We report here a case of a 30-year old woman who suffered from multiple organ neoplasms with PJS. The melanin pigmentation around lips appeared when she was 3 mo old, after that, melanin pigmentation increased and also appeared on the palm and planta. She presented with iterative abdominal pain and vomit in 1997, and was found having multiple polyps in colon by colonoscopy. The polyps had been resected several times, but the symptoms still existed.

The patient presented to us in April 2001. Physical examination revealed the pigmentation on the oral lips, the buccal mucosa (Figure 1A), and the hands and feet (Figure 1B), about 1-3 mm in diameter. Endoscopy and gastrointestinal tract contrast examination revealed multiple polyps in sinus ventriculi, small intestine and colon. Most polyps were resected and demonstrated hamartomatous polyps, some of which showed adenomatous changes (Figure 2A), and the one in small intestine revealed carcinomatous changes (mucinous adenocarcinoma, infiltrating full-thickness of the intestine) (Figure 2B). The patient received FOLFOX4 chemotherapy after surgery. Tumor markers and routine blood tests were mainly normal during the treatment. The patient gradually recovered, then we kept follow-up visit on her.

In November 2007, the patient complained of abnormal vaginal discharge for 2 mo, without vaginal bleeding and abdominal pain. Gynecological B-mode ultrasonography found occupying lesion located between inferior segment of cervix and vagina. Gynecologic examination revealed thick cervix, and cervical scraping smear confirmed cervical adenocarcinoma. After neoadjuvant chemotherapy ( Paclitaxel 120 mg/dL, Carboplatin 350 mg/dL, one day per wk for 6 wk )，total hysterectomy was performed in February 2008. Final pathological diagnosis was cervical adenosquamous carcinoma (Figure 3), and cancerometastasis of lymph nodes in left external iliac (1/1). The patient also received pelvic radiotherapy after surgery (50 GY in total).

PJS patients have an increased risk for several malignancies including small intestine, stomach, pancreas, colon, esophagus, ovary, uterus, lung, and breast cancer. PJS is associated with a markedly increased risk of malignancy that is not confined to the gastrointestinal tract. A metaanalysis found that, compared with the general population, patients with PJS have a relative risk (RR) of 15 times higher than for developing many kinds of cancer. And the cumulative risk for all cancers was 93% from age 15 to 64. Very high RRs for the development of cancer were observed in the small intestine (520), stomach (213), pancreas (132), colon (84) and esophagus (57), and RRs are greater than 10 for the development of breast, lung and ovarian cancer[ ²]. Several gonadal malignancies occur in PJS patients. In female patients, sex cord tumors with annular tubes (SCTAT) are found in the ovaries of many individuals examined. Patients with these tumors can present with menoxenia, hyperestrogenism or sexual precocity[ ³]. Minimal deviation of cervical adenocarcinoma has been reported in PJS patients. Presenting symptoms include abnormal vaginal bleeding or a mucoid vaginal discharge. It is an extremely well differentiated adenocarcinoma of the cervix. It usually shows poor malignant behavior and poor prognosis with mucinous type of adenocarcinoma[ ⁴].

STK11/LKB1 was identified strongly relative to the PJS, which is a tumor-suppressor involved in intracellular signal transduction and cellular polarity[ ⁵]. Some studies provided molecular evidences of a hamartoma-adenoma-carcinoma sequence in PJS. The second hit in LKB1 causing loss of heterozygosity (LOH) in adenomatous and carcinomatous lesions in PJS polyps was noted by several investigators[ ^{6 , 7}]. In addition, LOH of p53, K-Ras and β -catenin mutations were found in adenomas developing in hamartomatous polyps, indicating that molecular alterations in these genes drive carcinogenesis in PJS as well[ ⁸]. However, the precise frequency of LOH of LKB1 in PJS polyps in human remains unclear, and studies in mice showed that loss of the wild-type LKB1 allele is not a prerequisite for the formation of hamartomatous polyps[ ⁹]. Therefore, the need for the second-hit in LKB1 during polyp development in PJS, and the role of LKB1 as a typical ‘Knudson’ two-hit tumor-suppressor gene, is questioned. One theory suggests mucosal prolapse as a pathogenic mechanism underlying the development of typical hamartomatous polyps in PJS. In this hypothesis, PJS hamartomatous polyps represent an epiphenomenon to the cancer-prone condition and the hamartoma-adenoma-carcinoma sequence as such does not exist[ ¹⁰]. The important role of LKB1 in cellular polarity may provide new insights into the molecular mechanism of polyp and carcinoma development in PJS. Loss of polarity function may also affect asymmetric stem cell division in PJS and lead to expansion of the stem cell pool[ ¹¹]. It could contribute to polyp formation and explain the increased cancer risk as well. A recent study found STK11-deficient mesenchymal cells produced less TGF-β, and defective TGF-β signaling to epithelial cells coincided with epithelial proliferation. TGF-β signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant to PJS[ ¹²].