Cancer Risk of Peutz–Jeghers Syndrome and Treatment Experience: A Chinese Medical Center

Abstract

Peutz–Jeghers syndrome (PJS), also known as hereditary mucocutaneous pigmented gastrointestinal polyposis, is a clinically rare autosomal dominant genetic disease, which falls into the category of hereditary colorectal cancer. There are ∼7,000 new cases of PJS in China every year, and 170,000 PJS patients may survive for a long time in society. PJS polyps are characterized by an early age of onset, difficult diagnosis and treatment, and easy recurrence. With repeated growth, polyps can lead to serious complications such as intestinal obstruction, intussusception, gastrointestinal bleeding, and cancerization, which cause serious clinical problems. Due to repeated hospitalization and endoscopic follow-up, PJS patients and their families suffer from great physical and mental pain and economic burden. With the in-depth understanding of PJS and the development and popularization of endoscopic techniques in the past decade, an integrated treatment modality based on endoscopy plus surgery has gradually become the preferred treatment in most hospitals, which greatly improves the quality of life of PJS patients. However, there is still a lack of effective drug prevention and cure means. In this paper, the current clinical treatment means for PJS polyps were summarized by literature review combined with the treatment experience of our medical center, with a focus on their clinical diagnosis, treatment, and cancer risk.

Peutz–Jeghers syndrome (PJS) was first reported by a U.K. physician Connor in 1895, but the report only described the presence of mucocutaneous pigmented on lips and did not clarify the presence or absence of gastrointestinal polyps. In 1921, a Dutch scholar Peutz ¹ found a close association between mucocutaneous pigmented and gastrointestinal polyps in PJS patients. In 1949, Jeghers proposed that PJS is an autosomal dominant genetic disease conforming to Mendelian inheritance. ² In 1954, Bruwer et al ³ first described the disease with PJS. In 1969, some scholars summarized the cancer risk of PJS from patients worldwide, but the author was skeptical about high risk of cancer and suggested that more cases be included. ⁴ In 1997, Hemmink ⁵ determined that the causative gene of PJS was located on 19p13.3. It is currently believed that PJS is an autosomal dominant genetic disease caused by germline mutation of LKB1/STK11 gene. Due to the persistent growth of gastrointestinal polyps, PJS patients are prone to complications such as intussusception and intestinal obstruction, most of them need surgical treatment. Moreover, PJS carries a high risk of cancer in the digestive tract and beyond, such as pancreatic cancer, lung cancer, breast cancer, uterine cancer, ovarian cancer, and testicular cancer. ^{6 7} PJS is diagnosed based on the following criteria: two or more hamartomatous polyps in the gastrointestinal tract, characteristic mucocutaneous pigmentation, and presence or absence of a family history of PJS. Patients suspected of PJS should be tested for germline mutation of STK11/LKB1 . ^{6 8} At present, endoscopic polypectomy plus surgical treatment is the major treatment means for PJS, but there is still no effective drug prevention and cure means.

Clinical Manifestations of PJS

Pigmentation

Pigmented spots are usually distributed on lips, mouth, buccal mucosa, eyes, nasal mucosa, fingertips, palms, heels, and perianal regions, the most obvious are pigmented spots on the lower lip ( Fig. 1 ). According to the clinical data of 566 PJS cases in our medical center, pigmentation occurred in more than 90% of PJS patients before the age of 2 years, and almost all patients had mucocutaneous pigmented on lips and/or extremities, which was highly important for early diagnosis. Pigmented spots can be detected in the early stage of PJS, but child patients often first see a doctor in pediatrics and dermatology department. As a result, they are easily misdiagnosed by nonspecialist doctors, thus losing the valuable opportunity for early treatment, which deserves the vigilance of clinicians. Pigmentation may fade with age, and pigmentation canceration has not been reported at present. Patients can choose laser surgery according to their needs. ⁹

Fig. 1.

