Hereditary GI Cancer Syndromes: Hereditary GI Cancer Syndromes: Hamartoma Polyps

0:00Welcome to Board Pearls. This is episode four of five of the Hereditary GI Cancer Syndromes chapter, in the Special Populations and Acute or Supportive Care module. This episode is the two hamartomatous polyposis syndromes, Peutz-Jeghers and Cowden. The first patient is a young man with a bowel obstruction and dark spots inside his cheeks. His case shows how Peutz-Jeghers syndrome is recognized and confirmed, why its main danger is obstruction rather than cancer, which small bowel polyps must come out, and which cancers outside the gut need surveillance. The second patient is a woman whose esophagus gives the clue. Her case shows how Cowden syndrome is recognized at the bedside and at endoscopy, and why its main cancers aren't in the gut.

0:43Here's the first patient. A twenty-two-year-old man comes in with crampy abdominal pain and vomiting. Computed tomography, CT, shows a small bowel intussusception. He had an emergency laparotomy with a small bowel resection at fourteen for the same problem. On exam, he has dark brown macules on his lips and inside his cheeks. He doesn't know his family history well.

1:06He has Peutz-Jeghers syndrome, an inherited hamartomatous polyposis, and the clue is in his mouth. The syndrome is autosomal dominant, caused by germline mutation in STK11, also called LKB1, on chromosome 19p13.3. STK11 encodes a serine-threonine kinase that suppresses mTOR signaling, and its loss drives hamartomatous polyps throughout the gastrointestinal, GI, tract and a high lifetime risk of several cancers. Penetrance exceeds ninety percent by thirty. About eighty percent of patients have a family history, and the rest carry a new mutation, so his uncertain family history doesn't count against the diagnosis.

1:50The pigment in his mouth is the bedside sign. Mucocutaneous melanin pigmentation develops in early childhood in about ninety-five percent of carriers, on the lips, the skin around the mouth, the buccal mucosa, the fingertips, palms, soles, and the perianal skin. The skin pigmentation tends to fade at puberty, but the buccal pigmentation persists, which makes the inside of the cheek the most reliable place to look in an adult. Three features separate it from freckles: freckles are absent at birth, almost never occur on the buccal mucosa, and are rare around the nose and mouth. So a young adult with an intussusception gets a look inside the cheeks, and a young man with bowel obstruction and pigmented buccal mucosa has Peutz-Jeghers syndrome whatever his family history.

2:34The diagnosis is made formally when any one of four criteria is met: two or more confirmed Peutz-Jeghers polyps; any number of these polyps with the characteristic pigmentation; any number of these polyps with a first-degree relative who has the syndrome; or the pigmentation with a first-degree relative who has the syndrome. Germline STK11 testing confirms about eighty percent of clinically defined cases, and a positive result is what allows his relatives to be tested.

3:01The polyp itself confirms its type under the microscope. A Peutz-Jeghers polyp has hamartomatous epithelium around branching, arborizing bands of smooth muscle that extend from the muscularis mucosae into the lamina propria. That branching muscle separates it from a juvenile polyp, which shows cystically dilated, mucus-filled crypts in an inflamed lamina propria, and from the hamartomas of PTEN syndromes. At his surgery, the lead point is a three-centimeter polyp with arborizing smooth muscle, so with his pigmentation he meets the criteria, and his STK11 test is positive.

3:36His intussusception is the problem the syndrome usually causes, and it's the main danger for him, more than cancer. Peutz-Jeghers polyps occur most often in the small bowel, which holds sixty to ninety percent of them, followed by the stomach and colon. Their dominant complication is small bowel intussusception around a polyp acting as a lead point, often first presenting in childhood or early adulthood with obstruction or bleeding, and often needing emergency laparotomy and resection.

4:04Repeated emergency resections are the main cause of short bowel syndrome later in life in these patients, so the whole surveillance program exists to remove polyps before they reach the size that causes intussusception. Small bowel adenocarcinoma risk is enormously raised in relative terms, roughly five hundred times the general population, but the absolute lifetime risk is about thirteen percent. Preventing obstruction is the primary goal, and preventing cancer is secondary. He's already lost bowel to two operations, so from now on his surveillance is aimed at sparing him a third.

4:35That goal sets which of his polyps come out. Any small bowel polyp larger than one centimeter is removed, as is any polyp causing symptoms, and any polyp that grows quickly between studies whatever its size, because growth is the strongest predictor of an impending intussusception. Removal is by double-balloon enteroscopy, intraoperative enteroscopy, or surgical polypectomy, depending on where the polyps are and how they're spread. Stomach and colon polyps are removed once they exceed five millimeters, because they're easy to reach endoscopically and the cancer risk per polyp is similar.

