Unusually early presentation of small-bowel adenocarcinoma in a patient with Peutz-Jeghers syndrome

Abstract

Peutz-Jeghers (PJS) syndrome is an autosomal dominant cancer predisposition syndrome characterized by melanotic macules, and hamartomatous polyps. Small-bowel surveillance in the pediatric PJS population is not designed to identify small-bowel malignancy which is thought to arise in adulthood. A 13 year old male presented with lead-point intussusception, requiring emergent surgical resection. A mucinous adenocarcinoma was found arising from high-grade dysplasia within a polyp. Based on these findings and mucosal pigmentation he was diagnosed with PJS. DNA sequencing revealed a heterozygous c.921-1G>T STK11 mutation. This case is the earliest onset of small-bowel carcinoma in PJS, an observation relevant to surveillance guidelines.

BACKGROUND

Peutz-Jeghers (PJS) syndrome is an autosomal dominant cancer predisposition syndrome characterized by melanotic pigmented macules, hamartomatous polyps and an increased risk of cancer ¹. The unusual pigmentation on the lips and its inherited nature has been clinically known since the report of “Hutchinson’s twins” by British physicians Connor and Hutchinson, a finding which was assumed to be a curiosity ¹. However, its relationship to cancer risk was suggested when one of these twins subsequently died of intestinal obstruction and the other of breast cancer. In 1949, Jeghers proposed that a single pleiotropic gene was likely responsible for this cancer predisposition syndrome ². The diagnostic criteria of PJS are based on the clinical findings and require the presence of hamartomas and two of the following: 1) family history of PJS, 2) mucocutaneous hyperpigmentation, or 3) small bowel polyposis¹. PJS leads to life-threatening complications including lead-point intussusception due to the presence of the polyps and an array of solid tumors.

The genetics of PJS has been the subject of intensive study, and over time it has largely confirmed Jeghers proposed “single pleiotropic gene”² Germline mutations in the tumor suppressor gene STK11 are identified in the majority of cases of PJS ^{3, 4}. While some authors have proposed the existence of other loci, STK11 has been the only gene known to be associated with PJS. Both heterozygous point mutations and gene deletions of STK11 are responsible for the PJS phenotype⁵. As molecular technology has advanced, cases which were previously classified as “STK11 negative” were noted to be due to STK11 deletions which were not detected by sequencing methods⁵. Recent studies combining diagnostic methods sensitive to deletions and point mutations have suggested that all cases may be due to some type of STK11 mutation^{6, 7}. The genotype-phenotype correlation in PJS is complex but higher cancer risk may be associated with mutations in exon 3 or premature truncation alleles ⁸ While STK11 is the only known gene, there are also no reported cases in which an individual with an STK11 mutation does not show clinical manifestations leading some authors to suggest that these mutations are fully penetrant ⁶. STK11 is involved in epithelial polarity and in the regulation of proliferative signals of the mTOR pathway through phosphorylation of AMP kinase. The latter observation has led to promising therapeutic insight showing reduced polyp burden in PJS mouse models when treated with the mTOR inhibitor rapamycin ⁹.

The gastrointestinal complications of PJS are significant and because of the possibility of malignant transformation of hamartomatous polyps present in the colon and small bowel, surveillance is recommended ¹⁰. Current guidelines for GI tract surveillance are based on the expected age of onset of small bowel and colon cancers in PJS, generally after the second decade of life¹¹. In the pediatric population gastrointestinal surveillance is generally not undertaken although screening is recommended with follow-up if positive for polyps¹⁰. The risk of intussusception is significant for children and young adults with PJS⁸. Because of this the current recommendations for pediatric PJS patients suggest an initial endoscopy at age 8 years to evaluate for risk of obstruction, but subsequent screening which has been proposed involves contrast enema¹². This is proposed because of the risk of obstruction rather than cancer, and because of the high radiation burden it has not been uniformly adopted. In addition, tumor screening is not regularly initiated until after age 18 years¹⁰.

Here we report a case of a 13-year-old male who was first diagnosed with PJS after presenting with lead-point intussusception and was found to have a mucinous adenocarcinoma representing the earliest reported case of small bowel malignancy in PJS. We review the clinical course and the implications for surveillance guidelines for patients with PJS.

