GI polyps and nonpolyposis cancer syndromes

Types of colon polyps

1. Adenoma

2. Hyperplastic

3. Inflammatory

4. Hamartomatous

Adenoma

Pre-cancerous

- tubular adenoma (TA)

- tubulovillous adenoma (TVA) !!worst!!

- serrated adenoma

Hyperplastic

Benign

Inflammatory

This is not a real polyp

Hamartomatous

Benign

- juvenile polyps (JPS)

- Peutz-Jeghers (PJ) polyps

Polyp descriptors

1. Sessile

2. Pedunculated

3. Dysplasia

Sessile

Dome-shaped or flattened

**more difficult to remove, considered higher risk

Pedunculated

Hanging from the colon wall on a stalk

Dysplasia

How atypical do the cells look?

High-grade vs low-grade

Types of gastric cancers

1. Intestinal

2. Diffuse

Intestinal gastric cancer

1. Adenocarcinomas ~95%

2. Gastrointestinal stromal Tumor (GIST)

**almost never genetic

Diffuse gastric cancer

1. Signet ring cell

*Cancer of the lining of the stomach

*Highly metastatic

*removal of stomach

**may be genetic

Stomach cancer genes

High risk: CDH1

Moderate risk: APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, PMS2, SDHB, SDHD, SMAD4, STK11, TP53

Possible risk: CTNNA1, CHEK2, KIT, NF1, PDGFRA, SDHC

Hereditary diffuse gastric cancer syndrome (gene)

CDH1

CDH1

- chromosome 16

- AD inheritance

Features of HDGC

- diffuse gastric cancer (67-70% lifetime risk AMAB, 40-83% risk AFAB)

- average age of onset is 38y

- lobular breast cancer (41-60% lifetime risk)

- colorectal cancer

Clinical diagnostic criteria for HDGC

1. Diffuse gastric cancer and a family history of one or more first- or second-degree relatives with gastric cancer OR

2. A personal and/or family history of diffuse gastric cancer diagnosed before 40y OR

3. A personal and/or family history of diffuse gastric cancer and lobular breast cancer, one diagnosed before 50y

HDGC management

- consider gastrectomy, endoscopy every 6-12 months

- breast awareness (18), biannual clinical breast exam (25), annual mammography/MRI (30)

- consider increased colonoscopy frequency

Do mammograms prevent cancer?

NO

Do colonoscopies prevent cancer?

YES

Types of pancreatic cancer

1. Exocrine

2. Endocrine

Endocrine pancreatic cancer

- PNETs or Islet cell tumors (very rare <4%)

*tough to determine malignancy

**associated with a better prognosis

Exocrine pancreatic cancer

- Adenocarcinoma (~95%)

- Begins in glands surrounding the ducts of the pancreas

**Highly lethal

** Symptoms are nonspecific, inability to screen

**7% 5-year survival

Pancreatic cancer genes

High risk: APC, BRCA1, BRCA2, CDKN2A, CDK4, EPCAM, MEN1, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53, VHL

Moderate risk: ATM

Melanoma-pancreatic cancer syndrome (gene)

CDKN2A

Familial atypical multiple mole melanoma (FAMMM)

CDKN2A

CDKN2A

- tumor supressor gene

- encodes two proteins: p16INK4a + p14ARF

- chromosome 9

- AD inheritance

Features of FAMMM

1. melanoma (28-76% lifetime risk)

2. pancreatic adenocarcinoma (17% lifetime risk)

Clinical diagnostic criteria for FAMMM

1. malignant melanoma in one or more first- or second-degree relatives

2. High total body nevi (>50) including some of which are clinically atypical

3. Nevi with certain histologic features on microscopy

CDKN2A (p16INK4a)

1. Cutaneous melanoma

2. Pancreatic cancer

CDKN2A (p14ARF)

1. Cutaneous melanoma

2. Pancreatic cancer

3. Neural system tumors (astrocytoma) + nerve sheath tumors

FAMMM management

- monthly skin self-exams (10), sun protection

- pancreatic cancer screening (40 or -10y)

Colon cancer genes

High risk: APC, BMPR1A, EPCAM, MLH1, MSH1, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53

Moderate risk: CDH1, GALNT12

Possible risk: AXIN2, ATM, BLM, GREM1/SCG5, MSH3, NTHL1, POLD1, POLE, RPS20

Hereditary nonpolyposis colorectal cancer (HNPCC)

- aka Lynch Syndrome

- prevalence 1 in 279

- AD inheritance

HNPCC genes

MLH1

MSH2

MSH6

PMS2

EPCAM

HNPCC-associated cancers (AMAB)

1. Stomach

2. Colorectal

3. Pancreatic

4. Urinary tract

5. Prostate

HNPCC-associated cancers (AFAB)

1. Stomach

2. Colorectal

3. Pancreatic

4. Urinary tract

5. Ovarian + uterine

Features of HNPCC

- predominantly right-sided colorectal cancer

- multiple tumors

- more likely to see mucinous, signet-ring, infiltrating lymphocytes, Chrohn's-like lymphocytic reaction, medullary growth pattern

Average lifetime risk for colorectal cancer

5%

Untreated lifetime risk for colorectal cancer with HNPCC

up to 50%

Genetic testing criteria for HNPCC

1. Known HNPCC PV in the family

2. Personal history of an HNPCC-related cancer <50y

3. Family history of HNPCC-related cancer <50y or multiple family members diagnosed at any age

HNPCC Management

- colonoscopy every 1-2 years (20), aspirin

- annual pelvic exam (30), consider hysterectomy

- consider BSO (40), consider ultrasound (30), OCP

- upper endoscopy every 2-5 years (30)

- consider annual urinalysis (30)

- annual pancreatic cancer screening (50 or -10y)

- annual physical/neurological exam (25)

- consider regular DRE/PSA (45)

Time for colon polyp to turn into cancer

10 years

**may be as low as 1-2 years with HNPCC

HNPCC clinical diagnostic criteria (Amsterdam criteria)

3+ family members with HNPCC-related cancers

2+ successive affected generations

1+ HNPCC-related cancers diagnosed before age 50y

Naming scheme: HNPCC

Family meets Amsterdam criteria

*clinical diagnosis

Naming scheme: Muir-Torre

HNPCC + sebaceous gland tumors/keratoacanthomas

Naming scheme: Turcot variants

HNPCC + brain tumor (gliomas)

**Not to be confused with Turcot syndrome (variant of FAP)

Naming scheme: Lynch syndrome

Genetic mutation identified in a mismatch repair gene

*genetic/molecular diagnosis

Mismatch repair (MMR) pathway

MSH2-MSH6

MLH1-PMS2

Microsatellite instability testing

- presence of MSI in a tumor indicates a poorly functioning DNA MMR process

- 10% of SPORADIC colorectal cancers display MSI

- 95% of LYNCH SYNDROME colorectal cancers display MSI

Immunohistochemistry (IHC) staining

- loss of staining for specific proteins that are associated with hereditary cancer genes is suggestive of a mutation

MLH1 considerations

- BRAF (V600E) mutation

- Somatic promoter hypermethylation

BRAF (V600E) mutation

Somatic promoter hypermethylation

Constitutional mismatch repair deficiency (CMMRD) syndrome

- biallelic germline mutation in the MMR pathway

- severe autosomal recessive childhood onset cancer predisposition syndrome

- associated with increased risk for childhood diagnosis (~7y) of brain tumors, GI cancers, hematologic cancers

- associated with café-au-lait macules, polimatricomas (benign skin lesion), colon polyposis