Gastric-type mucinous adenocarcinoma of the cervix in a woman with Peutz-Jeghers syndrome

Background: Peutz-Jeghers syndrome(PJS) is a very rare autosomal dominant disorder with predisposition to multiple neoplasms. Gastric-type adenocarcinoma (GAS) is a less common carcinoma of the cervix than squamous cell carcinoma, which is more aggressive and has lower 5 year survival rate than usual type endocervical adenocarcinoma (ECA), and unrelated to human papilloma virus(HPV) infection as well. We present a 32 year-old patient with Peutz-Jeghers syndrome who was found to have gastric-type adenocarcinoma of the cervix. Case presentation: A 32-year-old woman without sexual life ever who was diagnosed Peutz-Jeghers syndrome when she was two years old presented with watery discharge for more than 6 months. A tumor around 6cm was found on the cervix and she was diagnosed gastric-type mucinous adenocarcinoma of the cervix clinical stage IB3. She was treated with artery intervention chemotherapy for one course followed by radical surgery and then systematic chemotherapy. Conclusions: The case suggests more thorough cancer screening for patients with PJS as the disorder is rare and has high risk of malignancies. Young patients with Peutz-Jeghers syndrome, including those without sexual life, who have watery discharge or bleeding should be screened for cervical carcinoma even if cytologic results or human papilloma virus (HPV) is negative.


Backgroud
Peutz-Jeghers syndrome(PJS) is a rare autosomal dominant disorder,which is characterized by mucocutaneous pigmentation, multiple hamartomatous polyps in the gastrointestinal tracts and predisposition to certain neoplasm 1 . The incidence of PJS was estimated from 1 in 50,000 to 1 in 200,000 live births 1,2 . Previous reports 3,4 shows that 11-17% of women with Peutz-Jeghers syndrome are found to have gastric-type adenocarcinoma (GAS). We report a case of adenocarcinoma of the cervix, diagnosed by cervical biopsy in a woman with Peutz-Jeghers syndrome, which was eventually histopathologically con rmed to be GAS after radical surgery.
Cervical adenocarcinoma is less common than cervical squamous cell carcinoma, but the incidence of cervical adenocarcinoma has been increasing in the recent years, especially in young women. It is estimated to account for up to 10%-25% of all invasive cervical carcinomas 5 . Gastric-type adenocarcinoma (GAS) is a novel variant of endocervical mucinous adenocarcinoma according to the 2014 WHO classi cation 6 . It represents more aggressive disease and poorer prognosis than the usualtype endocervical adenocarcinoma (UEA) 7,8 .

Case Presentation
The institutional review board (International Peace Maternity and Child Health Hospital) approved this work. A 32-year-old woman without sexual life ever presented with a history of recurrent watery vaginal discharge for more than 6 months and prolonged menstrual periods over the preceding 3 months in August 2020. Pelvic magnetic resonance imaging (MRI) revealed a cervical mass 5.8*5.6*7.6cm while enlarged lymph nodes were not seen ( Fig. 1A and 1B). The patient was diagnosed Peutz-Jeghers syndrome at 2 months old at a tertiary hospital for mucocutaneous pigmentations over the lips. She had a history of colon polyps resection by colonoscopy when she was 12 years old and since then had colonoscopy and biopsy every year. In 2002 when she was 14 years old, she had an emergent surgery for bowl obstruction. In 2018 she had a surgery for breast tumor and pathology con rmed benign. No other family members were found with Peutz-Jeghers syndrome.
Physical examination revealed mucocutaneous pigmentations over the lips, especially the lower lip and nostrils (Fig. 2). Laboratory data showed no blood, urine, or stool changes. HPV test was negative. Tumor We proceeded with a gynecological examination under anesthesia. A tumor around 6cm was found on the cervix, vagina and parametrium was not invaded on physical examination. Biopsy was taken and para n section pathology diagnosed moderate differentiated gastric-type mucinous adenocarcinoma of the cervix.
In accordance with the latest 2018 International Federation of Gynecology and Obstetrics criteria, gastrictype mucinous adenocarcinoma of the cervix clinical stage IB3 was diagnosed. We gave her artery intervention chemotherapy for one course 9,10 (intravenous taxol 135mg/m 2 and bilateral uterine artery cis-platinum 80mg/m 2 ). MRI was taken 2 weeks later for tumor assessment. On the second MRI, the tumor shrinked to 4 + cm, and there were some dartoid tissue fell out of vagina one week after the artery intervention chemotherapy told by the patient.
Eventually, the patient underwent laparoscopic radical hysterectomy, bilateral salping-oophorectomy, bilateral pelvic lymph node dissection and para-aortic lymph node dissection 3 weeks after the artery intervention chemotherapy. The nal histo-pathological analysis of the specimen from radical surgery con rmed moderate differentiated cervical gastric-type mucinous adenocarcinoma ( Fig. 3A and Fig. 3B). No myometrial invasion or metastasis to pelvic lymph nodes was observed, no lymphovascular space invasion and clear vaginal resection margins. Immuno-histochemistry shows MUC6(+), MUC2(-), P16 patchy, ER and PR all negative( Fig. 4A-4F). A gene test was also taken and a mutation of STK11 was con rmed. The patient had adjuvant chemoradiation therapy after the radical surgery: intravenous taxol (135mg/m 2 every 21 days) and carboplatin (area under the curve of concentration*time[AUC] = 5 every 21 days). We plan to give her 6 courses of intravenous chemotherapy in total and right now she already has 5 courses and tolerates well.

