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Peutz-Jeghers Syndrome

, MD, , MD, , MD, , PhD, , MD, , MS, and , MD.

Author Information
, MD
Assistant Professor of Medicine and Medical Genetics, Mayo Clinic College of Medicine
, MD
Assistant Professor of Medicine, Mayo Clinic College of Medicine
, MD
Research Fellow of Medicine, Mayo Clinic College of Medicine
, PhD
Research Fellow, National Human Genome Research Institute
, MD
Assistant Professor of Medicine, Mayo Clinic College of Medicine
, MS
Genetic Counselor
Mayo Clinic Florida
, MD
Assistant Professor of Medicine, Mayo Clinic College of Medicine

Created: ; Last Update: August 9, 2008.

Introduction

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by melanotic macules, intestinal polyps, and an increased cancer risk. It is caused by mutations in the serine/threonine kinase 11 gene (LKB1, STK11).

Epidemiology

PJS is a rare disease. (“Peutz-Jeghers syndrome is no frequent nosological unit”. (1)) There are no high-quality estimates of the prevalence or incidence of PJS. Estimates have included 1 in 8,500 to 23,000 live births (2), 1 in 50,000 to 1 in 100,000 in Finland (3), and 1 in 200,000 (4). A report on the incidence of PJS is available at www.peutz-jeghers.com. At Mayo Clinic from 1945 to 1996 the incidence of PJS was 0.9 PJS patients per 100,000 patients. PJS has been reported in Western Europeans (5), African Americans (5), Nigerians (6), Japanese (7), Chinese (8, 9), Indians (10, 11), and other populations (12-15). PJS occurs equally in males and females (7).

Background

PJS was first reported in a pair of identical twins with melanotic macules (MMs) described by Connor in 1895 and illustrated by Hutchinson in 1896 (Figure 1) (16, 17). Later in life, the twins developed what are now known to be additional features of PJS: one died of intussusception at age 20, the other died of breast cancer at age 52 (5, 18).

Figure 1

Figure

Figure 1. 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). (more...)

Johannes Peutz reported two boys who were members of the same family with MMs and small intestine polyps in 1921 (Figure 2) (19). Peutz’s paper may be viewed by linking to "Peutz's original report on Peutz-Jeghers syndrome". In 1949, Harold Jeghers and others reported an additional 10 cases from several families (Figure 3) (5). The eponym Peutz-Jeghers syndrome was first used in 1957 (20). A history of PJS with biographies of Peutz and Jeghers has been published, and many early PJS papers have been made available online by the Jeghers Medical Index (http://www.jeghers.com/pj_pubmed.aspx) (21). The website www.peutz-jeghers.com is another resource for PJS patients and health care providers.

Figure 2

Figure

Figure 2. Reproduction of the single figure from Dr. Johannes Peutz’s 1921 paper. Pictured are a segment of jejunum with polyps and the patient demonstrating melanotic macules on his lower lip. The original caption read, “Concerning the (more...)

Figure 3

Figure

Figure 3. Photo of the patient described in case 5 from the 1949 New England Journal of Medicine report by Drs. Jeghers, McKusick and Katz (this photo was not included in that publication). Note the perioral and periocular melanotic macules. Provided (more...)

Although Peutz described early jejunal adenocarcinoma in one of his patient’s polyps, it was controversial whether or not there was an increased cancer risk associated with PJS until the 1980s (22-27). For example, the author of a 1974 JAMA editorial estimated the lifetime intestinal cancer risk for PJS at only 2-3%, whereas the most recent estimate is 57% (23, 28).

In 1997 the PJS locus was localized to 19p13.3 using comparative genome hybridization, loss of heterozygosity studies, and targeted linkage analysis (29). One year later, mutations in the LKB1 gene at that locus were identified in PJS patients by two groups (30, 31). A follow-up study of Peutz’s original pedigree identified an LKB1 mutation in affected family members (32).

LKB1 is the original gene designation and is still used. SKT11 is the official designation for LKB1 by the Human Genome Organization (HUGO) (http://www.genenames.org/data/hgnc_data.php?hgnc_id=11389). LKB1 is the only gene associated with PJS. Mutations in LKB1 can be found in about 75% of PJS patients using sequencing and multiplex ligation-dependent probe amplification (MLPA) (Table 1).

Table 1

Table

Table 1. Identification of LKB1 mutations in Peutz-Jeghers syndrome patients

Pathophysiology

LKB1

The LKB1 protein is a serine/threonine kinase. It is the only known tumor suppressor kinase. LKB1 consists of 10 exons covering 22.6 kb of genomic DNA located at 19p13.3 (Figure 4). Nine exons are coding; the final exon is non-coding. Only one transcript isoform is known. LKB1 codes for the 433 amino acid LKB1 protein that is expressed in most epithelial tissues, myocytes, glia cells, and the cells of the seminiferous tubules (Figure 5) (33, 34). Fetal tissues have higher expression than adult tissues (33). LKB1 is present primarily in the cytoplasm (35).

Figure 4

Figure

Figure 4. LKB1 consists of 10 exons covering 22.6 kb of genomic DNA located at 19p13.3. Nine exons are coding; the final exon is noncoding.

Figure 5

Figure

Figure 5. Exonic boundaries and the protein kinase domain of LKB1.

A multispecies alignment of the amino acid sequence of LKB1 across human, chimpanzee, dog, rat, mouse, chicken, xenopus, zebrafish, and drosophila reveals a highly conserved core of 245 amino acids, corresponding to the C-terminal portion of the LKB1 kinase domain (Figures 5 and 6). Human and mouse share 98% identity and 99% similarity across this region, versus 89% identity and 93% similarity across the entire protein.

Figure 6

Figure

Figure 6. Sequence conservation of LKB1. A multispecies alignment of LKB1 amino acid sequence from nine vertebrates and one insect. Drosophila and Xenopus sequences have been truncated at C-terminal end for clarity. Colors denote amino acids with similar (more...)

Peutz-Jeghers syndrome patients without identifiable LKB1 mutations

Twenty-five percent of PJS patients do not have detectable LKB1 mutations (Table 1). These patients probably have large rearrangements of LKB1, including deletions, duplications, and inversions of areas larger than an exon. Large rearrangements are common in familial cancer syndrome patients who do not have mutations detected by sequencing. Most of these will be detected by MLPA, while some may not be. Conversion technology has increased the mutation detection rate in familial cancer syndromes, but to date there are no reports of the use of Conversion to identify LKB1 mutations (36).

Other possibilities less likely than large rearrangements include LKB1 promoter mutations, mosaicism, LKB1 intronic mutations, or a PJS locus other than LKB1. A search for promoter mutations in 33 PJS patients without an identifiable LKB1 mutation was negative (37). LKB1 mutation mosaicism has never been described in published report, although there are two possible cases (personal communications S. Sugarman, C. Stratakis). Three lines of evidence support the hypothesis that there is another PJS locus in addition to LKB1. First, there are three PJS families reported that do not show linkage to the LKB1 locus and one PJS family with linkage to 19p13.4 (38, 39). In the 19p13.4 family, analysis of four genes at 19q13.4 did not identify a mutation (40). Second, LKB1 sequencing has been able to identify a mutation in only 75% of patients with a diagnosis of PJS (Table 1). Finally, a chromosomal translocation at the previously identified 19p13.4 locus was identified in a PJS-type polyp taken from a 6-day-old PJS patient (41). Despite this data, identification of a second PJS locus has been elusive, and no mutations have been found in any of the genes investigated. These include genes whose protein products interact with LKB1 (STRAD25, MO25, BRG1, LIP), proteins activated by LKB1 (MARK family of microtubule associated kinases), and candidate genes identified in mouse models (CDX2) (40, 42-45).

