Peutz-Jeghers syndrome (PJS) is a clinical syndrome, occurring in sporadic and in autosomal dominant inherited forms, usually characterized by gastrointestinal, especially small bowel, hamartomatous polyposis, mucocutaneous melanin pigmentation and predisposition to certain neoplasms11. The first systematic descriptions of the inherited form of PJS are credited to Drs Jan Peutz and Harold Jeghers, who both described patients with gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation—the latter distinguishing PJS from other gastrointestinal polyposis syndromes12,13. PJS affects about 1 in 50,000 to 200,000 individuals. Right now PJS is diagnosed by clinical criteria in a proband with one of the following, based on a European consensus statement14: Two or more histologically confirmed PJS-type hamartomatous polyps; Any number of PJS-type polyps detected in one individual who has a family history of PJS in at least one close relative; Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative; Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation.
PJS is a rare autosomal dominant syndrome defined by germline mutation of STK11 (chromosome 19p13.3) which encodes a serine/threonine kinase involved in cell polarity, metabolism and growth15. Germline mutation of STK11 is detected in 94% of PJS patients16,17. In this case, the patient was found STK11 mutation on chromosome 19 in exon 4. Until now a variety of deletion, insertion, inversion, and nonsense mutations have been described in nearly every coding exon, predominately in exons 1, 5, 6, and 718,19. However, right now data on genotype-phenotype correlation related to STK11 pathogenic variants are conflicting. The major source of morbidity and mortality, besides intestinal intussusception in young patients, is the increased lifetime risk of cancer, the most common being breast, colon, pancreatic, gastric, small intestine and lung cancer, the cumulative risks were seen in table 11. PJS-specific cancer surveillance guidelines exist, see table 21.
If significant polyps are present at baseline, repeat upper endoscopy/colonoscopy every three years. If no significant polyps are present at baseline, repeat at age 18 years and then every three years.
CT enterography may be used as an alternative. The use of MR enterography allows for simultaneous surveillance for pancreatic cancer.
If few or no polyps at baseline, repeat at age 18 years.
Digital mammography if MRI not available
Discuss prophylactic mastectomy.
Discuss prophylactic hysterectomy and oophorectomy.
Gynaecological tumours are not a major manifestation of PJS but there are two with distinct pathological features20: (1)gastric-type adenocarcinoma of the endocervix (GAS) and (2) ovarian sex cord tumour with annular tubules (SCTAT). Much less commonly, ovarian oxyphilic Sertoli cell tumour may occur in PJS patients21. One meta-analysis of the literature estimated the lifetime risk of cervical cancer in PJS to be 9% and mean age at diagnosis in the third decade20. Most cases were so-called adenoma malignum (also known as minimal deviation adenocarcinoma, MDA), which is now considered to be equivalent to a well-differentiated form of GAS in the 2014 World Health Organization(WHO) classification system. On the other hand, among those who have GAS, about 11–17% have PJS22,23. Ovarian tumors occur in about 21% of PJS patients, most of which are SCTAT24.
The diagnosis of gastric-type adenocarcinoma is based on the histological criteria25,26 : 1) clear or pale eosinophilic cytoplasm, 2) voluminous cytoplasm, and 3) distinct cell borders. The immune-phenotype of GAS is defined by the presence of pyloric gland mucin (positive MUC6 and HIK1083 staining) and by the absence of high risk HPV(hrHPV) 1627–30, MUC6 is more widely available than HIK1083, both of which mark pyloric gland mucin of the stomach and are positive in most GAS and lobular endocervical glandular hyperplasia(LEGH) but not in normal endocervix or usual type endocervical adenocarcinoma(ECA)8,11. p16 staining is usually patchy or negative. Most GAS lack estrogen receptors, and is unrelated to HPV infection, as shown in our case.
The presenting sign of GAS is often mucoid or watery discharge or vaginal bleeding, and typically shows widespread involvement and advanced stage at initial diagnosis. Ovarian involvement is not uncommon as well. GAS is more aggressive than usual type ECA; the 5 year survival rate is less than half of that for usual type ECA31,20. The prognosis of patients with GAS is worse than that of patients with HPV-related adenocarcinoma because patients with GAS tend to represent an advanced-stage disease and unusual metastatic organs. So in our case, we suggested and finally performed bi-oophorectomy for the patient under her consent. In the meanwhile, as according to the 2018 LACC clinical trial, we improved the surgical procedures of laparoscopic radical hysterectomy. In the surgery, a tape was used for uterus manipulation instead of cup-type uterine trans-cervical manipulator; In addition, colpotomy was done vaginally and the uterus was taken out from the vagina with the cervix wrapped in the vaginal wall cut.
Because of the high risk of malignancy in Peutz-Jeghers syndrome, a more thorough cancer screening has been proposed. Annual pelvic sonography and cervical screening test have been recommended for cancer screening in females with Peutz-Jeghers syndrome11,20,1. Although cytologic or HPV tests are usually negative in GAS, the presence of an enlarged cervix with multiple cysts in a patient with Peutz-Jeghers syndrome is an indication for cervical biopsy even if the patient has no sexual life.