5:11Six months after his surgery, his capsule endoscopy shows an eight-millimeter jejunal polyp. A year later, it's thirteen millimeters, now over a centimeter and growing, so it's removed by double-balloon enteroscopy. A polyp that stays at eight millimeters on repeat study is watched, while one that grows from five to eight millimeters comes out, because growth matters more than size.

5:33His intestinal surveillance would ideally have started in childhood. Baseline upper endoscopy and colonoscopy are done at eight to ten, or earlier with symptoms. If polyps are found, they're repeated every two to three years, and if none are found, surveillance resumes at eighteen. Small bowel surveillance with capsule endoscopy or magnetic resonance, MR, enterography runs alongside, every one to three years from eight to ten. Diagnosed as a child, he'd have had polyps removed before they reached intussusception size. Diagnosed now, he has capsule or MR enterography every one to three years, and upper endoscopy and colonoscopy every two to three years.

6:16His STK11 loss also raises cancer risk outside the gut, and that surveillance begins in the mid-twenties, each organ starting when its tumors typically appear. For him, pancreatic surveillance with endoscopic ultrasound, EUS, or pancreatic-protocol magnetic resonance imaging, MRI, runs annually from thirty to thirty-five, because pancreatic tumors appear in the thirties and forties. Peutz-Jeghers is one of the few syndromes in which the gene alone qualifies for pancreatic surveillance, whatever the family history, as episode five explains. His lung risk is addressed with smoking cessation and, in selected patients, low-dose CT.

6:56His female relatives who carry the variant need a different program. STK11 loss brings breast cancer forward to the mid-twenties, on a timeline like that of BRCA carriers, so women have annual breast MRI from twenty-five, with mammography added and the two alternating every six months from thirty. They also have an annual pelvic exam, Pap smear, and transvaginal ultrasound, starting between eighteen and twenty-five. Boys in the family have an annual testicular exam and ultrasound from birth to twelve. Cascade testing of his family is how those relatives are found.

7:30Three tumors outside the gut point back to the syndrome when they turn up in an unrelated workup. The ovarian sex cord tumor with annular tubules is essentially pathognomonic. Minimal-deviation adenocarcinoma of the cervix, called adenoma malignum, is associated. And the Sertoli cell tumor of the testis secretes estrogen and presents with gynecomastia or precocious puberty in prepubertal boys, which is why a boy with either of those has his lips and cheeks examined and his family history taken.

7:59Now the second patient. A thirty-eight-year-old woman has an upper endoscopy for reflux. It shows many small whitish plaques throughout her esophagus, which biopsy as glycogenic acanthosis. Her colonoscopy the same day shows a dozen polyps with mixed histology: hamartomatous, juvenile-type, hyperplastic, ganglioneuromatous, and lipomatous. On exam, she has a large head, small skin-colored papules around her nose and mouth, and a cobblestone texture to her gums. She had a thyroid nodule removed at twenty-six.

8:34She has Cowden syndrome, and one gene explains her findings. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome make up the PTEN hamartoma tumor syndrome spectrum, autosomal dominant, from germline mutations in PTEN on chromosome 10q. PTEN restrains the PI3K, AKT, and mTOR pathway, and losing it removes the brake on proliferation in tissues that normally have high PI3K signaling. Cowden is the form that presents in adults. Bannayan-Riley-Ruvalcaba is the pediatric form, with macrocephaly, developmental delay, lipomas, hemangiomas, and pigmented penile macules. About eighty percent of clinically defined Cowden patients have a detectable PTEN mutation, and about sixty percent of Bannayan-Riley-Ruvalcaba patients. A contiguous deletion of PTEN and the neighboring BMPR1A gene causes a juvenile polyposis of infancy with Cowden features, one source of confusion at the pediatric end.

9:32Unusually among these syndromes, Cowden is recognized mostly by examination, before any test. The cardinal features are macrocephaly; facial trichilemmomas, small skin-colored papillomatous papules around the mouth, nose, and eyes, present in more than ninety percent of carriers; cobblestone papillomatosis of the gums, buccal mucosa, and tongue; acral keratoses of the palms and soles; and Lhermitte-Duclos disease, a cerebellar dysplastic gangliocytoma that's pathognomonic in adults, causing ataxia, raised intracranial pressure, and a striated cerebellar pattern on MRI. Her large head, facial papules, and cobblestoned gums could have raised the diagnosis before either scope.