LKB1 in normal physiology

LKB1 complexes with STE-20 related adaptor (STRAD) and mouse protein 25 (MO25). STRAD is an inactive pseudokinase and MO25 is an armadillo repeat scaffolding protein. The catalytic activity of LKB1 increases when bound to STRAD, and when LKB1 is complexed with STRAD/MO25 it is sequestered in the cytoplasm (35).

LKB1 functions are mediated through at least 13 downstream kinases that LKB1 activates by phosphorylation of threonine residues in a lysine-X-threonine motif (AMPK, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MELK) (46). The most well-described functions of LKB1 are as a sensor and regulator of cellular energy and in establishing cellular polarity. In stress conditions such as hypoglycemia or hypoxemia LKB1 down regulates protein synthesis. The measure of energy availability that activates LKB1 is an increased AMP/ATP ratio. When activated LKB1 phosphorylates AMPKinase, which in turn downregulates the mammalian target of rapamycin (mTOR ) pathway through tuberin (TSC2) (47).

LKB1 has also been shown to have a role in cellular polarity in cell systems, Drosophila, Caenorhabditis elegans, and mouse oocytes. Experiments in cell systems have shown that activation of LKB1 by inducing STRAD causes the formation of an apical brush border and that LKB1 is necessary for mammalian brain axonal polarization (48-50). Mutations in the Drosophila homolog of LKB1, AMPKα, result in the loss of epithelial cell polarity (51). Limited data support a role for LKB1 orthologs in the development of asymmetry in C. elegans and in mouse embryogenesis (52, 53).

Lkb1-deficient mouse models

Lkb1 -/- mice die in utero between 8.5 and 9.5 days postcoitum (54-57). These embryos have abnormal placental development, neural tube defects, vascular malformations, and a hypoblastic or absent first brachial arch (56).

Lkb1 +/- mice recapitulate the human polyp phenotype. By 6.5 months of life they have developed adenomas of the stomach; most are at the pylorus (Figure 7) (58). They have a median life expectancy of 14 months. Histologically, polyps from lkb1 +/- mice consist of mucus, pyloric gland epithelium, and arborization of connective tissue similar to the unique smooth muscle arborization seen in human PJS polyps (Figure 8). Unlike human PJS patients, lkb1 +/- mice rarely have small bowel polyps and do not have colon polyps or develop gastrointestinal, pancreatic, breast, or other carcinomas.

Figure 7

Figure

Figure 7. Panel (a) above, control mouse stomach and proximal small intestine; below, distended stomach of the lkb1 +/- mouse. Panel (b) Pyloric polyps in lkb1 +/- mouse (arrows). Reproduced from Rossi and others, Proc Natl Acad Sci USA 2002: 12327–12332. (more...)

Figure 8

Figure

Figure 8. Panels (a) and (b) are low and high power microscopic views, respectively, of a PJS-type polyp from a PJS patient. Panels (c) and (d) are low and high power microscopic views, respectively, of pyloric junction polyp from an lkb1 +/- mouse. Arrows (more...)

After 50 weeks of life, some lkb1+/- mice do develop hepatocellular carcinoma (HCC) (59). Analysis of the HCCs in these mice identified LOH at the lkb1 locus. Lkb1 -/+ mice have been crossed onto COX-2 and P53 deficient backgrounds showing decreased and increased neoplasia, respectively (58, 60, 61).

It has recently been reported that 12 lkb1+/- asymptomatic mice sacrificed at 300 days all had asymptomatic osteogenic tumors of the vertebral column (62). Hypomorphic Lkb1 mice (Lkbfl/fl) have been created that express 10% of the normal amount of Lkb1. These mice do not develop tumors or polyps (63).

Neoplasia in Peutz-Jeghers syndrome

Cancer paradigm: Two hits or one?

The paradigm for neoplasia in familial cancer syndromes is the two-hit model (Knudsen hypothesis) (64). The first hit is inherited as a germline mutation, and the second hit occurs by chromosomal deletion (loss of heterozygosity), chromosomal rearrangement, hypermethylation, or somatic mutation. PJS differs from other familial cancer syndromes in that there is data supporting both a one-hit (haploinsufficiency) and two-hit model. Data supporting the one-hit model includes that there is no LOH of lkb1 and 50% Lkb1 expression in lkb1+/- mouse polyps, LOH at the LKB1 locus is seen in only some human PJS polyps, and smooth muscle limited Lkb1 mouse knockouts have the same polyp formation regardless if one or both lkb1 alleles are knocked out (54, 65).

Some data from human PJS patients supports the two-hit model. Immunohistochemistry studies of PJS polyps show some have a complete loss of LKB1 staining, and LKB1 LOH is seen in about 50% of PJS polyps and cancers studied (Table 2) (66, 67). In the polyps without LOH there is evidence that either somatic mutations or hypermethylation are the second hit in some cases. In a study of 27 PJS polyps, 19 had LOH of LKB1, 5 had somatic mutations of LKB1, and 3 had neither (68). In the only study of LKB1 hypermethylation, four of 22 PJS polyps showed LKB1 hypermethylation (69).

Table 2

Table

Table 2. Loss of heterozygosity at the LKB1 locus in Peutz-Jeghers syndrome–associated polyps and cancers

Precursor lesions and pathways (hamartoma → carcinoma sequence)

Cancer precursors and pathways have only been well studied for intestinal cancer in PJS. The canonical precursor for cancer in PJS is the PJS hamartomatous polyp, and the canonical pathway for intestinal cancer in PJS is the hamartoma → carcinoma sequence (hamartoma → low grade dysplasia → high grade dysplasia → carcinoma). The hamartoma → carcinoma sequence also proposes that with each histological step toward carcinoma there are corresponding cumulative molecular events (e.g. KRAS mutations followed by APC mutations). This pathway is analogous to the adenoma → carcinoma sequence for sporadic colorectal neoplasia (Vogelstein paradigm).

The histological evidence supporting the hamartoma → carcinoma sequence includes reports of cancer developing in hamartomatous PJS polyps and no reports of cancer not associated with polyps. Also, dysplasia in PJS polyps is only seen in larger polyps which would agree with hamartoma → carcinoma sequence hypothesis that as polyps become larger there are more molecular events leading to the development of cancer. Many reports have followed the initial report of cancer in a PJS polyp in Peutz’s original description, and a 1994 review identified 24 reports in 20 patients (see appendix "Peutz's original report on Peutz-Jeghers syndrome") (7, 8, 70-75). Other than data showing somatic inactivation of LKB1 (reviewed above), there is little molecular data supporting the underlying cumulative molecular events presumed to be the basis of the hamartoma → carcinoma sequence.

An alternative theory to the hamartoma → carcinoma sequence was put forward by the authors of papers in 2006 and 2007 (76, 77). The authors proposed that PJS polyposis occurs through loss of cellular polarization and is not the result of cumulative genetic events as seen with sporadic colon polyps or the polyps of other colorectal familial cancer syndromes. They propose carcinogenesis in PJS occurs by well-established pathways, probably the Wnt/APC/β-catenin pathway, and is unrelated to events causing hamartomatous polyposis. Data supporting this hypothesis comes from their study of polyps from two PJS patients. The polyps were found by them to be polyclonal with an expanded progenitor zone. The authors interpret the polyclonality of the polyps as not supporting hamartoma → carcinoma sequence, as polyps progressing through a pathway would be monoclonal, and they speculate that the expanded progenitor zone indicates asymmetrical cell division as the pathway for carcinogenesis in PJS.

