Peutz-Jeghers Syndrome 

Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with a distinct pattern of skin and mucosal macular melanin deposition. Patients with PJS have a 15-fold increased risk of developing intestinal cancer compared with that of the general population. (See the images below.)^{[1, 2, 3] [4, 5, 6, 7, 8, 9]}

The syndrome was described in 1921 by Jan Peutz (1886-1957), a Dutch physician who noted a relationship between the intestinal polyps and the mucocutaneous macules in a Dutch family. (The dermatologic component had previously been reported by John McHutchinson in 1896 in identical twins, one of who subsequently died from intussusception).

Harold Jeghers (1904-1990), an American physician is credited with the definitive descriptive reports of the syndrome when he published "Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits," in 1949, with McKusick and Katz. The eponym Peutz-Jeghers syndrome was introduced by the radiologist Andre J. Bruwer in 1954.

The gastrointestinal polyps found in PJS are typical hamartomas. Their histology is characterized by extensive smooth muscle arborization throughout the polyp. This may give the lesion the appearance of pseudoinvasion, because some of the epithelial cells, usually from benign glands, are surrounded by the smooth muscle.

Cancer develops in the gastrointestinal tract of patients with PJS with a higher frequency than it does in the general population.^[8] Forty-eight percent of patients with PJS develop and die from cancer by age 57 years. Others may have a normal life span. The mean age at first diagnosis of cancer is 42.9 years, +/– 10.2 years.^{[10, 11, 12]}

During the first 3 decades of life, anemia, rectal bleeding, abdominal pain, obstruction, and/or intussusception are common complications in patients with PJS.^{[13, 14]} Nearly 50% of the patients experience an intussusception during their lifetime, most commonly in the small intestine. (See the image below.)^[15]

PJS should be diagnosed in patients as early as possible. Genetic counseling should also be provided. Many of the gastrointestinal lesions will start developing early in life, even if the syndrome is not clinically apparent until the second and third decades of life. Proper screening for intestinal cancers and extraintestinal cancers should be implemented.

The cause of Peutz-Jeghers syndrome (PJS) in most cases (66-94%) appears to be a germline mutation of the STK11/LKB1 (serine/threonine kinase 11) tumor suppressor gene, located on band 19p13.3. Penetrance of the gene is variable, causing varied phenotypic manifestations among patients with PJS (eg, inconsistent number of polyps, differing presentation of the macules) and allowing for a variable presentation of cancer.^{[9, 16, 17, 18, 19, 20, 21, 22, 23]}

Because the signaling pathway of the STK11 gene product is not currently identified, the mechanism of hamartomatous polyp formation and mucocutaneous pigmentation is not known. In cancer formation, STK11 inactivation appears to occur early and may be followed by interruption of the APC/β-catenin and p53 pathways, but this has not been fully elucidated. However, the cyclic adenosine monophosphate (cAMP)–dependent protein kinase A apparently can phosphorylate the murine STK11 protein in vitro; the significance of this is not currently known, but this phosphorylation may be important for STK11 regulation.

STK11 may be a tumor suppressor gene, in that its overexpression can induce a growth arrest of a cell at the G1 phase of the cell cycle and that somatic inactivation of the unaffected allele of STK11 is often observed in polyps and cancers from patients with PJS.

Hyperactivation of the mammalian target of rapamycin (mTOR) signaling has also been associated with PJS.^[23] Wei et al, in a study of rapamycin on a mouse model of PJS in which polyp size, burden, and phosphorylation levels of S6 were measured, reported that rapamycin decreased tumor burden in rapamycin-treated mice, compared with controls. This inhibition was also associated with a decrease in phosphorylated S6 levels. This finding suggested that rapamycin or its analogues may play a role in the treatment of PJS.^[24]

Other genes may also play a role in PJS, such as those which encode for the MARK protein, homologues of the Par 1 polarity protein that associates with LKB1. However, de Leng et al performed direct sequencing and probe amplification in 23 families with PJS and were unable to identify any mutations in the MARK genes.^[21] This again supports the evidence that LKB1 defects remains the major cause of PJS, although other mechanisms are involved; however, they remain to be elucidated.^[22]

An interesting study by Tobi et al demonstrated that Adnab-9, a premalignant marker found in Paneth cells, was more common in PJS. The authors evaluated 8 patients with PJS, 8 patients with juvenile polyposis, and 36 hyperplastic polyp sections (as controls).^[25] The investigators found that 89% of PJS polyps were labeled with Adnab-9, compared with 88% of familial juvenile polyposis sections and 11% of hyperplastic polyps.^[25] This study suggested Adnab-9 labeling may identify polyps at higher risk of malignant degeneration.

