Dr. Mapow on Mucinous Neoplasms of the Appendix, Pathology Perspective

– There’s really no finer
pathologist than the pathologist you’re gonna
meet today, Dr. Beth Mapow, who is kind of my… She’s got a great team
that she works with, but when it comes to
peritoneal surgeon (mumbles), she’s my go-to, and hence she’s the go-to for our presentation today, talking about how we
classify appendiceal cancer or pseudomyxoma peritonei. Just as a side note, when we were preparing
for this conference, I went to Beth and I said, “You know, Beth, we have our
third conference coming up.” And this takes a long time to put these conferences together, and
she looked at me quizzically and said, “Well, I’m giving
birth right around that time,” and I didn’t say anything. I just said, “What about my
conference, the symposium?” (laughing) So, she is– – Poor planning. – Poor planning. (laughing) She’s seven weeks, she’s on
maternity leave right now. Her son, Lane, doing great. I’ve been getting pictures from everybody. But she’s coming back on May 7th, so if everybody wants to know,
she’ll be back on May 7th, but she’s here today. I am privileged to have her today, and can you make some sense
out of the miss-classifications or the classifications,
because we need some answers. Speak the truth. Dr. Beth Mapow. – Well, I’m gonna try. (audience applauding) First, I guess, I just thank the dragon for the introduction. (audience laughing) We are so making that stick! Okay, so first of all,
I promise I’m not gonna teach you how to read everything
in Pathology this morning. I have no disclosures. Our goals, basically, for this
presentation are really just going to be to review some
of the classification systems and actually I’m gonna focus on the currently accepted classification, look at some of the difficult
areas in diagnostic criteria, and then summarize some of
our challenges with reporting. So, first of all, what
is the appendix, right? The appendix is this blind
tube that’s connected to the cecum and typically very small. And the thought for a long
time not to have any function, some still think that there’s
no function whatsoever. But theoretically serves as
a flora reserve for bacteria and also some immune
and lymphatic functions. Important thing to know about
the appendix is that the muscularis mucosa, which
is a very important area for distinguishing
invasion in a lot of areas, is not continuous in the appendix. It’s continuous in the colon
and a lot of other places, but in the appendix itself
it’s not a continuous layer, which leads to a lot of
diagnostic difficulties, especially for pathologists
that are not accustomed to examining these specimens. So Appendiceal Neoplasia. In order to assess completely
any neoplastic process that comes from the appendix, we really need all of these things. So we need to have a
very good medical history on the patient, physical
examination, imaging, complete exploration with
examination of the whole peritoneal cavity, pathologic
examination of the primary appendiceal tumor, which
we often don’t have; and then examination of lymph nodes. If peritoneal disease is
present, we also need sampling from multiple areas in the peritoneum. So the first thing to
understand is that the majority of the times that we’re
dealing with pseudomyxoma cases and these appendiceal tumors, we don’t have the majority of this. The presentation of these
tumors can be very subtle, so patients often will present
at centers that are not accustomed to dealing with this. They don’t have any dragons. (laughing) So we really don’t have
all of these things the majority of the time
when we’re examining these specimens and that
by itself really affects our ability to make an accurate
and complete diagnosis. So there is a huge spectrum
of tumors that can occur in the appendix, and that
ranges from an adenoma, all the way to carcinoma. We’re not gonna talk about
really anything except for the mucin-producing lesions today, because I’m gonna do my
very best to stay on time. So they come in two varieties really, low grade and high grade tumors. The low grade is the most debated, certainly amongst even people
that see these cases a lot. High grade is gonna be
the most agreed upon. The majority of the
problem with examination of these specimens has been
the fact that there have been really numerous classification systems that have been proposed and
used in different centers, which creates the problem
of pathologists have varying exposure to the different
classification systems, as do the surgeons have varying exposure. So this, by itself, creates
interpretation difficulties and then obviously lots of
frustration for patients; because they have a tumor
called one thing in one place, and maybe another thing when you have your case reviewed elsewhere. So these are the classification systems. I’m not gonna go over all of this, because it would take much
longer than what we have, but certainly I wanna
focus more on the WHO, or World Health
Organization classification, that really is the best
accepted terminology, and I think that hopefully we
can find much more consistence with pathological reporting
if everybody follows the WHO classification. For our Low Grade Appendiceal
Mucinous Neoplasms, they commonly present with
abdominal mass or ovarian mass, or often patients will
present with metastasis, which creates really lots
of diagnostic difficulties. Our gross or external
examination of the appendix, we sometimes can see a completely
normal-looking appendix. Sometimes the appendix itself
is really just a little bit dilated, but externally
looks fairly normal. Now for some patients, certainly
with more advanced disease, what we’re gonna see is
rupture of that appendix with mucin spread on the surface; and then sometimes with
