Background: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. Summary: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. Key Messages: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

© 2023 S. Karger AG, Basel

Introduction

Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. The germline variants of the causative genes of PJS may be identified by cancer gene panel tests to identify effective drugs. Novel diagnostic and therapeutic endoscopic procedures, such as small-bowel capsule endoscopy (SBCE) and balloon-assisted enteroscopy (BAE), have been developed in recent years. However, because of the diversity of clinical features and low incidence of this disease, there have been no Japanese guidelines for diagnosis, treatment, and surveillance. Medical management of patients and their relatives with this disease may be required as a result of cancer genome medicine or as a part of the characteristics of the disease, and it is difficult to apply overseas guidelines directly to Japanese patients in terms of cost, clinical applicability, and the medical health insurance system. Therefore, there is a need to develop seamless clinical practice guidelines for children and adults in Japan.

In 2017, as a project of “Research group to improve the medical standard and equalize the treatment of benign multiple tumors of the gastrointestinal tract” (representer: Ishikawa H.), which was the research on rare and intractable diseases granted by the Ministry of Health, Labour and Welfare, a working group was established to develop “Clinical Guidelines for Diagnosis and Managements of Peutz-Jeghers Syndrome in Children and Adults.” The committee members included specialists in internal medicine, gastroenterology, surgery, pediatric gastroenterology, pediatric surgery, dermatology, gynecology, pathology, genetics, genetic counseling, and nursing. From 2019, the Japanese Society for Hereditary Tumors, the Gastrointestinal Polyposis Study Group of the Japanese Gastroenterological Association, and Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition continued to work on the preparation of the guidelines with the cooperation of other organizations. In 2020, the “Research group for establishing a seamless medical care system from children to adults in the gastrointestinal hamartoma predisposition diseases” (representer: Nakayama Y.), granted by the Ministry of Health, Labour and Welfare as a research on rare and intractable diseases, published the clinical guidelines in Journal of Hereditary Tumors in Japanese [1]. Herein, we present an English version of the clinical practice guidelines for PJS.

Developing the Guidelines

In developing the guidelines, the concept of evidence-based medicine was emphasized, and a project to promote the distribution of the evidence-based medicine guideline development guide [2] and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [3] system were used. The guidelines included detailed explanations of the PJS and clinical questions (CQs) and recommendations.

Collecting the Evidence

Based on the identified key clinical issues and each CQ, evidence was extracted using P (Patients), I (Intervention), C (Control) or (Comparison), and O (Outcome) as search keywords. We searched PubMed from January 1998 to December 2018, and the Internet version of the Central Journal of Medicine was searched from inception until December 2018.

Evaluating the Articles and Defining the Quality of Evidence

Articles selected for use in the guidelines were classified based on the study design (clinical practice guidelines, systematic reviews, meta-analyses, randomized controlled trials, controlled clinical trials, cohort studies, case-control studies, cross-sectional studies, case series, case reports, and reviews). As PJS is a rare disease, case reports and case series were included in the systematic review. A structured abstract was developed for each article to evaluate the risk of bias. The overall evidence was determined using the systematic review method (Table 1); the overall level of evidence for each CQ is listed from A to D.

Table 1.Quality of evidence at the start of the evaluationSystematic review, meta-analysis, randomized controlled trial = “high”
Cross-sectional study, cohort study, case-control study = “low”
Case series, case report = “very low”When to lower the grade∗There are very serious limitations to the quality of the research
There are significant inconsistencies in the results
The directness of the evidence is somewhat or considerably uncertain
Data are inaccurate or inconsistent
Publication bias is highly likelyWhen to raise the grade∗The degree of effect is large
There is a dose-response gradient
Possible confounding factors weaken the true effectDefining the quality of evidence about research on outcomes in generalA: “High”It is certain that the estimated of effect is virtually identical to the actual effectB: “Moderate”Confidence in the estimate of effect is moderateC: “Low”Confidence in the estimate of effect is limitedD: “Very low”The estimate of effect is quite uncertainDefining the Strength of Recommendation

The strengths of these recommendations are listed in Table 2. Decisions were made upon agreement among committee members after careful consideration of the (i) quality of evidence and (ii) balance of benefits and harms (balance between disadvantages such as patient burden, cost, and benefits acquired by implementing the recommended practice). The consensus was formed by voting according to the GRADE grid method [4], and a decision was made when more than 70% of the votes were in favor.

