Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder
characterized by the presence of numerous hamartomatous intestinal
polyps and mucocutaneous melanin pigmentation. The polyps are located
mainly in the small intestine but may be found in the stomach and
colon as well. The syndrome is rare, occurring in approximately one in
200,000 births. In the first part of the topic clinical manifestation,
genetic consideration and diagnostic criteria has been posted:
Tuesday, October 14, 2008
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome (part one)
INTRODUCTION
Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by
the presence of numerous hamartomatous intestinal polyps and mucocutaneous
melanin pigmentation.
A polyp is a discrete mass of tissue that protrudes in the lumen of the bowel.
* Polyps are classified histologically as neoplastic (benign adenomas and
malignant adenocarcinoma) or nonneoplastic (hamartoma, mucosal polyp, lymphoid
aggregate). There are a number of familial syndromes characterized by the
occurrence of hamartomatous polyps in the gastrointestinal tract including the
Peutz-Jeghers syndrome (PJS), juvenile polyposis, and neurofibromatosis.
* The polyps in PJS are located mainly in the small intestine but may be
found in the stomach and colon as well.
The syndrome is rare, occurring in approximately one in 200,000 births.
* The classic mucocutaneous pigmentation spots occur in approximately 95%
of patients with PJS and appear most commonly on the lips and buccal mucosa but
can also be found on other areas of the skin such as the hands, feet, and
eyelids.
* The disease was first recognized in 1921 by Peutz in a Dutch family; the
pedigree of this family continues to be followed.
* This autosomal dominant disorder has high degree of penetrance for both
polyposis and skin pigmentation.
o Males and females are equally affected.
o It can occur in any racial or ethnic group.
o It is considered rare with prevalence estimates ranging between
1:25,000 and 1:280,000.
Genetic consideration :
* The PJ gene in most families has been mapped to chromosomal 19p13.3 close
to marker D19S886 (1-3). The defect in these families involves mutations in a
gene encoding a serine threonine kinase (LKB1 or STK11); the germline mutations
in this gene, probably in combination with acquired genetic defects of the
second allele in somatic cells, are responsible for the clinical manifestations
(2-4).
The role of this protein kinase is not known and PJS is the first cancer
susceptibility syndrome shown to be due to inactivating mutations in a protein
kinase.
* One possibility is that LKB1 functions as a tumor suppressor (5).LKB1
also appears to regulate cell polarity, an observation that may be important
for explaining how hamartomas develop and the apparent paradox that patients
with PJS develop these benign polyps yet are predisposed to cancer (6-7).
* A traditional theory has been that (for unclear reasons) some hamartomas
in patients with PJS proceed on a pathway to malignant transformation.
* However, an alternative theory suggests that dysregulation of cell
polarization leads concurrently to a cancer predisposition while also creating
a predisposition for mucosal prolapse (8).
*
Mucosal prolapse can lead to the development of polypoid lesions that are
histologically similar to hamartomas. Thus, the hamartomas seen in PJS may be
an epiphenomenon reflecting disruption of cell polarity pathways, which
predisposes simultaneously to mucosal prolapse (and hamartoma formation) and
cancer.
However, mutations in LKB1 are detected in only 50 to 60 percent of families
with PJS suggesting that there is a second PJS locus (4). Three PJS families
have been identified in which there was no linkage to 19p13.3; furthermore,
none of the polyps from these families showed allele loss at D19S886 (1).
CLINICAL MANIFESTATIONS
There are two manifestations of PJS:
1. pigmented mucocutaneous macules and
2. multiple gastrointestinal polyps, which are usually benign but may grow
progressively and produce symptoms or undergo malignant transformation.
In one series of 202 patients, the diagnosis was based upon the skin lesions in
52 patients and related to gastrointestinal polyps in 150 (9).
Pigmented spots The characteristic mucocutaneous pigmentations (melanin
spots) of PJS are present in more than 95 percent of patients and are caused by
pigment laden macrophages in the dermis.
