26. Tumors of the Bowel Flashcards
Large bowel neoplasms: what is the trend in terms of incidence in the past 15 yrs? What is the survival rate?
Seeing slow decrease in incidence of colon cancer (large intestine, rectum) over past 15 yrs.
Also seeing slightly increased survival rate (now around 60% survival)
What is the lifetime risk of colorectal cancer (CRC) in the US?
roughly 5%
We have identified the precursor to CRC: what is it?
How long is the general timeframe between appearance of the precursor and presentation of cancer?
When we see the precursor to CRC, what do we do?
Precursor to CRC is a benign polyp of the colon (but not all polyps will progress to cancer)
Progression is from normal –> adenoma –> carcinoma.
Takes 5-12 yrs from polyp to cancer.
We therefore remove ALL polyps so that we are sure we have removed all the ones that may become malignant.
Epidemiology of CRC: how prevalent?
M v F?
Third most common cancer in both men and women.
M have higher risk and worse outcome.
What are the risk factors for CRC over which the individul has no control (or little control)?
- Race (Black > White > Asian > Hisp >> Indian)
- Ethnicity (incr among Jews)
- Occupational exposures
- Age/gender
- Diabetes
What are the risk factors for CRC over which the individual does have control?
- Caloric intake/obesity
- Red meat consumption
- EtOH consumption (SHIT SHIT SHIT)
- Smoking (ok, fine on that)
CRC: anatomic distribution through the large int/rectum?
Polyps v cancer?
-Polyps evenly distributed throughout colon
-Majority of cancers distal to the splenic flexure (25% in sigmoid, 30% in rectum). (“Shittiest” areas to get CRC haha)
(However, distribution of cancers seems to be moving more proximal over the years)
More risk factors for CRC: recall that the lifetime risk for the general population is 6% or so.
How does the risk change if you have a first degree relative with CRC?
A personal history of colorectal neoplasia?
If you have IBD?
If you have the HNPCC mutation?
If you have FAP?
- First degree relative with CRC: risk doubles
- Personal history of colorectal neoplasia: risk triples (15-20%)
- If you have IBD: risk is 15-40%
- If you have the HNPCC mutation: risk is 60-80%
-If you have FAP: 95% aka you are screwed
What is the average age of diagnosis for CRC?
If pt is younger than this age, what should I consider?
Ave age is 62.
10% of cases occur before age 50: in these cases consider genetic disorders (FAP, HNPCC, MUTYH, PJS) or IBD.
Define Familial Adenomatous Polyposis.
What gene is mutated?
What is the progression?
Basis for diagnosis?
What is treatment?
- Autosomal dominant disorder related to a mutation in the APC gene leading to development of 100’s or 1000’s of adenomatous polyps which appear when pts are 20 to 30+ yrs old
- Dx if pt has > 100 polpys in colon/rectum
- Rate of progression is variable, presumed that all patients will eventually develop colonic carcinoma(s) in early adult life (age 39)
-Treatment is total colectomy. (though later slides will give other options)
CRC: overall, what is the pathogenesis?
What is the pathogenesis for sporadic CRC vs one due to inherited mutation?
Development of CRC represents the accumulation of 4-12 mutations in genes controlling the differentiation and repair of DNA replication errors.
–> growth advantage to mutated cells.
The pathway is the same for sporadic CRC and for an inherited predisposition to CRC
CRC: generally, it is due to what 3 broad factors?
Overlap of Environmental Factors, Genetic Susceptability, and Age/Time
CRC: what are some carcinogens and tumor promoters that have been identified in the region of the bowel?
Generally, stuff in the bowel that can be mutagenic.
-Fecal bile acids. (tumor promoters in animals). Concentration correlates with CRC risk
-Heterocyclic amines. breakdown products of proteins that are mutagenic
-Fecapentenes. Degradation products of fatty acids that can be mutagenic.
-3-Ketosteroids. From oxidation of cholesterol. Carcinogenic in vitro.
What can we do to try and prevent CRC?
- NSAIDs
- Calcium, Vit D (may bind fatty acids and bile acids), Folic Acid, Vit B6, Omega 3s
- High fiber, low fat, exercise.