Table 2.

Strength of recommendations

1. Strong recommendationImplementation is recommended as “do it”Implementation is recommended as “do not do it”2. Weak recommendationImplementation is proposed as “probably do it”Implementation is proposed as “probably do not do it”Public Comments

A draft of the guidelines was published on the website, and public comments were solicited from the members of the Japanese Society for Hereditary Tumors; the Japanese Gastroenterological Association; the Japanese Society of Gastroenterology; the Japan Gastroenterological Endoscopy Society (JGES); the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition; and the Japanese Society of Pediatric Surgery. Further revisions were made based on public comments, and the Japanese version was published in 2020 [1].

Detailed Explanations of PJSOverview

The PJS was first described in a family by Peutz in 1921, and the concept of the disease was proposed by Jeghers et al. in 1949 [5]. It is characterized by hamartomatous polyposis of the gastrointestinal tract, except the esophagus, and pigmentations on the skin, mucous membranes, mainly on the lips, oral cavity, and fingertips.

PJS is an autosomal dominant inherited disease with a germline pathogenic variant in the STK11 gene as the only currently known cause. Approximately 17–50% of cases are solitary cases with no family history of the disease [6]. The polyps are characterized by hamartomatous hyperplasia of the mucosal epithelium and dendritic growth of smooth muscle fiber bundles from the muscularis mucosae and are called Peutz-Jeghers polyps. The incidence of various tumors (including malignant) in the entire gastrointestinal tract, including the esophagus, breast, pancreas, uterus, ovary, lung, and testis, is frequently observed, and appropriate surveillance is necessary [7].

Clinical Features

Pigmentations are inconspicuous at birth but occur before the age of 5 years and increase until puberty [6]. They may become inconspicuous in adulthood, but they often remain on the buccal mucosa. Peutz-Jeghers polyps cause symptoms such as black stool, anemia, abdominal pain, and vomiting. Enlarged polyps cause intussusception, and surgical treatment is often necessary [8].

Disease Frequency

The prevalence of PJS in Japan is currently uncertain. The prevalence is estimated to be approximately 1 in 50,000–200,000 live births [9], and the number of patients in Japan with PJS is estimated to be approximately 600–2,400.

Causative Genes

The serine/threonine kinase 11 (STK11) gene is located on the short arm of chromosome 19 (19p13.3) and was previously named liver kinase B1 (LKB1) gene [10]. It has been reported that pathogenic variants in the STK11 gene can be detected in 94% of PJS patients by sequencing or copy number analysis within the gene region [11, 12]. STK11 is a serine/threonine kinase that phosphorylates and activates AMP-activated protein kinase (AMPK) [13] and is widely expressed in human tissues. Activated AMPK plays a variety of roles, including regulation of intracellular energy metabolism, inhibition of cell cycle progression, inhibition of cell differentiation, regulation of cell polarity, induction of apoptosis, and repair of DNA damage [13, 14]. Because of these various intracellular functions, STK11 is considered a tumor suppressor gene, and its variants have been identified in a variety of carcinomas, not just PJS [6].

Mechanism of Peutz-Jeghers Polyp Formation

In Peutz-Jeghers polyps that develop in STK11 knockout mice, the expression of factors involved in protein synthesis and cell proliferation, such as the mammalian target of rapamycin complex1 (mTORC1) and hypoxia-inducible factor-1α (HIF-1α), which are inactivated by activated AMPK, is upregulated. These factors are thought to play a key role in the development of Peutz-Jeghers polyps in humans, but the detailed mechanism has not been elucidated [15].

DiagnosisDiagnostic Criteria

Clinical diagnostic criteria have been proposed by the Research Group for Improving the Medical Standard of gastrointestinal polyposis syndromes in the Japanese Ministry of Health, Labour and Welfare and are used as diagnostic criteria for specific pediatric chronic diseases in Japan (https://www.shouman.jp/disease/instructions/12_02_011/). In this guideline, we have modified these criteria to clarify the position of diagnosis based on genetic testing (Table 3).

Table 3.