Molecular Pathways (Wnt/APC/β-catenin, DNA mismatch repair and COX-2)

It is unclear whether the molecular pathways involved in other familial cancer syndromes are also involved in PJS. PJS polyps do not have evidence of DNA mismatch repair defects as seen in Lynch syndrome (78). APC somatic mutations and APC LOH with resulting nuclear β-catenin accumulation are characteristic of familial adenomatous polyposis (79). Somatic APC inactivation as a result of LOH or somatic mutations is rare in PJS (Table 3). Two of three studies of β-catenin nuclear accumulation in PJS polyps have found abnormal accumulation (Table 4).

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Table

Table 3 APC mutations and 5 q loss of heterozygosity in Peutz-Jeghers syndrome polyps and cancers

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Table

Table 4 Nuclear β-catenin in Peutz-Jeghers syndrome polyps and cancers

Of the several downstream pathways of LKB1, it has not been possible to conclusively isolate which if any of them are responsible for PJS-associated neoplasia. Knockout mice of two of the downstream kinases activated by LKB1, AMPK α1/α2 and Emk/Park-1 (mouse homolog of LKB1 target MARK2), have not reproduced the PJS phenotype (80-82). As noted above, LKB1 is a proximal member of the mTOR pathway, and treatment of lkb1 +/- mice with the mTOR inhibitor rapamycin has been shown to suppress polyp formation (83).

Investigations in PJS patients and the lkb1+/- mouse show a role for COX-2 in PJS neoplasia. COX-2 is over expressed in 60-80% of PJS polyps (Table 5). One study showed COX-2 expression correlated with dysplasia, 24% of hamartomas compared to 64% of carcinomas having moderate or strong COX-2 expression (84). Another study found a correlation between COX-2 and LKB1 staining in PJS polyps (67). Crossing lkb1+/- mice onto a COX-2-/+ or COX-2-/- background or treating them with a COX-2 inhibitor decreases polyp burden (61). In the only study of chemoprevention in PJS patients, six patients were treated for six months with celecoxib 200 mg twice daily (61). Two of six patients met the primary endpoint of a decrease in gastric polyps as assessed by endoscopy.

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Table

Table 5 COX-2 expression in Peutz-Jeghers syndrome polyps

Pathology

PJS-type intestinal polyps are disorganized normal tissue (hamartomas). PJS-associated polyps can be differentiated from sporadic hamartomatous polyps and hamartomatous polyps associated with other syndromes by a unique smooth muscle core that arborizes throughout the polyp (Figure 9). PJS-type polyps do not have specific endoscopic features and can only reliably be distinguished from other types of polyps by histopathology.

Figure 9

Figure

Figure 9. PJS-type polyp histology. Note the arborizing smooth muscle architecture unique to PJS-type intestinal polyps (arrows). See also figures (10, 11 and 12).

The unique PJS polyp pathology is best appreciated in PJS small intestine polyps (85). The histopathology of PJS-associated gastric polyps can be similar to hyperplastic gastric polyps. Mucosal prolapse colon polyps can have a smooth muscle core similar to the one seen in PJS-associated polyps. A few PJS patients have been reported to also have adenomatous and hyperplastic polyps, and there is one case report of osseous metaplasia of PJS-type polyps (26, 86, 87).

Pseudo-invasion

The epithelium of PJS polyps can invade into the wall of the intestine without transforming into cancer (Figures 10, 11, and 12) (88, 89). This is termed pseudo-invasion. Pseudo-invasion can mimic malignant invasion and has been misdiagnosed as small intestine cancer. It has been reported only in PJS small intestine polyps and not in PJS colon or stomach polyps (90). In a review of PJS-type polyps at St. Mark’s Hospital, 10% had pseudo-invasion (90).

Figure 10

Figure

Figure 10. High power microscopic view of a PJS-type jejunal polyp with pseudo-invasion. Arrow indicates an area of low grade dysplasia. For lower power views see Figures (11) and (12).

Figure 11

Figure

Figure 11. Low power microscopic view of a PJS-type jejunal polyp with pseudo-invasion. Arrows indicate hamartomatous small intestine mucosa in the intestinal wall. See also figures (10 and 12).

Figure 12

Figure

Figure 12. Medium power microscopic view of a PJS-type jejunal polyp with pseudo-invasion. Arrows indicate hamartomatous small intestine mucosa in the intestinal wall. See also figures (10 and 11).

Sporadic Peutz-Jeghers-type polyps not associated with PJS

Sporadic PJS-type polyps not associated with PJS are rare. Only 12 sporadic PJS duodenal polyps have been reported (91). A study of 121 PJS-type polyps at Johns Hopkins Hospital was unable to definitively identify a patient with a PJS-type polyp who did not have PJS (85). At the Cleveland Clinic, over a period of approximately 20 years, eight patients with solitary PJS-type polyps were identified. On follow-up, none of these patients developed features of PJS, although one patient died of colon cancer 12 years after identification of the solitary PJS polyp.

The most common location for sporadic PJS-type polyps is the colon, followed by the rectum and the duodenum. Patients typically present later in life; in one study the mean age of presentation was 55 years (92). The malignant potential of sporadic PJS-type polyps is unknown. Two sporadic PJS-type polyps have been reported to have a focus of adenocarcinoma (91, 93). The authors recommend that all patients with a solitary PJS-type polyp be evaluated for PJS.

Melanotic Macules

PJS MMs have increased basal pigmentation and melanocytes with long pigment-filled dendrites (94). Electron microscopy has shown a blockage in pigment transfer from melanocytes to keratinocytes in MMs of the fingers and toes (95).

Diagnosis

PJS is a clinical diagnosis based on MMs, PJS-type intestinal polyps, and family history. Genetic testing is usually not necessary (see LKB1 Genetic testing in the diagnosis and management of Peutz-Jeghers Syndrome). There is no consensus or society-endorsed diagnostic criteria. Table 6 shows the diagnostic criteria used at Mayo Clinic and that of Tomlinson and Houston.

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Table

Table 6 Diagnostic criteria for Peutz-Jeghers syndrome

Clinical Genetics

LKB1 mutations in PJS patients

Approximately 75% percent of PJS patients have identifiable mutations in LKB1 (Table 1). Two-thirds of mutations are detectable by sequencing and one-third by MLPA. A review of 145 germline PJS LKB1 mutations found that 34% were deletions, 21% missense, 14.5% insertions, 12% nonsense, 14% splice site, and 4.5% deletions/insertions, inversions, genomic rearrangements, and others (96). One PJS family with a complete deletion of LKB1 has been reported (97). Seven percent of PJS families have been found to have either a 1-bp deletion or 1-bp insertion in a 6-cysteine repeat mutation hotspot (c.837–c.842) (13, 96).

A higher proportion of PJS patients has new mutations and no family history than do patients with other inherited cancer syndromes. The percentage of PJS patients without a family history is about 45% (98). For comparison, only 15% of familial adenomatous polyposis (FAP) patients do not have a family history. The reason for the high degree of new mutations in PJS is probably the low reproductive fitness of PJS patients prior to the introduction of effective treatment for intussusception.

LKB1 genetic testing in diagnosis and management

LKB1 genetic testing plays a limited role in the diagnosis and management of PJS patients (see Diagnosis). As 25% of confirmed PJS patients will have a negative genetic test, a clinical diagnosis of PJS stands even when genetic testing is negative. As there are no clinically significant genotype/phenotype correlations, a positive or negative genetic test does not change management.

Molecular diagnostic laboratories advertise LKB1 testing for PJS, including sequencing of coding regions, deletion/duplication testing by MLPA, linkage analysis, prenatal and preimplantation testing. A list of laboratories offering LKB1 testing can be found at www.geneclinics.org. LKB1 genetic testing can be difficult to coordinate and is expensive (>1,000 US$).

