Welcome. In this talk, we're going to
cover colorectal cancer.
A very important cause of malignancy in the total human
population and a major cause of cancer-related deaths.
So, a little bit first about the epidemiology. It is the third
most common cancer among both men and women.
It is the second most common cause
of cancer-associated deaths in the United States.
The majority of these tumors, the vast
majority, are adenocarcinomas.
And most colorectal cancers arise
from preexisting adenomatous polyps.
This is an important point because
if you have routine surveillance,
you may be able to find polyps at a stage
before they become frankly malignant
and that's why we have the colon screening
procedures that we do. General risk factors.
So, most of these cancer occur
after the age of 40 or 45.
There are some hereditary syndromes that are associated
with colorectal cancer such as familial adenomatous polyposis,
hereditary non-polyposis colorectal cancer also known
as Lynch syndrome and Peutz-Jeghers syndrome.
Clearly, inflammatory bowel disease, most typically,
ulcerative colitis is associated with colorectal cancer.
And then, smoking and diets that are rich in
processed meats are also epidemiologically associated
and may be of - may be causal in the sense
that they are inducing new mutations.
Let's cover some of the pathophysiology. We're looking here
at a normal colon and the epithelium is totally appropriate.
They're not much in the way of inflammatory cells
but it's at this point that we get a first hit.
The total pictures that you're going to see here,
there's something generically called a Vogelgram.
This is based on the work of Bert
Vogelstein who is a pathologist
and who described the various genetic changes that
can occur in colorectal cancer and other malignancies.
We will see the accumulation of various
mutations as we go along.
It's important, however, to realize that they don't always
happen in the sequence that I'm going to show you.
Some may happen out of turn.
But that the accumulation of various additional mutations
is what drives us along the pathway, finally, to malignancy.
So, as an example of a first hit,
you can have a known or an acquired mutation
in adenomatous polyposis coli, the APC gene.
Mucosa at risk now are -
includes the cells that have this mutation.
And then, we, on top of that, add some additional
methylation or other inactivation of normal genes,
a so called second hit and this may involve the APC B-catenin
gene as well or may involve other genes.
We will have progression. Now, to the point where
we have adenomas. These are not frankly malignant.
Adenomas are pre-malignant. Left to their
own devices, they will eventually turn
into malignancy by the acquisition
of additional mutations.
But it's at this stage with screening that
we may be able to pick them up.
At this point, they have developed the epithelial cells
that originally had the first and the second hit,
have acquired additional mutations. So, this can be KRAS which
will be very much involved in epithelial proliferation.
There may be tumor-suppressor genes
that are mutated, so, p53 is mutated
and we lose some of that ability to protect the genome.
You may have overexpression of COX-2.
We're moving along.
And then, the final step is that we have carcinoma.
So, at this point, the cells that had acquired
in each, in order to be malignant, a single cell
has to have all of these acquisitions.
Those abnormal cells now acquire things
like mutations that will reactivate telomerase,
so, that we can immortalize the cell lines.
There are just a whole host of mutations
and I don't want you to memorize the different genes
that are indicated in this figure but to be familiar
with the concept of first and second hits
and additional mutations that are accumulated,
eventually, leading to malignancy.
Clinical presentation. Depending on where the tumor is within
the colon, we're talking about colonic adenocarcinoma,
depending on where it is, you may
or may not be symptomatic.
Frequently, regardless of location,
your patient will be bleeding
Frequently, regardless of location,
your patient will be bleeding
because of erosion of the over lined epithelium and exposure
of the underlying submucosal vasculature.
And so, there will be an iron deficiency anemia associated with chronic,
perhaps, not even apparent bleeding into the stools.
So, we will also want to look
for occult blood within the stools.
In left-sided carcinomas, particularly those more
distally within the sigmoid, you may have constipation
because the tumor grows so much that it obstructs the lumen.
The right-sided carcinomas are rarely obstructed.
There's a lot more room for expansion
within the cecum and the ascending colon.
Making a diagnosis, colonoscopy is going to be our most sensitive
and specific and it's colonoscopy with biopsy.
And then, sending that biopsy off
to your friendly neighborhood pathologist, me.
You can also evaluate this by CT
but it's much less sensitive and much less specific.
Increasingly, we have other new techniques.
So, swallow a pill that involves a camera
and let it go from top to bottom and as it goes through the colon,
you can have it take little pictures as it goes all the way through.
Again, this is more of experimental and I would say
first step in a patient that you suspect
of having colon carcinoma, do a colonoscopy.
Laboratories are not necessarily sensitive or specific.
So, carcinoembryonic antigen is something
that you can use to follow a known diagnosis of colon cancer.
So, if you treat the colon cancer
and you remove it and they had a high CEA
and then, it goes to zero once you do the resection, you can follow
a CEA to see if you have recurrence in metastatic disease.
But as a primary diagnostic modality,
not all that useful.
And a complete blood count is obviously
useful for documenting anemia
but as you already are abundantly aware,
there are a bunch of causes for anemia.
So, the laboratory testing is not going to be making the diagnosis.
Again, it's colonoscopy.
How do we manage this
and what's the prognosis?
What is being shown there are different stages of malignancy
and there are various staging criteria?
The Dukes, Kirkland and others.
You don't need to memorize those
but you do need to remember that stage
one disease is superficial, small and localized.
Stage two is more invasive. And stage three,
more invasive with nodal involvement.
Stage four, tumor is metastatic disease.
An outcome for your five-year survival
is going to be very much dependent on the stage
at the time of the original diagnosis and resection.
Overall five-year survival for all colon cancers,
all-comers is about 65% which is not great
but it's not terrible. Five-year survival
with curative surgical resection is better than 70%.
However, if there's distant metastasis or in other words,
stage four disease, the five year survival is not very good at all.
It's about 15%. That speaks to the fact that surgery
can be helpful if you have localized disease.
But if there's metastatic spread,
not amenable to surgical intervention.
Our chemotherapy for colorectal cancer is not very good.
So, the clinical staging clearly dictates what you're going to do.
If there's no distant metastatic
disease by imaging preoperatively,
then, chemotherapy as an adjuvant,
new adjuvant therapy may be indicated or not.
And then, you can do laparoscopic
or more commonly, it's going to be open surgery.
The open surgery is going to be important because we
can take out the portion of the colon that's affected.
But also, we can do a nodal dissection which may be a bit
more difficult to do just by laparoscopic procedures.
With clearly distant metastatic disease diagnosed
by preoperative imaging, you may do palliative surgery
so the patient doesn't bleed or the patient doesn't have an obstruction.
But that surgery is not going to be curative.
And then, you will do your very best with
the existing chemotherapy strategies.
With that, we have covered colorectal cancer.