Diagnostic criteria of PJS

A. Symptoms 1. Mucocutaneus pigmentations of 1–5 mm on the lips, mouth, and fingertipsB. Examination findings 1. Endoscopic findings: Upper gastrointestinal endoscopy, colonoscopy, and small-bowel endoscopy (capsule endoscopy or balloon-assisted endoscopy) show hamartomatous polyps in any gastrointestinal tract except the esophagus 2. Pathological findings: Hamartomatous polyps have hamartomatous hyperplasia of the mucosal epithelium and dendritic growth of smooth muscle fiber bundles from the muscularis mucosae, which can be diagnosed as Peutz-Jeghers polypsC. Differential diagnosis Differentiate from the following diseases Familial adenomatous polyposis, juvenile polyposis syndrome, Cowden syndrome/PTEN hamartomatous syndrome, tuberous sclerosis, inflammatory polyposis, serrated polyposis syndrome, Cronkhite-Canada syndrome, hereditary mixed polyposis syndrome, and Laugier-Hunziker-Baran syndromeD. Genetic testing Germline pathogenic variants in STK11 gene<Diagnosis Category*> 1. A is fulfilled, two of B are fulfilled, and the differential diagnoses in C are excluded 2. A is fulfilled in an individual who has a family history of PJS in close relation, and the differential diagnoses in C are excluded 3. Two of B are fulfilled in an individual who has a family history of PJS in close relation, and the differential diagnoses in C are excluded 4. B-1 is fulfilled, B-2 is met for multiple lesions, and the differential diagnoses in C are excluded 5. D is fulfilledClinical Characteristics

Hamartomatous polyposis (Fig. 1): Peutz-Jeghers polyps are pathologically characterized by hamartomatous hyperplasia of the mucosal epithelium and dendritic growth of smooth muscle fiber bundles from the muscularis mucosae (Fig. 2). They are found in the entire gastrointestinal tract except the esophagus and are especially common in the duodenum and upper jejunum. Endoscopic findings reveal polyps that are pedunculated or semi-pedunculated and slightly erythematous. Some lesions are branched, bifid, or multinodular, reflecting dendritic growth of the muscularis mucosae. The surface structure displays a mixture of tubular and dendritic structures. Small intestinal polyps may present with pseudo-invasion, in which they invade the muscular layer without cellular atypia and may be mistaken for malignant tumors [16]. Enlargement of polyps causes gastrointestinal bleeding and anemia. Polyps larger than 15 mm may cause intussusception, and endoscopic or surgical treatment is required [8]. The number of PJS patients who do not require surgery is approximately 30% at the age of 18–20 years. However, in many cases, surgical treatment has been performed when PJS is initially diagnosed in childhood [17, 18].

Fig. 1.

Endoscopic findings of Peutz-Jeghers polyp. a Hamartomatous polyps of approximately 10 mm in diameter are congregated. b Pedunculated hamartomatous polyp 10 mm in diameter.

Fig. 2.

Pathological findings of Peutz-Jeghers polyp (HE staining). a Loupe image. b Low magnification. Hamartomatous hyperplasia of the mucosal epithelium and dendritic growth of smooth muscle fiber bundles from the muscularis mucosae are observed.

Pigmentations (Fig. 3) (see CQ4): Pigmentation is often found on the lips but may also be found on the buccal mucosa, fingertips, phalanges, and heels. The lesions are blackish brown or brown, 1–5 mm in diameter, and usually longitudinal in shape. Pathologically, there is an increase in melanin pigment and melanocytes in the basal layer of the epidermis, and it is speculated that this may be due to inflammation inhibiting the migration of melanin from melanocytes to keratinocytes [19]. Pigmentations occur at birth, in early childhood, and increases until puberty. They may become inconspicuous in adulthood, but they often remain on the buccal mucosa. Although there are no reports of malignant transformation, laser treatment has been used from a cosmetic point of view [20].

Fig. 3.

Pigmentations in PJS. a Lips. b Fingertips. Pigmentations are blackish-brown or brown, 1–5 mm in diameter, and usually longitudinal in shape.

Malignant tumor (see CQ3): PJS is associated with a high incidence of various malignancies, including those of the entire gastrointestinal tract; including the esophagus, breast, pancreas, uterus, ovary, lung, and testis. For early detection of malignancy, the American College of Gastroenterology (ACG) guidelines recommend surveillance for PJS [7].

