Exocrine Pancreatic Cancer: Epidemiology and Pathophysiology

00:01 Welcome.

00:02 In this talk, we're going to cover Exocrine Pancreatic Cancers.

00:07 This is an exceptionally bad actor.

00:09 Elsewhere in this collection of talks on gastrointestinal pathology, we've dealt with esophageal cancer, that's a bad actor.

00:19 Gastric cancer, that's bad actor.

00:22 Carcinoma of the colon, bad actor.

00:25 This has got them all beat.

00:27 This is the worst.

00:28 It has a very terrible prognosis overall.

00:31 And we really need to get some better therapies developed for pancreas cancer.

00:37 But let's get into it.

00:39 So, pancreatic cancer, exocrine cancers of the pancreas, more than 95% are ductal adenocarcinoma.

00:47 So they come from the ductal epithelium, not from the actual acinar cells that are making most of the enzymes.

00:56 As I've already kind of implicated, this has the highest mortality of any major cancer.

01:03 And interestingly about 10% of these will have a heritable component, so there will be a familial association.

01:11 So greater than 95% are ductal adenocarcinoma, about 1% of exocrine pancreas cancers are acinar carcinomas coming from the cells responsible for making pancreatic enzymes.

01:23 Those cells can produce tryptase, and lipase and other pancreatic enzymes.

01:28 And that can cause metastatic fat necrosis.

01:30 They are releasing lipases into the bloodstream which will cause breakdown of fat, and other cells throughout the body.

01:38 Less than 1% of these are pancreatoblastoma.

01:42 Those are malignant, immature tumors, they mostly occur in children.

01:46 And about 2% of pancreatic cancers overall are neuroendocrine in origin so called islet cell tumors, and if you know anything about Steve Jobs, that's what he died of.

01:57 It was a neuroendocrine pancreatic tumor.

02:01 In terms of the epidemiology.

02:03 So it is a relatively uncommon cancer, only about 3% of all new cancers are pancreatic cancers.

02:10 But it has over represented in terms of cancer deaths, and 7% or so of all cancer deaths are associated with pancreas.

02:18 It's the fourth leading cause overall of cancer related deaths in the United States.

02:23 And it's the 11th leading cause of death due to all causes or worldwide.

02:29 The most common age group a diagnosis is in the 60s to 70s.

02:34 And men are typically more involved than women.

02:39 The nonhereditary risk factors include smoking, and that seems to be the greatest risk factor in terms of epidemiology.

02:46 Older age, chronic inflammation, diabetes mellitus, obesity, and physical inactivity are all associated with pancreatic exocrine carcinomas.

02:57 Of the relatively smaller percentage that are due to hereditary or genetic factors, roughly 10% Is that already mentioned are associated with known gene mutations.

03:09 Peutz-Jeghers syndrome with a STKll genetic mutation, hereditary pancreatitis with a PRSS1 mutation, familial atypical multiple mole melanoma with p16 or CDKN2A checkpoint mutations, Lynch syndrome, which is due to defects in mismatch repair, and familial breast or ovarian cancer associated with BRCA2 mutations.

03:35 Probably don't need to remember all of these, but do realize that about 10% of pancreatic cancers will have a genetic basis and have a familial association.

03:48 The pathophysiology overall.

03:52 It really makes a difference in terms of overall prognosis and our ability to treat where the pancreatic cancers arise.

04:02 And the majority, about 60% will arise in the head of the pancreas, as you see there, another 15% or so in the body and a much smaller percentage ultimately in the tail.

04:13 It said here that 20% of pancreatic cancers will involve the entire pancreas, they probably started someplace else and have spread diffusely before we even can detect them.

04:23 Now, the important part about all of this is that, depending on where they arise, tail or head, will really determine how quickly we may be able to diagnose them.

04:36 I'll come back to that.

04:37 On the pathway though, to pancreatic adenocarcinoma.

04:41 There is a stepwise progression with the accumulation of various mutations.

04:46 So in the same way that we have talked about adenocarcinoma of the colon, where there seems to be an accumulation step by step by step, various known genetic mutations that lead to abnormal proliferation.

04:59 The same thing probably obtains for pancreatic carcinoma.

05:04 There is a precursor of pancreatic intraepithelial neoplasia or PanlN that precedes probably 90% or so of the pancreatic cancers.

05:14 You can see on the bottom that there are going to be various mutations that will lead to improved or increased predilection for proliferation, and will decrease the tendency of proliferating cells to die or undergo apoptosis.

05:31 Early on, there's usually telomere shortening as initial change, but at some point, we get telomerase overexpression, so that these cells are allowed to proliferate indefinitely.

05:45 KRAS mutations, a normal intracellular signaling molecule occur in greater than 90% of tumors.

05:54 There are variations on this theme, so what I just described for you is the typical ductal adenocarcinoma.

06:00 There are variants that are recognized pathologically and again, probably don't have to get into the sort of details on this.

06:07 But there is a cystic mucinous variant.

06:10 It's about 30% of the pancreatic adenocarcinoma is more common in women, more commonly occurring in the tail of the pancreas.

06:18 On the other hand, intraductal papillary mucinous neoplasms, typically involve the larger main ducts in the head of the pancreas.

06:25 It's going to be men greater than women in terms of prevalence.

06:28 It's multifocal in a significant proportion of the patients who have this, and it's associated with a signaling proto-oncogene mutation in over three quarters.

06:41 So, the pathophysiology of pancreatic adenocarcinoma, in addition to the proliferation of the epithelial cells, and their failure to die appropriately through apoptosis, there will also typically be an intensive fibrous response.

06:57 This is called Desmoplasia.

06:59 This gives the tumors a very firm scar-like consistency.

07:04 And they will typically be very, almost rockhard stellate.

07:09 They look gray-white, they're poorly defined masses.

07:12 And interestingly, if you look at this, and we'll see it in a minute, they're relatively small numbers of tumor cells, but a very prominent desmoplastic response to those tumor cells.

07:24 If you are so fortunate as to have pancreatic cancer that starts in the head of the pancreas, that will obstruct the distal common bile duct leading to obstructive jaundice so that you can pick this up relatively early on in the course.

07:38 And it gives you a better chance of survival.