CASE REPORT

A 13 year old otherwise healthy Hispanic male developed sudden onset periumbilical abdominal pain which worsened over a 24 hour period. He had associated anorexia, and multiple episodes of watery brown emesis. He presented to an outside emergency department where a CT scan demonstrated a “U-shaped” pelvic mass (11×5cm) with calcifications, concerning for teratoma or duplication cyst (Figure 1A, B), and a WBC count of 18,000. He was transferred to our institution for evaluation by pediatric surgery. Upon arrival he was ill appearing. On physical examination the patient was noted to have hyperpigmented macules over the lips, buccal mucosa, and similar macules on the fingertips (Figure 1C, D). Abdominal ultrasound revealed a large intussusception (Figure 1E). A comprehensive four-generation family history included four unaffected siblings and unaffected parents. The father’s maternal uncles were reported to have freckles on the face, although neither the father nor his mother had these findings and no photographs were available to confirm this report. There was no family history of GI abnormalities.

Figure 1.

A. Computed Tomography (CT) scan of the abdomen and pelvis at the level of the sacral spine showing a U-shaped mass in the pelvis indicated by the arrow.

B. CT scan at the level of the lumbar spine showing the U-shaped mass with a calcification indicated by the arrow.

C. Digital photograph of the labial mucosa of the patient revealing the presence of hyperpigmented macules which include some extending beyond the vermillion border.

D. Digital photograph of the palmar surface of the patent revealing the presence of hyperpigmented macules on the digits

E. Abdominal Ultrasound showing a complex fluid filled structure which contains within it fluid filled loops of bowel. These findings were diagnostic of a lead-point intussusception.

The patient was brought to the operating room for a diagnostic laparoscopy which revealed tightly distended loop of small bowel, felt to be small bowel intussusception. As this segment had to be resected the decision was made to proceed to an open procedure. The mesentery was divided and the segment was resected and was found to contain small bowel polyps, one of which was large and a likely pathologic lead-point. After resecting the involved segment an end-to-end anastomosis was performed.

Gross pathologic examination of the resected segment revealed a lead-point intussusception (Figure 2A). Mucosal polyposis was also evident (Figure 2B-D). The histology of this hamartomatous polyp was characteristic with extension of the muscularis propria into the substance of the polyp. (Figure 2D). In addition, an invasive mucinous adenocarcinoma was identified (Figure 3A-D), arising from an area of high-grade dysplasia within one of the polyps. This tumor was stage IIa (T3, N0, M0) with subserosal invasion (Figure 3E), and absence of lymph node involvement.

Figure 2. Hamartomatous Polyp in Intussusception in PJS.

A. Gross specimen of resected small bowl demonstrating intussception.

B. Opened small bowel resection revealing gross appearance of polyps, indicated by circles

C & D. A hamartomatous polyp from the small bowel resection with both gross (C) and histologic (D) cross-sections demonstating extension of the smooth muscle layer from the muscularis propria into the core of the polyp, characteristic of a hamartomatous polyp.

Figure 3. Mucinous Adenocarcinoma Arising From Hamartomatous Polyp in PJS.

A & B: Gross (A) and histologic (B) appearance of hamartomatous polyp with invasive mucinous adenocarcinoma.

C: Dysplasia of small bowel mucosa with a hamartomatous polyp organized into a glandular pattern

D. Invasive mucinous adenocarcinoma from a hamaratomous polyp with invasion of the submucosa, and through the muscularis propria

E. Invasive mucinous adenoncarcinoma from a hamartomatous polyp with invasion of the small bowel serosa.

Due to the presence of malignancy a second operation with small bowel resection with 10 cm tumor free surgical margins and expanded lymph node sampling was performed. Follow up upper and lower endoscopy and imaging revealed additional hamartomatous polyps without evidence of additional primary masses or liver metastases. We concluded based on available evidence there was no indication for adjuvant chemotherapy or radiation therapy in our patient¹³. At last office visit two years after his initial diagnosis he was well without abdominal pain or other symptoms. He underwent capsule endoscopy approximately 1 year after diagnosis and is currently on a screening regimen involving capsule endoscopy every 2 years with additional studies to follow up the capsule endoscopy findings.

The patient’s diagnosis of PJS was confirmed by molecular testing. Sequence analysis of the STK11 gene revealed a heterozygous c.921-1G>T (IVS8-1G>T) mutation. This mutation is pathogenic based on its predicted alteration of the splice acceptor site at the intron7/exon 8 boundary of the STK11 gene and by its previous association with PJS¹³. Testing of the parents and siblings of the patient was declined by the family. The clinical impression was that this was a de novo case in this family given the highly penetrant nature of STK11 mutations and the fact that the parents had never been affected with gastrointestinal complaints or mucosal pigmentation.

