Peutz-Jeghers syndrome

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 13000/µL (reference range, 4000-11000/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?

Pathologic Diagnosis: Peutz-Jeghers Syndrome

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 1921(1); 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 sexcord 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 19p13.4, 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.

References

1. Peutz JLA. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentation of skin and mucous membrane. Ned Maandschr Geneeskd. 1921;10:134-146.

2. Jeghers H, MCKUSIC VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips, and digits: a syndrome of diagnostic significance. N Engl J Med. 1949;241:993-1005.

3. Wirtzfeld DA, Petrelli NJ, Rodriquez-Bigas MA. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol. 2001;8:319-327.

4. Spigelman AD, Arese P, Phillips RK. Polyposis: the Peutz-Jeghers syndrome. Br J Surg. 1995:82:1311-1314.

5. Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987:316:1511-1514.

6. Petersen VC, Sheehan AL, Bryan RL, Armstrong CP, Shepard NA. Misplacement of dysplastic epithelium in Peutz-Jeghers polyps: the ultimate diagnostic pitfall? Am J Surg Pathol. 2000;24:34-39.

7. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128:896-899.

8. Wang Z-J, Churchman M, Avizienyte E, et al. Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients. J Med Genet. 1999:36:365-368.

9. Olschwang S, Markie D, Seal S, et al. Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J Med Genet. 1998:35:42-44.

10. Mehenni H, Blouin JL, Radhakrishna U, et al. Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19p13.4. Am J Hum Genet. 1997:61:1327-1334.

Bobby L. Boyanton, Jr, MD, MT(ASCP); Stephen S. Shinault, DO

Accepted for publication November 24, 2003.

From the Departments of Pathology (Dr Boyanton) and Radiological Sciences (Dr Shinault), University of Oklahoma Health Science Center, Oklahoma City. Dr Boyanton is now with the Department of Pathology, Baylor College of Medicine, Houston, Tex.

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

Corresponding author: Bobby L. Boyanton, Jr, MD, MT(ASCP), Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-3498 (e-mail: boyanton@bcm.tmc.edu).

Reprints not available from the authors.

Copyright College of American Pathologists Apr 2004
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