Pearls in the management of Peutz-Jeghers syndrome.

1. Pearls in the evaluation and management
of Peutz-Jeghers Syndrome
Douglas Riegert-Johnson, MD
Mayo Clinic Florida
Genetics and Gastroenterology

2. Case 1
A 45 year-old man presented for medical
genetics evaluation. Between the ages of 20
and 30 years, the patient had nasal polyps and
several large stalked colon polyps removed. At
43 years-old, he was diagnosed with jejunal
adenocarcinoma (T1N0) after intussusception (
discussed on next slide) of a polyp.
Upper endoscopy following surgery showed
several stomach and small bowel polyps. A
genetic test for familial adenomatosis polyposis
(APC gene) was negative. There was no family
history of cancer.

3. What is a Peutz Jeghers syndrome
Intussusception?
Wall of intestine
polyp Step 1.
Have a polyp attached to wall of
intestine by a long stalk.

4. Intussusception: Step 2.
Polyp is pulled by contractions of the intestine
(peristalsis).
polyp

5. Intussusception: Step 3.
Polyp drags wall of intestine behind it causing pain.
polyp
In PJS, a polyp is “grabbed” and pulled by intestinal contractions
(peristalsis). The polyp pulls the wall of the intestine behind it. If
enough intestine is pulled, the patient has pain. Intussusceptions
are usually temporary. If enough intestine is pulled the polyp can
be trapped and the pain does not stop.

6. Return to Case 1:
45 year old man with 1) nasal polyps 2) stalked
colon polyps 3) jejunal adenocarcinoma.
What is the next most appropriate test?
A. Next generation hereditary cancer panel.
B. Obtain the jejunal adenocarcinoma HE glass
pathology slides.
C. Physical examination.
D. Further history.

7. Answer: D.
Obtain further
history.
Question to ask when considering PJS: “Have you
ever had freckles or spots on your lips, tips of your
fingers, tips of your toes, eyelids, behind the ears, or
in the groin?”
Case 1 patient’s answer: “Yes”..but they faded.
Patients often comment on teasing in childhood and
nicknames.
Does this patient have PJS?
If they do have PJS, they
should have PJS “spots” =
melanotic macules MMs.

8. Case 1 – Clues for Peutz-Jeghers
syndrome.
A 45 year-old man presented for medical genetics
evaluation. Between the ages of 20 and 30 years, the
patient had nasal polyps and several large stalked colon
polyps removed. At 43 years-old, he was diagnosed
with jejunal adenocarcinoma (T1N0) and polyp after
intussusception.
Peutz’s 1921 article: “Concerning the unusual
syndrome of familial polyposis of the gastrointestinal
mucosa with that of the nasal cavity also in
combination with strange pigmentation of the skin
and mucosa.”

9. Case 1 – Clues for Peutz-Jeghers
syndrome.
A 45 year-old man presented for medical genetics
evaluation. Between the ages of 20 and 30 years, the
patient had nasal polyps and several large stalked
colon polyps removed. At 43 years-old, he was
diagnosed with jejunal adenocarcinoma (T1N0) and
polyp after intussusception.
The three S’s of PJS polyps
• Stalked polyp with intussusception
• Small bowel > colon (small polyps rare in population)
• Smooth muscle “tree”pathology further details later.

10. Reproduction of the single
figure from Dr. Johannes
Peutz’s 1921 paper.
Pictured are a segment of
jejunum with polyps.
The original caption read,
“Concerning the unusual
syndrome of familial
polyposis of the
gastrointestinal mucosa
with that of the nasal
cavity also in combination
with strange pigmentation
of the skin and mucosa.”
“Head” of stalked jejunal polyp
Stalk

11. Q1: What is the next most appropriate
test?
• A. Next generation panel including > 10 genes.
• B. MYH associated polyposis testing.
• C. Obtain the archival jejunal adenocarcinoma for
testing.
• D. Physical examination.
• E. Further history.
“Have you ever had freckles on your lips, tips of your
fingers, tips of your toes, eyelids, behind the ears, or
genital area”
A: Yes.

13. PJS“spots” “freckles” melanotic macules.
Often appear on the buccal mucosa.
PJS MMs fade.

14. Illustration of the identical twins reported by Conner as rendered by Sir Jonathan Hutchinson’s artist.
Connor’s report was published in Lancet(1895;2:1169) and the illustration was published in Archives of
Surgery (London 7:290,1896). Note the perioral melanotic macules. The text of Connor’s report reads, “Dr. J.
T. Connor showed two cases of Pigmentation, of the Lips and the Mouth, in twins, both girls, aged twelve
years, of dark complexion and anaemic. The pigment spots, which were only noticed two years ago, were ink
black in colour, mostly of very small size and scattered over the lips, (especially the lower), gums, hard
palate, and not on the tongue.” Later in life, the twins developed additional features of PJS – one died of
intussusception at age 20, the other died of breast cancer at age 52 (5, 18). Courtesy of Victor McKusick,
MD, Johns Hopkins Hospital.