Treatment (See CQ2)

Peutz-Jeghers polyps can be resected endoscopically to avoid symptoms associated with their growth. Surgical resection is required for polyps that cannot be treated endoscopically. Resection of Peutz-Jeghers polyps in the small intestine using balloon-assisted endoscopy may avoid the need for subsequent surgical treatment [21, 22]. Surgery is the most common treatment for intussusception due to enlarged polyps, but in some cases, endoscopic resection after reduction of intussusception with balloon-assisted endoscopy may be possible [23].

Risk Assessment of Patient’s Relatives of the Proband

If a germline pathogenic variant of the proband is known, it is appropriate to offer genetic testing to determine whether close relatives have the same variant, but adequate genetic counseling and privacy considerations are important. Morbidity and mortality can be reduced by early diagnosis, treatment, and surveillance in individuals identified as having pathogenic variant [6]. If a germline pathogenic variant has not been identified, the presence or absence of characteristic pigmentation or Peutz-Jeghers polyps should be evaluated to determine whether the diagnostic criteria for PJS are met in order to identify close relatives who would benefit from early diagnosis and treatment [6].

Parents of the Proband

It is necessary to confirm that the diagnostic criteria for PJS are met. If a germline pathogenic variant of the proband has been identified, it is also useful to confirm if the parents have the same variant [6].

Sibling of the Proband

The likelihood that siblings of the proband will have the same pathogenic variant as the proband is essentially 50% in both sexes. If the proband’s parents do not have PJS, it is more likely that only the proband will have the de novo variant and less likely that his or her siblings will have the same variant. However, because of the possibility of gonadal mosaicism (somatic mutations in the germline), it should be confirmed that the affected siblings meet the diagnostic criteria for PJS, regardless of whether the parents have symptoms [24].

Child of the Proband

The likelihood that children of the proband will have the same pathogenic variant as the proband is 50% for both sexes. Because of the risk of developing intussusception in childhood and requiring surgical treatment, it is strongly recommended that endoscopic surveillance be performed at least once before the age of 8 years if the child has the germline pathogenic variant in STK11 gene [6]. Even if the pathogenic variant in STK11 has not been confirmed, endoscopic surveillance is recommended at least once by the age of 8 years if the child has characteristic pigmentations [6].

Medical Expense Subsidy System

PJS is certified as one of the Specific Pediatric Chronic Diseases in Japan. Pediatric patients can receive financial support for medical costs from a government-funded and medical aid project for children with chronic diseases.

CQs and RecommendationsCQ1: Is It Recommended to Perform Genetic Testing on Patients Who Meet the Diagnostic Criteria for Peutz-Jeghers Syndrome?

It is strongly recommended that patients who meet the diagnostic criteria for Peutz-Jeghers syndrome should not be genetically tested for the purpose of their own diagnosis or medical management.

• Evidence level: B

• Recommendation level 1: strong

Genetic testing for diagnostic purposes is weakly recommended for patients who meet some of the diagnostic criteria for PJS.

• Evidence level: B

• Recommendation level 2: weak

Explanation

In patients who meet the diagnostic criteria for PJS, germline pathogenic variants in the STK11 gene are identified in 80–94% of cases, and approximately one-third of these cases are associated with large deletions [12, 25, 26]. Therefore, it is necessary to combine both direct sequencing and multiplex ligation-dependent probe amplification to detect large deletions and duplications [26]. In solitary cases, the detection rate of pathogenic variants is 25–57% [7, 27], suggesting the possibility of somatic mosaicism [24].

There are no reproducible reports on the genotype-phenotype relationship, and the genotype-phenotype relationship is unclear in clinical guidelines [6, 8, 19, 28]. There are no reports on genotype-phenotype relationships in Japanese patients with PJS, and it is hoped that a nationwide registry system will be established and genotype-phenotype relationships will be examined in Japanese patients with PJS. It has been reported that the risk of cholangiocarcinoma is higher in patients with PJS with no identified STK11 mutation [29], but reproducibility has not been reported, and there is no clear difference in the clinical features between patients with a pathogenic variant and those in with no detected pathogenic variant [19]. A germline pathogenic variant of the STK11 gene can be identified even in atypical PJS cases [30–32], whereas genetic testing of patients with a single Peutz-Jeghers polyp does not completely rule out PJS, even if the result is negative [33].

