications
of axillary lymph node dissection such as lymphedema,
which is very disfiguring and debilitating.

Other complications from axillary lymph node dissection
include nerve damage and hematoma.

So lymph node mapping can allow careful histopathologic
evaluation, which can allow us
to identify micrometastatic disease.

And also we
can sample the nodes in the axilla
with a markedly reduced risk of complications.

So as you see here, here's the breast tumor,
here's the sentinel lymph node, which is reflective
of this whole nodal basin.

Notice is occasionally there can be a barren drainage,
as you can see here, drainage directly into the
internal mammary region.

When we're doing sentinel lymph node mapping,
we can deliver the radiopharmaceutical technetium 99 m
sulfur colloid, peritumoral, subdermal or periareolar.

And here we see the injection.

We're gonna give about four ml
of Technetium 99 M sulfur colloid.

The patient would go to nuclear medicine,
to identify the sentinel lymph nodes.

And here we can see the injection site
again in the sentinel node.

Again, note this does not necessarily mean
that it's a metastatic node, just means
that this is the node with the activity.

This would be what we call the sentinel lymph node
by sentinel lymph node.

And then the surgeon would try to identify that node
with a handheld gamma camera
or looking for a blue node or a blue lymphatic.

So as you see here, here's our handheld gamma camera,
and we've identified the blue node and the blue lymphatic.

So this node or group of nodes would be excised
and then carefully examined by the pathologist.

And with the small sample taken out,
the pathologist can do thin sections
and can do immunohistochemistry as you see here, to identify
an area that took up with the immunohistochemistry,
on this section right here.

So sentinel lymph node biopsy allows us
to excise a smaller number of lymph nodes compared
to axillary lymph node dissection allows
for a more detailed pathologic evaluation,
and then you can do very thin serial sectioning with
or without immunohistochemistry.

This should lead to the identification
of small volume metastatic disease, including micro,
micrometastases and isolated tumor cells.

Furthermore, screening mammography has led
to the identification of earlier, smaller cancers,
which should lead to a reduced axillary tumor burden.

ACOSOG Z0011 Trial

When we look at the Z 11 trial, this was performed in 1999
to 2004 T one to T two breast cancers,
and there was breast conserving therapy
and whole breast radiation therapy mastectomy.

Patients were not eligible. Patients were eligible
with one
or two positive lymph nodes on sentinel lymph node mapping
on sentinel lymph node dissection
with hematoxylin and eosin staining.

The patients were randomized to axillary lymph node dissection
or no further treatment.

And when we look at the trial, there was no mention
of ultrasound, although ultrasound was done at many
of the sites or several of the sites,
for eligibility,
they had one
or two positive lymph nodes on
sentinel lymph node dissection.

So that really was low volume axillary
disease to be eligible.

Then the patients were randomized
to axillary lymph node dissection or no further treatment.

IE sentinel lymph node dissection alone.

The trial was intended to include 1900 patients.

It closed after 891 patients had enrolled.

There was a slow enrollment rate
and there was a low event rate.

And what this trial showed was
that sentinel lymph node dissection was equivalent
to axillary lymph node dissection in this carefully
selected group of patients in terms
of local regional control, disease-free control
and overall survival.

So when there was,
when a axillary lymph node dissection was omitted,
there was no adverse effect on disease-free survival,
overall survival or local regional control.

And that was proven in the N-A-C-A-B-P-B 32 trial.

So if we look at the follow-up
after the B 32 trial,
there was really no difference in sentinel lymph node
dissection versus axillary dissection over 10 years
and no difference in disease-free survival
or overall survival.

When we look at N-S-A-B-P-B 32,
local regional recurrences were uncommon
about 4% in the axillary lymph node dissection group
and about 4% in the sentinel lymph node biopsy group.

However, I think one of the things we need to consider is
that axillary ultrasound detected metastasis are not
equivalent to sentinel lymph node detected metastasis.

So when we look at the metastasis detected with ultrasound,
there is an association for more positive lymph nodes,
larger metastasis, and extra nodal extension is more likely.

Role of Ultrasound Post-Z0011

So our question really is does ultrasound play a role in
staging new breast cancer patients
or those suspected of having breast cancer?

And at my institution, MD Anderson Cancer Center,
the radiologist and the surgeons would both answer this,
yes, that ultrasound still plays a role in staging
new breast cancer patients
or those suspected of having breast cancer.

So at our institution, there has been no change in the role
of axillary ultrasound.

After the Z 11 trial,
we do axillary ultrasound on our new cancer patients,
and then we would do FNA ultrasound guided FNA
of suspicious lymph nodes.

And that really has not changed,
since the trial.

The Z 11 trial really looked at selected patients
with good prognosis.

So these were selected patients
with low axillary tumor burden.

The real question here is,
is the Z 11 population equal to your population?

So is your population, is the person you're putting into
that Z 11 bracket likely to be node negative
because that's really where the Z 11 patients were.

On the other hand, we must consider
that actually ultrasound has the ability
to detect unsuspected non palpable axillary lymph nodes,
and this information can result in a management change.

And when we say a management change, that would mean
that when we identify axillary metastasis,
that usually will obligate the patient
to chemotherapy at our institution.

Oftentimes this is gonna be neoadjuvant chemotherapy
preoperative, and oftentimes in addition,
this may obligate the patient
to axillary lymph node dissection.

So when we think about it, in terms
of using our axillary ultrasound
and axillary ultrasound guided biopsy for triage,
negative axillary ultrasound
and axillary biopsy goes to sentinel lymph node biopsy.

If it's positive, it would go to axillary dissection
and oftentimes chemotherapy.

And at many institutions, including ours,
this would be usually be neoadjuvant chemotherapy.