What % of CRC is sporadic v genetic?
Roughly 75% sporadic, 25% genetic
The process of accumulating mutations to cause CRC is accelerated in genetically predisposed pts, so they have earlier onset of disease.
Generally, what are the types of inherited colorectal cancer? which diagnoses fit into each broad category?
- Adenomatous Polyposis Syndromes - causes formation of a large number of polyps (FAP, MUTYH)
- Hamartomatous Polyposis Syndromes (Peutz-Jeghers, Juvenile Popyposis)
- Non-Polyposis Syndromes - onset of CRC at early age, NOT associated with neoplastic polyps (HNPCC, aka Lynch)
FAP: intestinal manifestations?
Extra-intestinal manifestations?
Most common cause of death?
Intestinal manifestations: polpys in colon, rectum, stomach, duodenum.
Extra-Intestinal: desmoid tumors (ie fibrotic), osteomas, brain tumors, hypertrophy of part of teh retina, hepatobiliary tumors, thyroid tumors, adrenal tumors
Most common cause of death in FAP patients not CRC: it’s the associated duodenal cancers or desmoid tumors
FAP: treatment principles?
Treatment options?
Principles: nearly 100% of FAP patients will develop cancer. therefore do prophylactic surgery at diagnosis (usually prior to 25 yrs old)
Options:
-Proctocolectomy with ileostomy = gold standard. Remove entire large intestine.
- Colectomy with Ileo-Rectal Anastomosis. Preserves the rectum.
- Proctocolectomy with Ileopouch Anal Anastamosis (IPAA). Preserves the anal canal.
FAP Treatment: What are the advantages and disadvantages to the Proctocolectomy with Ileopouch Anal Anastamosis (IPAA)?
In what patients is it NOT recommended?
Adv: Colon and rectum are removed, but anal canal is preserved. No permanent stoma. Preserves anal defecation
Disadv: higher morbidity. Risk of pouch failure, Requires a good sphincter.
Due to good sphincter requirement, not recommended for pts over 60.
MYHPP - what gene is mutated? What does that gene do?
MutY Homolog Polyposis
Mutation in the MutY Homolog gene (which does DNA repair).
MYHPP: Clinical presentation?
Autosomal recessive polyposis
Patients generally have 15-100 adenomas (polyps). May have clinical presentation identical to FAP.
MYHPP typically presents in what part of the colon?
What are the options for treatment?
66% occur in ascending colon.
Tx: surgical options similar to those for FAP (3 options: Proctocolectomy with ileostomy, Colectomy with Ileo-Rectal Anastomosis (rectum preserved), Restorative proctocolectomy with IPAA
HNPCC. Is there a precursor lesion? How long is progression from polyp to cancer?
What is the mutation?
How can we distinguish this from sporadic CRC?
Hereditary Non-Polyposis Colorectal Cancer (aka Lynch Sx)
There is a precursor lesion (adenomatous polyp) which progresses to cancer in 3.5 yrs
Clinically indistinguishable from sporadic CRC: only way to know without testing is via personal and family history.
Mutation is in mismatch repair genes (MMR genes). Specifically: MSH2, MLH1, MSH 6, PMS2
HNPCC: what is the lifetime risk of colorectal cancer?
What is the penetrance of the gene mutation? Do we recommend prophylactic treatment for HNPCC?
Lifetime risk is 40-80% (comparison: risk for general population is 6%, and for FAP is 95%)
Penetrance is 40-60%, therefore do not recommend prophylactic treatment.
HNPCC aka Lynch Syndrome: What is the difference between Lynch Syndrome 1 and Lynch Syndrome 2?
_Lynch Syndrome 1: _Colorectal cancers only
Lynch Syndrome 2: Colorectal cancers PLUS Other cancers – Endometrial (most common), ovarian, pancreatic, gastric, small bowel,
transitional cell of kidney/ureter
Define Polyp. What are the 2 main types? Describe each.
Polyp = lesion that protrudes above the level of the surrounding mucosa.