* They are typically flat, blue-gray to brown spots 1 to 5 mm in size that
look like freckles. However, the onset and location of PJS spots is different
than that of freckles.
* PJS lesions occur most commonly on the lips and
o perioral region (94 percent),
o hands (74 percent),
o buccal mucosa (66 percent) and
o feet (62 percent) (9) .
+ They also occur on the nose, perianal area, and genitals, and
are rarely found in the intestines.
+ They usually occur during the first one to two years of life,
increase in size and number over the ensuing years, and finally fade after
puberty with the exception of those on the buccal mucosa.
* Freckles, in contrast, are typically sparse near the nostrils and mouth,
are absent at birth, and never appear on the buccal mucosa.
Malignant degeneration of these lesions is extremely rare.
Gastrointestinal polyps
* Gastrointestinal hamartomatous polyps are present in most patients with
PJS.
* These polyps contain a proliferation of smooth muscle extending into the
lamina propria in an arborization-like fashion; the overlying epithelium is
normal (12).
At endoscopy, the polyps have no major distinguishing features, and may be
sessile, pedunculated, or lobulated.
One series found the following frequency and location of polyps in patients
with PJS (9) :
* Small intestine 64 percent
* Colon 64 percent
* Stomach 49 percent
* Rectum 32 percent
Symptoms suggestive of PJS usually appear by the second decade and include
abdominal pain (intussusception), gastrointestinal bleeding, or anemia(10).
* The number of polyps ranges from 1 to more than 20 per segment of bowel,
although some patients have solitary lesions. The size of the polyps is also
variable, ranging from 0.1 to more than 5 cm in diameter.
Polyps begin to grow in the first decade of life and most patients become
symptomatic between the age of 10 and 30. The following distribution of
presenting gastrointestinal symptoms was noted in one series (9) :
* Obstruction caused by intussusception or occlusion of the lumen by the
polyp 43 percent
* Abdominal pain caused by infarction 23 percent
* Acute or chronic rectal bleeding caused by ulceration 14 percent
* Extrusion of the polyp through the rectum 7 percent
Nearly one-half of the patients experience an intussusception during their
lifetime, most often in the small intestine (9,11) .
Patients with PJS are at risk for multiple operations and postoperative
complications. It has been suggested that a combined endoscopic and
laparoscopic approach can be used to treat proximal small bowel
intussusception, markedly reducing the need for repeated laparotomies in these
patients (13) .
DIAGNOSIS The diagnosis was traditionally based upon clinical criteria
proposed in 1987 (14).
* For individuals with a histopathologically confirmed hamartoma, a
definite diagnosis of PJS requires two of the following three findings:
1. Family history consistent with autosomal dominant inheritance
2. Mucocutaneous hyperpigmentation
3. Small-bowel polyposis
* For individuals with a first-degree relative with PJS, presence of
mucocutaneous hyperpigmentation is sufficient for presumptive diagnosis.
Genetic testing is also available. However, as noted above, not all mutations
associated with PJS have been identified. Thus, a negative genetic test does
not exclude the diagnosis.
RISK OF MALIGNANCY PJS is associated with a high risk of colorectal (~20%),
gastric (~5%), small bowel, pancreas, breast, ovary, lung, cervix, uterus, and
testes cancers (lifelong risk approaches 80-90%)(15).
Most intestinal cancers are adenocarcinomas that arise from foci of dysplasia
or malignant degeneration of hamartomatous polyps. The risk of cancer is in the
range of 50 percent by the time patients reach their sixties as illustrated by
the following reports :
* Follow-up of the original family described by Peutz revealed that only 17
of 22 affected family members survived into adulthood (16) .
* The mean age of death for affected family members was substantially
younger than for unaffected family members (38 versus 69 years).
* Causes of death included intestinal carcinoma, bowel obstruction, and
extraintestinal cancers (breast and squamous-cell carcinoma of the nasal
cavity).
