Continuing Education Activity

Peutz-Jeghers syndrome (PJS) is a hereditary syndrome characterized by gastrointestinal (GI) polyposis, mucocutaneous pigmented macules, and predisposition to certain cancers. Patients with Peutz-Jeghers syndrome are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric systems, in addition to a wide variety of non-GI epithelial malignancies including breast, uterine, cervical, lung, ovarian, and testicular cancers. Among the various malignancies, colorectal is most common with a lifetime risk of 39 percent, and is followed by breast cancer in females with a lifetime risk of 32 to 54 percent. This activity reviews the evaluation, management and surveillance for Peutz-Jeghers syndrome and highlights the role of an interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the presentation of Peutz-Jeghers syndrome.

• Describe the surveillance that should be done routinely in patients with Peutz-Jeghers syndrome.

• Explain the management of Peutz-Jeghers syndrome.

• Incorporate a structured interprofessional team approach to provide effective care and appropriate surveillance for patients with Peutz-Jeghers syndrome.

Introduction

Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome characterized by gastrointestinal (GI) polyposis, mucocutaneous pigmented macules, and cancer predisposition. Patients with Peutz-Jeghers syndrome are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric organs, in addition to a wide variety of non-GI epithelial malignancies such as breast, uterine, and cervical cancers, lung cancer, and tumors of the ovaries and testicles. Among the various malignancies, colorectal is most common, with a lifetime risk of 39%. Followed by breast cancer in females with a lifetime risk of 32% to 54%.

Females with Peutz-Jeghers syndrome are also at risk for gynecological cancers such as benign ovarian sex cord tumors with annular tubules (SCTATs) and mucinous tumors of the ovaries and fallopian tubes. Males with Peutz-Jeghers syndrome are at risk of Sertoli cell tumors of the testes, which are often hormonally active, secreting estrogen. Males present with gynecomastia, advanced bone age, and rapid growth with short stature. Due to the increased risk for various malignancies, diligent surveillance is recommended.[1]

Etiology

The clinical course of Peutz-Jeghers syndrome manifests when germ-line STK11 mutations are accompanied by an acquired defect in the second STK11 allele in somatic cells. The STK11/LKB1 gene functions as a tumor suppressor, which plays an important role in regulating the cell cycle.[2]

Epidemiology

Peutz-Jeghers syndrome is a relatively rare disorder with an estimated incidence of about 1 in 25,000 to 300,000 births. The syndrome can occur in any ethnic group, with males and females affected equally. Patients with Peutz-Jeghers syndrome are at an increased risk for developing malignancies; the average age of developing cancer is 42 years.

Pathophysiology

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder. It is most often due to germ-line mutations in the STK11 (LKB1) on chromosome 19p13.3. STK11 is a tumor suppressor gene that regulates cell polarity. The gene encodes serine/threonine kinase 11, which plays an important role in regulating the cell cycle. Mutations in STK11 are detected in 50% to 80% of families with PJS; for the remaining patients, PJS likely resulted from de novo mutations.[3]

History and Physical

The two classic clinical manifestations of Peutz-Jeghers syndrome are mucocutaneous pigment macules and hamartomatous GI polyps. The average age of diagnosis is 23; the first presentation is often from bowel obstruction due to intussusception from the hamartomatous polyps in the GI tract.

Pigmented mucocutaneous dark blue, brown, to black macules are present in over 95% of individuals with Peutz-Jeghers syndrome. Most commonly distributed on the lips, perioral areas, buccal mucosa, eyes, nostrils, fingertips, palms, soles, and perianal areas. The macules are rarely present at birth but appear in childhood, usually before the age of 5, with oral pigmentation being the first to appear during the first year of life. The macules may fade during puberty and adulthood, except for those on the buccal mucosa, which remain into adulthood. No malignant transformation is associated with the melanocytic macules.

Benign hamartomatous polyps with low malignancy risk develop within the first decade of life and are found anywhere along the GI tract, most commonly the jejunum and extraintestinal sites, including but not limited to the bronchus, renal pelvis, and urinary bladder.

Complications of Peutz-Jeghers syndrome include intussusception or obstruction of the GI lumen by the polyps. This may result in abdominal pain or ulceration of the bowels. Up to 69% of patients experience intussusception of the small intestine, with the first event occurring between the ages of 6 and 18 years. GI polyps can also cause chronic bleeding leading to anemia.

