Case 3 -

Peutz-Jeghers Syndrome David N. Lewin Medical University of South Carolina Charleston, SC

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Bullet Points: A variety of polyposis syndromes (including familial adenomatous polyposis, juvenile polyposis and Peutz-Jeghers polyposis) affect the gastrointestinal tract and must be distinguished from one another. Differentiating epithelial displacement (pseudoinvasion) from true invasive carcinoma can be a diagnostic dilemma. Evaluation of previous pathologic material is helpful in difficult frozen section and surgical pathology diagnosis. Diagnosis: Peutz-Jeghers Syndrome; Peutz-Jeghers polyp with epithelial misplacement (pseudoinvasion) of the bowel wall. Clinical History: A 26-year-old-male with a two year history of epigastric pain, nausea, vomiting, and rectal bleeding recently underwent upper GI endoscopy and colonoscopy. The colonoscopy showed a greater than 100 polyps throughout the colon with biopsies at an outside facility called adenomatous polyps. The upper endoscopy revealed a duodenum carpeted with polypoid lesions. The patient stated he has a ten pound weight loss over two months and noted pain in the epigastrium and nausea and vomiting after eating. He has a known history of iron deficiency anemia and a history of a gastric ulcer in 1985. His mother has a history of lupus and his father's family history is unknown. He uses neither tobacco nor spirits. He is an active duty sailor (a nuclear technician). Physical examination was unremarkable. The patient was recommended to undergo pancreaticoduodenectomy and colectomy with restorative proctocolectomy either as a staged or simultaneous procedure. The patient was taken to the operating room. There were multiple intraabdominal adhesions of small and large bowel. A right hemicolectomy was performed and sent to pathology for evaluation. Multiple polyps were identified within both the cecum and terminal ileum. The largest polyp in the ileum was fixed to the underlying muscularis. On cut sectioning, mucus was identified in the muscularis mucosa. A gross photograph of the specimen, cut section and representative histologic images are presented. Case 3 - Figure 1 Gross image of terminal ileum and cecum. Polyp seen in subsequent microscopic images is the 2 cm dome lesion in the terminal ileum. A number of small polypoid lesions are present in the terminal ileum and a pedunculated polyp with a green head is present in the cecum. Case 3 - Figure 2 Cross section gross image of the polyp in question in the terminal ileum. The bowel is being squeezed and white mucoid material is identified in the bowel wall and the adjacent mesentery. Case 3 - Figure 3 Whole mount view of section through the polyp, bowel wall and adjacent mesentery. The polyp has a central core of smooth muscle that shows tree-like branching covered by normal small intestinal mucosa. At the base of the polyp, glands can be identified extending through the muscularis propria and into the adjacent mesentery. Case 3 - Figure 4 Medium power of the tip of the polyp. There is again the arborizing architecture with normal enterocytes. There is no evidence of dysplasia. Case 3 - Figure 5 Medium power focusing on the muscularis propria of the bowel. There is prominent placement of glands in and through the muscular wall. Case 3 - Figure 6 Medium power of the base of the bowel with extension of the glands through the bowel wall into the adjacent mesenteric fat. Case 3 - Figure 7 High power of glands present in the muscular wall. The epithelium is normal with no evidence of dysplasia. Presence of lamina propria is identified around the glands. Case 3 - Figure 8 High power of glands present in the muscular wall. The epithelium is normal with no evidence of dysplasia. Presence of lamina propria is identified around the glands. Case 3 - Figure 9 High power of glands present in the muscular wall. The epithelium is normal with no evidence of dysplasia. Presence of lamina propria is identified around the glands. Case 3 - Figure 10 Highest power of deepest gland present in the mesenteric fat. The nuclei are all basally oriented with cytologically normal nuclei. Discussion: Peutz-Jeghers syndrome (PJS) was initially described by Peutz [11] in 1921 and subsequently Jeghers [7] again in 1949. The syndrome is characterized by intestinal polyposis and mucocutaneous melanin pigmentation. The polyps are hamartomatous (Peutz-Jeghers type) polyps and are found predominately in the small intestine, however can be identified throughout the gastrointestinal tract. These patients have a predisposition for a number of carcinomas (stomach, small bowel, colon, pancreas, breast, ovarian and testicular). The cumulative lifetime risk for cancer in patients with PJS is 93%; 18 times greater than expected in the general population [6]. PJS is a rare autosomal dominant syndrome. Mutations in the gene LKB1 (STK11) on chromosome 19p13.3 has been identified in the majority of PJS families. The gene product is a serine/threonine kinase protein and there is the suggestion that it is a tumor suppressor gene [4]. The WHO criteria [1] for diagnosis are as follows: Three or more histologically confirmed Peutz-Jeghers polyps or Any number of Peutz-Jeghers polyps with a family history of PJS Characteristic, prominent, mucocutaneous pigmentation with a family history of PJS Any number of Peutz-Jeghers