Therefore, we do not recommend genetic testing because there is no evidence that identification of pathogenic variants in STK11 is useful in the medical management of clinically diagnosed PJS patients. Genetic testing for STK11 is recommended for patients who do not meet the diagnostic criteria based on symptoms and gastrointestinal findings alone because the results of the test can benefit the patient in terms of appropriate medical management.

CQ2: Is Surveillance and Treatment of Gastrointestinal Lesions Recommended in Peutz-Jeghers Syndrome?

Surveillance of the stomach, small intestine, and large intestine is strongly recommended.

• Evidence level: B

• Recommendation level 1: strong

It is weakly recommended that the first surveillance should be performed around the age of 8 years, even if there are no symptoms.

• Evidence level: C

• Recommendation level 2: weak

Resection of polyps larger than 15 mm (10 mm, if possible) is strongly recommended.

• Evidence level: B

• Recommendation level 1: strong

Explanation

The purpose of surveillance in PJS is to identify polyps that are large enough to cause symptoms such as intestinal obstruction or bleeding and to detect malignancy at an early stage. With regard to malignant tumors that develop in PJS patients, a number of articles and reviews have shown a high risk of occurrence in all parts of the gastrointestinal tracts, and the lifetime risk of cancer has been reported to be 0.5% in the esophagus, 29% in the stomach, 13% in the small intestine, and 39% in the large intestine, which is a high risk compared to the general population [7, 34]. A review of papers on malignant tumors in Japanese patients with PJS also reported a high lifetime risk of developing malignant tumors 24.0% in the stomach, 10.3% in the duodenum, 13.8% in the small intestine (jejunum/ileum), and 36.4% in the large intestine [35]. These results are similar to those reported in Europe and the USA. The youngest age of onset is 7 years in the stomach and 12 years in the colon, and therefore, the risk of carcinogenesis should be considered even in children.

In PJS, polyps are found in the stomach (24%), small intestine (96%), colon (27%), and rectum (24%) [7]. Polyps occur by the age of 10 years, but bleeding, infarction, intestinal obstruction, and intussusception usually occur by the age of 20–30 years. The median age of the first onset of intussusception is 16 years (3–50 years), and 50% of these cases are reported to occur before the age of 20 years [8]. Ninety-five percent of intussusceptions occur in the small intestine, and 80% of these present as an acute abdomen. Although PJS is a rare disease and there have been no controlled trials on the effectiveness of surveillance, we strongly recommend surveillance of the entire gastrointestinal tract in consideration of the risk of carcinogenesis and prevention of polyp-associated symptoms.

Regarding the timing and interval of gastric and colorectal surveillance, European and American guidelines recommend initial upper gastrointestinal endoscopy and full colonoscopy at age 8 years and surveillance every 1–3 years if polyps are found [7, 36, 37]. If no polyps are found at the initial examination, the second surveillance should be performed at the age of 18 years and then every 3 years thereafter. If symptoms appear before the age of 18 years, the second surveillance should be performed earlier. The risk of cancer increases rapidly after the age of 50 years, and surveillance every 1–2 years is recommended. However, there is no evidence of the benefits of this surveillance method.

Surveillance methods for the small intestine include SBCE, BAE, small-bowel series, magnetic resonance enterography (MRE), and computed tomography enterography. SBCE and MRE are often used to reduce invasiveness and radiation exposure. The sensitivity of SBCE is higher than that of small-bowel series [38–40] and MRE, for smaller polyps; the sensitivity of these respective imaging modalities for larger polyps (>1 cm) is similar [41–43]. It is recommended that the first SBCE should be performed at the age of 8 years and earlier if symptoms are present, and surveillance should be performed every 1–3 years if polyps are found [7, 36, 37]. The interval between examinations should be determined based on the rate of polyp growth. SBCE can be inserted into the duodenum with an insertion aid attached to the tip of the endoscope, even in patients who cannot swallow capsules, and it can be performed even in infants [44]. It has been reported that SBCE was able to observe the entire small intestine in a 10-month-old infant weighing 7.9 kg [45]. A case of a 3-year-old girl with intussusception in the context of a 2-year history of recurrent abdominal pain and vomiting has also been reported [46]. SBCE should be considered for patients of any age when the presence of polyps is suspected. Computed tomography enterography and small-bowel series are also options, but they are not preferred in children because of radiation exposure. For small intestinal polyps, if postoperative adhesions occur due to surgical treatment, it would become difficult to insert BAE into the deep small intestine; therefore, endoscopic treatment should be attempted whenever possible, and efforts should be made to avoid surgical treatment as much as possible. For this reason, it is necessary to diagnose and start endoscopic treatment before intussusception occurs, and surveillance for small intestinal polyps should be performed once around the age of 8 years for patients diagnosed with PJS or suspected of having PJS. If there are few polyps or no polyps at the initial examination, a second surveillance is recommended at the age of 18 years.