So just to emphasize,
ultrasound detects macro metastatic disease, these tend
to be associated with larger lymph nodes, more lymph nodes,
and more likely to have extra nodal extension.

Whereas sentinel lymph node
dissection in general detects micrometastatic disease.

And the macro metastatic disease that we identify
with ultrasound can be proven with ultrasound guided FNA
or ultrasound guided core biopsy.

One could do
ultrasound guided FNA if there is expert cytology support.

If expert cytology is not available,
then core biopsy could be performed.

Institutional Approaches: Memorial Sloan Kettering

Let's look at the approach.

At Memorial Sloan Kettering Institute,
their preoperative ultrasound is not used routinely
to assess the axilla.

If outside imaging reveals possible nodal metastasis at
Sloan Kettering, then the disease is managed on the basis
of the number of abnormal lymph nodes visualized.

So three or four abnormal lymph nodes would go to FNA.

If the FNA is positive,
the patient would undergo axillary lymph node dissection.

If two or less abnormal lymph nodes were identified,
then the patient would undergo sentinel lymph node biopsy.

So when we look at the Memorial Sloan Kettering approach
after Z 11, it's important
that we do a careful review of outside images.

A caveat would be that we are not present for
looking at the real time assessment when we're looking at
outside images, and we'll need to count the number
of abnormal lymph nodes
and the number of abnormal lymph nodes should
be documented in the report.

Post-Z0011 Studies

So let's look at a few studies after Z 11.

In this study, there were 679 patients
who underwent preoperative axillary ultrasound 296
with a positive lymph node.

169 were detected by axillary ultrasound and staging.

88% were FNA and 12% were core biopsy.

So what were the factors that were associated
with a high risk of additional nodal disease
greater than three positive sentinel lymph nodes,
extracapsular extension, and matted nodal disease?

So matted nodal disease is something we should look
for on sonography.

We tend to probably not emphasize
or not report this finding as frequently,
but we should be tuned into it
after Z 11.

When we look at the work by Feral, when we look at
actually ultrasound and sampling, there was a sensitivity
of 86.2%, a specificity of a hundred percent.

The PPV was a hundred percent, and the NPV was 71.9%.

And also we should really consider
that there really is a
nodal multiplier effect, if you will.

So patients identified with nodal metastasis identified
by ultrasound had a mean burden
of 7.3 positive lymph nodes on histology.

So if one lymph node was identified
and ultrasound is likely to have greater than five lymph
nodes on histology, two lymph nodes on ultrasound meant
that there would be about seven and a half
lymph nodes on histology.

And greater than two lymph nodes on ultrasound meant that
there would be about 10 lymph nodes identified on histology.

And we can contrast this to sentinel lymph node biopsy
where the mean burden of nodes in that,
in the sentinel lymph node biopsy group was 2.2 lymph nodes.

What about the cases outside of the Z 11 guidelines?

What is the value of preoperative axillary imaging
and ultrasound guided needle biopsy?

Well, post Z 11, we can really look at axillary ultrasound
and axillary ultrasound guided biopsy,
and we can see that with axillary ultrasound,
the NPV is 78% with biopsy, it goes to 70%.

For axillary ultrasound, the PPV is 54%,
but it with biopsy, it rises to about a hundred percent.

And also there really is a multiplier.

So about a third of the patients
with one abnormal lymph node on ultrasound had greater than
two positive lymph nodes at surgery.

Two thirds of the patients with T one slash T two,
disease with multiple suspicious lymph nodes had more than
two positive lymph nodes at surgery.

So in this case, the appropriate approach would probably be
axillary lymph node dissection.

Axillary ultrasound helps us
to identify lymph node positive patients outside
of the Z 11 guidelines.

Axillary ultrasound is essential in guiding appropriate
management in breast cancer,
and we can do this by axillary ultrasound with sampling either
with FNA if you have cytology or core biopsy.

And axillary ultrasound can help us to triage patients.

And furthermore, there should be an increased
emphasis on the number of lymph nodes seen on ultrasound,
which can help us give a more detailed
and accurate evaluation.

So axillary ultrasound is essential in guiding appropriate
management in breast cancer patients in current practice.

Future Directions: Targeted Axillary Lymph Node Dissection

But what about the future? So let's look at that in view
of targeted axillary lymph node dissection.

Here the aim is to remove the known metastatic clip node,
clip lymph node and avoid a full axillary dissection.

So here would be an example. We had a staging ultrasound,
a 39-year-old woman
with a left breast invasive duct carcinoma.

There was an enlarged hypoechoic, left axillary lymph node
ultrasound guided, left axillary lymph node biopsy showed
evidence of metastatic disease.

And thereafter a clip was placed into the node.

You can see the clip right there.

The patient was treated with neoadjuvant chemotherapy
and thereafter the node has decreased in size and iodine.

1 25 seed was placed into the metastatic lymph node,
that had the clip.

Here we see where the yellow arrow is.

There's the clip marker and the iodine 1 25 seed.

And the targeted axillary lymph node
and also seeds were placed into the malignancies in the left
breast at 12 o'clock and two o'clock.

And the patient underwent excision of the clip node,
using the radioactive seed as the guide here,
the seed was removed
and we can see the targeted clip marker in the node,
that was excised.

Take Home Points

So what are our take home points?

We should continue to use ultrasound
for nodal staging in the axilla.

We want to document and report the number
of abnormal lymph nodes and also document
and report the number of matted lymph nodes.

Ultrasound continues
to have an important role in identifying lymph node positive
patients prior to sentinel lymph node biopsy.

So if the ultrasound
and ultrasound-guided biopsy are negative,
the patient should proceed to sentinel lymph node biopsy.

If ultrasound and ultrasound-guided biopsy are positive,
the patient should proceed to axillary lymph node dissection
or targeted axillary lymph node excision.

Thank you very much.