patients that are even further along there really is nothing
left of the appendix at all, which certainly prevents
the pathologist from doing an examination of the
primary appendiceal tumor and causes lots of issues
as far as interpretation. Histologically, or under the microscope, what we see is varying
from either a villous projection or a very flat
neoplastic epithelium, which produces lots of mucin. The cells themselves will have
abundant intracellular mucin, and then one of the biggest
problems with these tumors is that they invade the tissue
by this pushing invasion. And again, this is really
difficult to diagnosis, especially because our
muscularis is not completely continuous in that
appendix, so that by itself, that pushing invasion
can be very difficult, especially for non-experienced
pathologists, to interpret. Cells themselves usually only
show mild nuclear atypia, and this is really what
created a lot of the classification systems
that people used for years, where they didn’t feel that
this was actually cancer. The cells, even though they
were disseminated elsewhere, were not really considered
as severely by pathologists, because they really don’t
have the amount of atypia that we see in the majority
of malignant lesions. You can also see some
fibrosis in the wall. So Diagnostic Difficulties. I talked about this a little
earlier, so I alluded to this. This pushing invasion, and again, the fact that the muscularis
there is not continuous, the tumor itself pushes
easily into the wall. Now, since there is really
not a tissue response from that invasion into the
tissue, it’s very very easy for people to misinterpret
that as a non-invasive process. And again, this is what
leads to really diagnostic discrepancies between different centers and between different pathologists. Sometimes, especially
with an advanced tumor, the wall itself may be entirely breached, and if we have that then
it’s really really difficult to establish invasion
when we’re looking at it under the microscope, because
we really do rely upon having those histologic structures there to actually make a diagnosis. So these are just images showing
you the pushing invasion. And again, all it really
looks like is a fistula tract. It looks like the tissue
itself just kind of left. Well it didn’t leave. The tumor itself invaded into the tissue. It doesn’t cause the typical
response that most pathologists are looking for when we’re
talking about an invasion lesion. So again, this is a significant
problem in these lesions and it’s why Dr. Richard
talked about going to centers where your surgeons and
people are experienced. It’s really equally important
to go to a center where the pathologist is experienced
in looking at these lesions, because they are really
difficult to interpret and can be easily be misinterpreted
as a noninvasive process. Okay, so other problem is
gonna be distinguishing from mucinous carcinoma. Histologically, under the microscope, they can actually look exactly the same. We really are gonna rely
upon that pushing invasion for diagnosis, as well as
peritoneal dissemination. However, we have a second problem with, even under the current 8th Edition AJCC, there’s still debate about
peritoneal dissemination; what we actually classify
that as when we look at it. So the appendiceal tumor
really can either be diagnosed as a low grade mucinous lesion
with peritoneal involvement, or a mucinous adenocarcinoma. Certainly here at this center
and when I’m looking at cases, I certainly prefer
mucinous adenocarcinoma, given the potential for these lesions. High grade appendiceal
mucinous lesions are a little bit of a different animal. Histologically they meet
the entire criteria for your low grade mucinous lesions,
but what we see cytologically is that those cells
themselves look much worse. So, they have lots of cytologic atypia. I could throw lots of words
out that you don’t wanna hear, but they definitely show much more atypia than what we see in the low grade lesions. Whenever we see that, we
really should be using the staging system for
invasive carcinomas, even if that’s only focally
present in the tumor. Again, this is another
thing that pathologists in centers where they’re
not seeing a lot of cases are gonna struggle with,
because focal changes in the majority of tumors
as pathologists usually don’t define the entire lesion. However, for these lesions themselves, significant cytologic
atypia, even if focal, really should be considered
a high grade lesion and should be treated and
followed more aggressively. So Adenocarcinoma. Again, once we get to this
stage of classification, then we only have a couple
of choices for these lesions. So Adenocarcinoma, not
otherwise specified, or NOS. Mucinous Adenocarcinoma,
and the lesion needs to be greater than 50% mucinous; that’s gonna be the majority
of these lesions that we’re talking about, which are gonna
be predominantly mucinous. Our other choices, Signet
Ring Cell Adenocarcinomas. Some of our high grade
mucinous lesions are gonna have signet ring cells. If there’s a significant
amount of signet ring cells in that tumor, it should
be considered straight signet ring cell adenocarcinoma
because that’s the exact behavior and biology
that tumor is gonna follow. And then also we have
patients that present with non-mucinous adenocarcinomas
in the appendix, and these are gonna be our
colorectal-type tumors, which are gonna again follow a much more colorectal-type process. So for our Mucinous Adenocarcinomas, again this is typically what
we’re gonna be talking about for our pseudomyxoma cases, grossly peritoneal disease is
really often gonna be present. Histologically, we’re
gonna see clear invasion into the wall, which
typically has ruptured. We can also see
hematogenous dissemination, and again, our peritoneal
