—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 4 - Peutz-jeghers Polyp (PJP) with Low Grade Dysplasia, Possibly Occurring in Association with Peutz-jeghers Syndrome (PJS)

Christine Hobbs
ENDOLAB
Nashville, TN


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient's history was obtained from copies of her treating physician's operative/colonoscopy report and office notes, as well as a telephone conversation between the treating physician and the pathologist.

This 17 year-old female from a small, rural town presented to a general surgeon (or possibly was referred to this surgeon by her primary care physician) in the spring of 2005 complaining of a "self-limited" period of intermittent blood per rectum. At the surgeon's office she was found to be positive for fecal occult blood and to have mild anemia (hemoglobin 11.5). Subsequent colonoscopy revealed a single 1.5 cm "definitely pedunculated" polyp at 25 cm. A snare was used to completely excise the polyp and cauterize its base. The colonoscopy report's "Impression" section says "we will check the pathology of the polyp and schedule her next colonoscopy accordingly, it will probably be somewhere around three years."

The patient's first post-colonoscopy follow-up visit was one month later. The first thing the office note mentions is that this young had a single polyp on colonoscopy. "This was read by the pathologist as a ____ polyp." (See Diagnosis section below.) The note goes on to say the patient hadn't noticed any further blood per rectum and that her hemoglobin was better, but not quite normal (11.8 with a MCV of 75). The surgeon planned to check additional stool Hemoccult tests since "her bleeding should have resolved with removal of the polyp." The patient was started on iron (Feosol 325 mg t.i.d.) and she was told to come back in 3 months. No mention is made of plans for evaluation of the patient's upper gastrointestinal (GI) tract.

The next office note documents a phone call from the patient stating her three Hemoccult tests were negative. The patient was seen back at her surgeon's office four months after the colonoscopy. The surgeon mentions the need for a repeat CBC and that the patient should be in his recall file for repeat colonoscopy in April of 2006. In this note, nothing is written regarding the type of polyp or its possible implications. Similar to the note of the last office visit, there is no indication of a plan to evaluate the upper GI tract.

No further notes are in the patient's medical records from her general surgeon; however, a phone call to the surgeon by the pathologist revealed that the patient has an uncle and cousin (father and daughter) who have a history of "polyps." Neither of the patient's parents have a history of polyps or cancer. The pathologist was told the patient has no signs or symptoms of a polyposis syndrome, particularly PJS. At the urging of the pathologist, the surgeon agreed to perform an EGD when the patient comes back for her repeat colonoscopy in April 2006. The surgeon was not interested in having the patient return before this date.


Case 4 - Figure 1 - Scanning view of colonic polyp.
Case 4 - Figure 2 - Distal half of polyp.
Case 4 - Figure 3 - Polyp at higher magnification [showing low grade dysplasia].


Case 4 - Figure 4 - Periphery of polyp at still higher magnification [with obvious low grade dysyplasia].
Case 4 - Figure 5 - Polyp immunostained with smooth muscle actin.


Diagnosis
Peutz-jeghers Polyp (PJP) with Low Grade Dysplasia, Possibly Occurring in Association with Peutz-jeghers Syndrome (PJS).

Histopathologic Findings
Sections of the 1.5 cm polyp with a wide stalk show prominent branches of smooth muscle extending from the muscularis mucosae into the periphery of the polyp. The arborizing splays of smooth muscle divide the crypts into lobules. None of the crypts show significant hyperplastic epithelium or prominent cystic dilatation. The superficial epithelium of the polyp has a villiform appearance and demonstrates low grade dysplasia evidenced by cytoplasmic hyperbasophilia and nuclear features such as enlargement, hyperchromasia, crowding and mild stratification. These cytologic epithelial changes are in a background of lamina propria without significant inflammation. No neutrophils are present in the epithelium and no erosions are seen in the initial sections. In the additional recut sections made for this presentation, the concentration of mononuclear inflammatory cells in the lamina propria appears mildly increased, slightly obscuring the peripheral splays of smooth muscle. Also on the recut sections, the surface shows a focal suggestion of early erosion. No granulation tissue, hemorrhage, or ischemic features are seen. The dysplastic epithelium in the recut sections appears more prominent, but is still low grade and predominantly superficial.