15. Melantoic macules
of Peutz Jeghers
syndrome, as seen
on one of Dr.
Peutz’s patients.

16. Melanotic Macules (MMs) of
Peutz-Jeghers syndrome : They fade.
• They begin fading in early adulthood. They can
persist in the buccal mucosa.
• The macules are usually 1 to 5 mm in diameter and
vary in color from “ink black” to dark chocolate to
latte.
• Almost all, but not all, of PJS patients have melanotic
macules.
• I’ve only seen two PJS patients who never had MMs.
• Peutz-Jeghers melantoic macules are not pre
malignant, they do not transform into melanoma.

17. Ephilides “Freckles”
Across the malar surface

18. Ephilides “Freckles”
Across the malar surface
Peutz-Jeghers Syndrome
Ephilides inversae, Inverse of freckles.
“Spots” Melanotic macules
Not on malar surface, on lips and eye lids
Patient of Dr. Jeghers
Georgetown, USA

19. Q1: What is the next most appropriate
test?
A. Next generation hereditary cancer syndrome
panel.
B. Obtain the jejunal adenocarincoma HE glass
pathology slides (Third S = is smooth muscle).
C. Physical examination
D. Further history.
“Have you ever had freckles on your lips, tips of your
fingers, tips of your toes, eyelids, behind the ears, or
genital area”
A: Yes.

20. Peutz–Jeghers polyp with arborizing smooth muscle separating
the glands into lobes
Vasen, H. F. A. et al. (2015) Clinical management of hereditary colorectal cancer syndromes
Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.229

21. Peutz–Jeghers polyp with arborizing smooth muscle separating
the glands into lobes

22. Peutz-Jeghers syndrome polyps have
arborizing smooth muscle
• Arborizing smooth muscle in PJS is not
commented on in most pathology
reports (pathologist focused on mucosa).
• So slides have to be re examined for smooth
muscle. You can not rely on the original reading.
• Case 1 jejunal adenocarcinoma slides were found
and smooth muscle tissue arborization was
present.

23. STK11 genetic testing and family
history have limited utility in PJS.
• STK11 testing has low sensitivity (75%) and
there are no useful genotype phenotype
correlations.
• Family history also insensitive, 50% of
patients with no family history.

24. Case 1:
Clinical Management Pearl

25. Case 1: 45 year old man with PJS dx.
The same patient complains of chronic fatigue,
difficulty concentrating, restless legs, and eating ice. He
is not anemic (hemoglobin is normal).
What is the most likely cause of these
symptoms?
A. B12 deficiency.
B. Iron deficiency.
C. Vitamin D deficiency.

26. Case 1: 45 year old man with PJS dx.
What is the most likely cause of these
symptoms?
B. Iron deficiency
• PJS patients often iron deficient.
• Iron deficient patients do not have to be
anemic.
• Rest leg syndrome and eating ice (and other
unusual things, picca, sx of iron deficiency).

27. Case 1: Follow up
• Patient given intravenous iron.
• “I just woke up”.
• Oral iron is poorly tolerated and
often ineffective.
• Dr. Riegert-Johnson uses Feraheme
IV iron. Ferahemenewer formulation
of IV iron not associated with side
effects seen with older preparations.

28. Case 2
35 yo woman referred for PJS. There is a family
history of pancreatic adenocarcinoma.
= Pancreatic Adenocarcinoma
Panc CA
41 yo
Panc CA
54yo
4
70 years old
No cancer
35 yo
A+W
35 yo
A+W

29. Case 2: 35 yo woman Fhx Panc CA
Genomic testing results from
referring provider
STK11 Ala205Thr gene change
“Expected pathogenic”
Never been reported in a Peutz-Jeghers syndrome
patient.
• Not seen in 6,500 individuals
• Non conservative AA substitution
• AA position is conserved
• In silico predictions inconsistent

30. A hereditary pancreatic cancer
genomic panel was ordered
• These panels include STK11.
• Assumption being: hereditary pancreatic
cancer can be caused by STK11 mutations.
• Patients with PJS have a lifetime risk of 10-20%
for pancreatic cancer.
• So, I would challenge the assumption that
hereditary pancreatic cancer is common in PJS
in families without the melanotic macules or
characteristic polyps.

32. Case 2 – 35 yo woman with STK11
gene change
• No signs or symptoms of intestinal polyps
(anemia, weight loss, abdominal pain, blood in
stool)
• No personal or family history of
– Melanotic macules
– Intestinal polyps of any kind
– Intestinal surgery

33. Case 2: Assessment
Patient and family do not have features of PJS.
Does this patient have PJS or not?
• Recommendations:
– Set phase for STK11 gene change. Maternal
history of pancreatic cancer is assumed to be
attributed to the STK11 gene change.
• PLAN: Test father for STK11 gene change.
– Evaluate phenotype: EGD, colonoscopy, CT scan
and wireless capsule endoscopy for polyps and
cancer.