Peutz–Jeghers syndrome mouth, buccal mucosa, fingertips, palms, heels pigmented spots.

Multiple Hamartomatous Polyps in the Gastrointestinal Tract

Studies have shown that hamartomatous polyps of PJS can distributed on the whole gastrointestinal tract, and they are mostly in the small intestine ( Fig. 2 ). According to the clinical data of 566 PJS cases in our medical center, polyps could be distributed in the stomach ( n   =  421, 74.4%), small intestine ( n   =  546, 96.5%), and colorectum ( n   =  445, 78.6%), which is consistent with previous reports. ¹⁰ The distribution, size, and diameter of PJS polyps are significantly heterogeneous. Wu et al ¹¹ found that the diameter of polyps ranged from 0.2 to 7.0 cm among 38 PJS patients in China. In our medical center, the diameter of gastric polyps was 2 to 80 mm, that of small intestinal polyps was 1 to 160 mm, and that of colorectal polyps was 1 to 120 mm, and the median diameter of gastric polyps was significantly smaller than that of small intestinal and colorectal polyps. Moreover, the polyps load and diameter also vary in the same patient and among different patients, and some patients the number of polyps can reach over 100 in severe cases. PJS polyps can lead to secondary ulceration and bleeding, polyp prolapse from anus, intussusception, and intestinal obstruction, thus resulting in abdominal discomfort, abdominal pain, abdominal distension, and hematochezia, which become the reasons for most patients' first visit. A survey of PJS patients showed that 68% of adult patients had a history of laparotomy, 70% of which was done by emergency surgery. ¹² In our medical center, 71.6% of PJS patients underwent surgery, 75.6% of whom received abdominal surgery before the age of 35 years. Hence, PJS patients should undergo routine endoscopic surveillance of gastrointestinal polyps to achieve early detection and early treatment and avoiding emergency surgery as much as possible.

Fig. 2.

Hamartomatous polyps in the gastrointestinal tract (HE ×10).

Family History

PJS is an autosomal dominant genetic disease, with a 50% probability of disease in offspring, and it is mostly genetically characterized by family aggregation. Among the 566 PJS patients in our medical center, 236 cases (41.7%) were married and 330 cases (58.3%) were unmarried. A total of 183 patients were married and had children, including 106 cases (57.9%) who had healthy children and 77 cases (42.1%) who had children with PJS. Considering that some of the healthy children born to the above 106 patients are young and show no disease characteristics temporarily, they cannot be correctly diagnosed and may have a higher prevalence rate. Next-generation sequencing (NGS) can be performed on patients with suspected or confirmed PJS, and genetic testing can reliably quantify the PJS incidence, penetrance, mutation type, and expression. When the patient has fertility demand, preimplantation genetic testing can be used for preimplantation genetic diagnosis or preimplantation genetic screening, ^{13 14} so that the familial transmission of disease can be effectively blocked and the birth of offspring with disease can be avoided. Pregnancy can be terminated if the fetus is a carrier of STK11 gene mutation, and healthy fetuses can be successfully born through screening. ¹⁵

Association Between Pigmentation and Polyps

The clinical manifestations are obviously heterogeneous among different PJS patients and even in the same PJS patient at different time points. Significant differences can be observed in the number and size of mucocutaneous pigmented, number and distribution of intestinal polyps among patients with different phenotypes of PJS. Currently, whether the color and number of pigmented spots are associated with the number and diameter of polyps has not been reported in literature. Therefore, it is of great importance to choose an appropriate examination method and develop an individualized follow-up protocol for PJS patients.

