12. Pancreatic Carcinoma

Question 1

Why is pancreatic cancer such a complicated topic? What are we focusing in on?

Answer 1

Complex because the pancreas has so many different tissue types, all of which can give rise to neoplasms.

We’re focusing on Exocrine Neoplasms from duct and acinar cells – most from ductal cells

[Other types are neuroendocrine neoplasms (covered during Endocrine), Primitive and Mixed neoplasms (from stem cells) and Sarcomas from stromal cells (extremely rare).]

Question 2

At the basic level, what do we mean when we say “pancreatic cancer”?

Answer 2

Unless otherwise specified, we mean ductal adenocarcinoma or one of its subtypes. These are the dominant types of pancreatic neoplasms (90% of pancreatic neoplasms are ductal adenocarcinomas).

Question 3

What is this? Features?

Answer 3

Pancreatic ductal adenocarcinoma.

See a few ducts which look abnormal, lots of fibrous tissue. Desmoplastic neoplasms -> simulate growth of fibrous tissue -> Become hard masses.

Question 4

These are 3 grades and 2 subtypes of ductal adenocarcinoma: what differentiates the 3 grades?

Answer 4

Grade 1: Can still recognize duct structures.

Grade 2: Moderate; hard to recognize ducts

Grade 3: Advanced; hard to idenfity ducts, poorly-differentiated neoplasm

Don’t worry about the subtypes.

Question 5

Ductal adenocarcinoma: risk factors?

Answer 5

Chronic pancreatitis incr risk 10-15x

Cig smoking incr risk 2-3x

T2DM incr risk 2x

Hereditary pancreatitis incr risk 50x

CF incr risk as well.

Bottom line: not much that you can control; don’t smoke!

Question 6

Pancreas cancar: what is the 5yr survival rate relative to other cancers (breast, colon, esop, liver)?

Answer 6

VERY LOW 5yr survival. Around 5% (don’t need to know number)

Question 7

Why is pancreatic cancer such a bad disease?

Answer 7

• Early diagnosis is rare. There’s no self-exam, no cytologic screening, no antigen to test for.
• Usually it’s not noticed until there is pain or jaundice, by which time it is advanced.

Question 8

Why is it so hard to excise pancreatic tumors? What structures are nearby?

(pic of tumor in the head of the panc)

Answer 8

Majority of cancers occur in the head of the panc.
Proximity to major vessels means that you cannot widely excise tissue.

May extend into retroperitoneal tissues

Structures: portal vein, superior mesenteric vessels and nerves, spleen, adrenals, vertebral column, transverse colon, and stomach

Question 9

Besides nearby structures, another reason it is so hard to excise pancreatic tumors?

Answer 9

Perineural invasion is common in panc carcinoma.

Most tumors recur at the head of the pancreas, which is very nerve-rich.

Question 10

Trends concerning pancreatic cancer:

• as grade of carcinoma increases, what happens to survival?
• the majority of cancers are what grades?

Answer 10

-as carcinoma grade increases, survival drops.

-the majority of cancers are grade 2 or higher.

Question 11

INfluence of genetics in panc adenocarcinomas: what genes are involved? typically a single mutation or several?

Answer 11

There are mult genes that are mutated in panc adenocarcinomas. Most common are K-ras, p15, p53 and DPC4.

Most tumors are result of multiple mutations, not just one.

Question 12

What is PanIN?

Answer 12

**Premalignant change in ductal epithelium. **

characterized by columnar to cuboidal cells, with mucin and some arthitectural atypia.

Common in older people, part of genesis of ductal adenocarcinoma

PanINs involved ducts <5mm in diameter.

Question 13

What is this?

Answer 13

PanIN3 (carcinoma in situ - premalignant change in ductal epithelium)

epithelial neoplasm arising in pancreatic ducts.

some free-floating abnormal cells in this duct.

Question 14

These are PanINs of various grades. What is notable on each?

Answer 14

Left: MILD. nuclei are small, at base of epithelium. Main change is overgrowth of epithelium and mucinous metaplasia. More mucus here than in normal duct cells
Center: MODERATE. enlarged nuclei, beginning to move away from basement membrane.
Right: ADVANCED. significant cytologic growth/abnormalities. Carcinoma in situ. If you find this, may do pancreatectomy to prevent cancer.

