Follow-up and surgical management of Peutz-Jeghers syndrome in children.

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Follow-up and Surgical Management of Peutz-Jeghers Syndrome in Children

Isabelle Vidal,

Guillaume Podevin, y Hugues Piloquet, z Marc Le Rhun,

§Benjamin Fre´mond, ô Didier Aubert,

Marc-David Leclair, and

Yves He´loury

Services de Chirurgie Pe´diatrique,^{Clinique Me´dicale Pe´diatrique,^{Gastro-ente´rologie, Institut des Maladies de L’appareil Digestif, Centre Hospitalier Universitaire, Nantes, France, Centre Hospitalier Universitaire^§Rennes, and^ôBesanc¸on, France

ABSTRACT

Background: Peutz-Jeghers syndrome (PJS) is an autosomal dominant syndrome with an increased risk of polyposis complications and intestinal and extraintestinal tumours.

Methods: During the last 15 years, we reviewed a series of 11 children with PJS, with special attention to evolution and follow-up. Diagnosis was based on at least 1 hamartomatous polyp associated with 2 of the 3 following criteria: family record of PJS, polyposis localised on small bowel, and mucocutaneous pigmentation. Diagnosis of PJS also could be raised by a single genetic analysis ofSTK11gene.

Results:Median age at beginning of symptoms was 6 years old.

Seven of the 11 children had genetic tests, which were positive forSTK11gene mutation. Among the 10 children presenting with gastrointestinal complications, 8 were operated on, 6 had at least 1 small bowel resection, and 4 had repeat surgery for recurrent intussusceptions. In case of complications leading to a surgical procedure, we performed intraoperative enteroscopy to

remove all large polyps. To prevent any polyposis complications, we suggest a complete check-up of polyposis topography with some of the new endoscopic tools, either double-balloon endoscopy or videocapsule endoscopy.

Conclusions:Children with PJS have a high risk of numerous laparotomies due to polyps’ complications. Therefore, a screening of intestinal polyposis by videocapsule endoscopy is recommended, as well as a screening of the most frequent sites of cancers for the patient’s whole life. During any abdominal procedure, they should have an intraoperative endoscopy, this management allowing an increased time interval between 2 laparotomies. JPGN 48:419–425, 2009.

Key Words: Intraoperative endoscopy—Peutz-Jeghers syndrome—Videocapsule endoscopy. ^# 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

First described in 1921 by Peutz and in 1940 by Jeghers, Peutz-Jeghers syndrome (PJS) is a rare syndrome inherited in an autosomal dominant pattern, with variable penetrance. It associates hamartomatous polyposis of the gastrointestinal tract, mucocutaneous hyper- pigmentation, and intestinal and extraintestinal tumours.

Incidence of this syndrome ranges from 1 in 8300 (1) to 1 in 120,000 births (2), depending on series. One-third of cases are diagnosed before the patient is 10 years old (3).

Since 1980, this pathology was correlated with higher risk of malignancies and cancers, compared with the general population. In 1998, the serine threonine-protein kinase 11 (STK11) gene responsible for this syndrome was isolated. The aim of the study was to review cases of

PJS in childhood, and to give guidelines for pediatric surgeons confronted with this rare syndrome.

MATERIALS AND METHODS

We reviewed medical charts and follow-up of 11 children from 3 pediatric centres with PJS diagnoses for the last 15 years (January 1991 to January 2006). Criteria of inclusion were either those described by Giardiello and Trimbath (4) or genetic analysis that assessed PJS. Giardiello and Trimbath (4) diagnosed PJS when they found at least 1 gastrointestinal histo- pathologically verified hamartomatous polyp associated with 2 of the 3 following criteria: family record of PJS, polyposis localised on small bowel, and mucocutaneous pigmentation.

However, since the discovery of theSTK11gene mutation, PJS can be diagnosed by this single genetic analysis.

RESULTS

The 11 children studied had a median age of 13 years and 2 months, ranging from 7 years and 10 months to

Received November 7, 2007; accepted May 19, 2008.

Address correspondence and reprint requests to Guillaume Podevin, Service de Chirurgie Infantile, HME, Centre Hospitalier Universitaire, 7 quai Moncousu, 44093 Nantes, France (e-mail: guillaume.podevin@

chu-nantes.fr).

The authors report no conflicts of interest.

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22 years and 4 months. There were 6 boys. Four children had a family history of PJS (Table 1). All had labial pigmentation and 1 presented pigmentation of fingers.

Ten of the 11 children responded to the Giardiello criteria, but 1 (child 5 of Table 1) had only lip pigmentation that led to the investigation of theSTK11mutation, which confirmed PJS. This child is 8 years old and remained asymptomatic until now. He will undergo further endoscopic polyposis research.