Genotype/phenotype correlations

LKB1/PJS genotype/phenotype correlations are of great interest as they could allow for targeted cancer surveillance. Unfortunately, no clinically significant genotype/phenotype correlations for LKB1/PJS have been identified. A review of the largest cohort of PJS patients to date, 416 patients, found a nonsignificant trend for increased cancer risk in patients with truncating mutations as compared with nontruncating mutations (28). Other reports of genotype/phenotype correlations have included an association between LKB1 exon 6 mutations and increased cancer risk, an increased risk for bile duct cancer in patients without detectable mutations, and no genotype/phenotype association (99-101).

A somatic mutation/phenotype correlation for cancer has been reported. Entius and others found that polyps from PJS patients with cancer had a higher proportion of loss of heterozygosity (LOH) at the LKB1 locus than PJS patients without cancer (102). Studies are contradictory on the presence of a genotype/phenotype correlation for intussusception in PJS (103, 104).

Penetrance, expressivity, mosaicism, and modifiers

PJS is highly penetrant with variable expression. Only one case of nonpenetrance of an LKB1 mutation has been reported (38). Almost all PJS patients will display the two cardinal features of the disease (MMs and PJS-type intestinal polyps) and most will develop a PJS-related cancer (Figure 13). There is significant variability in the timing and extent of the MMs, polyps, and cancers (1) (Tables 7 and 8, and Figure 14). There are two reports of possible LKB1 mutation mosaicism which have not yet been published (personal communications S. Sugarman, C. Stratakis). No genetic or environmental modifiers of the LKB1/PJS phenotype have been identified.

Figure 13

Figure

Figure 13. A graphical representation of the natural history of Peutz-Jeghers syndrome. Most patients will develop melanotic macules during the first year of life and a patient’s first intussusception usually occurs between the ages of six and (more...)

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Table

Table 7 Intra- and inter- familial variability of Peutz-Jeghers syndrome

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Table

Table 8 Youngest and oldest reports of cancer in Peutz-Jeghers syndrome patients

Figure 14

Figure

Figure 14. Cancer diagnosis in three well-described Peutz-Jeghers syndrome families. Some family members who died at a young age from causes other than cancer are not included. See Table 7 for source data.

Natural History

Overview

MMs usually develop on the lips by the end of the first year of life and are almost always present by 5 years of age (Figures 1-3) (32). Unless a family history of PJS is present, the MMs are usually interpreted as freckles and a diagnosis of PJS is not made.

Between the ages of 6 and 18 years most PJS patients will present with symptoms of obstruction due to small intestine intussusception. Some patients will present subacutely with intermittent bouts of abdominal pain while others present emergently with severe abdominal pain, nausea, and vomiting. Most patients will undergo surgery at their initial presentation with abdominal pain, often before the diagnosis of PJS is made. Rarely patients will initially present with rectal bleeding or a prolapsing rectal polyp (105).

Almost all PJS patients will be diagnosed with one or more cancers during their lives, usually in middle age or later (Table 9). There is no current data available on the long-term survival of PJS patients. In a report of 72 PJS patients published in 1989, 48% had died from cancer by the age of 57 years (25). A study of the psychosocial impact of PJS found patients had mild depression but did not feel physically impacted by PJS (106).

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Table

Table 9 Cumulative cancer risk by site and age (population risk) from a study of 416 Peutz-Jeghers syndrome patients

Melanotic macules

Melanotic macules (MMs) on and around the lips are a cardinal feature of PJS (Figures 1-3). They can also be seen on the buccal mucosa, surrounding the eyes and ears, on the tips of the dorsal surface of fingers and toes, on the eyelids, and surrounding the anus and genitals. In a Japanese cohort, 94% of patients had MMs surrounding the lips, 65% on the buccal mucosa, 73% on the finger tips, 62% on the toe tips, and 21% in other locations (7).

The facial distribution of the MMs is the inverse to that of freckles (ephilides); they have been referred to as ephilides inversae (107). PJS MMs also can be distinguished from freckles by their presence on the buccal mucosa and hard palate. The macules are usually 1 to 5 mm in diameter and vary in color from “ink black” to dark chocolate to latte (Figure 1 caption(16)).

MMs typically develop on the lips by the end of the first year of life and are almost always present by 5 years (Table 7) (32). They are rarely present at birth (108). In puberty and adulthood PJS MMs fade and in some cases can disappear. Therefore, the absence of MMs in an adult patient presenting for PJS evaluation should not rule out the diagnosis of PJS. There is wide variation between patients in the distribution, intensity, and timing of appearance and disappearance of the macules.

A few PJS patients will not have MMs at anytime. In a series of 170 PJS patients, there were two cases of PJS with documented LKB1 mutations without MMs (84). Possible explanations include incomplete expressivity, slightly noticeable pigmentation in childhood that was not noted and then faded, or mosaicism.

PJS-associated MMs can be removed for cosmetic reasons with laser treatment (109-111). MMs associated with PJS have never been reported to develop into melanoma or other malignancy. Two patients with PJS have been diagnosed with melanoma not associated with a melanotic macule (112, 113). MMs have been reported in the psoriatic plaques of PJS patients with psoriasis (94, 114).

Laugier-Hunziker syndrome (LHS) and isolated mucocutaneous melanotic pigmentation (IMMP) patients can have MMs on the lips similar to PJS. LHS can be differentiated from PJS by a later onset of pigmentation in adulthood, pigmentation of the finger nails (longitudinal melanonchyia), and lack of family history (115). LHS is not associated with an increased risk of cancer or PJS-type intestinal polyps. The etiology of LHS is unknown; sequencing of LKB1 in a patient with LHS did not identify a mutation (115). IMMP patients have PJS-type MMs without any PJS-associated polyps, malignancies, or LKB1 mutations. Female IMMP patients have an increased risk for gynecological cancers (116).

For discussion of the pathology of MMs see Pathology.

Nasal polyposis and other sites of extra-intestinal polyps

Nasal polyposis and nasopharyngeal carcinoma

A recent study found nasal polyps in eight (15%) of 52 PJS patients studied (117). Six of 22 members of the original Peutz pedigree have been diagnosed with nasal polyposis (32). Three PJS patients with nasopharyngeal carcinoma have been reported (32, 99).

Nasal polyposis has been molecularly confirmed as a manifestation of PJS by LOH at the LKB1 locus in the nasal polyps of PJS patients (118). A comparative histological study of PJS-associated nasal polyps and sporadic nasal polyps found fewer eosinophils in the PJS polyps (117). In the same study, 11 of 12 PJS-associated nasal polyps were found to express COX-2 compared with 19 of 28 sporadic nasal polyps.

There are no published recommendations for the surveillance and management of PJS nasal polyps. St. Mark’s Hospital, Johns Hopkins Hospital, and Mayo Clinic PJS management protocols do not recommend routinely evaluating PJS patients for nasal polyps. PJS patients with sinus obstruction caused by polyps have been treated with surgery (119, 120).

Gallbladder and bile duct polyps and cancer

In a series of 72 PJS patients, three (4.1%) had gallbladder polyps (11). Also reported are one PJS patient requiring cholecystectomy for gallbladder obstruction by polyps and one PJS patient with common bile duct obstruction by polyps (121, 122). Two PJS patients with gallbladder cancer have been reported; one had gallbladder cancer arising near but not in hamartomatous gallbladder polyps (7, 123). Several PJS patients have been reported with bile duct cancer (cholangiocarcinoma) (89, 100).