- Pedunculated has a stalk (like a mushroom)
- Sessile does not have a stalk (like a raised mossy bed)
Either can be neoplastic or non-neoplastic
What type of polyp is this? Describe the polyp itself and the stalk
Pedunculated polyp
the polyp part is abnormal; the stalk is normal mucosa
What kind of polyp is this?
Sessile
Polyps: neoplastic polyps are divided into what subtypes?
Non-neoplastic: what subtypes?
Which are more common?
Neoplastic polyps are all adenomas – all are composed of dysplastic epithelium and are precursors of adenocarcinoma.
Non-neoplastic polyps are divided into hyperplastic, hamartomatous, or inflammatory pseudo-polyps
Non-neoplastic polyps are 90% of all epithelial polyps in the large intestine.
Hyperplastic polyps: neoplastic or non?
Size? Most common where?
Describe architecture.
Small (<5mm), sessile.
Most common in rectum/sigmoid.
Architecture: elongated and serrated SAWTOOTH configuration. Stellate crypts, lined by hypernature goblet cells
Non-neoplastic: NO metastatic potential
Juvenile/Retention Polyp: neoplastic or non?
Most frequent where? what patients?
Describe architecture and cytology.
(Hamartomatous: benign overgrowth of normal tissue. Can resemble a neoplasm. Composed of tissue elements normally found at that site, but which are growing in a disorganized mass.)
Juvenile/Retention: most frequent in rectum of children under 5y.
Large (1-3 cm), round, smooth lesions with stalks.
Inflamed lamina propria with dilated glands.
NO malignant potential
Peutz-Jeghers Polyp:
neoplastic or non?
Most frequent where? what patients?
Describe architecture and cytology.
Hamartomatous malformation.
Branching smooth muscle and glands, lined by goblet cells.
Slight malignant potential (LOH at LKB1 locus)
These pts at incr risk of developing cancer of pancreas, breast, lung, ovary, uterus.
Neoplastic polyps: what are types of gross and histologic architecture that can be seen?
What 4 features of these polyps increase the risk of malignant behavior?
Gross: pedunculated, sessile.
Histologic: tubular, villous, tubulovillous
Risk of malignant behavior increased by:
Size > 2cm
Villous architecture > Tubulovillous > Tubular
High grade dysplasia
Multiplicity (as in pic)
Tubular adenoma: what is typical architecture for this type of polyp?
What is the histology?
Tubular adenoma usually pedunculated. The stalk is derived from submucosa, usually covered by normal mucosa.
Histo: closely packed tubules/glands, lined by columnar epithelial cells.
Typically small and removed with screening colonoscopy.
What kind of polyp? notable features?
Tubular adenoma.
Note round crypts at top of pic (top of polyp), note demarcation between polyp and underlying normal mucosa.
Villous adenoma: found where?
Potential for carcinoma?
What is the architecture and histology?
Most often in rectum and sigmoid.
Uncommon adenoma but up to 1/3 may harbor carcinoma
Architecture: sessile, velvety masses up to 10 cm (!)
Histo: frond-like villiform extensions into the mucosa. Pseudostratification.
(high carcinoma makes sense, since there is no stalk as a buffer zone as with tubular)
Tubulovillous adenoma.
Risk for harboring carcinoma?
What is architecture?
Risk of harboring in situ or invasive carcinoma generally correlates with the proportion that is villous (more villous –> more carcinoma).
Architecture: combination of tubular and villous.
Treatment of adenomas?
Treatment of carcinomas?
Adenomas: complete excision.
Carcinomas/malignant polyps: controversial based on depth and extent of invasion, histologic differentiation
Amount of black in pic indicates increasing amount of adenocarcinoma. With more of this, higher risk for access to lymph nodes and metz. (harder to resect)
What is the adenoma-carcinoma sequence?
An accumulation of genetic mutations within a polyp that allows progression from benign adenoma to malignant carcinoma. (activated of oncogenes like K-ras, mutated tumor suppressor genes like p53)
Pics: progression from benign –> premalignant dysplasia –> malignant within the same polyp.
L pic: normal colonic mucosa with goblet cells. At top, some adenoma (similar crypts, larger, nuclei are dysplastic, darker, crowded, pseudostratification)
R: adenoma on left part, darker nuclei, pseudostrat. On R of this pic, adenocarcinoma w atypia of cells, glandular complexity of configuration.