In terms of treatment, guidelines published by the JGES and the European Society of Gastrointestinal Endoscopy (ESGE) strongly recommend polypectomy using BAE for small intestinal polyps larger than 10–15 mm confirmed by SBCE or other imaging studies [36, 37, 47]. It is well known that polyp size is the most significant risk factor for intussusception, which is generally caused by polyps larger than 15 mm [8, 21, 22, 48–51]. Endoscopic resection of small-bowel polyps with BAE has been reported to reduce the need for surgical treatment in both the short and long term [21, 22]. Polyps larger than 10–15 mm, symptomatic polyps, and rapidly growing polyps should be resected, and polyps smaller than 10–15 mm may be considered for resection, while the procedure is easy as they are expected to grow in the future. Endoscopic resection using BAE is a relatively safe procedure for adults and children [8, 21, 22, 48–51]. BAE has been reported to be performed in infants as young as 1 year old and weighing 8 kg [51], and BAE can generally be performed in patients 3 years old and weighing 14 kg or more [52]. Acute pancreatitis and post-polypectomy syndrome have been reported as complications [21, 22, 48, 50]. Deep within the small intestine, it is inevitably difficult to maneuver BAE to apply a snare to the stalk of the polyp, and ischemic polypectomy using a detachable snare or clip has been described [53, 54]. It has been reported that ischemic polypectomy can treat many polyps in a shorter period than endoscopic resection, and it is less likely to cause complications [18]. Therefore, it is desirable to verify the efficacy and safety of ischemic polypectomy in larger cohorts. When polyps are exceptionally large and difficult to resect or cannot be reached by BAE, intraoperative endoscopic polypectomy or removal through an intestinal incision should be considered.

Regarding the usefulness of endoscopic resection of gastric and colorectal polyps, there is an expert opinion that polyps larger than 10 mm should be resected endoscopically [9]. Therefore, it is difficult to make a clear recommendation, but endoscopic resection should be actively considered for polyps that are large enough to cause intussusceptions, polyps that are thought to cause symptoms such as anemia or abdominal pain, and polyps that have structural irregularities and are suspected to contain malignancy. At present, there are no studies on whether resection of gastrointestinal polyps reduces the risk of carcinogenesis, and this is a subject for future study.

CQ3: Is Surveillance for Extragastrointestinal Lesions Recommended in Peutz-Jeghers Syndrome?

It is weakly recommended that surveillance be conducted for each organ with a high incidence of malignancy.

• Evidence level: C

• Recommendation level 2: weak

Explanation

The cumulative risk of overall cancer, including cancer of the gastrointestinal tract, increases sharply after the age of 40 years and occurs in more than half of the patients by the age of 60 years [7, 35, 55]. In a systematic review of Japanese patients with PJS, the cumulative risk of malignancy was 2.8% at age 20 years, 16.3% at age 30 years, 35.2% at age 40 years, 64.1% at age 50 years, 76.5% at age 60 years, and 83.0% at age 70 years [35]. The frequency of malignancy at the following locations has been reported [28]: breast cancer (24–54%), ovarian cancer (21%), cervical cancer (10–23%), uterine cancer (9%), testicular cancer (9%), lung cancer (7–17%), and pancreatic cancer (11–36%). The mean (or median) age of onset is 37–59 years for breast cancer, 28 years for ovarian cancer, 34–40 years for cervical cancer, 43 years for uterine cancer, 6–9 years for testicular tumors, 47 years for lung cancer, and 41–52 years for pancreatic cancer [7].