* In another report of 31 patients, a malignancy developed in 15 (48
percent) (17). Only 4 of the 15 cancers were in the gastrointestinal tract.
* In another series of 26 patients with PJS-like mucocutaneous pigmentation
but without the other features of PJS (termed isolated melanotic mucocutaneous
pigmentation, or IMMP), 10 patients developed malignancy (38 percent) (18).
Only 1 of the 12 documented malignancies was in the gastrointestinal tract,
while 60 percent of the women with IMMP developed a breast or gynecologic
cancer.
* A fifth report focused on 33 families with PJS (4). Germline mutations of
LKB1/STK11 were identified in 52 percent of cases. The risk of cancer
(gastrointestinal and breast) in these patients was 47 percent by age 65.
* The overall incidence of cancer was estimated in a study of 240
individuals with known mutations in STK11 (19). The overall risk of developing
cancer at ages 20, 30, 40, 50, 60, and 70 was 1, 3, 19, 32, 63, and 81 percent,
respectively. The most common cancers were gastrointestinal in origin (ie,
gastroesophageal, small bowel, colorectal, and pancreatic). The risk for these
cancers at ages 30, 40, 50 and 60 was estimated to be 1, 10, 18, and 42
percent, respectively. In women, the risk for breast cancer was substantially
increased (32 percent by age 60).
Gastrointestinal cancers
* Because hamartomatous polyps are benign, they were initially not thought
to represent a premalignant condition.
* However, the distribution of gastrointestinal cancers in these patients
is similar to that of the hamartomatous polyps and carcinoma arising in
hamartomas has been clearly documented.
In other follow up studies (20,21) major cancer sites were:
* Small intestine 48 percent
* Stomach 24 percent
* Colon 24 percent
* Pancreas 5 percent
Non-gastrointestinal cancers
* The risk of non-gastrointestinal cancers is increased in both males and
females with PJS (14) . In one series, for example, 26 cases of noncutaneous
cancer developed in 18 of 34 (53 percent) affected patients; 16 of these 26
tumors were non-gastrointestinal (22).
Another report summarized six publications with a total of 210 individuals with
PJS (23). The cumulative risk of cancer was 93 percent from age 15 to 64 years
old. Extracolonic cancers accounted for 55 of the 66 malignancies (83 percent).
Compared to population-based controls, the risk was increased for cancers of
the lung, breast, uterus, and ovary.
* Females have an increased incidence of cervical, uterine, ovarian, and
breast cancers (often bilateral). Cervical tumors include cervical adenoma
malignum, a highly differentiated mucinous adenocarcinoma with a highly
aggressive behavior (24). In addition, small, asymptomatic, benign ovarian
tumors known as "sex-cord" tumors with annular tubules (SCTAT tumors) occur
commonly in women with PJS. These tumors are often associated with signs of
hyperestrogenism which can lead to sexual precocity (25, 26).
* Males appear to have an increased incidence of Sertoli cell testicular
tumors that are often hormonally active (24, 27). Some present with
gynecomastia, rapid growth, and advanced bone age with markedly elevated levels
of estradiol (28).
References :
1. Olschwang, S, Markie, D, Seal, S, et al. Peutz-Jeghers disease:
Most, but not all, families are compatible with linkage to 19p13.3. J Med Genet
1998; 35:42.
2. Jenne, DE, Reimann, H, Nezu, J, et al. Peutz-Jeghers syndrome is
caused by mutations in a novel serine threonine kinase. Nat Genet 1998; 18:38.
3. Hemminki, A, Markie, D, Tomlinson, I, et al. A serine/threonine
kinase gene defective in Peutz-Jeghers syndrome. Nature 1998; 391:184.
4. Lim, W, Hearle, N, Shah, B, et al. Further observations on
LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 2003;
89:308.
5. Boudeau, J, Sapkota, G, Alessi, DR. LKB1, a protein kinase
regulating cell proliferation and polarity. FEBS Lett 2003; 546:159.