Mental Health

Pigmentation and repeated hospitalization seriously affect the patient's appearance, self-confidence, and social competence. With the in-depth understanding that PJS is a genetic disease with cancer risk and requires repeated long-term hospitalization, adolescent PJS patients may gradually develop a sense of inferiority and helplessness, hate their parents, and even retaliate against society. Alice Woo et al surveyed 38 PJS patients with a quality-of-life questionnaire and found that PJS patients suffer from mild depression as compared with the general population. ¹⁶ van Lier et al ¹⁷ also conducted a questionnaire survey of 61 PJS patients and found that PJS patients exhibit a strong emotional reaction to recurrence and malignant transformation of polyps, and poor mental life is the major determinant of low quality of life. Mendelson and Tandon ¹³ pointed out that the lifetime prevalence of depression in adolescents aged 15 to 18 years is 11 to 14% in the general population and that about half of the first episodes of depression occur in adolescence. Therefore, more attention should be paid to the mental health of PJS patients, and clinicians should give a professional interpretation of PJS to patients with health concerns to relieve their anxiety and depression. If the above measure is ineffective, it is recommended that the patient see a psychologist, because we are not professional psychologists and cannot assess the patient's depression degree.

Research Progress on Pathogenesis of PJS

The pathogenesis of PJS has always been a hot spot in the research on PJS. The germline mutation of STK11 gene is currently considered the genetic basis of PJS. ¹⁴ STK11 gene, located on chromosome 19p13.3, is a tumor suppressor gene ¹⁵ widely expressed in human tissues. STK11 also known as LKB1 , is 23 kb in length and consists of nine coding exons and one noncoding exon, ¹⁶ whose expression products are important players in cell polarization, cell energy metabolism, VEGF regulation, Wnt signal transduction, and p53-dependent apoptosis. ^{15 18 19 20} Studies suggest that ∼90% of PJS cases have STK11 mutations. ^{21 22} In the Human Gene Mutation Database, more than 500 pathogenic mutations of STK11 gene have been reported, most of which are microtypes, and different types of mutations have varying effects on clinical phenotypes. With the use of NGS and NGS  +  multiplex ligation-dependent probe amplification, the combined mutation rate of STK11 gene has been detected to be 80 to 94% in PJS patients. ^{23 24} However, PJS may have other multiple gene mutations besides STK11 mutations, and STK11 mutations cannot even be detected at all in some PJS patients. ²⁵ No obvious difference is found between cases with or without STK11 mutations. If no STK11 pathogenic variation is found, the possibility of cellular chimerism should be considered. Seven PJS patients with somatic chimerism have been identified so far, and polygenic combinations involving STK11 and other target genes may also be considered. ^{26 27} STK11 and other target genes have a variety of mutation types and loci, most of which are frameshifts or insignificant variations. ^{11 25 28} At present, effective mutation targets cannot be found from the complex and redundant massive data on gene mutation. Since the pathogenic gene mutation modes are diverse and complex, and new mutation loci are constantly discovered, ^{29 30 31} PJS may not only be a genome-level issue but involve multiple cellular and molecular levels.

Therapeutic Methods of PJS

Medication

Chemoprophylaxis methods to reduce the PJS polyps burden are under investigation and have not yet been put into use. Overexpression of cyclooxygenase-2 (COX-2) is exhibited in PJS polyps, suggesting that COX-2 inhibitors may be useful in reducing polyps. In a study on celecoxib used in the treatment of PJS polyps, ³² PJS patients (2/6) responded well to celecoxib with a reduction in gastric polyps, suggesting that COX-2 chemoprophylaxis may be beneficial in the treatment of PJS. However, among nine PJS patients treated with celecoxib capsules for 9 months to prevent polyps growth in our medical center, six cases quickly discontinued the drug due to sulfonamide allergy and gastrointestinal bleeding, and only one out of three cases who completed the treatment for more than 6 months had responses. The above findings suggest that COX-2 inhibitors may not be the therapeutic target-oriented drug for PJS. In addition, 30 PJS patients also used to undergo treatment with traditional Chinese medicine, but the response rate was only 40%.

