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Peutz-Jeghers syndrome (PJS) is characterized by melanotic macules, hamartomatous gastrointestinal polyps, an increased risk of cancer and germline mutations in the LKB1 gene. The first patients now thought to have had PJS were a pair of identical twins reported in 1895 [1]. Through the reports by Peutz and later Jeghers et al. the cardinal features of PJS were characterized [2, 3].

Several review papers on PJS associated cancer risks and cancer surveillance have been published [4, 5]. Latchford and Phillips review the state of the art surveillance for PJS gastrointestinal tract cancers elsewhere in this issue. In this paper, several common scenarios that are often encountered when caring for PJS patients are presented and discussed. Details of the scenarios have been changed to protect patients’ confidentiality.

Scenario #1

Diagnosing PJS

A 45 year-old woman presented for medical genetics evaluation. Between the ages of 20 and 30 years, the patient had nasal polyps and several large colon polyps removed. At 43 years-old, she was diagnosed with jejunal adenocarcinoma (T1N0). Upper endoscopy following surgery showed several stomach and small bowel polyps. A genetic test for familial adenomatous polyposis (APC gene) was negative. There was no family history of cancer.

On physical examination, there was a single melanotic macule on the buccal mucosa. There were no melanotic macules on the lips or elsewhere. The patient underwent another upper endoscopy and several small bowel polyps were removed. These polyps had typical microscopic features of hamartomatous PJS polyps with polypoid, hyperplastic mucosa and bands of arborizing smooth muscle (Fig. 1). The original pathology report for the jejunal adenocarcinoma was retrieved and described arborizing smooth muscle tissue but made no mention of PJS.

Fig. 1
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Photomicroscopy of a harmatomatous polyp from a patient with Peutz-Jeghers syndrome, characterized by hyperplastic epithelium and arborizing bands of smooth muscle (hematoxylin and eosin stain, magnification ×40)

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Personal and family history, physical examination and pathological interpretation are all crucial components in the diagnosis of PJS. Patients should be asked and examined closely regarding melanotic macules. Almost all PJS patients have or have had melanotic macules on their lips; only a few patients have been reported without them. For a further discussion of disorders of oral pigmentation, please see the paper by Stratakis and others in this issue. The “spots” fade during puberty and may be very subtle or absent in adult patients. When examining for melanotic macules one should look not only at the lips, but also the buccal mucosa, eyelids, around the eyes and ears, along the hairline, on tips of toes and fingers and in the groin region. The patient’s combination of characteristic melanotic macules and arborizing smooth muscle pathology meet the diagnostic criteria for PJS (Table 1). Genetic testing later confirmed the clinical diagnosis of PJS with identification of a mutation in LKB1.

Table 1 Diagnostic criteria for Peutz-Jeghers syndrome
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About 15% of patients with PJS have nasal polyps [6]. They are often an overlooked feature of PJS, although they were included in the original description by Peutz (“Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane”[2]).

The pathological description of smooth muscle in small intestine polyps is highly sensitive and specific for the disease. There are only a few cases reported where PJS type polyps were seen in patients without PJS [7]. In cases where the diagnosis is unclear, re-evaluation of all pathological material by a gastrointestinal pathologist should be routine. In a study of patients with unexplained hamartomatous and hyperplastic polyposis, review by a gastrointestinal pathologist made the diagnosis in most cases [8].

PJS polyps are rarely seen by pathologists in common clinical practice, and may therefore not be easily recognized. Even if seen, as in this case, the connection to PJS may not be made. For these reasons, when a PJS patient, or suspected PJS patient, has polyps removed, the pathologist should be informed.

Summary

A comprehensive approach is needed in the diagnosis of PJS.

Scenario #2

New patient diagnosis

The patient discussed above has just received a diagnosis of PJS.

Healthcare providers should be mindful that the diagnosis of PJS is a milestone in the life of any individual and should be handled with the appropriate sensitivity. If the patient is receptive, we recommend the genetics, natural history, and treatment of PJS be reviewed. An individual management plan should be formulated including referral to a genetic counselor. Even though it may not be apparent, most patients benefit from seeing a genetic counselor for a detailed review of the genetics and genetic counseling. PJS patients are at an increased risk for lung cancer and smoking probably increases this risk further. Therefore, nicotine dependence counseling should be included in the management plan of PJS patients who smoke. Online PJS resources can be invaluable for patients (Box 1).