STK11/LKB1 seems to regulate cell polarity and tumor suppression, predisposing patients to mucosal prolapse first, leading to polypoid lesions and at the same time as cancer. Although the LKB1 gene is located on the short arm of chromosome 19, which is frequently deleted in tumors of sporadic origin, this has not been observed in non–small cell lung cancer, in which nearly 50% of these tumors harbor mutations of LKB1.^[26]

Mehenni et al, reporting on the molecular and clinical characteristics of 46 families with PJS, demonstrated an increase in the mutational spectrum of LKB1/STK11 allelic variants worldwide. They suggested that this new information would be helpful for clinical diagnosis and genetic counseling.^[18]

Peutz-Jeghers syndrome (PJS) is rare in the United States, with a frequency of encounter from polyposis registries one tenth that of familial adenomatous polyposis. This would place the frequency between 1 case per 60,000 people and 1 case per 300,000 people.

The international frequency of PJS is unknown, but given the rarity of this condition, the frequency is probably similar to that reported in the United States. Specific mutations of the STK11/LKB1 gene, however, may be more common in certain ethnic groups. For example, Zuo et al reported 2 new mutations in 3 Chinese families that had not been previously described in white families.^{[13, 14, 27, 28, 29, 30, 31, 32]}

Age-related demographics

Peutz-Jeghers syndrome polyps commonly occur and present in adolescence and early adulthood.^[33] One third of the affected individuals experience symptoms during the first 10 years of life.^[34] The median time of first presentation with polyps is age 11-13 years; approximately 50% of individuals have experienced symptoms by age 20 years.^{[14, 27, 35]}

Cancer is the main consequence of Peutz-Jeghers syndrome (PJS) as patients age. The major sites of cancer occurrence, in order of relative risk (RR) over the general population, are as follows:

• Small intestine - RR 520
• Stomach - RR 96
• Pancreas - RR 132
• Colon - RR 84
• Esophagus - RR 57
• Ovary - RR 27
• Lung - RR 17
• Uterus - RR 16
• Breast - RR 15.2

In addition, other reproductive site cancers have been associated with PJS, including adenoma malignum of the cervix, Sertoli cell tumors, and sex cord tumors with annular tubules.^{[36, 37, 38]}

The cumulative risk of developing any cancers associated with PJS in patients aged 15-64 years is 93%. The cumulative risks of developing particular cancers from ages 15-64 years are as follows:

• Esophagus - 0.5%
• Stomach - 29%
• Small intestine - 13%
• Colon - 39%
• Pancreas - 36%
• Lung - 15%
• Testes - 9%
• Breast - 54%
• Uterus - 9%
• Ovary - 21%
• Cervix - 10%

Breast cancer in patients with PJS may occur at a young age, and it may also be bilateral.^[5] Due to the increased risk of pancreatic adenocarcinoma in PJS, screening with endoscopic ultrasonography has emerged as a relatively new tool for early diagnosis.^{[39, 40]}

Gastrointestinal complications

In a series of 222 patients with Peutz-Jeghers syndrome (PJS), Utsunomiya et al noted the following distribution of presenting gastrointestinal symptoms^[10] :

• Obstruction - 42.8% of patients
• Abdominal pain caused by infarction - 23% of patients
• Rectal bleeding caused by ulceration - 13.5% of patients
• Extrusion of polyp - 7% of patients

Polyps

Polyps in the Utsunomiya study’s patients occurred as follows:

• Small intestine - 64% of patients
• Colon - 63.2% of patients
• Stomach - 48.6% of patients
• Rectum - 32% of patients

The incidence of polyps within the small intestine is greatest in the jejunum and progressively decreases in the ileum and duodenum.^{[41, 14, 42, 43, 44, 35]}

Other rare reported complications include GI obstruction and vomiting secondary to gastric polyps.^{[10, 45, 46, 47]} Extraintestinal polyps are also reported although they are rare; they include nasal polyps,^[48] gall bladder polyps,^[49] ureteric polyps,^[50] and respiratory tract polyps.^[51]

The principal causes of morbidity in PJS stem from the intestinal location of the polyps (ie, small intestine, colon, stomach). Morbidity includes small intestinal obstruction and intussusception (43%), abdominal pain (23%), hematochezia (14%), and prolapse of a colonic polyp (7%); these typically occur in the second and third decades of life.

Intestinal obstruction can occur in about 50% of patients, and it is usually localized in the small bowel. Obstruction can be complete or incomplete and is caused by the polyp itself or by the subsequent intussusception that may occur, as seen in the images below.

A retrospective study by Burkhart et al examined the incidence of sporadic PJS polyps over a 22-year period.^[52] The investigators reported that sporadic PJS polyps are very rare; however, individuals who may have even a single PJS polyp may have an accumulative lifetime risk of cancer that is similar to those with the syndrome.