Question 15

This is the progression model for pancreatic ductal carcinoma. What is occuring at each stage?

Answer 15

Left/normal: note cells not very mucinous.

PanIN-1a: cells have become papillary

PanIN-1b: cells no longer flat

PanIN-2: nuclear enlargement, movement of nuclei away from BM.

PanIN-3: cytologic abnormalities.

Note associated with genes (K-ras ->p16 -> p53 -> DPC4)

Question 16

Panc cancer: is there any good news?

Answer 16

Not all pancreatic neoplasms are malignant.

May be benign, or in situ.

May be a cystic neoplasm (benign) that has been mistaken for a cystic tumor.

Possible that it is pancreatitis that looks like a neoplasm on imaging.

Question 17

What is this? what is the prognosis?

Answer 17

Serous cystadenoma, most common of the BENIGN tumors of the exocrine pancreas.

Question 18

What is this? what is prognosis?

Answer 18

Intraductal Papillary-Mucinous Neoplasm (IPMN)

One of the non-malignant tumors of the pancreas. Has moderate dysplasia. Remove it and the prognosis is very good.

Question 19

These are Intraductal Papillary-Mucinous Neoplasms (IPMNs) of various grades. what is unique to each one?

Answer 19

Left: low grade. well differentiated gastrin-secreting foveolar epithelium. Benign

Middle: Moderate grade. Resect this one.

Right: High grade. Carcinoma in situ. Resect because it will invate and become a ductal tumor.

Question 20

What if your pancreatic tumor patient is a 4 yo? What kind of cancer? what is survival?

Answer 20

Pancreatoblastoma is most common. Not highly differentiated. 5 yr survival is 60%.

Question 21

what if your pancreatic tumor patient is a 20 yo female? what is the tumor likely to be? what is survival?

Answer 21

Pseudopapillary neoplasm is characteristically found in teenage or young women.

Low grade malignant neoplasm. Excision usually is curative.

Question 22

What if your patient is a 49 yo woman with a cystic mass in teh tail of her pancreas? what is it likely to be? what is prognosis?

Answer 22

Mucinous cystic neoplasms have peak incidence in 45-50 yo women. Rare in men

More likely in body/tail than head of panc.

Good prognosis; don’t invade. 10-20% are malignant.

Question 23

Ductal carcinoma: epidemiology? If your patient is atypical for this, what should you think of?

Answer 23

Median age 66y. Uncommon under age 50.

In patients under 50, think of other types of neoplasms. o needle biopsy to dx.

If it turns out to be ductal adenocarcinoma in someone under 50, consider an inherited disease. Consider testing family members.

Question 24

Major points:

• Pancreatic neoplasms occur in both sexes at any age.
• There are many types of pancreatic neoplasms, some are benign or in situ and curable.
• Accurate diagnosis guides management.
• Pancreatitis can cause masses and cysts that are indistinguishable from neoplasms by imaging.
• Histologic diagnosis is important.
• A diagnosis of pancreatic ductal adenocarcinoma remains bad news.

Answer 24

That was the final slide for one lect, thought it was helpful…

Question 25

What 5 of pts end up being long-term survivors of pancreatic cancer? what are the rough %s of tumors we can resect?

Answer 25

only 6% are long term survivors. most patients are not resectable: only about 25%. Of those that are not resectable, approx 1/3 is metastatic, and the rest will have invovement of nearby structures.

Question 26

Pancreatic cancer: symptoms?

Answer 26

Depends on where in the panc the tumor is. in HEAD: **weight loss, jaundice** *(blocked bile duct)*, **pain, anorexia** in BODY/TAIL: **weight loss, pain,** weakness, jaundice (only 7%)

Question 27

ways to diagnose pancreatic cancer? 4 methods were mentioned.

Answer 27

- **Ultrasound**. - **CT**. good for staging - **ERCP and EUS**. useful for biopsy, can be palliative (stent in the bile duct to relieve jaundice/itching) - **serum tumor marker CA 19-9** (pre-op: prognostic. post-op: proxy for response to therapy)

Question 28

Another bunch of numbers about what % of panc tumors are resectable: overall, what % resectable? what % will have distant metastases? what % will have mesenteric vessel involvement?