Box 1 Online Peutz-Jeghers syndrome (PJS) resources
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Patients, and especially parents of young PJS patients, are understandably very concerned about the impact of PJS on long-term survival and psychological well being. There is no current, high quality, data on the survival of PJS patients. The available data comes from patients studied over many decades before the recent dramatic improvements in PJS care. The most recent report on PJS survival studied 54 patients seen at Mayo Clinic from 1950 to 2002. The median age at death was 51 years [9].

Study results are mixed on the psychological impact of PJS [10, 11]. One study showed PJS patients suffer from mild depression but physically are not impacted by their condition. In another, PJS patients had similar levels of depression and anxiety as seen in the general population, but did have lower general health perception and more limitations due to emotional problems.

Summary

For each patient with PJS a comprehensive, personalized patient care plan should be implemented.

Scenario #3

Pancreatic cancer surveillance

A 40 year-old woman with PJS is referred for pancreatic cancer screening using endoscopic ultrasound (EUS). She recently had a normal abdominal computed tomography (CT) scan with and without intravenous contrast.

Patients with PJS are at increased risk for pancreatic cancer. The most current and complete data on cancer risk in PJS patients (2006) is from a multicenter collaborative series of 416 PJS patients [12]. The cumulative risks for pancreatic cancer were 3% at 40 years, 5% at 50 years, 7% at 60 years, and 11% at 70 years. By comparison, the population risk at 70 years is 0.5%.

Pancreatic cancer has the worst prognosis of any of the PJS-associated cancers. Less than 5% of general population pancreatic cancer patients are long-term survivors (>5 years). No PJS patient has been reported to be a long-term survivor of pancreatic cancer. Therefore, early detection and treatment of pancreatic cancer is of great interest to PJS patients and physicians treating PJS patients. However, the unfortunate fact is that all pancreatic cancer surveillance investigations have significant limitations. It is unclear if any one of them, or any combination of them, could decrease pancreatic cancer morbidity and mortality 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 [13]. Evaluated approaches included “do nothing,” total pancreatectomy, endoscopic ultrasound (EUS), and EUS with fine needle aspiration (FNA). 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, determined that EUS screening was not cost-effective and recommended that it only be performed in a research setting [14].

EUS is probably the most sensitive test in detecting precancerous and cancerous pancreas lesions that could potentially be cured by surgery. It is more sensitive than the CT scan the patient recently had, however, EUS is limited by intra- and inter-observer variability for findings other than cysts [15] and false positive test results. Highly sensitive cancer screening tests, such as EUS, are plagued by false positive results when used in populations that are unlikely to have cancer. EUS testing may identify an abnormality (example: a cyst) that may or may not indicate a very early pancreatic cancer. Once a PJS patient is found to have an abnormal EUS finding suggesting the possibility of pancreatic cancer, many patients will opt for pancreatic surgery. However, in some of these patients, pancreatic cancer will not be found in the surgical specimen [16].

Based on the fact that cancer surveillance is needed for all intra-abdominal organs, including the pancreas, the Mayo Clinic and other groups recommend an annual abdominal MRI (magnetic resonance imaging). Annual abdominal MRI with an added enterography protocol, magnetic resonance enterography (MRE), offers “a one stop shop”. MRE surveys all abdominal organs including the pancreas and also detects small intestine polyps. What had previously been performed with three investigations (EUS, computated tomography (CT), and capsule endoscopy) in many centers can now be performed with one. MRE has the added benefit of not being associated with radiation exposure, as CT is, and the possibility of increased cancer risk from that radiation exposure [16, 17]. MRE is further discussed in Scenario #4.

As most PJS patients will have an annual MRE, the question is whether or not to add EUS to their list of investigations. The authors review the pancreatic cancer risk associated with PJS and the available strategies, including EUS, with patients. In the authors’ collective experience, patients are undecided on whether or not to add EUS to their cancer surveillance protocol. This particular patient elected to have an EUS; the results were normal.

Summary

How and when to perform pancreatic cancer surveillance continues to be an unclear area in the management of PJS patients.