It has been found that overactivation of mammalian target of rapamycin (mTOR) is associated with PJS, and inhibiting mTOR has been verified to be able to reduce polyps burden in mouse models of PJS. ²⁵ Brabander et al ³³ treated two PJS patients with everolimus (an mTOR inhibitor, a derivative of rapamycin). As a result, one patient had pancreatic cancer that progressed after 2 months, and the other patient refused to continue treatment due to severe toxicity and quit the trial.

At present, PJS and immune-related research is ongoing. Gastrointestinal polyps emerge in mice after knockout of STK11 gene in mouse T cells, ³⁴ whereas an inflammatory response occurs in polyps accompanied by the production of IL-11 and activation of the JAK/STAT3 pathway in tumor epithelium after knockout of STK11 gene in mouse stromal cells. Treatment of STK11 -deficient mice with ruxolitinib (a JAK1/2 inhibitor) can significantly reduce polyposis. ³⁵ This suggests that immune blockade is a potential therapeutic method for PJS.

Endoscopy

Since its advent in 2001, balloon-assisted endoscopy (BAE) has quickly become a major method for diagnosis and treatment of small intestinal diseases. ³⁶ BAE can promptly remove small intestinal polyps and reduce the times of surgical operations. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are the major treatment means for PJS polyps. ^{37 38} Cao et al ³⁹ performed single-balloon enteroscopy on 129 PJS patients and found that complications occurred in 7.8% of patients. After 566 PJS patients received EMR or ESD in our medical center, complications occurred in 10.6% of patients, and only 2.3% of them suffered severe gastrointestinal perforation or bleeding and thus were converted to intestinal perforation repair or partial small bowel resection. Hence, endoscopy is effective, safe, and feasible in reducing polyp-related complications. ^{40 41} PJS patients should undergo exploration of the whole digestive tract by peroral enteroscopy and transanal enteroscopy. First, the presence or absence of intussusception, intestinal obstruction, and intestinal perforation is explored, and the position of polyps is marked. Intraoperative assessment is conducted to determine whether conservative treatment such as endoscopic inflation balloon, titanium clipping hemostasis methods, and so on can be used to repair perforation or intussusception. Otherwise, surgery should be performed as soon as possible. After exploration of the digestive tract, the size of polyps is intraoperatively assessed according to the width of biopsy forceps. If found that polyps are flat, broad-based, and sessile with diameter <10 mm, then it should use cold forceps polypectomy, cold snare polypectomy, or argon plasma coagulation methods, combined with submucosal injection of epinephrine and 0.9% sodium chloride solution at 1:10,000; after the lesion is obviously raised, it can be completely resected by snares or high-frequency electrotomy, with a low risk of complications such as hemorrhage and perforation. ^{37 42} In contrast, EMR can be used for resection of polyps ≥10 mm in diameter, and to resect 30 polyps is appropriate. ESD can be performed on polyps >30 mm in diameter, and the number of polyps to be resected at one time should not exceed 5, otherwise perforation may occur. Large broad-based polyps with a maximum diameter >50 mm need to be treated separately with fractional or even staged resection. If the polyps cannot be completely resected, it is recommended that endoscopic polypectomy of small intestine be performed again within 3 months. Titanium clipping can be used for lesions with a deep burn of residual polyp root, large wound surface, or bleeding tendency after surgery, thereby preventing perforation or bleeding.

Surgical Treatment

PJS complicated with intussusception and intestinal obstruction is not uncommon. ^{6 43} Air enema is feasible for intussusception reposition in a few cases, but intussusception easily recurs after repositioning, so surgery is still required. Hamartoma polyps of PJS occur at multiple sites in the gastrointestinal tract, and the patients may undergo laparotomy many times, so intra-abdominal adhesions are serious, making laparoscopic surgery difficult. Therefore, laparoscopy is not recommended as a routine treatment for PJS, but can be used for abdominal exploration of untreated patients or patients with moderate intra-abdominal adhesions, and for local salvage treatment in resection of localized giant gastrointestinal polyps with endoscopy plus laparoscopy, resection of polyp and dense intestinal segments, or occurrence of perforation or bleeding during endoscopy. ^{44 45} Laparoscopic perforation repair or hemostatic suture can be used as an adjunct to endoscopy.