There are no published recommendations for the surveillance and management of PJS gallbladder and common bile duct polyps. We recommend that gallbladder polyps greater than 10 mm be removed by cholecystectomy. Smaller gallbladder polyps should be monitored at three and six months after diagnosis, and if stable then yearly.

Rare sites of extra-intestinal polyps in PJS patients

Hamartomatous polyps in PJS patients have also been reported in the ureter (124), respiratory tract (125, 126), and on the tonsils (127).

PJS-type polyps

PJS patients have polyps throughout the gastrointestinal tract. The jejunum is the most common location, followed by the ileum, colon, rectum, stomach, duodenum, appendix, and esophagus (Figures 15, 16, 17, 18, and 19) (128). Some patients may develop thousands of small polyps carpeting the small intestine, others only a handful of polyps. The natural history of PJS-type polyps has not been well studied. From the authors’ and anecdotal experience, polyp growth is erratic, with polyps remaining the same size for many years. Some polyps may regress or autoamputate and spontaneously pass (7). The pathology and surveillance regimens for PJS-type polyps are discussed separately (Pathology, Small intestine polyp and cancer surveillance).

Figure 15

Figure

Figure 15. Section of jejunum removed from a Peutz-Jeghers patient at surgery with multiple pedunculated polyps. Courtesy of Victor McKusick, MD, Johns Hopkins Hospital.

Figure 16

Figure

Figure 16. Stomach polyps in a Peutz-Jeghers syndrome patient.

Figure 17

Figure

Figure 17. Duodenal polyp in a Peutz-Jeghers syndrome patient.

Figure 18

Figure

Figure 18. Ileal polyp in a Peutz-Jeghers syndrome patient.

Figure 19

Figure

Figure 19. Colon polyp in a Peutz-Jeghers syndrome patient.

PJS polyps should be removed before they cause intussusception/obstruction, develop dysplasia, or become too large to remove endoscopically. Polyps occurring in the stomach, duodenum, and colon are easily reached and removed by standard endoscopy. The authors recommend polyps in these areas usually be removed. Small intestine PJS polyps can be much more difficult, if not impossible, to remove by endoscopy. Therefore, a cutoff for which small intestine polyps to invest the resources to attempt to remove has great clinical importance.

The first proposed cutoff for small intestine polyp removal was 1.5 cm, proposed in 1994 by the Danish polyposis registry (129). Further reports have expanded the cutoff range to between 1.0 and 1.5 cm (76, 129, 130). In the authors’ experience, the 1.5 cm cutoff is appropriate. Small intestine polyps rarely intussuscept in adults until they are larger than 1.5 cm, dysplasia is rare until polyps are larger than 3.0-5.0 cm, and double balloon endoscopy (DBE) has been used to remove polyps as large as 3 cm. The authors have developed a protocol for management of PJS small intestine polyps using extended endoscopy, DBE, and laparoscopic intraoperative endoscopic polypectomy (Figure 20).

Figure 20

Figure

Figure 20. Mayo Clinic Peutz-Jeghers syndrome small intestine polyp management algorithm.

Double balloon endoscopy

DBE was approved by the U.S. Food and Drug Administration in 2004, and the first DBE procedure for PJS was reported in 2005.54 Since then, several case reports or small case series of DBE for the removal of small intestine polyps in PJS patients have been published (131-134). There is no data on the long-term efficacy of DBE-assisted polyp removal in PJS patients in preventing intussusceptions or cancer. Removal of a small intestine PJS polyp using DBE is demonstrated in Movie Clip 1.

Pre-DBE imaging with MRI enteroclysis and other small intestine imaging techniques provides the information needed to plan either an antegrade (oral) or retrograde (anal) approach in order to target the largest polyps. The primary objective at DBE is to remove the large polyps inaccessible to standard endoscopy. The authors do not usually remove small polyps (≤5 mm).

The DBE system (Fujinon Inc., Saitama, Japan) consists of a 200-cm long endoscope, an overtube, and a balloon pump controller to inflate and deflate two balloons affixed at the tip of the endoscope and overtube (Figure 21). The objective is to advance and reduce the endoscope and overtube in a repetitive sequential fashion that allows pleating of the small intestine onto the overtube. Yamamoto has published a review of the technical details (135). The DBE procedure can be performed via the antegrade (oral) or retrograde (anal) approaches without or with intraoperative assistance (136). The insertion route is selected according to the estimated location of the target polyps based on clinical impression and imaging studies. With antegrade DBE, the scope can usually be inserted to the distal jejunum or proximal ileum. With retrograde DBE, the scope can typically be advanced to the proximal ileum. Using both ante- and retrograde approaches, complete small bowel examination can be performed in 30-60% of patients (137, 138). For patients with polyps unresectable by the ante- or retrograde approaches, intraoperative endoscopy with standard or double balloon endoscopy is recommended (136).

Figure 21

Figure

Figure 21. Fluoroscopic image of a retrograde double balloon endoscope at maximum insertion.

DBE is a safe procedure and serious complications are rare. The risk of perforation is approximately 0.5%. Thirty percent of cases will be complicated by post-procedure abdominal pain, 46% by asymptomatic hyperamylasemia, and 1% or less by pancreatitis (139, 140). Most PJS patients have intra-abdominal adhesions from multiple surgeries. Adhesions can cause sharp intestinal bending, hinder effective small bowel pleating, and limit the depth of insertion. Adhesions may also increase the risk of perforation. The only DBE complication reported in a PJS patient was an intestinal perforation in an infant (141).

Intraoperative endoscopy

During intraoperative endoscopy the surgeon guides the endoscope through the small bowel and can lysis adhesions blocking the endoscope. These maneuvers increase the reach of the endoscope, and often the entire small bowel can be seen using a combination of antegrade and retrograde approaches. Usually standard endoscopes are used for intraoperative endoscopy, but double balloon scopes have also been used (136).

Intraoperative endoscopy can be used during open or laparoscopic surgery to remove polyps that cannot be removed using standard endoscopy or performed as an additional procedure when abdominal surgery is being performed for another indication. When PJS patients do undergo surgical polypectomy or other abdominal surgical procedures, it is recommended that the opportunity be used to perform a total polyp clearance (“clean sweep”) by intraoperative endoscopy.

Two retrospective studies have confirmed the value of intraoperative endoscopy in PJS patients (142, 143). In one, 25 PJS patients who underwent small bowel clearance by intraoperative endoscopy had a significantly decreased reoperation rate compared with historical controls (142). In another, intraoperative endoscopy was superior to palpation for polyp detection, with a median of 12 additional polyps that could not be palpated removed endoscopically.

Intussusception

The distribution of intussusceptions follows the distribution of polyps: jejunum, ileum, and colon. Rare and unusual intussusceptions have also been reported in PJS patients including gastroduodenal intussusceptions (9, 105, 144), double and triple intussusceptions (patients presenting with two or more different intussusceptions at the same time) (1, 105), appendiceal intussusceptions (145-147), and retrograde intussusceptions (144). Most PJS patients present with an intussusception between the ages of 6 and 18. Patients as young as 15 days old and as old as 35 years have presented with their first intussusception (108, 148).

Symptoms of intussusception include abdominal pain, nausea, vomiting, and bloody stool. PJS patients presenting with symptoms of intussusception should have an emergency evaluation with an abdominal computated tomography (CT) scan and surgical consultation (149). Treatment of acute intussusception with intestinal obstruction is surgical. Endoscopic management is not recommended.