Surveillance without invasion or radiation exposure can be recommended at a young age because of the high incidence of extragastrointestinal cancers. However, it is necessary to consider the burden on the patient and the usefulness of each examination when deciding on invasive and radiation exposure-associated examinations. Table 4 lists the surveillance organs (including gastrointestinal organs included in CQ2), methods, intervals, and starting points for each organ that has been described in overseas guidelines (ACG [7], National Comprehensive Cancer Network [NCCN] [56], and European expert groups) [19] and are considered appropriate. There is no evidence that these surveillance methods improve the prognosis, and further validation is needed.

Table 4.

Recommended surveillance for patients with PJS [7, 19, 28, 34, 35, 56]

OrganFrequency (%)Risk ratio (95% confidence interval)Surveillance starting ageSurveillance intervalSurveillance methodStomach29
Japan 24213 (96–368)8 years old1–3 years*1Upper gastrointestinal endoscopyColorectum39
Japan 36.484 (47–137)8 years old1–3 years*1Total colonoscopySmall intestine13
Japan 13.8 (duodenum 10.3)520 (220–1,306)8 years old1–3 years*1SBCE
MREMammary gland54
Japan 19.315.2 (7.6–27)18 years old1 yearSelf-checking25 years old1 yearBreast MRI/USAfter 50 years old1 yearMammographyOvary21
Japan 10.127 (7.3–68)18–25 years old1 yearInternal examination/transvaginal (transabdominal) USUterine cervix10
Japan 46.5 (as uterine cancer)1.5 (0.31–4.4)18–25 years old1–3 yearsCervical smearUterine body916 (1.9–56)18–25 years old1 yearInternal examination/transvaginal (transabdominal) USTesticle94.5 (0.12–25)From birth to adulthood1 yearPalpation/US (if palpation is abnormal or gynecomastia is observed)Lung15
Japan 7.617 (5.4–39)None (consider starting earlier than general medical checkups)*2Pancreas36
Japan 29.4132 (44–261)30 years old1–2 yearsMRCP/EUS

The tumor characteristics of female patients with PJS include ovarian sex cord tumors with annular tubules (SCTAT), ovarian mucinous tumors, and minimal deviation adenocarcinoma, while those of male patients include large cell calcifying Sertoli cell tumors. SCTAT accounts for the majority of ovarian tumors in patients with PJS and is thought to occur in almost all female patients with PJS [7]. It occurs from childhood but is more common in individuals in their 40s and 50s. Malignant transformation is estimated to occur in approximately 20% of the cases. Internal examinations and transvaginal (transabdominal) ultrasound examinations are recommended at 1-year intervals from the age of 18–25 years to monitor the ovary and uterus, but CA125 is not recommended. However, the effectiveness of periodic surveillance is unclear, and there is concern that screening and surveillance at a young age may increase unnecessary surgical treatment of benign tumors. There are some case reports of ovarian mucinous tumors associated with PJS, but the exact incidence and rate of carcinogenesis are unknown, and the appropriate surveillance interval is unclear. Minimal deviation adenocarcinoma is a subtype of hyperdifferentiated gastric-type mucinous adenocarcinoma that is often difficult to differentiate from benign lesions and has been reported in a number of cases associated with PJS [57]. However, it is a malignant tumor that invades the deep cervix and paracervical connective tissue from an early stage, resulting in lymph node metastasis and poor prognosis. SCTAT-induced hyperestrogenism is thought to induce lobular endocervical glandular hyperplasia, which is a precursor lesion of, at least, some malignant adenomas and cervical adenocarcinomas [58]. In a systematic review of Japanese patients with PJS, case reports have been accumulated from patients aged 20 years, and surveillance from a young age is important [35]. Experts recommended that cervical smears using liquid-based cytology be performed every 2–3 years starting at the age of 21 years [35]. Lack of cytological atypia means that cytology is not sensitive, and cervical histology, transvaginal (transabdominal) ultrasound, and pelvic MRI should be considered, as necessary. Large cell calcifying Sertoli cell tumors occur in 9% of male patients with PJS before puberty and produce gynecomastia [7, 19]. The malignancy rate has been reported to be 10–20%. Testicular palpation should be performed every year from birth, and ultrasonography should be performed if palpation is abnormal or if gynecomastia is observed.

CQ4: Is Treatment of Pigmentations in Peutz-Jeghers Syndrome with the Expectation of a Cosmetic Benefit Recommended?