Laparotomy is usually performed on PJS, and approximately one-third of PJS patients undergo laparotomy before the age of 10 years. ⁴⁶ PJS patients undergoing laparotomy can undergo intraoperative whole small bowel and colon exploration when possible, to clarify the involvement of the whole gastrointestinal tract. The whole small bowel should be carefully examined during surgery, and all palpable polyps >1 cm in diameter should be resected as much as possible. However, the principle of organ preservation should be followed, i.e., the small bowel, especially the high jejunum, should be preserved as much as possible to avoid short bowel syndrome. In addition, attention should be paid to the choice and aesthetics of the surgical incision, and the incision is suggested to be extended along the midline, so that all the small intestinal polyps can be explored from the initial part of jejunum to the ending part of ileum.

The principle of organ protection should be followed in PJS surgery. To this end, intestinal adhesion lysis is recommended to avoid large intestinal segment resection, and all palpable intestinal polyps are removed through multiple small incisions on the intestinal wall. Resection of the diseased intestinal segment is recommended for the intestinal segment with dense polyps or intussusception that cannot be repositioned, necrosis, and perforation. The patients diagnosed with malignant transformation should undergo radical resection  +  regional lymph node dissection according to the treatment principle of gastrointestinal malignancy ( Fig. 3 ). As the endoscopic technique has been popularized in the treatment of PJS, the indications of surgical operations are generally as follows: (1) patients with polyps that cannot be reached by the endoscope, (2) polyps patients who cannot be treated with endoscopy due to acute intussusception and intestinal obstruction, (3) patients with large, broad-based, or dense polyps that cannot be resected by the endoscope, (4) patients pathologically diagnosed with malignant transformation of polyps, or highly suspicious malignant transformation observed under the endoscope, (5) patients with perforation during endoscopic polypectomy or delayed perforation after surgery that cannot be treated with conservative medical treatment, (6) patients with massive hemorrhage during endoscopy or delayed massive hemorrhage after surgery that has no response to conservative medical treatment, and (7) patients who or whose families require surgical resection of polyps at one time.

Fig. 3.

Surgical resection of polyps and malignant polyps.

PJS duodenal polyps are difficult to be treated surgically. Due to the hidden position of the duodenum and involvement of the bile duct, pancreatic duct, and other vital organs, it is highly difficult to explore and resect PJS duodenal polyps. Due to large polyps, iatrogenic injury is often caused in the major duodenal papilla, leading to severe complications such as cholangitis, pancreatitis, and liver abscess. Endoscopic cauterization of polyps can even lead to obstruction of the major duodenal papilla due to mucosal edema, resulting in fatal cholangitis and pancreatitis. Once the duodenal polyps become malignant, pancreaticoduodenectomy and other greatly invasive operations may be required, with a poor prognosis, thus seriously affecting quality of life and survival time of patients.