The surgical approach is dependent on the location and extent of the intussusception, suspicion for malignancy, and extent of associated inflammation, edema, and ischemia (150). For the most common intussusception in PJS, jejunal/jejunal by a nonmalignant polyp, the recommended surgical technique is reduction, enterotomy, and polyp resection. After reduction, the base of the polyp that served as the lead point can be identified by a dimple in the wall of the small intestine (7). The polyp can be removed through a small incision adjacent to the dimple. If there is concern for malignant invasion after the incision is made, the base of the polyp and adjacent small bowel can be excised by extending the initial incision. In the rare case where the lead point of the intussusception is suspected to be a polyp with cancer, reduction should not be performed before the enterotomy is made to prevent dissemination of malignant cells. If possible, intra-operative endoscopy should also be performed to remove other polyps. One group recommends prolapsing the small intestine through the enterotomy incision so that 2 or 3 feet of mucosa can be inspected for polyps (143).

Cancer Risk

PJS patients have an increased risk for cancers of the colon, stomach, small intestine, pancreas, breast, and other organs. The most current and complete data on cancer risk in PJS patients is from a multicenter collaborative series of 416 PJS patients published in 2006 (Figure 22, Table 9) (28). The cumulative cancer risk for a PJS patient was 85% by age 70 (control population risk 18%). Thirteen percent to 15% of PJS patients will be diagnosed with two cancers (28, 101).

Figure 22

Figure

Figure 22. Cumulative lifetime cancer risk for Peutz-Jeghers syndrome patients. Adapted from Hearle and others, with permission from the American Association for Cancer Research (28). See Table 9.

Rare cancers that have a special association with PJS

Several cancers have a special association with PJS. In female PJS patients these include a rare tumor of the cervix called adenoma malignum (ADM) and a rare tumor of the ovary known as sex cord tumor with annular tubules (SCTATs). In male PJS patients the corresponding tumors to SCTATs are Sertoli cell testicular tumors. ADM and SCTATs sometimes occur in association with one another; eight patients with both SCTATs and ADM have been reported (151). Therefore, patients presenting with either SCTATs or ADM should be carefully followed for development of the other.

Adenoma malignum (ADM)

ADM is a very rare, highly differentiated adenocarcinoma of the endocervical glands. The number of female PJS patients who develop ADM is low, probably 5% or less. Several large case series of PJS patients have not reported a single case (25). About 10% of patients with ADM have PJS (152).

Patients with ADM present with a watery vaginal discharge or vaginal bleeding. Establishing the diagnosis of ADM can be difficult. On examination the cervix has alternatively been described as being normal, having a firm or nodular appearance, or resembling a polypoid mass (153). Papanicolaou smear or cervical biopsy can be diagnostic in some but not all cases (153). Imaging studies show multiple cervical cysts (153, 154).

Histologically, ADM closely resembles normal endocervical glands and for this reason it is sometimes referred to as a minimal deviation adenocarcinoma. Histological clues to the diagnosis of ADM include an associated desmoplastic response, nuclear atypia, deep invasion of the cervical wall, and identification of a focus of undifferentiated adenocarcinoma. Using a standard criteria for ADM, the diagnosis of ADM has been found to be reproducible between pathologists (155). Staining with Alcian blue periodic acid Schiff and with the HIK1803 monoclonal antibody to gastric gland mucous cell-mucin endocervical glands has been reported to help make the distinction between ADM and normal endocervical glands (156, 157).

Surveillance for ADM should include a yearly gynecological exam with Papanicolaou smear and pelvic ultrasound (Table 10). If the diagnosis of ADM is suspected or confirmed, the patient should be referred to a gynecologic oncology surgeon. In the most recent series of ADM patients, published five-year survival was 60% (155).

Image

Table

Table 10 Peutz-Jeghers syndrome management protocols

Sex cord tumors with annular tubules (SCTATs)

Most female PJS patients of reproductive age have ovarian cysts. It is unclear how many of these represent physiological cysts versus stable SCTATs. The authors estimate about 10% of female PJS patients will develop SCTATs that require surgery. About one third of patients with SCTATs have PJS (158).

Histologically, SCTATs are either simple or complex tubules lined by cells with peripherally placed nuclei that surround a hyaline-filled lumen. PJS-associated SCTATs are bilateral, multifocal, often microscopic, and contain focal calcifications. Sporadic SCTATs are large and unilateral. PJS-associated SCTATs have a low malignant potential and a good prognosis. Only two cases of malignant SCTATs have been reported in PJS patients (159, 160).

PJS patients with SCTATs usually present with an asymptomatic adnexal cyst or mass identified by cancer surveillance testing (Movie Clip 2). SCTATs sometimes produce estrogen, causing precocious puberty. Most PJS patients with SCTATs are young. A conservative approach with preservation of fertility and avoidance of surgical menopause is recommended (161). PJS patients with known or suspected SCTATs should be referred to both a gynecologic oncology surgeon and a reproductive endocrinologist.

Sertoli cell testicular tumors

These tumors probably are the corresponding male tumor to the SCTATs seen in female PJS patients. The authors’ experience is that most male PJS patients will have bilateral multifocal testicular calcifications on testicular ultrasound consistent with asymptomatic Sertoli cell testicular neoplasia (Movie Clip 2 and Figure 23). These lesions rarely progress to invasive large calcifying Sertoli cell tumors (ILCST), and only six cases of ILCST have been reported in PJS patients (162). ILSCT patients typically present as children with testicular enlargement or prepubertal gynecomasty (ages ranging from 1 to 14 years, Table 8) (162). (Sertoli cells express aromatase, which converts testosterone to an estrogen precursor, causing prepubertal gynecomasty.)

Figure 23

Figure

Figure 23. Testicular ultrasound of a PJS patient showing multifocal microcalcifications consistent with Sertoli cell testicular neoplasia.

Yearly surveillance with testicular ultrasound for ILCST is recommended (Table 10). The authors do not recommend routine testicular biopsy of asymptomatic PJS patients with microcalcifications on testicular ultrasound. Historical treatment has been orchiectomy, but as with SCTATs, given the usually benign nature of these tumors in PJS patients, conservative observation of asymptomatic non-large calcifying tumors is recommended (162). There is a single report of successful treatment with the aromatase inhibitor anastrozole and use of inhibin-alpha as a tumor marker (163).

Other cancers and neoplasia associated with PJS

Cancers and other neoplasia associated with PJS and reported as a single case or as a few cases are shown in Table 11.

Image

Table

Table 11 Neoplasia reported in a single or few Peutz-Jeghers syndrome patients

Cancer surveillance protocols

Cancer surveillance is standard of care for PJS patients. However, no cancer surveillance protocol has been shown to decrease cancer incidence or increase survival in PJS patients. Highlighting the limitations of surveillance, only one of 96 cancers was identified in a surveillance program in the largest cohort of PJS patients reported to date (28). It was not reported how many patients were under surveillance or what surveillance protocol was used.

There is no consensus or organization-approved guideline for cancer surveillance in PJS patients. Table 10 summarizes the PJS cancer surveillance and management protocols used at Johns Hopkins Hospital, St. Mark’s Hospital, and Mayo Clinic (164-166). The University of Edinburgh, Danish polyposis registry, and the University of Newcastle (Australia) have also published protocols (129, 167, 168). There are many differences between the protocols, and those for small intestine and pancreatic cancer screening are discussed in detail below. Whichever protocol is used, it should be modified according to available resources, an individual patient’s disease manifestations, psychosocial situation, and personal preferences (1).

Screening of at-risk individuals

At-risk groups for PJS include the children and other relatives of PJS patients. For other hereditary cancer syndromes (e.g., Lynch syndrome), there are many individuals at risk for whom the diagnosis can neither be proved nor disproved. These at-risk individuals also require cancer surveillance even though it is unclear whether or not they are affected. However, for PJS there are very few at-risk individuals as the diagnosis is usually easily made by the presence of MMs and by screening for PJS-type intestinal polyps.

