So what is cancer?

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.