Of the 10 children presenting symptoms from their intestinal polyposis, 8 children had polyps located in the small bowel, 5 in the colon or rectum, 4 in the stomach, and 2 in duodenum. The median age of the first clinical sign was 6 years old, ranging from 4 years and 7 months to 15 years.

Six children first presented with intussusception, 2 with blood rectal emissions, and the 2 youngest with anal prolapse of rectal polyp. Five of these 9 children presented with chronic abdominal pain, without any acute complication of their gastrointestinal polyposis (Table 2).

Median follow-up since the appearance of the first clinical sign was 5 years and 7 months (from 6 months to 16 years). Six children presented new episodes of polyposis manifestation. They occurred in a median time of

33 months (from 1 month to 8 years) after the first episode, and 7 new episodes required surgery, whereas 3 were treated endoscopically.

Only 1 symptomatic child had no surgery, all of his polyps being removed by endoscopy. Among the others, 8 children underwent surgery, and 6 had at least 1 small bowel resection because of intussusception (Fig. 1). Four children underwent 2 or 3 laparotomies.

Except for obvious diagnosis of polyp (anal prolapse), all of the clinical manifestations of polyps were diagnosed by abdominal ultrasound or by computed tomo- graphic scan, showing intussusception or polyp itself.

Gastrointestinal opacifications to search the polyps failed to diagnose a part of them, when compared with endoscopy performed afterward, in 2 of 3 of children with upper tract complications and 2 of 2 children with small bowel polyps.

Routine endoscopy was efficient for all of the subjects.

Three children benefited from videocapsule endoscopy (Figs. 2–5), for regular follow-up, and 1 underwent an endoscopy after his second videocapsule to remove polyps measuring more than 1 cm, located in the first jejunal loop. All removed polyps were hamartomas at histological analysis, typical of PJS. No child had either

TABLE 2. Gastrointestinal polyposis complications, and their characteristics, for each child

First gastrointestinal manifestation Polyposis complications

Age, y Type Total Interval, y Intscn Surgery

1 4.8 Anal prolapse of rectal polyp 1 — 0 1

2 5.3 Anal prolapse of rectal polyp 1 — 0 0

3 6.0 Jejunojejunal intussusception 4 8, 1, 1 2 3

4 6.4 Anaemia, anal bleeding 3 8, 7 1 1

5 8.0 Asymptomatic 0 — 0 0

6 9.5 Colocolic intussusception 3 1, 1 3 2

7 9.8 Jejunojejunal intussusception 2 1 2 2

8 10.1 Anal bleeding, occlusion (without intussusception) 2 0.6 1 1

9 11.0 Jejunojejunale intussusception 1 — 1 1

10 12.8 Colocolic and jejunojejunale intussusception 1 — 2 2

11 15.1 Ileocolic intussusception 2 0.1 1 1

Interval¼time between each complication; Intscn¼number of episodes of intussusception; Surgery¼number of laparotomies.

TABLE 1. Peutz-Jeghers syndrome (PJS) criteria in our series

Child no. Mucocutaneous pigmentation Family history of PJS Verified GI polyposis Hamartomatous histology STK11mutation

1 X 0 X X X

2 X 0 X X X

3 X X X X X

4 X X X X X

5 X 0 ? ? X

6 X 0 X X X

7 X X X X ?

8 X 0 X X ?

9 X 0 X X ?

10 X X X X X

11 X 0 X X ?

An ‘‘X’’ indicates the condition was present, ‘‘0’’ if not, and ‘‘?’’ means it was not assessed. GI¼gastrointestinal.

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extraintestinal polyps or malignant tumour. Seven children had genetic analysis, and mutation of the STK11 gene was found in all of them.

DISCUSSION

Peutz-Jeghers syndrome is a triad including mucocutaneous pigmentation (the most apparent sign), gastrointestinal polyposis, and increased risk of malignancy.

Polyposis occurs most often in the intestinal tract but can be found in nasal, bladder, or gallbladder mucosa and in

FIG. 1. Jejunal intraintestinal polyp, responsible for intussusception, requiring bowel resection.

FIG. 2. Videocapsule endoscopy imaging of gastric prepyloric polypoid lesion that was resected by upper endoscopy in a second procedure.

FIG. 3. Videocapsule endoscopy imaging of (A) duodenal polyp, and (B) polypoid lesion developed in the first jejunal loop, measuring more than 1 cm that was resected by upper endoscopy in a second procedure.

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the pelvis or lungs (5). In the intestinal tract, early polyposis leads to clinical signs. One-third of the time its first manifestations occur during the first decade of life, 50% of the time before the patient is 20 years old, and sometimes it occurs in the neonatal period (3,5,6).