Small intestine polyp and cancer surveillance

The purpose of small intestine surveillance in PJS is to identify polyps before they serve as the lead point for an intussusception, develop dysplasia, or become too large to remove endoscopically. The current standard for adult PJS patients is to remove all polyps 1.0-1.5 cm or larger. (For discussion, see PJS-type polyps.) For pediatric patients, polyp management is individualized depending on symptoms, age, previous surgeries, location and size of the polyp(s) in question, and available resources.

The small intestine can be screened for polyps using magnetic resonance (MR) and CT enterography and enteroclysis, capsule endoscopy, and small intestine X-ray (Figures 24, 25, and 26; Movie Clips 2 and 4-6). The characteristics of small intestine polyp screening tests are shown in Table 12. Few studies have compared the different techniques for detecting small intestine polyps. One study showed similar information was gained from enteroclysis and enterography techniques for both CT and MR, but small intestine polyp detection was not specifically studied (169). Other studies in PJS patients have shown MR enterography and capsule endoscopy equivalent in identifying small intestine polyps greater than 1.5 cm and that capsule endoscopy detects more polyps than small intestine X-ray (170, 171).

Figure 24

Figure

Figure 24. CT enteroclysis study of a 29-year-old Peutz-Jeghers syndrome patient showing several large jejunal polyps. See Movie Clips 4 and 5.

Figure 25

Figure

Figure 25. CT enterography study of a Peutz-Jeghers syndrome patient showing 1.2 cm jejunal polyp. See Movie Clip 6.

Figure 26

Figure

Figure 26. Capsule endoscopy image from a Peutz-Jeghers syndrome patient showing small intestine polyp. Courtesy Mark Stark, MD, Mayo Clinic, Jacksonville.

Image

Table

Table 12 Characteristics of small intestine imaging tests

Mayo Clinic recommends MR enterography for small intestine surveillance. It has adequate sensitivity for 1.5 cm polyps, surveys the extraluminal abdominal organs, and does not involve exposure to radiation (172, 173). MR enterography is not widely available, so screening with CT enteroclysis or enterography are acceptable alternatives. CT enteroclysis is also used at Mayo Clinic. In the authors’ opinion, it provides the highest quality images but is associated with radiation exposure and the discomfort of a naso-small intestine tube. Patients should be forewarned that CT and MR enteroclysis require insertion of a naso-small intestine tube that is unpleasant for all and not tolerated by some.

Pancreatic cancer surveillance

Background

More than 90% of sporadic and PJS-associated pancreatic cancers are pancreatic ductal adenocarcinomas. Pancreatic cancer in a PJS patient was first reported in 1957, and an increased incidence of pancreatic cancer in PJS patients was reported in 1987 (27, 174). Eighty-five percent of PJS patients with pancreatic cancer are diagnosed over the age of 40 (ranging from 16 to 91 years old) (Tables 8 and 9). The cumulative lifetime risk of pancreatic cancer for PJS in the study with the most patient follow-up was 11% (Table 9) (28).

The most quoted estimate of the lifetime pancreatic cancer risk in PJS is 40%. This comes from a 36% estimate reported in a review of six published case series published in 2000.[98] This may be an overestimate due to selection bias. In that study, six cases of pancreatic cancer were reported in a total of 201 patients. One study included in the analysis contributed 31 of the 201 patients and a very disproportionate four of the six pancreatic cancer cases. Other studies have not confirmed the high pancreatic cancer risk reported in 2000. As noted above, the most comprehensive natural history study of PJS found an 11% risk, and a study of 147 PJS patients with proven LKB1 mutations published in 2006 identified no cases of pancreatic cancer (99, 175). No PJS patient followed at Mayo Clinic has ever been diagnosed with pancreatic cancer. Other than selection bias, another explanation for the different rates of pancreatic cancer reported is that populations under intensive surveillance for colon and other preventable cancers may have a higher rate of pancreatic cancer because of the low number of deaths due to colon and other cancers.

Pancreatic cancer has the worst prognosis of any of the PJS-associated cancers. The median lifespan for sporadic pancreatic cancer patients treated with neoadjuvant therapy is nine to 11 months (176). Less than 5% of pancreatic cancer patients are long-term survivors (>5 years). No PJS patient has been reported to be a long-term survivor of pancreatic cancer. A review of 14 PJS patients diagnosed with pancreatic cancer found surgery was attempted in only three; the remaining 11 are assumed to have died of pancreatic cancer. Of the three surgically managed patients, one had locally advanced disease and is assumed to have died from pancreatic cancer. The two remaining patients had pancreatic cystadenocarcinoma, a rare tumor of the pancreas associated with a better prognosis than pancreatic ductal adenocarcinoma (145, 146).

The only chance for cure of pancreatic cancer is early surgery in the narrow window of resectability prior to the development of locally advanced or metastatic disease. Therefore, any successful screening test for pancreatic cancer must be able to identify a premalignant lesion or cancer in the narrow time window when surgical cure is possible. Two candidates for the premalignant lesion of pancreatic cancer in PJS are pancreatic intraepithelial neoplasia (PanINs) (177) and intraductal papillary mucous neoplasms (IPMNs) (178). PanINs are microscopic areas of intraductal neoplasia and are graded from low (grade 1) to high grade dysplasia (grade 3). Only PanINs-3 are clearly associated with pancreatic cancers; PanINs-1 and -2 can be seen in normal pancreas parenchyma and in acute and chronic pancreatitis. PanINs cannot be reliably detected on imaging, and IPMNs have a cystic mucinous component that may be detected by imaging.

Although both PanINs and IPMN have been reported in individual PJS patients, it is unclear which one, if either, is the premalignant lesion of PJS-associated pancreatic cancer. Limited molecular evidence supports the conclusion that IPMNs are a manifestation of PJS. A study of IPMNs from two PJS patients showed loss of heterozygosity at the LKB1 locus (178).

Screening tests

Potential screening tests for pancreatic cancer include serum CA19-9 and imaging studies including CT, MRI (magnetic resonance imaging), and endoscopic ultrasound (EUS). CA19-9 is the only blood-based pancreatic cancer biomarker in use. The positive predictive value of CA19-9 is 59% in patients undergoing imaging of the pancreas and 0.9% in the general population (179, 180). CA19-9 is of limited value as it usually is only elevated when the tumor is unresectable. The value of CA19-9 testing in PJS patients has never been reported, and the American Society for Clinical Oncology does not recommend that CA19-9 be used for screening in the general population (181). Other serum biomarkers proposed for pancreatic cancer detection include glucose intolerance (182), serum RCAS1 (183), PGK1 (184), REG4 (185), and CEACAM1 (186). The utility of these biomarkers in PJS has not been reported.

Pancreatic cancer imaging screening strategies for high-risk groups, including PJS patients, were recently reviewed by Canto (187). Limited data is available concerning CT and EUS screening in the PJS patients from two studies. A third collaborative multisite EUS-CT study for pancreatic cancer surveillance in high-risk groups, including PJS patients, is ongoing. The first study of CT and EUS screening for pancreatic cancer in high-risk individuals included six PJS patients. One PJS patient had a cystic lesion identified in the head of the pancreas by both EUS and CT (188). This patient underwent a pancreatic duodenectomy and was found to have an IPMN with carcinoma in situ. In a second high-risk pancreatic cancer CT and EUS study, a mass was identified in the pancreatic head of a PJS patient by CT and EUS (177). The patient had a pancreatic duodenectomy, and pathology showed diffuse grade 1-2 PanINs without evidence of pancreatic cancer. The limitations of EUS were further shown in a study of interoperator variability in interpreting surveillance EUS studies performed on hereditary pancreatic cancer syndrome patients including PJS (189). There was significant interoperator variability for features other than cysts. There are no reports of the value of MRI screening in PJS patients.

