In 2021, a 40-year-old male patient came for consultation. He had chronically recurrent gastrointestinal bleeding for 15 years, developed malignant lesions of the descending part of the duodenum, and then underwent pancreaticoduodenectomy in our hospital. The patient has lost 15 kg of weight since the onset in September 2020. Moreover, he had no notable family medical history.
The patient was admitted to the local hospital on March 8, 2019, and operated on a partial enterectomy with a 150 cm intestine because the enteroscopy found bleeding in a part of the intestine. However, the patient was still under anemia after the operation (Figure 1). After then, the patient suffered from jaundice and incomplete ileus with the feeling of ventosity and nausea in October 2020. The local hospital implemented PTCD to improve jaundice and treat fasting, nasogastric drainage, and total parenteral nutrition for incomplete ileus. However, they did not find a solution to handle the bleeding event. Therefore, the patient came to our hospital for further medical consultation. Tracing the history, we found that the patient had anemia before he was 16 and was given blood transfusion therapy. This situation recurred 3-4 times before.
We did regular pre-operation examinations after the patient was admitted to our hospital. Enhanced computer tomography showed dilatation of the duodenum and stomach, and there was a space-occupying lesion that tended to be malignant. Magnetic resonance imaging revealed duodenal malignancy, slight dilatation of the bile duct, and fatty liver (Figure 2). Obviously, the gastrointestinal obstruction was caused by the occupying lesion of the descending part of the duodenum.
Upper gastrointestinal endoscopy revealed multiple diffused polyps located in the stomach and the duodenum, and colonoscopy showed the same extent polyps of varying sizes localized in the rectosigmoid region. The onset of small intestinal malignant tumors combined with upper and lower gastrointestinal tract polyps might suggest MUTYH-associated polyposis syndrome (MAP) or Lynch syndrome. Nevertheless, further physical examination revealed that the patient had macrocephaly, and dermatologic examination was remarkable (Figure 3). Miliary papules were scattered on the face, especially on the forehead. Also, there was papilloma of the tongue, hyperkeratosis of soles, and melanosis spots on the glans of the penis. Therefore, we considered the possibility of other diseases such as Cowden syndrome and P-J syndrome and performed a radical pancreaticoduodenectomy (classic Whipple) to remove the malignant lesion in the duodenum on March 23, 2021.
The gross pathology showed a 6 x 5 x 4 cm cauliflower-like protrusion lesion (Figure 2). The cut surface of the tumor was pale, soft, and fragile and visually infiltrated the muscular layer of the duodenum. Diffuse hyperplastic grayish-brown polyps could be seen in the entire intestinal wall, ranging from 1 to 4 mm. The common bile duct was dilated, and the pancreas was undisturbed. Microscopic pathology (Figure 4) reported that the cauliflower-like elevated tumor of the duodenum was considered a hamartomatous polyp, with malignancy in some areas (80% non-mucinous adenocarcinoma, 20% mucinous adenocarcinoma). Also, the carcinoma tissue had infiltrated into the subserous layer. Other polyps were described as polypoid hyperplasia of mucosal glands. No metastasis was observed in perigastric lymph nodes and peripancreatic lymph nodes. In addition, it is suggested that the mesentery nodules were hemangioma. Immunohistochemical results showed Ki-67(40% positive), CDX2(+), MSH2(+), MSH6(+), PMS2(+), CK20(+), STK11(+/-), PTEN(expression deletion), Her-2(weak +), SATB2(little +), D2-40(no apparent lymphatic tumor thrombus was found), and p52(DO7) (70%+); special staining showed no definite venous invasion of elastic fibers. Immunohistochemical results showed that PTEN protein expression was lost in the tumor and surrounding mucosal tissues, which may be an important factor in tumorigenesis. However, MLH1 and STK11 proteins were normally expressed. Therefore, we believed Cowden syndrome was the most likely diagnosis. At the suggestion of the pathologist, further NGS gene testing was carried out.
Gene testing of the tissue samples suggested multiple germline gene mutations. A frameshift mutation was detected in the PTEN gene, leading to amino acid p.E242fs alternation. We refined the localization to position 89717695 of chr10, which might lead to a premature terminator in the new reading frame, resulting in protein dysfunction and having pathogenic significance. According to the large population databases (gnomAD, ExAC, 1,000 genome, ESP6500, etc.), this was a rare mutation that has never been discovered before. Partial genetic mutations of the PTEN gene are related to PTEN hamartoma tumor syndrome/Cowden syndrome. This autosomal dominant genetic disease is associated with an increased risk of breast cancer and thyroid disease and may increase the risk of endometrial cancer and central nervous system tumors. On chr13, missense mutation occurred in two-locus:32906558 and 142274875, causing P.C315S of the BRCA2 gene and p.T729A of ATR change. Missense mutations occurred in PALB2 and MC1R gene on chr16, causing p.Q1114R and p.A166G changes. All mutations of these germline genes were heterozygous mutants, and their clinical significance for CS has not been clarified except for PTEN. Four critical tumor driver gene mutations were detected in the patient. Tumor mutational burden was 2.20 muts/Mb, and microsatellite instability was detected as microsatellite stable. The mutation in exon 2 of KRAS changed P.G12A inactivated GTPase, leading to the accumulation of tumor-associated KRAS in the active GTP-bound conformation. That possibly promoted the development of malignant tumors. Currently, there are drugs targeting KRAS gene mutations in the market. Nevertheless, the detection of KRAS mutation also suggested that patients with colorectal cancer may be resistant to Cetuximab(A) and Panitumumab(A). These discoveries can be expected to guide the follow-up treatment. The other three mutations, resulting in p.R714H, p.A4083P, and p.D351G alternations, were detected in exon 11 of CREBBP, exon 48 of KMT2C, and exon 9 of SMAD4. However, the clinical significance of these mutant genes is unknown. PD-L1 immunohistochemical staining score is as follows: TC >= 1% and IC+:2%; the result was positive.
Based on that evidence, the diagnosis of Cowden syndrome is confirmed. Since there were no indications such as regional lymph node metastasis, postoperative adjuvant chemotherapy was not performed. The patient was followed up for 1 year, and there was no postoperative obstruction of bilioenteric anastomotic stenosis. Gastrointestinal bleeding did not recur, and the anemia had been corrected. Repeated reexamination of tumor markers did not suggest recurrence. All these suggest a good prognosis.