This hamartomatous polyposis is located in the small bowel in 90% of patients, most often in the jejunum, followed by the ileum and duodenum (2). It also can be found in the colon (9%) and stomach (24%). Most polyps are pedunculated, except on the gastric wall where they

are sessile. They are mainly diagnosed during clinical manifestations secondary to complications, such as acute intestinal intussusception (43%), ferriprive anemia (14%) linked with polyp ulceration or infarcisement, chronic abdominal pain (23%), anal prolapse of rectal polyp (7%), or transforming in gastrointestinal tract adenocar- cinoma (2%–3%) (3). As seen in our results, in childhood intussusception is the most frequent cause of morbidity, followed by chronic intestinal bleeding. Intussusception has a high incidence of recurrence (7).

Cancer predisposition has been studied by meta- analysis (4,8), showing an overall relative risk (RR) of developing cancer of 15.2 in a population of patients with PJS from 20 to 64 years old. This mostly concerns the adult population because the mean age at first cancer diagnosis was 42 years old. This tumor risk concerns the small bowel (RR¼520), stomach (RR¼213), pancreas (RR¼132), colon (RR¼84), and also sites outside the gastrointestinal tract, such as breast (RR¼15.2), uterus (RR¼16), and ovary (RR¼27; cystadenoma, granulosa cell tumor, sex cord tumor with annular tubules) (9).

Cancer risk in childhood is basically genital tract malignancy in young boys and Sertoli cell tumor of a testis until puberty. Rare cases of female genital tract malignancy were described, occurring early in puberty (10).

Intestinal polyps can transform in cancer, with risk correlated to their dimension. It seems that there is no risk for polyps smaller than 1 cm (11). This cancer risk is not linked with familial predisposition, nor with type of mutation ofSTK11(12,13).

Follow-up of this polyposis disease raises the problem of its main localisation in the small bowel, which is difficult to investigate. We could separate 2 situations, the planned follow-up for a well-known patient and

FIG. 5. Videocapsule endoscopy imaging of ileal polypoid lesion.

FIG. 4. Videocapsule endoscopy imaging of (A) large and (B) small polyps of the first jejunal loop.

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investigations during complication of polyposis. In the first situation, the regular follow-up should involve both the most efficient and the less invasive procedures. In the other situation, this checkup may have to be performed in an emergency situation of polyposis complication, even- tually during surgical procedure.

Unfortunately, most diagnoses of PJS are made when gastrointestinal polyposis becomes symptomatic.

In children, PJS is more symptomatic by gastrointestinal polyposis complications than by development of malignancies. As seen in our series, PJS usually is revealed by digestive complications, by intussusception or anal prolapse of polyp for the youngest children. Treatment in emergency nearly always required surgery (13 operations for 13 intussusceptions, in our series) with at least enterotomy to remove polyps responsible for intussusception and sometimes enterectomy. When the diagnosis of PJS is known or at least suggested before the procedure (eg, by family history, mucocutaneous pigmentation, previous or atypical intussusception), an intraoperative enteroscopy should be planned, allowing removal of all polyps larger than 1 cm that could lead to other gastrointestinal complications. This ‘‘cleaning’’ permits the physician to make a map of the polyposis and to space surgery, increasing the intervals between 2 laparotomies to at least 4 years in patients at high risk for multiple operations and repeated intestinal resections (14,15). It has been proved that this intraoperative enteroscopy detects polyps that were not diagnosed by the surgeon, neither by transillumination nor by palpation of the small bowel. A study reported a median of 12 polyps ‘‘mis- diagnosed’’ by surgical research, detected by enteroscopy, and removed, in which some were larger than 1 cm (16). Polypectomy could be performed by endoscopy, or if that is not possible, through a small enterotomy. This has been done in children as young as 4 years and can be performed laparoscopically (17,18).

For patients who are known to be stricken with PJS, regular surveillance is recommended every 2 years after the patient is 8 years old. Different methods of follow-up have been proposed, but classical magnetic resonance imaging is not useful compared with endoscopic tech- niques (19,20).

There are various endoscopic tools, but videocapsule endoscopy seems to be the easiest to use and of best quality for standard polyposis screening. Among endoscopic tools, double-balloon enteroscopy is less invasive than enterotomy, and presents all of the advantages of endoscopy: It raises diagnosis and location of polyps and permits the surgeon to resect or biopsy them (21,22). It can detect more polyps than capsule endoscopy, and allows removing them at the same time (22). In practice, however, it rarely results in a complete screening of the small bowel and of the upper and lower gastrointestinal tract, even when performed by combined oral and anal approach. It can take more than 3 hours to see most of the

small bowel’s length, and it requires 2 experts in endoscopy. Thus, this technique is not rationally usable for a screening every 1 or 2 years. Nonetheless, it is the method of choice for big polyps located in the proximal jejunum.