Two studies of the effectiveness of pancreatic cancer screening in PJS or similar populations have been published. A Markov model analysis studied surveillance strategies for patients with hereditary pancreatic cancer (190). Approaches studied included “do nothing,” total pancreatectomy, EUS, and EUS with fine needle aspiration. The “do nothing” approach provided the longest number of years of life. The second study, a review and cost-effectiveness evaluation of pancreatic cancer screening specifically in PJS, found that EUS screening was not cost-effective and recommended it only be performed on a research basis (166).

In summary, all pancreatic cancer screening tests have significant limitations, and it is unclear if any of them, or any combination of them, would decrease pancreatic cancer mortality and morbidity in PJS patients.

Recommendations

St. Mark’s Hospital recommends no screening. Mayo Clinic and Johns Hopkins Hospital recommend CA19-9 in combination with MRI or EUS evaluation, respectively. The Mayo Clinic protocol recommends MRI over EUS because of the low specificity and interobserver variability with EUS. In contrast to EUS, MRI surveys the entire abdomen, does not require sedation, and has less interobserver variability. However, MRI is not as sensitive as EUS and is less likely to identify premalignant lesions and pancreatic cancers when they are small enough to still be cured by surgery.

In reference to MRI versus CT, all pancreatic neoplasms identified in PJS patients participating in the EUS/CT studies over time have been seen by CT and should also be seen by MRI. A key benefit of MRI over CT in PJS patients is that MRI does not expose the patient to possibly carcinogenic doses of ionizing radiation (191).

Chemoprevention and Chemotherapy

COX-2 inhibitors

Chemoprevention using the COX-2 inhibitor celecoxib has been studied in the lkb1 +/- PJS mouse model and in PJS patients. Lkb1 +/- mice treated with celecoxib have both a decrease in the formation of new polyps and the size of preexisting polyps (61). In the only study of chemoprevention in PJS patients, six patients were treated for six months with celecoxib 200 mg twice daily (61). The primary end point was decrease in gastric polyps as assessed by endoscopy. Two of six patients had a significant decrease in gastric polyps at the end of the study.

The authors do not recommend treating PJS patients with celecoxib or other COX-2 inhibitors. This recommendation is based on the lack of any data showing COX-2 inhibitors impact any clinically significant endpoint (e.g., cancer, intussusception), advances in endoscopic therapy for PJS polyps, and the increased risk of myocardial infarction and stroke associated with COX-2 inhibitors (192).

Selective estrogen receptor modulators (SERMs) and prophylactic oophorectomy

Tamoxifen and raloxifen are selective estrogen receptor modulators (SERMs). Tamoxifen is effective for primary and secondary breast cancer prevention in high risk patients (193). In a case-control study of BRCA1/2 patients who had had breast cancer, tamoxifen reduced a second contralateral breast cancer by 75% (194).

The putative mechanism by which tamoxifen decreases breast cancer risk is by blocking the action of estrogen. However, data from BRCA1/2 patients is mixed on whether tamoxifen decreases the incidence of ER-expressing breast cancers or all breast cancers (195, 196). In the one case of PJS-associated breast cancer where tumor estrogen receptor status was reported, the tumor did not express estrogen receptors (197). Chemoprevention of breast cancer in PJS using SERMS has not been reported.

In retrospective and prospective studies, prophylactic oophorectomy decreases breast cancer in BRCA1/2 mutation carriers (198, 199). Prophylactic oophorectomy for breast cancer prevention has not been reported in PJS. Side effects of SERMs and oophorectomy include deep venous thrombosis, infertility, and osteoporosis. Given these adverse side effects and that their efficacy in PJS is unproven, the authors do not recommend SERMs be used for chemoprevention in PJS patients.

Rapamycin and rapalogs

LKB1 is a proximal member of the mammalian target of rapamycin (mTOR) pathways. mTOR signaling is increased in PJS and probably is responsible for neoplasia in PJS. However, knockout mice of AMPKinase, which follows LKB1 in the mTOR pathway, do not develop features of PJS (81, 200). Rapamycin is a suppressor of the mTOR pathway and putative chemo-preventive and therapeutic agent for PJS (201). It decreases polyp growth in preclinical trials with PJS lkb1 +/- mice (83). There are no reports of rapamycin use in PJS patients. A clinical trail of the rapalog RAD001 (everolimus) for PJS has begun enrollment (http://clinicaltrials.gov/ct2/show/NCT00811590?term=peutz&rank=1).

Rapamycin has been shown to be effective in treating angiomyolipomas and astrocytomas in small numbers of tuberous sclerosis (TS) patients (202, 203). TS is characterized by angiofibromas, rhabdomyosarcomas, and subependymal nodules, and is caused in some patients by mutations in TSC2, which is downstream from LKB1 in the mTOR pathway.

Metformin

Metformin has been shown to inhibit mTOR activity in breast cancer cells but was unable to inhibit mTOR in cells lacking LKB1 (204). Based on this data, it is unclear how effective metformin would be in PJS patients who are germline haploinsufficient for LKB1 and in PJS neoplastic tissue that does not express LKB1.

Prophylactic Surgery

Prophylactic surgery has been shown to be effective in patients with Lynch syndrome and the BRCA1/2 syndromes (205, 206). Prophylactic surgery in PJS patients has not been reported. The authors review the option of prophylactic bilateral mastectomy, hysterectomy, and oophorectomy with female PJS patients.

Lifestyle Modification

Lifestyle factors including excess weight, lack of exercise, smoking, and alcohol use are risk factors for the cancers associated with PJS. Although no study of PJS patients has shown that modification of these risk factors reduces cancer risk, all PJS patients should be advised to adopt a healthy lifestyle.

Movie Clip Captions

Movie Clip 1

Piecemeal removal of a large ileal polyp in a Peutz-Jeghers patient using double-balloon endoscopy.

Movie Clip 2

CT enteroclysis study of a 23-year-old female Peutz-Jeghers patient. Food in the stomach and food material in the distal ileum limit mucosal detail. Findings include a 12 mm polyp in the proximal ileum, an 8 mm duodenal polyp, and a 20 cm in diameter septated cystic mass in the pelvis and lower abdomen arising from the left ovary. The patient was referred to a gynecologic oncology surgeon and underwent laparotomy. The cystic mass was removed from the left ovary and found to be a sex cord tumor with annular tubules.

Movie Clip 3

Testicular ultrasound of a PJS patient showing multifocal microcalcifications consistent with Sertoli cell testicular neoplasia.

Movie Clip 4

Coronal images from a CT enteroclysis study of a 29-year-old Peutz-Jeghers syndrome patient showing several large jejunal polyps. See Figure 24 and Movie Clip 5.

Movie Clip 5

Transaxial images from a CT enteroclysis study of a 29-year-old Peutz-Jeghers syndrome patient showing several large jejunal polyps. See Figure 24 and Movie Clip 4.

Movie Clip 6

Coronal images of a CT enterography study of a Peutz-Jeghers syndrome patient showing 1.2 cm jejunal polyp. See Figure 25 for annotation.

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Footnotes

1

“. . . For each living being has his own individual peculiarities and whatever his disease must be necessarily peculiar to himself – a new and complex malady unknown to medicine . . .” War and Peace, Leo Tolstoy.

Copyright © 2009-, Douglas L Riegert-Johnson.
Bookshelf ID: NBK1826PMID: 21249755

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