Laser treatment of pigmentations is weakly recommended if the patient requests treatment for cosmetic reasons.

• Evidence level: C

• Recommendation level 2: weak

Explanation

Laser therapy for pigmentations in patients with PJS has been performed using a Q-switched ruby laser [59, 60], Q-switched alexandrite laser [20, 61–63], Q-switched Nd (YAG) laser [64], pulsed ruby laser [65], argon laser [66], potassium titanyl phosphate (KTP) laser [67], erbium (YAG) laser [67], carbon dioxide laser [68], and intense pulsed light [69], all of which are effective. There were several reports indicating that Q-switched laser irradiation was effective, and among them, the Q-switched alexandrite laser was effective in a total of 60 cases [20, 61–63], including 14 cases in which non-recurrence was confirmed during a median observation period of 2 years [61]. Although treatment with carbon dioxide laser evaporation was reported to be useful, patients refused treatment for all pigmentations, suggesting that the burden of pain and postirradiation care seemed to be a deterrent [68]. Therefore, there was no literature that could recommend robust evidence because there was no literature with a sufficient number of patients who met the power of detection, and there was no randomized clinical trial. However, all these articles recommend laser treatment for pigmentations for cosmetic effects, and a certain recommendation can be made.

Acknowledgments

The authors thank the systematic review team identified in the in online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000527999) and Ms. Eri Okuda for her support in preparing these clinical guidelines. We would like to thank Editage (www.editage.com) for English language editing. Finally, we also thank members of the Japanese Society for Hereditary Tumors (JSHT), Japanese Gastroenterological Association (JGA), Chairperson Kazuhide Higuchi, Japanese Society of Pediatric Surgeons (JSPS), and Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN) for their total support to these guidelines.

Statement of Ethics

The authors have no ethical conflicts to disclose.

Conflict of Interest Statement

Prior to the preparation of these clinical guidelines, all members of the Guidelines Committee declared any conflict of interest. H.Y. has consultant relationship with S.R.J. Y.K.; honoraria for lectures from Takeda Pharmaceutical Co., Ltd.; Fujifilm Co.; Fujifilm Medical Co.; Eisai Co., Ltd.; and Daiichi Sankyo Co., Ltd. H.S. has received grants from Fujifilm Co. and Fujifilm Medical Co. K.B. has received payment for lectures from ASKA Pharmaceutical Holdings Co., Ltd.; grants from Sanofi, S.A.; Sysmex Co.; Taiho Pharmaceutical Co., Ltd.; KISSEI Pharma, Co., Ltd.; Fuji Pharma, Co., Ltd.; Astellas Pharma, Inc., and HEARZEST Co., Ltd. T.Y. has received honoraria for lectures from Taiho Pharmaceutical Co., Ltd. N.T. has received grants from Taiho Pharmaceutical Co., Ltd. H.I. has received grants from Taiho Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd. The other authors declare no conflict of interest.

Funding Sources

This article was supported by grants-in-aid from Health, Labour and Welfare Sciences Research on rare and intractable diseases (Grant No. 201711053A and 20FC1007; to H.I. and Y.N.).

Author Contributions

Hironori Yamamoto and Yoshiko Nakayama: conception and design, data analysis and interpretation, writing the manuscript, and final approval of manuscript. Hirotsugu Sakamoto: data collection, data analysis and interpretation, drafting the manuscript, writing the manuscript, and final approval of manuscript. Hideki Kumagai, Takashi Abe, Shingo Ishiguro, Keiichi Uchida, Yuko Kawasaki, Yoshihisa Saida, Yasushi Sano, Yoji Takeuchi, Masahiro Tajika, Takeshi Nakajima, Kouji Banno, Yoko Funasaka, Shinichiro Hori, Tatsuro Yamaguchi, Teruhiko Yoshida, Takeo Iwama, Yasushi Okazaki, Yutaka Saito, Nariaki Matsuura, Michihiro Mutoh, Naohiro Tomita, and Takashi Akiyama: data analysis and interpretation and final approval of the manuscript. Hideki Ishikawa and Hideyuki Ishida: data analysis and interpretation, writing the manuscript, and final approval of manuscript. Toshiki Yamamoto: collecting data, data analysis and interpretation, and final approval of the manuscript.

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