Videocapsule endoscopy is a more recent technique that permits the surgeon to map polyposis and to pre- cisely determine size, aspect, and location of polyps on the entire length of the digestive tube. It is a safe procedure avoiding patient discomfort, performed on an ambulatory basis, even after anterior enterotomies.

It can be used even in small children, and if they are unable to swallow it, it can be pushed endoscopically into the duodenum. Its efficiency has been proved for children older than 10 years old, with results comparable to endoscopic and radiological tools for polyposis detection, Crohn disease, occult gastrointestinal bleeding, and protein losing enteropathy (23). For intestinal polyposis, the capsule can detect polyps that would not been seen on small bowel series (24,25).

Nevertheless, this technique can miss smaller polyps that could be found by enteroscopy. That is why it is often proposed as a first-line examination, and if it diagnoses polyps that should be removed, an enteroscopy is then performed to complete the polyposis topography, and to remove the largest polyps (26–29). The fact that videocapsule endoscopy can miss small polyps is not an obstacle for recommendations of resection concerning polyps larger than 1 cm.

The only possible contraindication is a known intestinal stenosis that could cause capsule retention (23,30).

A recent study relates an increased risk of complication in children, compared with adults. These complications are delayed passage either in the stomach or small bowel, requiring surgery to extract the capsule (24).

This high rate (20%) is not described in other studies (31).

Because it is less invasive than enteroscopy, and more efficient than other noninvasive follow-up tools, videocapsule could be used as a first-line surveillance procedure (32,33). It can also be used as an initial approach to diagnosing polyposis in nonsymptomatic familial cases (28).

Among other endoscopic investigations is intraoperative enteroscopy. This is the more efficient method, visualizing the entire small bowel, but it remains invasive. Therefore, it should be scheduled when any laparo- scopy or laparotomy is required for a patient with PJS, whatever the reason for the operation.

The contribution of genetics must be underscored because early diagnosis via genetics can permit early management, even before clinical manifestations occur.

Recently, a genetic mutation has been found to be responsible for Peutz-Jeghers syndrome: theSTK11gene, located on chromosome 19p13.3 and encoding for serine threonine kinase (34). It acts as a tumour suppressor gene.

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This mutation is not responsible for all PJS. It is iden- tified in 60% of familial cases and in 50% of sporadic cases (2,5). In the most recent study, this mutation was found in 90% of patients presenting clinical manifestation of the disease (35). This mutation may occur de novo. There seems to be a link between the type of mutation and the age of onset of gastrointestinal symptoms (36). Moreover, STK11 could be involved in the earliest steps of pathogenesis of hamartomas into ade- nocarcinomas (8). This genetic mutation was present in 7 of the 7 tested children of our series, and permitted diagnosis of PJS in an asymptomatic boy. Genetics screening should be proposed to relatives of patients with PJS, or if faced with mucocutaneous pigmentation suggesting PJS.

Screening should not be restricted to the gastrointestinal tract. Because of the increased risk of malignancy development, it is essential to set surveillance guidelines based on a high cancer risk adjusted for the patient’s age and the organ involved. All reports recommend establish- ing a familial register and screening all possible patients with genetic analysis. During childhood, the 2 most frequent localisations of malignancy are the testes for young boys and the gastrointestinal tract for adolescents.

A few cases of genital tract tumor developing during the first years of puberty have been described in the literature, this risk concerning more adult women than young girls (9).

The most recent literature suggests the following surveillance for children (4,8): testes, from birth to 12 years old, physical examination and ultrasound if in doubt; gastrointestinal tract, as early as 8 years old, with endoscopy of the upper tract and double-balloon or videocapsule endoscopy every 2 to 3 years. Screening should be expanded to the colon, breast, uterus, cervix, ovaries, and pancreas at adulthood. Parents and children should be forewarned of this malignancy risk. The importance of regular follow-up and screenings during the course of their entire life should be stressed.

CONCLUSIONS

PJS is a disease that will require total commitment from the patient to follow-up screening and surveillance because he is at significantly high risk of developing cancer and polyposis manifestation that could lead to iterative intestinal resections. Screening includes regular testes examination from birth and biannual enteroscopy after 8 years of age. Videocapsule endoscopy should become a first-line surveillance procedure with which to follow-up asymptomatic patients.

Surgeons should remember that care should be taken to minimise intestinal resection and reduce the long-term risk of short bowel syndrome, and thereby should plan intraoperative enteroscopy whenever an abdominal procedure is required.

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