disease in these tumors tends to have more cellularity. Sometimes in our lower grade
lesions that have disseminated, what we’ll actually see as
pathologists are really just pools of mucin in the peritoneum
that don’t have any cells. If I have that and there’s no cells, then I can’t consider that really disease. But if I have cells, then
it’s a different story. So this is an example, again, of peritoneal dissemination
of adenocarcinoma. You can see that those
pools are what looks like clear spaces in the
middle of the pink stuff, is all gonna be mucin pools
and it’s all lined by cells in all of those spaces. So again, our diagnostic
difficulties really, so distinguishing adenocarcinoma from a low grade mucinous neoplasm. Again what we really need
to see is our infiltrative growth patterns and where
it actually is invading into that tissue. Often it’s easier to diagnose
if we see some single cells. You may or may not have desmoplasia, and what that means is a
stromal response to that tumor. Stromal response happens
in the majority of lesions. It doesn’t happen most of
the time for these low grade mucinous lesions, but if present, then there’s no pathologist
that’s gonna miss invasion. And then Distinguishing from Metastasis. Sometimes this really is
the majority of our job as pathologists, because
patients will present with late stage disease. So they may have a
little bit of complaint. Surgeon, dragon, takes them to the OR, finds disseminated disease everywhere, sends us a specimen for
frozen section diagnosis, and what we see is a mucin-producing tumor that’s in the peritoneum. Well at that point, as a
pathologist our job is to make sure of where that tumor came from. So we need to distinguish
it from all tumors that can produce mucin. So in those cases we often
have to do immunostains to try to differentiate
where the primary is. Even immunostains by
themselves are not gonna be 100% diagnostic. It really relies on good
surgeons to make sure that they’re looking for an appendix. Give us the history of the appendix. A primary tumor, if it’s there, sampling from multiple areas. All of these things are
gonna make it easier for us to not make a mistake. So for the AJCC Staging,
we are on the 8th Edition, so the 8th Edition actually
had a lot of improvements from prior systems, so again
we shouldn’t have as much discrepancy with staging
between pathologists at different centers now
with the 8th Edition; because it clearly states
that you can have an in situ carcinoma, but your T1
and T2 tumors do not apply to a low grade appendiceal
mucinous lesion. So again, we’re not gonna
have those errors popping up on pathology reports, because
the 8th Edition really took care of that. So we’re really gonna
either have an in situ tumor or we’re gonna have a T3
tumor which invades through the muscularis into the subserosa
and then again or higher. Pseudomyxoma. We’ve talked about it,
you’ve seen photos of it, and certainly lots of
you are very familiar. Pseudomyxoma characterized
by mucinous ascites and peritoneal implants. Generally these originate
from peritoneal spread of low grade appendiceal mucinous lesions or mucinous adenocarcinomas. Again, my preferred terminology, especially if there’s cells there, is gonna be that mucinous adenocarcinoma. The morphology tends to
correlate with the invasiveness of the primary tumor. So if we have peritoneal
disease that has high grade cytologic atypia in it, that’s
gonna be a bad-acting tumor and it typically correlates
with a clearly invasive lesion. Staging System for Peritoneal Disease. Again, we have a better staging system, so discrepancies between
pathology reports really aren’t gonna be there that much. Certainly your metastasis includes intraperitoneal mucin and also includes no tumor cells, although
the higher stages don’t. And then Summary. I think I’ve covered all of
this, but determining your invasion is really gonna
be an important thing. It’s difficult for pathologists, patients that are going to
centers where a pathologist maybe only sees one case a year, or maybe they’ve never even seen a case. That’s one thing to note. It’s possible to have a
pathologist that’s actually never seen in practice
a case of pseudomyxoma, or a case of an appendiceal
mucinous lesion. So in looking at a case like
that, it’s very difficult for them to make the correct
interpretation of a case. At larger centers where people
are seeing lots of cases, again we’re familiar with
looking for the invasion, how that invasion looks, and being able to do correct staging. Histologic grading,
again is another issue, because any area with high
grade cytologic atypia is really gonna speak to
the behavior of that lesion and really should be looked for. Signet ring cells themselves
automatically are gonna make the lesion high grade and
definitely need to be examined. Pseudomyxoma grading. Again, this requires
sampling from multiple areas, which we often don’t have. Sometimes, and especially for
centers that aren’t used to dealing with these cases and
treating patients like this, may only do one peritoneal biopsy; whereas, what we really
need is multiple biopsies. Because you may only have one
area of the peritoneal disease that actually shows you
the high grade atypia. If you haven’t done multiple
samples and examined multiple areas, you’re not
gonna be able to diagnose it. And then finally, Reporting. Again, I didn’t talk about all the old different classification systems. But we really shouldn’t be using
any of the archaic systems, because lesions should be
reported with WHO terminology and AJCC staging, and once we do that, then the literature and
everybody is going to agree on everyone’s prognosis and
everything for these lesions. And that is all. Thank you. (audience applauding)

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