CONCLUSIONS

Peutz-Jeghers syndrome is an autosomal dominant condition which is thought to have an age-depending predisposition to gastrointestinal malignancy as well as other types of cancer. Adenocarcinoma in the GI tract is extremely rare in children. The incidence of adenocarcinoma of the colon in children is estimated to be 1 in 10 million ¹⁴. Adenocarcinoma of the colon is associated with a number of genetic conditions in addition to PJS, including Familial Adenomatous polyposis, Hereditary non-polyposis colorectal cancer (HNPCC) in addition to ulcerative colitis. Children that do develop adenocarcinoma of the colon are diagnosed at a later stage and have more aggressive histology because of delayed diagnosis¹⁴. Small bowel adenocarcinoma in children is even more rare with only a handful of cases reported¹⁵. Patients with PJS have an estimated cumulative risk of small bowel adenocarcinoma of 13% before age 64¹¹. The age of onset has varied between studies, but has uniformly been reported after the second decade^{11, 16}. In a study of 30 patients with PJS from Korea, four probands and four first-degree relatives of an affected proband had small bowel cancer, with an overall mean age of onset of cancer of 36 years¹⁷. In a large study of 240 patients with STK11 mutations who were ascertained by positive family history of PJS, there was a 66% cumulative risk of all gastrointestinal tumors, however all occurred after age 20 years¹⁶. An extension of this study which included additional cases brought the total number of patients up to 419, but without any gastrointestinal cancers prior to age 20 years ¹⁸. There is only one report in the literature of a preadolescent with gastrointestinal cancer in PJS, and in this case the patient had colon cancer¹⁹.

The absence of such early onset small bowel cancers in the literature raises the question of whether our patient’s specific STK11 mutation is unique and could have a stronger association with early onset cancer. This specific splice site mutation has been reported in two other patients with PJS both of which were familial¹³. In one of these patients a family history of colon cancer was reported, although the proband did not have cancer¹³. The age of these patients at the time of the study was not reported as it focused on identifying novel mutations. Clearly further studies would be needed to provide evidence of a unique association between this specific mutation and age of onset of cancer. Currently, the genotype-phenotype relationship in PJS suggests that more severe mutations such as deletions may predispose to an earlier age of cancer than missense mutations⁸. At present the genotype does not affect the screening guidelines for patients with PJS. Another possibility to explain a severe phenotype in an otherwise monogenic disease like PJS would be the presence of modifiers. However, there are no other known loci that affect or influence PJS and a much larger study would be required to ascertain modifiers of cancer risk in patients with STK11 mutations.

Given the extremely high lifetime relative risk of cancer in PJS including small intestinal malignancy screening guidelines are important to assist clinicians in caring for these patients. Screening and surveillance guidelines for gastrointestinal tumors in PJS are available¹⁰. For pediatric patients however, regular screening is not uniform and its purpose is to avoid urgent laparotomy rather than screen for malignancy. Current recommendations call for upper and lower endoscopy at age 8 years in patients with PJS, and then at age 18 years followed by every 2-3 years¹⁰. Screening from 8 years to 18 years with barium contrast enema has been proposed but has not been adopted. The recommendation for the initial screening at 8 years of age in asymptomatic cases of PJS is based on a review of 51 cases of PJS where 30% of the patients had already required a laparotomy by 10 years of age¹². Of the total laparotomies reported in the review 70% of the initial laparotomies were performed urgently for intestinal obstruction mainly due to presence of small bowel polyps. Based on our case and the other case of a child with PJS and gastrointestinal cancer (Saranrittichai et al 2009), we propose that guideline for cancer screening in this age group are called for. Capsule endoscopy allows the unique advantages of a full survey of the GI tract and does not have the radiation risks of barium studies. A screening program involving capsule endoscopy every 2 years in patients with PJS between ages 8 and 18 years would be reasonable and could be studied for efficacy. Children with PJS are also at risk for intestinal obstruction such that patients and parents should be aware of the need for prompt medical attention if acute abdominal pain develops. Our case represents the earliest reported case of small bowel cancer in PJS at age 13 years and suggests that between ages 8 years and 18 years, there is a certain risk of malignancy which could be screened for using semi-annual capsule endoscopy in adolescent patients with PJS.²⁰.