The patient with Peutz-Jeghers syndrome (PJS) should be educated on the potential symptoms of intestinal obstruction and instructed on the need for cancer surveillance.

In wake of the discovery of the genetic cause(s) of PJS, genetic counseling by someone knowledgeable in this disease should be provided if genetic testing is being considered, particularly as high penetrance autosomal dominant alleles has been described. Genetic counseling relays the risks and benefits and consequences of genetic testing to the patient. It also informs the patient of the consequences of a positive, negative, or inconclusive genetic test result.

Genetic counseling also includes information on the risk of transmission to offspring and may provide guidance for the patient regarding testing of other family members.^{[9, 53]}

Peutz-Jeghers syndrome (PJS) is characterized by the combination of pigmented lesions in the buccal mucosa and gastrointestinal polyps. The number, as well as the size and the location, of the polyps may vary from patient to patient. Isolated melanotic mucocutaneous pigmentation without gastrointestinal polyps has also been described, because of the genetic variability of the syndrome. The risk of cancer remains elevated regardless of the presence or the absence, as well as the number, of gastrointestinal polyps.

Well-established clinical diagnostic criteria are noted for Peutz-Jeghers syndrome. One set includes the following elements: 3 histopathologically proven Peutz-Jeghers syndrome polyps with classical mucocutaneous pigmentation and a positive family history.^[54]

Giardiello et al's diagnostic criteria for Peutz-Jeghers syndrome includes histopathologically verified hamartomatous polyps with at least 2 of the following: small-bowel location for polyposis, mucocutaneous melanotic pigmentation, and a family history of Peutz-Jeghers syndrome.^[1]

The following patient characteristics may be noted in the Peutz-Jeghers syndrome (PJS)^{[13, 14]} :

• Family history of Peutz-Jeghers syndrome
• Repeated bouts of abdominal pain in patients younger than age 25 years
• Unexplained intestinal bleeding in a young patient
• Prolapse of tissue from the rectum
• Menstrual irregularities in females (due to hyperestrogenism from sex cord tumors with annular tubules)
• Gynecomastia in males (possible due to the production of estrogens from Sertoli cell testicular tumors)^[55]
• Precocious puberty
• Gastrointestinal intussusception with bowel obstruction
• Mucocutaneous pigmentation, which may have faded
• Melena or rectal bleeding
• Hematemesis
• Weakness due to anemia

The most frequent symptom is recurrent colicky abdominal pain caused by obstruction and transient intussusceptions.^[56] Melena and rectal bleeding occur less frequently, and hematemesis is uncommon.^[57] Certain reports suggest that nearly 50% of the patients experience an intussusception during their lifetime, most often in the small intestine.^[15]

Protein-losing enteropathy should be considered as a possible clinical manifestation or presentation of the polyposis.

Hyperpigmented mucocutaneous macules may be present on the lips and buccal mucosa and around the mouth, eyes, and nostrils, as well as sparsely on the fingers, soles of the feet, palms, anal area, and intestinal mucosa. The macules are flat, blue-gray to brown-black spots 2-4 mm in size. They tend to develop within 5 years of birth. Some may fade during onset of puberty, but buccal mucosa lesions tend to persist. (See the images below.)^{[58, 34, 41, 59, 60]}

Mucocutaneous pigmentation and melanin spots are typical of patients with Peutz-Jeghers syndrome (PJS), and they are present in more than 95% of cases. They appear as small, flat, brown or dark blue spots with an appearance of freckles, most commonly in the peribuccal area.

Cutaneous pigmentation (1- to 5-mm macules) is usually located in the perioral region, crossing the vermilion border (94%), in the perinasal and perioral areas.They may be present on the fingers and the toes, on the dorsal and volar aspects of the hands and the feet (62-74%), and around the anus and genitalia. The macules may fade after puberty.

Mucous membrane pigmentation primarily appears on the buccal mucosa (66%) but rarely in the intestinal mucosa.

Localization in the oral mucosa is typical of patients with PJS and does not happen with other types of dermatologic pigmented lesions, such as common lentigo (see image below). Freckles do not localize in the buccal mucosa.

A rectal mass (rectal polyp) may be found during a rectal examination. In rare cases (7% of cases), the polyp can prolapse outside the anus if it reaches a significant size.

