So what is cancer, anyway?
By Josh & Rochelle
As Pathologists we deal with this question every day and
while this might seem like a straightforward question, it requires some careful
consideration. Like any good question,
trying to answer “what is cancer” leads us to a series of additional, equally
interesting questions. Before reading
on, take a minute and fix a definition of cancer in your mind.
Got one? Ok,
good.
Cancers – and I emphasize the plural, because there are a
great many different diseases that are all “cancer” – are a type of something that
we generically call neoplasms (neoplasia simply means “new growth”). But not
all neoplasms are cancers – so what’s the difference?
I think most people would agree with us in saying that neoplasm
is an uncontrolled, clonal proliferation of cells carrying a mutation in their
genetic material (a “somatic mutation”) and that this uncontrolled growth may
damage the patient. That’s a good start,
but let’s dig a little deeper. This
process starts from some precursor cell with
the potential to divide that acquires genetic changes. These changes (mutations) allow the cell to
divide and give rise to daughter cells that keep dividing, all ignoring the
usual signals that tell them to stop and/or die when they should. We usually talk about “two hits” being
required for this process called “transformation.”
So when does a neoplasm become cancer? We argue that “cancer” identifies a neoplasm
that is locally destructive and/or can metastasize (spread to a different
site). It is these two features – local destruction
and metastatic disease – that are clinically so very dangerous for patients.
Pre-Cancer vs Cancer
The body has stem cells to replenish damaged or shed normal
cells at the end of their lives. The gut
and skin, for example, routinely and rapidly turn over new cells in
predictable, genetically-regulated cycles that ensure we have an intact
covering over our body to prevent infections, retain moisture, and absorb
nutrients. But the body has stem cells
ready to replenish essentially every part of itself!
Overtime, these stem cells can acquire transforming
mutations either by chance, because the person has inherited a defective copy
of the genetic proof-reading machinery, or due to an infection. These cells can start to grow, ignore
boundaries and stop signals, and produce a change that we can see with our eyes
or a microscope. These growths are also
neoplasms! Often, the body’s immune
system can find a way to kill these misbehaving cells – especially when helped
by a doctor cutting out this neoplasm.
When neoplasms occur in the colon, the gastroenterologist
typically sees polyps. In the cervix (think HPV
infection), a gynecologist finds discolored or eroded tissue. In the breast, we might call this “ductal (or
lobular) carcinoma in situ.” In the
colon we call these “adenomas” and in the cervix we call this “intraepithelial
neoplasia.” The difference between each
of these three processes is only in the spelling. These processes are all
neoplasms arising from the lining of the body (mucosal surface or “epithelium”)
and at the time of detection have not “invaded” into the underlying
tissue. Invasion is a complex process
that requires eating and/or squeezing through some sophisticated networks of
proteins that the body builds to separate its different compartments.
The above examples – adenoma, carcinoma in situ, and intraepithelial neoplasia – are all types of
“pre-cancers.” This means they all have
the potential to invade, but right now they are contained. It’s like a misbehaving child who is grounded
and stays in the house. Catching these
lesions early is precisely the goal of screening programs, like getting a Pap
smear. If left to their own devices,
these lesions may (many do not) invade and from their spread throughout the
body and wreak havoc.
Examples in Pictures:
Colon: Normal, Intraepithelial, and Invasive
 |
| Panel A shows normal colonic epithelium. Part B shows an overgrowth of cells confined to the surface, an intra-epithelial neoplasm. Part C shows glands running around beneath the surface; this is an invasive neoplasm (cancer), or in this case, an adenocarcinoma which indicates the cancer arose from gland-forming epithelium. Panel A & C are from a case in Kijabe. |
Breast: Intraepithelial and Invasive
 |
| Panel A shows a hypercellular duct, but all this new cells growth is contained within the duct. If you look closely, you can see thin, spindled cells lining the duct and separating the glandular cells (in the duct) from the pale, pink, whispy supportive tissue (stroma). Panel B is quite different, with duct-like structures invading throughout the stroma. Unfortunately I don't have a great picture of normal breast epithelium to share, but it's basically a much smaller, less cellular version of Figure A with some glands hanging off the end. Both of these figures are from a case we had recently in Kijabe. |
Cervix: Normal, Intraepithelial, and Invasive
 |
| Panel A shows essentially normal epithelium (the layered, pink part that looks kind of like a basket weave at the "top" of the tissue in the image). Panel B shows bigger, irregular cells in the epithelium with loss of the basket weave appearance. Panel C shows destruction of the epithelium with those bigger, uglier cells invading the pink stroma in clusters and single cells. All of these images are from cases here in Kijabe. |
Benign vs Malignant
These two terms, “benign and malignant,” are highly fraught
and used quite imprecisely. Benign means
innocuous, but is an adenoma in the colon really innocuous? How about ductal carcinoma in situ (DCIS) of the breast? What about cervical intraepithelial neoplasia
(CIN)? None of them have invaded, all
have the potential to invade and to go on and kill the person, but not all will
progress.
Many people – clinicians included – might call a colon
adenoma “benign”, while deciding that DCIS is malignant – but biologically they
are the
exact same process.
Even the major US initiative that collects
data on neoplastic diseases, the Surveillance, Epidemiology, and End Results
program (
SEER)
run by the
National Cancer Institute,
includes DCIS as cancer but does not count colonic adenomas
(non-invasive).
Many of us in pathology
and the basic sciences object to this; why this distinction is made is an open
question.
Let’s ask the question one more time, but in a different
way. Are invasive colon cancer, invasive
breast cancer, or invasive cervical cancer benign or malignant? Of course they are malignant! So perhaps the best thing we can say is that
the pre-cancerous lesions “have the potential to invade and become cancers.”
I'll add that "benign" doesn't necessarily mean "safe no matter what." A couple of non-epithelial neoplasms demonstrate this nicely. A meningioma is a "benign" brain neoplasm that doesn't infiltrate like a glioma and doesn't metastasize, but if in the wrong location can be fatal. Similarly, uterine fibroids are a smooth muscle neoplasm called a leiomyoma. Usually the worst that accompanies a fibroid is pain or heavy
periods, but someone with heavy bleeding from a fibroid could die from blood loss or secondary infection.
Conclusions
I hope this has been a useful discussion of the terms
“cancer,” “neoplasm,” “benign,” and “malignant.” These terms and diagnoses like
those above carry enormous emotional impact for patients. What we call these entities doesn’t
necessarily reflect their biological behavior. For example, many people would
consider DCIS to be “cancer” but wouldn’t be particularly perturbed by the
diagnosis of a tubular adenoma in the colon.
However, they are fundamentally the same biological process.
You are probably used to seeing an enclosed tissue processor such as this one. All of the tissue is in one container (or retort) and the solutions are heated as needed and pumped into and out of the retort. In the "dip and dunk" processors that we use in the Kijabe lab, the specimens are moved from solution to solution in a rotating carousel fashion. These models don't have as many features for increased temperatures and pressures to reduce processing times and increase efficiency as the enclosed processors do, but they are less expensive and easier to maintain, making them a good choice for Kijabe's pathology lab where turnaround time is less valued and cost, reliability, and maintenance issues are more important. I had never seen the dip and dunk design before, and I'm glad I got to help install and dedicate this shiny new piece of equipment!