Scenario #4

Small intestine polyp tests

A 25 year-old male PJS patient presents with iron deficiency anemia and abdominal pain. The abdominal pain has been present for 3 months and is located in the right upper quadrant of the abdomen. He describes it as sharp and it lasts up to 3 h. Five years ago he had an upper endoscopy, colonoscopy, and barium enterography (“small bowel series”) that were normal.

The patient’s history is consistent with an internment small intestine polyp intussusception. The pain of intussusception is intermittent, consistently occurs in the same general location and often reported as “attacks” lasting a few hours. Iron deficiency anemia is often associated with intussusception. For confirmation of the clinical diagnosis of intussusception, the authors would order magnetic resonance enterography (MRE). Where MRE is not available, capsule endoscopy is an acceptable alternative. A recent study compared MRE and capsule endoscopy for small bowel polyp detection in 19 PJS patients. MRE did have less inter-observer variability than capsule endoscopy and detected more polyps than capsule endoscopy, however the difference was not statistically significant [18].

Patients with pacemakers can not have MRE and other implantable hardware may or may not be a contraindication to MRE. Patients with claustrophobia can usually still have MRE, most needing only sedation with an oral benzodiazepine. The procedure for MRE is different than other radiology tests and it maybe useful to review the procedure with the patient (Box 2).

Box 2 Magnetic resonance enterography (MRE) protocol
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MRE was performed on the patient above. A 4 cm ileal polyp was identified (Fig. 2) and later removed by lower double balloon endoscopy.

Fig. 2
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An approximately 4 cm ileal polyp in a Peutz-Jeghers syndrome patient as seen by magnetic resonance enterography (arrow). Image reproduced from Postgate et al. with permission [29]

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Summary

MRE should be the first small bowel polyp test considered for the PJS patient.

Scenario #5

Gynecological cancer risks and surveillance

A 25 year-old female PJS patient comes to arrange surveillance. She is concerned about the risk for adenoma malignum (ADM). Her aunt, who also had PJS, died of metastatic breast cancer and ADM at age 65. The patient’s only manifestations of PJS to date are melanotic macules and an intussusception of a small intestinal polyp at age 16 requiring surgery.

Female PJS patients are at increased risk for common gynecological cancers and two rare gynecological cancers, adenoma malignum (ADM) and sex cord tumor with annular tubules (SCTATs). ADM is a highly differentiated adenocarcinoma of the endocervical glands. The number of female PJS patients who develop ADM is low (<5%). Several large case series of PJS patients have not reported a single case [19]. About 10% of patients with ADM have PJS [20].

Patients presenting with ADM often report a history of watery vaginal discharge and/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 [21]. Papanicolaou (Pap) cervical smear or cervical biopsy can be diagnostic in some but not all cases. Imaging studies show multiple cervical cysts [21]. Most PJS protocols recommend surveillance for ADM by yearly gynecologic exam with Pap smear and pelvic imaging generally by transvaginal ultrasound [5]. Patients with ADM should be referred to a gynecological oncologist for surgery and possible systemic treatment.

The authors estimate about 10% of female PJS patients will develop SCTATs that require surgery. About one-third of patients with SCTATs have PJS [22]. PJS-associated SCTATs are bilateral, multifocal, often microscopic, and contain focal calcifications. In contrast, sporadic SCTATs are large and unilateral. PJS-associated SCTATs have a low malignant potential and generally a good prognosis. Only three cases of malignant SCTATs have been reported in PJS patients [23–25]. PJS patients with SCTATs often present with an asymptomatic adnexal cyst or mass identified by one of the cancer surveillance tests discussed above. SCTATs sometimes produce estrogen, causing precocious puberty in prepubescent female patients. A conservative approach to SCTATs with preservation of fertility and avoidance of surgical menopause is recommended. PJS patients with known or suspected SCTATs should be referred to both a gynecological oncologist and, if of reproductive age, a reproductive endocrinologist.

Summary

Although PJS is considered primarily a gastrointestinal disease, gynecological cancer surveillance should not be neglected.

Conclusion

These case studies illustrate the complex and multi-system nature of PJS. We recommend a care plan with both medical and non-medical support. Medical support should include a “medical home” with a physician and other care providers such genetic counselors experienced with PJS to coordinate cancer surveillance and, if needed, cancer treatments. For non-medical support, patients should be put in contact with other PJS patients and social services.