polyps and characteristic, prominent, mucocutaneous pigmentation. Presenting signs and symptoms include bleeding, anemia, abdominal pain, and intussusception. Patients typically present between the ages of 2 to 20 years. The polyps are hamartomatous polyps that may be found throughout the gastrointestinal tract, however predominate in the small intestine. The may be sessile or pedunculated (both are seen in the gross image in this case), often with a smooth lobulated surface. They may measure up to several centimeters in diameter. Histologically they are characterized by a mixture of hyperplastic mucosa appropriate for the anatomic site. The architecture is distorted with a central core of smooth muscle and the characteristic arborizing (tree-like) architecture of epithelium and admixed smooth muscle. The typical cellular components of the organ site are also usually present (goblet cells, Paneth cells, absorptive cells, and endocrine cells). The lamina propria is normal. There may be erosion of the surface epithelium with associated reactive epithelial changes. Dysplasia is reported, although relatively uncommon in these polyps. Differential Diagnosis: Invasive Adenocarcinoma: This case illustrates epithelial misplacement (pseudoinvasion) within a Peutz-Jeghers polyp in the setting of PJS which is a major pitfall and diagnostic dilemma [2, 9, 10, 11, 13, 14, 15] . The features helpful in the diagnosis of pseudoinvasion are as follows: Morphologically normal or hyperplastic epithelium However dysplastic epithelium may be displaced as well Associated lamina propria No evidence of stromal desmoplastic response Associated hemosiderin laden macrophages Fortunately in this case there is no dysplasia present in the polyp. While there is an increased risk of carcinoma in patients with PJS, it is unclear whether the invasive carcinoma arises in the hamartomatous polyps or adjacent mucosa. As noted above dysplasia and invasive carcinoma present in a hamartomatous polyp are rare (although reported) [4, 5, 6]. Sporadic Peutz-Jeghers polyp: The presence of numerous polyps exclude this possibility. Sporadic Peutz-Jeghers polyps are relatively unusual with a study at Johns Hopkins University suggesting that "if they exist, they are extremely rare" [3]. Juvenile Polyposis: This polyposis syndrome also has numerous polyps throughout the gastrointestinal tract, although more commonly found in the colon, rather than the small intestine. Juvenile polyps have a significant granulation tissue present in the lamina propria with cystic dilatation of the glands and loss of the entire surface epithelium, in contrast to the focal erosion that may be seen in Peutz-Jeghers polyps. The prominent smooth muscle proliferation of PJ polyps is typically lacking in juvenile polyps. Familial Adenomatous Polyposis: This individual was initially diagnosed with FAP. These polyps should predominate in the colon, however may also be present in the small intestine, typically in the duodenum. As the name implies, these should be adenomatous polyps, rather than hamartomatous polyps. While dysplasia may be identified focally in rare PJ polyps, it should be much more profound in FAP adenomatous polyps. References: Aaltonen LA, Jarvinen H, Gruber SB. Peutz-Jeghers Syndrome. In Pathology & Genetics; Tumours of the Digestive System. Eds. Hamilton SR, Aaltonen LA. IARC Press Lyon 2000. Bolwell JS, James PD. Peutz--Jeghers syndrome with pseudoinvasion of hamartomatous polyps and multiple epithelial neoplasms. Histopathology. 3(1):39-50, 1979 Burkart AL, Sheridan T, Lewin M, et al. Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital Am J Surg Pathol 31(8):1209-14, 2007 Entius MM, Keller JJ, Westerman AM, et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol 54(2):126-31, 2001 Flageole H, Raptis S, Trudel JL, et al. Progression toward malignancy of hamartomas in a patient with Peutz-Jeghers syndrome: case report and literature review. Canadian J Surg 37(3):231-6, 1994 Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 316:1511-1514, 1987. Gruber SB, Entius MM, Petersen GM, et al. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58(23):5267-70, 1998 Jeghers H, McKusick VA, Katz KH. Generalised intestinal polyposis and melanin spots of the oral mucosa, lips and digits. A syndrome of diagnostic significance. N Engl J Med 241:993-1005, 1031-6, 1949. Kyriakos M, Condon SC. Enteritis cystica profunda. Am J Clin Pathol 69;77-85, 1978. Muto T, Bussey HJR, Morson BC. Pseudocarcinomatous invasion in adenomatous polyps of the colon and rectum. J Clin Pathol 26:25-31, 1973. Petersen VC, Sheehan AL, Bryan RL, et al. Misplacement of dysplastic epithelium in Peutz-Jeghers Polyps: the ultimate diagnostic pitfall? Am J Surg Pathol 24(1):34-9, 2000 Peutz JLA. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Ned Maandschr Geneeskd 1:134-46, 1921. Rautou PE, Hammel P, Couvelard A, et al. Suspected malignant cancer of the pancreas associated with pseudo-invasive duodenal hamartomas in a patient with Peutz-Jeghers syndrome [French] Gastroenterologie Clinique et Biologique. 31(5):547-51, 2007 Shepherd NA, Bussey HJ, Jass JR. Epithelial misplacement in Peutz-Jeghers polyps. A diagnostic pitfall. Am J Surg Pathol 11(10):743-9, 1987 Westerman AM, van Velthuysen ML, Bac DJ, et al. Malignancy in Peutz-Jeghers syndrome? The pitfall of pseudo-invasion. J Clin Gastroenterol 25(1):387-90, 1997