Evaluation

Peutz-Jeghers syndrome is based on clinical findings of having at least 2 of the 3 listed clinical criteria for a positive diagnosis:

1. Family history 
2. Multiple dark blue to brown pigmented (macules) lesions on the mucous membranes and skin are most often intraoral on the buccal mucosa or gingiva, lips, perioral, fingertips, palms, and soles
3. Hamartomatous intestinal polyps

Mucocutaneous findings are non-specific for Peutz-Jeghers syndrome; other differentials must be considered. Molecular and genetic testing can aid in confirming the diagnosis

Treatment / Management

The mainstay of management of patients with Peutz-Jeghers syndrome includes surveillance, prevention of manifestations of the condition, and treatment of complications.[1][2][3]

Surveillance

Peutz Jeghers patients may develop GI polyposis as early as 10 years old, with the small intestine as the most common site. Therefore, it is imperative to evaluate the small intestine with upper endoscopy in addition to colonoscopy beginning in early adolescence.

Due to the increased risk of malignancy in Peutz-Jeghers syndrome, surveillance recommendations include the following:

Upper GI Tract 

Upper endoscopy 

• Baseline screening beginning at 12 years old
• If polyps found repeat annually 
• In absence of polyps, repeat every 2 to 3 years into adulthood

Colorectal

Colonoscopy

• Baseline screening beginning at 12 years old or earlier if reported symptoms
• If polyps found repeat annually
• In absence of polyps, repeat at 1 to 3-year intervals

Pancreatic

Magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound: Beginning at 25 to 30 years old; Repeat every 1 to 2 years

Breast

Breast examination: 6-month clinical breast examination beginning at age 25

Breast mammogram: Beginning at age 25Gynecologic

Papanicolaou smear: Annually

Transvaginal ultrasound: Consider yearly transvaginal ultrasound beginning at the age of 18

Testicular

Consider annual examination and yearly ultrasound beginning at age 10.

Prevention

Genetic counseling is recommended for individuals that have a family history of Peutz-Jeghers syndrome and are planning to have children

In female patients with Peutz Jeghers, prophylactic mastectomy to manage the increased risk for breast cancer and hysterectomy and bilateral salpingo-oophorectomy after childbearing completion or age 35 to prevent gynecologic malignancy could be considered.[4][5]

Differential Diagnosis

Juvenile polyposis (JPS) is an autosomal dominant inherited condition that presents with hamartomatous polyps of the small intestine due to mutations in the BMPR1A, SMAD4, or ENG genes; however, dermatological findings of PJS are not appreciated.[6][7]

Peutz-Jeghers syndrome, Bannayan-Riley Ruvalcaba syndrome (BRRS), and Cowden Syndrome belong to a family of hamartomatous polyposis syndromes. Therefore, they share similar clinical features, such as gastrointestinal polyposis, but they differ in genetic loci mutation. BRRS and Cowden syndromes belong to the PTEN1 gene mutations, with pigmented lesions most commonly on the glans penis. Bannayan-Riley Ruvalcaba patients present with macrocephaly, developmental delay, lipomas, and vascular abnormalities, and Cowden syndrome patients present with trichilemmomas, facial papules/oral papillomas, and acral keratoses.

Pigmented intraoral mucocutaneous macules can be found in Laugier-Hunziker syndrome (LHS) but appear later in life after childhood. Additional dermatological findings of longitudinal hyperpigmented bands (melanonychia) on the toes and fingernails are also present. Laugier-Hunziker syndrome is not associated with gastrointestinal polyposis.

Prognosis

Peutz-Jeghers syndrome patients are at an increased risk for malignancies. Earlier screening and surveillance are recommended.

Complications

• Bowel obstruction
• Rectal bleeding
• Mesenteric ischemia
• Gastric outlet obstruction
• Iron deficiency anemia

Enhancing Healthcare Team Outcomes

An interprofessional approach to PJS is recommended. Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome characterized by GI polyposis, mucocutaneous pigmented macules, and cancer predisposition. Patients with PJS are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric organs, besides a wide variety of non-gastrointestinal epithelial malignancies such as breast, uterine and cervical cancer, lung, and tumors of the ovaries and testicles. An interprofessional team consisting of a geneticist, gastroenterologist, general surgeon, dermatologist, urologist, and gynecologist is recommended to decrease the morbidity and mortality of this syndrome. The primary care provider and nurse practitioner should refer these patients to the appropriate specialist as soon as the diagnosis is made. A consult should take place with a board-certified oncology pharmacist regarding the patient's medication regimen for both cancer and non-cancer meds, and an oncology specialty nurse can assist in the monitoring, answer patient questions, and report any changes in status to the managing clinician immediately. The outlook for most patients is guarded. For those who remain cancer-free, the long-term outlook is good, but once malignancies develop, the lifespan is shorter.[8][9][10]