Answer 28

Generally: 25% resectable 40% distant mets 35% mesenteric vessel involvement

Question 29

what can we do to predict whether a panc tumor is going to be resectable?

Answer 29

CT is very good at predicting which patients are going to be resectable and which are not. Some pts may still undergo surgical exploration and end up not being resectable.

Question 30

what are the resectability criteria? what are they based on?

Answer 30

Based on contiguity to mesenteric vessels **Resectable** if there is a **fat plane** between the tumor and the SMA, celiac artery and portal vein/superior mesenteric vein **Borderline** resectable if the tumor **abuts the SMA or celiac artery** \< 180 degress, or abuts or occludes a short segment of the portal vein **Unresectable** if **the tumor surrounds the SMA**, celiac artery or occludes the portal vein over a long distance. High morbidity, indicates an aggressive tumor.

Question 31

What's so special about the SMA - can't we just take part of it out and graft it?

Answer 31

One can resect and graft part of the **portal vein**, but resection of the **SMA has been tried in small numbers of patients with very poor results.**

Question 32

Do we have chemo drugs that can help with panc cancer? what are they, what is the response rate?

Answer 32

Chemo: **Gencitabine** is FDA-approved. Only 5% response rate (measured by tumor shrinkage). Median survival is 6m. 1 yr survival is 18%. **Gemcitabine in combination** with other cytotoxins and molecular therapeutics has NOT improved survival. **Folfirinox** is more toxic but has improved medial survival to 11 months.

Question 33

Given that the chemo options are not very effective for panc cancer, what can we do for these patients?

Answer 33

**Palliative** care. Can **stent** the bile duct to reduce jaundice and itching. Can do a **nerve block on the celiac plexus** nerves to help with pain from tumor invasion (can do radiation here as well).

Question 34

If we are going to resect a tumor in the head of the pancreas, what is the procedure called? What about in the tail of the pancreas?

Answer 34

Head: Whipple procedure (Pancreaticoduodenectomy. Say that word right in 3rd year and impress someone.) Tail: distal pancreatectomy.

Question 35

What does the Whipple procedure entail? (aka Pancreaticoduodenectomy)

Answer 35

Take out the distal stomach, all of the duodenum, the bile duct, gallbladder, and half of pancreas.

Question 36

Post-whipple procedure: there are 3 anastomoses as below.

Answer 36

There were a few b&w drawings of the Whipple procedure in this lect: I'd be shocked if we had to know details, but just FYI.

Question 37

Whipple procedure: morbidity?

Answer 37

- Poor gastric emptying (10-20%) - Infections (10%) - Leaks from the pancreaticojejunostomy (5%)

Question 38

Whipple procedure: mortality? what does mortality rate depend on?

Answer 38

30-day mortality varies a lot: from 4-16% on the chart in lect. Overall mortality depends on how many procedures per year a center does. DHMC does a lot: mortality is around 2%.

Question 39

Whipple: if we completely resect the tumor, is that curative?

Answer 39

If tumor completely resected with negative margins, 25% of patients will be alive 5 yrs post-op. Only 15% will be alive 10 yrs post-op. And remember that we could only resect 25% of presenting tumors to begin with.

Question 40

Anything we can do post-Whipple to improve survival?

Answer 40

Can use radiation and/or chemo ("Adjuvant Therapy after Resection") after Whipple to increase survival. However, survival is still around 20-22 months. Local recurrence with surgery alone is 70% Local recurrence with surgery plus post-adjuvant chemo/radiation is 40%

Question 41

What is Neoadjuvant therapy? what is the rationale?

Answer 41

Start out with adjuvant therapy (chemo/rad). THEN do surgery. Rationale: -allows distant mets to be detected (so we don't do resection on pts who won't benefit) - shrinks tumors so some borderline resectables -\> resectable - increases chance that all patients get any adjuvant therapy at all

Question 42

With the Neoadjuvant therapy, what was the rate of local tumor recurrence?

Answer 42

In one study at Dartmouth, only 6% of the patients given neoadjuvant therapy had local recurrence. Contrast with 33% of patients receiving adjuvant therapy. This was done with patients whose tumors were **borderline** resectable. But the trend appears to be the same with patients whose tumors are **initially resectable**