Gynecomastia and growth acceleration (due to Sertoli cell tumor), as well as testicular mass, may also be noted in PJS.^{[52, 61, 62]}

Laboratory studies include the following:

• Complete blood count (CBC) - The polyps of Peutz-Jeghers syndrome (PJS) may ulcerate and be a source of blood loss and anemia; gastrointestinal bleeding may be massive but also microscopic, with subsequent iron deficiency, so cell counts and iron studies should be monitored
• Iron studies
• Fecal occult blood – Hemoccult, a type of fetal occult blood test, should be performed to check for blood in the stool
• Carcinoembryonic antigen (CEA) – This test has been used by some physicians for screening and monitoring of cancer degeneration
• Cancer antigen (CA) 19-9, CA 125 - CA 125 testing is indicated every year starting at age 18 years, and CA 19-9 is indicated every 1-2 years starting at age 25 years^[63]

Genetic testing is available; however, not all families with Peutz-Jeghers syndrome map to the STK11/LKB1 locus.^{[16, 18, 64, 65]} Thus, a negative genetic test does not exclude the diagnosis.

Imaging studies include the following:

• Capsule endoscopy
• Magnetic resonance imaging (MRI) enteroclysis
• Computed tomography (CT) scanning with oral contrast
• Colonoscopy
• Push enteroscopy
• Intraoperative enteroscopy (IOE)
• Double-balloon enteroscopy
• Endoscopic ultrasonography
• Endoscopic retrograde cholangiopancreatography^[66]

Enteroclysis study (preferred) and dedicated small-bowel follow-through radiographs are used to determine the presence and the location of small intestinal polyps, as shown below.

Imaging studies of the liver and the pancreas are indicated because of the risk of pancreatic cancer as well as of gallbladder polyps and cancer. These imaging studies may include ultrasonography as well as CT scanning with pancreatic details or magnetic resonance cholangiopancreatography (MRCP).

Endoscopy

Symptoms such as abdominal pain or anemia/melena require investigation with upper and lower endoscopy. Earlier primary surgical resection and IOE were the only available options for treating polyps in the mid ̶ small bowel in patients with Peutz-Jeghers syndrome (PJS).^{[67, 68, 69, 70]} Double-balloon endoscopy and video capsule enteroscopy have made it possible to not only to perform endoscopic surveillance and diagnose these lesions but also resect them.^{[42, 67, 71, 72]}

Hemorrhagic or large polyps (>5 mm) should be removed by endoscopic polypectomy to confirm the diagnosis and help control symptoms.

Polyps in Peutz-Jeghers syndrome (PJS) can reliably be differentiated from other types of polyps only by histopathology.^[73] Smooth-muscle hyperplasia, with an elongated, arborized pattern of polyp formation towards the epithelial layer, can be seen.^{[13, 53]} This results in the formation of islands of epithelium within the underlying smooth muscle,^{[74, 56]} which is best appreciated in Peutz-Jeghers syndrome small intestine polyps. (See the image below.)^[52]

Patients with Peutz-Jeghers syndrome (PJS) usually undergo numerous surgeries during their lives. These surgeries include laparotomies and laparoscopies for both gastrointestinal problems and extraintestinal problems. Surgical treatment of extraintestinal cancers detected by surveillance and diagnosis is required.

Push enteroscopy and IOE with polypectomy are used to remove larger polyps and may defer the need for repeated small-bowel resections.

Laparotomy and resection may be necessary, as indicated, for small intestinal intussusception, obstruction, or persistent intestinal bleeding.

Complications

Adhesions and intestinal obstruction or short bowel syndrome from repeated abdominal surgeries can be limited with the use of endoscopic methods for intestinal polyp resection, such as IOE and push enteroscopy.

Diet

Diet is unrestricted, except for those who have surgical resections and or strictures, wherein avoiding food with kernels (eg, popcorn) is indicated.

Follow-up care of patients with Peutz-Jeghers syndrome (PJS) should be supervised by a gastroenterologist familiar with this condition. Genetic consultation and counseling, as well as urologic and gynecologic consultations, are required in the management of these patients.

Consultation with surgery, oncology, urology, and gynecology specialists may be necessary in the management of patients with PJS. Psychiatric consultation may also be beneficial, as mild depression has been reported to be common in individuals with PJS; however, a study by Woo et al did not show that patients were affected by their condition.^[75]

Periodic surveillance and removal of larger polyps aim to reduce the likelihood of complications in Peutz-Jeghers syndrome (PJS). Hence, surveillance for gastric and small-bowel polyposis should begin at age 10 years and continue at 2-year intervals.^[76] Follow-up care should be supervised by a gastroenterologist familiar with PJS.

Patients with PJS should undergo an annual CBC, as well as an annual physical examination that includes evaluation of the breasts, abdomen, pelvis, and testes.

Lifelong cancer surveillance is advocated.^[3] Some suggestions for surveillance for cancer include the following:

• Small intestine with small-bowel radiography every 2 years
• Esophagogastroduodenoscopy and colonoscopy every 2 years
• Ultrasonography of the pancreas annually
• Ultrasonography of the pelvis (women) and testes (men) annually
• Mammography (women) at ages 25, 30, 35, and 38 years, then every 2 years until age 50 years, then annually
• Papanicolaou (Pap) test every year