A 27-year-old man presented to the emergency department with a 3-day history of progressively worsening abdominal pain, nausea, emesis, and obstipation following a weekend drinking binge. The patient's medical history was significant for smoking and alcohol abuse. Family history was significant for “intestinal problems” in 2 uncles. Physical examination revealed an afebrile patient with epigastric pain and high-pitched bowel sounds. Results of laboratory tests were within normal limits, except for an amylase level of 254 U/L (reference range, 25–115 U/L), and a mildly elevated white blood cell count of 13 000/μL (reference range, 4000–11 000/μL). A computed tomographic scan with oral contrast demonstrated multiple pedunculated intraluminal masses (Figure 1, red arrows) throughout the small intestine and jejunojejunal intussusception (Figure 1, black arrows).

Surgical intervention consisted of partial jejunectomy with primary anastomosis after failed attempts at reduction; enterotomy removed the remaining palpable masses from the small intestine. Pathologic inspection of the ischemic segment of resected jejunum revealed 5 cerebriform-like polyps ranging from 0.5 to 4.5 cm, the largest of which served as the lead point of intussusception. Enterotomy produced 4 additional cerebriform-like polyps ranging from 0.5 to 2.5 cm; 3 of these polyps were near the ligament of Treitz, and 1 was in the distal ileum.

Hematoxylin-eosin–stained sections confirmed ischemic necrosis of the resected jejunum. The polyps demonstrated a core of smooth muscle arising from the muscularis mucosae with extensive “treelike” branching, lined by normal small bowel epithelium (Figures 2 and 3). The smooth muscle component was verified by immunohistochemical staining for smooth muscle actin (Figure 4).

What is your diagnosis?

Peutz-Jeghers syndrome is a rare autosomal dominant condition characterized by gastrointestinal polyps, mucocutaneous hyperpigmentation, and an increased risk of gastrointestinal and extraintestinal carcinoma. The original link between hyperpigmentation and gastrointestinal polyposis was described by Peutz in 19211; however, it was not until 1949 that Jeghers associated those clinical findings with the risk of invasive carcinoma.2 

Patients with Peutz-Jeghers syndrome usually present in their 20s with sequelae of gastrointestinal polyposis, including abdominal pain, obstruction, intussusception, or bleeding.3 The polyps, primarily located in the small bowel with a predilection for the jejunum,3 may be found throughout the entire gastrointestinal tract.4 Mucocutaneous hyperpigmentation invariably involves the perioral region and buccal mucosa, and less commonly the genitalia, hands, or feet.3,4 Rarely, pigmentation fails to develop, leading to delays in diagnosis and appropriate management, especially when a family history of the syndrome is absent. The diagnosis of Peutz-Jeghers syndrome is made by histologic verification of characteristic hamartomatous polyps and 2 of the following: small bowel polyposis, mucocutaneous pigmentation, and a family history of the syndrome.5 

Histologically, the hamartomatous polyps exhibit a smooth muscle core arising from the muscularis mucosae, which branches into the polyp in a treelike or arborizing pattern, lined by epithelium native to the area of involvement.6 Approximately 10% of polyps will demonstrate the diagnostic pitfall of “pseudoinvasion,” whereby epithelium is ectopically displaced into the submucosa, muscularis propria, or subserosa through defects in the bowel wall during episodes of elevated mechanical pressure, such as obstruction or intussusception,6 thereby mimicking invasive carcinoma. However, the absence of dysplastic epithelium, a stromal desmoplastic response, and mitoses strongly suggests pseudoinvasion and not invasive carcinoma.3,6 

Patients with Peutz-Jeghers syndrome have an estimated 10- to 18-fold increased relative risk for the development of cancer compared to the general population.5,7 Two long-term independent studies following 65 patients with Peutz-Jeghers syndrome demonstrated the development of cancer in roughly 50% of patients, with the mean age of cancer onset at 40 years and a 20-year mean interval between the diagnosis of Peutz-Jeghers syndrome and cancer development.5,7 Gastrointestinal cancers (in decreasing order of frequency) involved the colon, duodenum, stomach, and esophagus.7 Extraintestinal cancers involved the breast (usually bilateral), lung, cervix, uterus, and thyroid.7 Additional neoplasms associated with this syndrome are mucinous ovarian cystadenofibromas, Sertoli-Leydig cell stromal tumors, pancreatic cancer, and sex-cord tumors with annular tubules.4,7 

Molecular linkage analysis has shown genetic alterations in the LKB1/STK11 gene (19p13.3), the product of which is a serine-threonine kinase involved in cellular signal transduction, to be the pathologic etiology in roughly 50% to 75% of cases.3,8–10 However, a second locus was recently mapped to 19q13.4, providing evidence for genetic heterogeneity in the Peutz-Jeghers syndrome.10 

In summary, Peutz-Jeghers syndrome is an uncommon condition with profound clinical sequelae. By unraveling the complex inheritance of this syndrome, molecular analysis will not only be an invaluable tool for disease verification, but will provide a vital role in screening and early detection of patients with a family history of the syndrome, thereby permitting appropriate therapeutic intervention.

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The authors have no relevant financial interest in the products or companies described in this article.

Author notes

Corresponding author: Bobby L. Boyanton, Jr, MD, MT(ASCP), Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-3498 ([email protected])

Reprints not available from the authors.