Cancer Risk of PJS

PJS is a cancer susceptibility syndrome, ^{8 47 48} so the risk of digestive system cancers (colorectal cancer, pancreatic cancer, and gastric cancer) and nondigestive system cancers (breast cancer, cervical cancer, lung cancer, and urogenital tumor ^{42 49} ) is higher in PJS patients than that in the general population. However, some scholars have questioned this, i.e., the cancer risk may be overestimated because of the influence of sample size and publication bias. ⁵⁰ Nevertheless, it was found in a retrospective study on the cancer risk involving 412 PJS patients in China that the incidence rate of gynecological and lung cancers was second only to that of gastrointestinal cancer in PJS patients, and the age of cancer onset was earlier than that in previous studies. The association between PJS and lung cancer has been rarely noticed, ⁷ and no data show that lung cancer surveillance can benefit PJS patients. Annual lung cancer surveillance with low-dose computed tomography can be adopted for smoking patients with PJS at high risk of lung cancer. ⁴⁸ Currently, no uniform clinical follow-up protocol for patients with PJS polyps is available. It is recommended by the European Hereditary Tumour Group (EHTG) that asymptomatic PJS patients undergo gastrointestinal endoscopy at the age of 8 years. ⁴² Latchford et al ⁶ suggested that gastrointestinal surveillance should be performed no later than 8 years of age, except for those with early symptoms. As recommended by the guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG), ⁵¹ asymptomatic PJS patients begin to undergo gastrointestinal endoscopy, capsule endoscopy, and colonoscopy at the age of 8 years, or at the age of 18 years, if negative. At present, a total of 566 PJS patients have been treated in our medical center, and we have accumulated rich experience in diagnosis and treatment ( Fig. 4 ). Gynecological cancer frequently occurs in PJS patients. In particular, cervical cancer can be manifested as special gastric adenocarcinoma, with a typical symptom of watery vaginal discharge, which cannot be detected early in general cervical cancer screening for HPV infections. PJS gastric adenocarcinoma is characterized by a poor prognosis, rapid progression, a low cure rate, and a short overall survival period. ^{52 53} Therefore, early diagnosis is of great importance for improving the cure rate. A general consensus has been reached on breast cancer surveillance in PJS. To be specific, it is recommended that female PJS patients aged 25 to 30 years undergo breast ultrasound, mammography, or magnetic resonance imaging (MRI) surveillance once a year, ^{8 42 54} and patients with a family history of breast cancer receive early surveillance and BRCA gene testing. At present, there is a lack of research data on prospective surveillance of gynecological tumors in PJS patients, most of which are case reports. It has been shown that PJS patients have a risk of gynecological cancer of 18 to 50% at the age of 50 years. ^{42 55} Therefore, it is suggested that female PJS patients undergo regular gynecological ultrasound screening after the age of 25 years. The recommendations from the Cancer of the Pancreas Screening (CAPS) Consortium state that pancreatic cancer surveillance be performed no later than 50 years of age on patients with a familial risk. ⁵⁶ Beggs et al ⁸ did not recommend pancreatic cancer surveillance, arguing that ∼90% of pancreatic cancers are sporadic ⁵⁷ and benefit little from routine surveillance. Research has shown that PJS can also be complicated with testicular canceration, ^{42 48} and testicular screening is suggested for men with PJS in most reports. ⁶ However, the author was skeptical about this, because there is little literature on PJS with testicular tumor; it is described only in case reports and no statistical analysis is available. In our medical center, no testicular canceration was found in a retrospective study involving 566 patients with PJS over a period of ∼28 years ⁵⁸ . Therefore, PJS with testicular diseases is probably accidental. MRI of the testes should be performed promptly if the testes are found to be enlarged, nodular, hardened, or different on palpation.

Fig. 4.

Peutz–Jeghers syndrome diagnosis and treatment process.

Conclusion

The clinical phenotype of PJS is significantly heterogeneous, but its genetic reason remains to be explored, and it may involve genes, immunity, cytokines, and signaling pathways according to the latest research. PJS carries a high risk of cancer and requires long-term medical surveillance. Endoscopy is still the first choice for the treatment of PJS, but most patients are still likely to undergo surgery in their lifetime. With tactile exploration of the whole small intestine, traditional laparotomy is often adopted for surgical treatment. In contrast, laparoscopic surgery cannot completely resect the gastrointestinal polyps due to the lack of tactile exploration. With in-depth research on the pathogenesis of PJS, gene editing may become a radical cure for PJS in the future.

Funding Statement

Funding This study was funded by Beijing Capital Medical Development Research Fund, No. Shoufa2020-2-5122; Outstanding Young Talents Program of Air Force Medical Center, PLA, No. 22BJQN004; Clinical Program of Air Force Medical University, No. Xiaoke2022-07.