6. Baas, AF, Kuipers, J, van der, Wel NN, et al. Complete polarization
of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell
2004; 116:457.
7. Martin, SG, St Johnston, D. A role for Drosophila LKB1 in
anterior-posterior axis formation and epithelial polarity. Nature 2003; 421:379.
8. Jansen, M, de Leng, WW, Baas, AF, et al. Mucosal prolapse in the
pathogenesis of Peutz-Jeghers polyposis. Gut 2006; 55:1.
9. Utsunomiya, J, Gocho, H, Miyanaga, T, et al. Peutz-Jeghers
syndrome: Its natural course and management. Johns Hopkins Med J 1975; 136:71.
10. Tovar JA, Eizaguirre I, Albert A, et al.: Peutz-Jeghers syndrome in
children: report of two cases and review of the literature. J Pediatr Surg
1983, 18:1-6.
11. Hinds, R, Philp, C, Hyer, W, Fell, JM. Complications of childhood
Peutz-Jeghers syndrome: implications for pediatric screening. J Pediatr
Gastroenterol Nutr 2004; 39:219.
12. Haggitt, R, Reid, B. Hereditary gastrointestinal polyposis
syndromes. Am J Surg Pathol 1986; 10:871.
13. Cunningham, JD, Vine, AJ, Karch, L, Aisenberg, J. The role of
laparoscopy in the management of intussusception in the Peutz-Jeghers syndrome:
Case report and review of the literature. Surg Laparosc Endosc 1998; 8:17.
14. Giardiello, FM, Welsh, SB, Hamilton, SR, et al. Increased risk of
cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987; 316:1511.
15. Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk
of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000,
119:1447-1453.
16. Westerman, AM, Entius, MM, de Baar, E, et al. Peutz-Jeghers
syndrome: 78 year follow-up of the original family. Lancet 1999; 353:1211.
17. Giardiello, FM, Welsh, SB, Hamilton, SR, et al. Increased risk of
cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987; 316:1511.
18. Boardman, LA, Pittelkow, MR, Couch, FJ, et al. Association of
Peutz-Jeghers-like mucocutaneous pigmentation with breast and gynecologic
carcinomas in women. Medicine (Baltimore) 2000; 79:293.
19. Lim, W, olschwang, S, Keller, JJ, et al. Relative frequency and
morphology of cancers in STK11 mutation carriers. Gastroenterology 2004;
126:1788.
20. Spigelman, AD, Murday, V, Phillips, RKS. Cancer and the
Peutz-Jeghers syndrome. Gut 1989; 30:1588.
21. Giardiello, FM, Welsh, SB, Hamilton, SR, et al. Increased risk of
cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987; 316:1511.
22. Boardman, LA, Thibodeau, SN, Schaid, DJ, et al. Increased risk for
cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 1998;
128:896.
23. Giardiello, FM, Brensinger, JD, Tersmette, AC, et al. Very high
risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;
119:1447.
24. Srivatsa, PJ, Keeney, GL, Podratz, KC. Disseminated cervical
adenoma malignum and bilateral ovarian sex cord tumors with annular tubules
associated with Peutz-Jeghers syndrome. Gynecol Oncol 1994; 53:256.
25. Young, RH, Dickersin, GR, Scully, RE. A distinctive ovarian sex
cord-stromal tumor causing sexual precocity in the Peutz-Jeghers syndrome. Am J
Surg Pathol 1983; 7:233.
26. Young, RH, Welch, WR, Dickersin, GR, Scully, RE. Ovarian sex cord
tumor with annular tubules. Review of 74 cases including 27 with Peutz-Jeghers
syndrome and 4 with adenoma malignum of the cervix. Cancer 1982; 50:1384.
27. Boardman, LA, Thibodeau, SN, Schaid, DJ, et al. Increased risk for
cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 1998;
128:896.
28. Young, S, Gooneratne, S, Straus, FH 2nd, et al. Feminizing Sertoli
cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol 1995; 19:50.
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