Describe the histology.
Invasive Adenocarcinoma of sigmoid colon.
Left: normal colonic mucosa with normal config of crypts, nl goblet cells
Right: darker, pseudostratification, architectural dysplasia (complex glandular config).
Colorectal Adenocarcinoma of the LEFT side (distal bowel) tend to grow how? What symptoms do they tend to cause?
- Left-sided tumors (distal) tend to grow as annular, circumferential, ulcerated masses
- “Napkin ring lesions”
- Obstruction (change in bowel pattern) is common
Colorectal Adenocarcinoma of the RIGHT side (prox, ascending bowel) tend to grow how? What symptoms do they tend to cause?
- Right-sided tumors (proximal colon) tend to grow as polypoid, exophytic masses
- May still be deeply infiltrating
- Obstruction is uncommon
- Occult bleeding (anemia) or melena
HNPCC: clinical features?
where are lesions located?
age of onset?
Prognosis?
70% of proximal colon cancers (ascending)
Early age onset (45y)
Prognosis: better cancer-specific survival: fewer metz, better prognosis than pts with sporadic CRC.
High rate of synchronous and metachronous cancer so need to do total colectomy with ileo-rectal anastamosis to prevent recurrence.
Besides the Amsterdam and Bethesda criteria, what is another way to identify patients with HNPCC?
Presence of microsatellite instability.
Genetic loci with 1-6 BPs repeated. DNA replication tends to mess up most frequently at repeated sequences (think Huntington’s). If someone has a MMR gene mutation, it will prevent these errors from being corrected. So, presence of microsatellite instability indicates MMR disorder which indicates possible HNPCC.
•MSI present in >90% of CRC in pt’s w/ HNPCC
Besides Bethesda/Amsterdam Guidelines and MSIs, what is another way to screen for HSPCC?
immunohistochemical stain for mismatch repair genes.
Absence of these repair genes indicates they may be mutated –> possible HSPCC.
Pic below: Brown stain indicates presence of mismatch repair genes. So the pic on the left below is more suspicious for HNPCC (no brown = the genes we were looking for are mutated.)
Colorectal overall staging using the TNM system: What do T, N, M stand for?
What is the spectum of 5 yr survival rates based on TNM/staging?
T: pathologic stage?
N: nodes
M: # mets
If 1 met, automatically –> stage 4.
stage 1 = 95% 5 yr survival
Stage 4 = 5% 5 yr survival
What’s this?
Apple core lesion. pathongmonic for CRC. area of narrowing, loss of normal folds.
also note diverticula in distal bowel.
CRC surgery: how do we decide how much bowel to remove?
Remove sections based on lymph drainage from that area.
Difficult to visualize lymphatics, so recall that they run along vasculature. Remove the area of bowel served by common vasculature - that way you will also remove the associated lymphatics.
Why is recurrence of rectal cancer more common that for other bowel segments?
Anatomic constraints of the bony pelvis limit the ability to resect widely. May be unable to resect some regional lymphatics.
Therefore local recurrence is more common (10-30%).
Give adjuvant chemo to reduce this risk.
What is this a pic of? what point are they trying to make with this?
CRC that has metastasized to the liver. Probably trying to drive home the point that CRC death is often from metastases, and that mets usually go to the liver first.
What is this, and what’s going on?
Small bowel, which is very dilated. May be due to an obstruction.
Can tell because of the small white lines within the mucosa
What is this?
What sx might the patient have had?
Small bowel: adenoma.
This patient had crampy abdominal pain but otherwise normal physical exam, normal labs.
Colonoscopy did catch this adenoma.
What’s this? what type of tumor?
Neuroendocrine tumor of the small bowel (carcinoid).
Red granules in cytoplasm = secretory (for serotonin)
Apparently you can also see the secretory granules on EM
What’s shown here?
Interface between adenoma and invasive carcinoma of the small bowel.
“Remarkable difference.”
Adenoma on R: dark cells
Carcinoma on L: significantly more pleomorphism