34. Case 3: Second hand Follow up
• Upper endoscopy, colonoscopy, CT scan
wireless capsule endoscopy - all normal.
• Updated report from laboratory:
– Mutation changed to VUS. ? Maybe based on
testing of father showing he carried the STK11
gene change.

35. Case 2: 35 yo with STK11 gene change
• PJS is rare! 1 in 100,000 Mayo Clinic pts.
• In absence of a defining feature of
PJS in the patient or family member
it is unlikely the patient has PJS.
• Defining features are
– Melanotic macules
– Polyps (Stalked with intusussception, Small intestine,
smooth muscle)
– Signature PJS neoplasia
• Adenomatous changes of the cervix (adenoma malignum)
• Rare primative tumors of the ovaries or testicles (sex cord tumors
with annular tubules).

36. Scenario of 9s
• 1 in 99,999 incidence (for example, PJS)
• 1 in 999 pretest probability due to history consistent,
but without defining features. For example PJS and
pancreatic cancer.
So odds are higher, but still very unlikely given how rare
these disorders are.
• 99% sensitivity, 99% specificity almost perfect test.
Q: Patient has a positive test. What is the likelihood this is a
true positive, and the patient has PJS?
A: 9%. So 92% of positive tests in this scenario are wrong,
false positives.
? Should you even do testing when the pre test probablity is
so low.

37. 2015-2016 Downgrading of gene
changes found by panel testing.
In all cases, the patient and family history was
not strongly suggestive of the disease.
Gene Original Re interpretation Indication
BARD1 Likely pathogenic VUS Family history
ovarian cancer
PMS2 Pathogenic Normal Breast cancer
PMS2 Pathogenic Normal Breast cancer
PMS2 Pathogenic Likely pathogenic Breast cancer
STK11 Expected
Pathogenic
VUS Fhx Pancreatic
cancer

38. Case 3: After dx, cancer control
• 50 year old woman from Wales. First small
bowel surgery at 12 for intussusception.
Diagnosed with PJS at that time based on
small bowel polyps, melanotic macules and
family history of the same.
• What should the cancer control be?

39. Cumulative cancer risk by site and age from a study
of 416 Peutz-Jeghers syndrome patients (2006)
Site Age
20 yrs 30 yrs 40 yrs 50 yrs 60 yrs 70 yrs
All
cancers
2 5 17 31 60 85
GI - 1 9 15 33 57
Breast - - 8 13 31 45
GYN - - 3 8 18 18
Pancreas - - 3 5 7 11
Lung (m) - - 1 4 13 17

40. GI cancer risk should be near 0 in dx PJS patients:
Precancerous polyps can now be removed by endoscopy.
Site Age
20 yrs 30 yrs 40 yrs 50 yrs 60 yrs 70 yrs
All
cancers
2 5 17 31 60 85
GI - 1 9 15 33 57
Breast - - 8 13 31 45
GYN - - 3 8 18 18
Pancreas - - 3 5 7 11
Lung
(males)
- - 1 4 13 17

41. Double ballon endoscopy (DBE)
has been the biggest advance in the
care of PJS
• About 80% of patients can have total
enteroscopy (mouth the rectum, 20+ feet) by
bidirectional DBE (mouth and rectum).
• DBE scope about 2 meters long with balloons.
• Procedure time at least 180 min.
• General anesthesia, often endotracheal.
• Out patient procedure, complications rare.

42. In female patients, breast and gyn cancers are the most
common malignancies.
Site Age
20 yrs 30 yrs 40 yrs 50 yrs 60 yrs 70 yrs
Breast - - 8 13 31 45
GYN - - 3 8 18 18
Pancreas - - 3 5 7 11
Lung
(males)
- - 1 4 13 17

43. Individualized Cancer Control
Prescription
• GI
– Identifying and removing polyps
– DBE every year, “bidirectional” upper and lower
• Breast cancer
– High risk screening or preventive surgery
• GYN
– Annual close examination of cervix
– Pelvic MR
– Preventive surgery
• Abdomen, pancreas
– MRI
• Lifestyle: No smoking, BMI 25 or less.
• Chemoprevention: Consider curcumin (tumeric) 1000mg po twice daily
may be of some benefit.

44. Peutz-Jeghers syndrome
• Almost all patients have melanotic macules
“spots”. Melantoic macules are the inverse of
freckles and they fade.
• Polyps S’s
• Small bowel > colon.
• Stalked with intussusception.
• Smooth muscle, second check needed.
• 25% of PJS patients have negative genetic testing.
50% of PJS patients have no family history.
• PJS is rare! Beware the Scenario of the 9’s: Pretest
probality: 1/999, only 9% of positives are true.