10:14Her endoscopies supplied the GI signature. Diffuse glycogenic acanthosis appears as small whitish plaques throughout the esophagus and shows benign squamous epithelium full of glycogen on biopsy. It also occurs sporadically, but a dense, diffuse pattern in a young patient with macrocephaly marks Cowden. Multiple polyps of mixed histology in one patient is itself a Cowden clue, and the syndrome is often first suspected from these scopes.

10:42Her polyps can mimic other syndromes, so the histology alone doesn't settle it. Juvenile polyps show cystically dilated, mucus-filled glands in an inflamed, edematous lamina propria, and Peutz-Jeghers polyps show arborizing smooth muscle. Cowden is identified by the mix of polyp types together with the cardinal clinical features. When the polyp histology is ambiguous, a germline panel covering PTEN, SMAD4, BMPR1A, and STK11 decides it. Hers shows a PTEN mutation.

11:12Her diagnosis matters most for organs outside the gut. Her lifetime cancer risks are twenty-five to eighty-five percent for breast cancer; five to thirty-five percent for thyroid cancer, follicular more than papillary, with thyroid adenomas or cysts in about seventy percent; five to twenty-eight percent for endometrial cancer; about fifteen to thirty-four percent for renal cell carcinoma; and nine to twenty percent for colorectal cancer. Breast epithelium, thyroid follicular epithelium, and endometrium normally run high PI3K signaling, so they're the most vulnerable when PTEN is lost, while the colon, with lower baseline signaling, accumulates cancer at a lower rate. That's why colorectal risk in Cowden is meaningfully lower than in Lynch syndrome, and why her thyroid nodule at twenty-six fits.

12:00Her surveillance follows those organs, each starting when its cancers appear. Breast surveillance starts with a clinical exam every six to twelve months from twenty-five, with annual mammography, tomosynthesis, and breast MRI from thirty to thirty-five. Thyroid ultrasound runs every year from diagnosis, and from age seven in children who carry the mutation, because thyroid nodules appear in childhood. Endometrial biopsy, with transvaginal ultrasound after menopause, is done every one to two years from thirty-five. Renal imaging is done every one to two years from forty, because renal cancer rarely appears earlier. A dermatology exam is done every year from diagnosis.

12:41Her GI program starts colonoscopy at thirty-five, or five to ten years earlier if a relative had colorectal cancer before forty, repeated every three to five years, or every one to three years when polyps are found, along with upper endoscopy from thirty-five every three to five years. Risk-reducing mastectomy and hysterectomy are discussed once childbearing is complete. At thirty-eight, she's past the start age for breast imaging, endometrial sampling, and colonoscopy, so all of those begin now, thyroid ultrasound and dermatology begin now, and renal imaging begins at forty.

13:15Her gastroenterologist's job is to recognize the syndrome, refer her into this multi-organ program, and deliver its GI parts. Managed only as a patient with polyps, she'd be left exposed to the breast and thyroid cancers that are her real risk.

13:29Here are the traps the boards set in these patients. Calling buccal pigmentation freckles. Requiring a family history to diagnose Peutz-Jeghers syndrome. Mistaking arborizing smooth muscle for a juvenile polyp. Focusing on cancer instead of obstruction in Peutz-Jeghers. Leaving a growing small bowel polyp because it's under a centimeter. Starting Peutz-Jeghers surveillance in adulthood rather than at eight to ten. Forgetting breast MRI from twenty-five and pancreatic surveillance from thirty to thirty-five. Missing the ovarian, cervical, and testicular tumors that point to the syndrome. Dismissing diffuse glycogenic acanthosis in a patient with macrocephaly. And treating Cowden syndrome as a colon syndrome.

14:10So, start to finish. Buccal pigmentation with hamartomatous small bowel polyps or an intussusception in a young patient means Peutz-Jeghers syndrome, from STK11. Upper endoscopy, colonoscopy, and small bowel imaging begin at eight to ten, and small bowel polyps over a centimeter, symptomatic polyps, and growing polyps are removed to prevent intussusception and short bowel. Breast surveillance starts at twenty-five, pancreatic surveillance at thirty to thirty-five, and gynecologic and testicular surveillance as scheduled. Ovarian sex cord tumors and estrogen-secreting Sertoli cell tumors point to the syndrome.

14:48Macrocephaly, facial trichilemmomas, oral papillomas, diffuse glycogenic acanthosis, and polyps of mixed histology mean Cowden syndrome, from PTEN. Its main cancers are breast, thyroid, endometrial, and renal rather than colorectal, so the patient is referred into multi-organ surveillance, with colonoscopy and upper endoscopy from thirty-five.

15:12Episode five is hereditary diffuse gastric cancer and hereditary pancreatic cancer.

15:19For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode four of five of chapter thirty-six, and I'll see you in the next one.