Discussion And Conclusions
Peutz-Jeghers syndrome (PJS) is a rare clinical syndrome, occurring in autosomal dominant inherited forms, which is characterized by gastrointestinal, commonly small bowel, hamartomatous polyposis, mucocutaneous melanin pigmentation and predisposition to certain neoplasms 11 . Drs Jan Peutz and Harold Jeghers are the rst to systematically describe the inherited form of PJS, who both reported patients with gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation, which could distinguish PJS from other gastrointestinal polyposis syndromes 12,13 . The incidence of PJS is estimaed about 1 in 50,000 to 200,000 individuals. According to a European consensus statement 14 , PJS is diagnosed by the clinical criteria as the following: Two or more histologically con rmed 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 could be de ned by the mutation of STK11 (chromosome 19p13.3). STK11 encodes a serine/threonine kinase which participates in cell metabolism and growth 15 . In about 94% of PJS patients 16,17 , germline mutation of STK11 could be detected. In this case, the patient was found STK11 mutation on chromosome 19 in exon 4. Right now a variety of mutations, including deletion, insertion, and inversion mutations, have been reported in almost every coding exon, mainly in exons 1, 5, 6, and 7 18,19 . However, the reports on genotype-phenotype correlation related to STK11 pathogenic variants are con icting. The major source of morbidity and mortality in young patients is intestinal intussusception. Another is the increased cumulative risk of cancer. The most common are breast and colon, with the cumulative risk being more than 30%, while the general population is 12.4% and 5%, respectively 1 . The risk of cervical cancer in PJS patients is 10%, while the general population is < 1%. PJS-speci c cancer surveillance guidelines exist, see table 1 1 . 6. Discuss prophylactic hysterectomy and oophorectomy.
In PJS patients there are two characteristic gynaecological tumours 20 : gastric-type adenocarcinoma of the endocervix (GAS) and ovarian sex cord tumour with annular tubules (SCTAT). Occasionally, ovarian oxyphilic Sertoli cell tumour may occur in PJS patients 21 . One meta-analysis of the literature reported the cumulative risk of cervical cancer in PJS patients to be around 9%, with the mean age at diagnosis in the third decade 20 . Adenoma malignum is commonly seen (also known as minimal deviation adenocarcinoma, MDA), which is now categorized to be a well-differentiated form of GAS in the 2014 World Health Organization(WHO) classi cation system. On the other hand, among the patients who are diagnosed GAS, about 11-17% have PJS 22,23 . While ovarian tumors, most of which are SCTAT 24 , occur in about 21% of PJS patients.
The histological criteria 25,26 for the diagnosis of gastric-type adenocarcinoma is as follows: 1) clear or pale eosinophilic cytoplasm, 2) voluminous cytoplasm, and 3) distinct cell borders. The characteristic immune-phenotype of GAS is the presence of pyloric gland mucin, which means positive MUC6 and HIK1083 staining. Both MUC6 and HIK1083 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 . However, MUC6 is more widely available than HIK1083, as in our case, we just did MUC6 staining. As GAS is unrelated to high risk HPV(hrHPV) 16 27-30 , p16 staining is usually patchy or negative. The lack of estrogen receptors is seen in most GAS, as shown in our case.
The presenting sign of GAS is often mucoid or watery discharge or vaginal bleeding, and widespread involvement and advanced stage are commonly seen when the initial diagnosis is established. Ovarian metastases is not uncommon as well. The biological behavior of GAS is more aggressive compared to usual type ECA; the 5 year survival rate is less than half of that for usual type ECA 31,20 . As patients with GAS usually have an advanced-stage disease and widespread organ involvement, the prognosis of patients with GAS is much worse than that of patients with usual type adenocarcinoma. So in our case, we suggested and nally 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 transcervical 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.     Immunohistochemical staining is negative for MUC2; (C) Immunohistochemical staining is patchy for