Differential Diagnosis
The differential diagnosis includes: tubular adenoma with secondary prolapse change, juvenile polyp with secondary prolapse change, primary mucosal prolapse-induced (inflammatory) polyp (similar to polyps occurring in association with solitary rectal ulcer syndrome and inflammatory cloacogenic polyps). Why is this particular polyp favored to be a PJP with dysplasia? Firstly, PJPs more often occur as part of a hereditary polyposis syndrome than sporadically. [1] In addition, despite the somewhat villous architecture of PJPs, most PJPs over 1 cm, like this one, are pedunculated while villous adenomas tend to be sessile. Furthermore, at age 17 the presence of a tubular adenoma would be unusual outside of a polyposis syndrome, but by this age, a patient with familial adenomatous polyposis should have more than a single colonic adenoma. The presence of obvious dysplasia in this polyp argues against a primary mucosal prolapse-induced polyp.

Discussion of Peutz-Jeghers Polyps Syndrome
Criteria

The latest edition of the World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System (2000) recommends the following

diagnostic criteria for Peutz-Jeghers syndrome: (1) three or more histologically confirmed PJPs, or (2) any number of PJPs with a family history of PJS, or (3) characteristic, prominent, mucocutaneous pigmentation with a family history of PJS, or (4) any number of PJPs and characteristic, prominent, mucocutaneous pigmentation. [1]

Clinical features

PJS is a cancer syndrome with autosomal dominant inheritance with near complete penetrance with an estimated incidence of 1 in 120,000 births. Phenotypic expression of the syndrome varies widely. Approximately 50% of cases are familial, and 50% have new mutations (no family history of polyps). The syndrome is characterized by gastrointestinal hamartomatous polyposis preferentially affecting the small intestine (where they are the most common hamartomatous polyp), particularly the jejunum and, in the vast majority of cases, mucocutaneous melanin pigmentation. The melanin spots of PJS are apparent in >95% of patients. They may appear after the onset of the polyposis. These spots occur most commonly on the lips and buccal mucosa but can also found on circumoral facial skin, around the eyes and nose, on the palms and soles, and on the digits. The circumoral spots may fade in puberty and adulthood. The presence of a solitary Peutz-Jeghers polyp is not pathognomonic of the syndrome. Signs and symptoms include intestinal bleeding, anemia, abdominal pain, intussusception, obstruction, and prolapse of pedunculated PJPs through the rectum. The growth of PJPs typically begins during the first decade, while the usual age at which the syndrome presents is between two and twenty years (average 26-mid 30's, median age 11) [2]. Identification of the polyps is most often accomplished by evaluation of the small intestine and the large intestine. Macroscopically, the polyps tend to be lobulated with a dark/hyperemic head and closely resemble adenomas, but lack their velvety texture. The stalk is short, broad or may be absent. They are described as being tightly anchored to the underlying bowel wall. The typical size of PJPs is 0.5 to 5 cm. Histologically PJPs typically contain a core of smooth muscle that shows tree-like branching. This muscle is surrounded by mucosa native to the region, heaped into folds producing a villous pattern. Dysplasia in PJPs is rare. Epithelial misplacement (pseudoinvasive herniation of crypts) occurs in up to 10% of small intestinal PJPs and may involve all layers of the bowel wall and even extend into the serosa. [3]

Associated Malignancies

While the PJS is associated with a 10 to 18-fold excess of gastrointestinal and non-gastrointestinal cancers, it is still somewhat controversial as to whether the PJP itself is precancerous. The evidence that the increased risk of malignancy in the stomach, small bowel and colon is due to malignant progression from hamartoma to adenocarcinoma is threefold: (1) dysplasia, as in this polyp, although uncommon, has been described in PJPs (foci of dysplasia and invasive carcinoma are present in two to three percent of PJPs) [4]; (2) carcinoma may occur in contiguity with PJPs; (3) the PJS gene, serine threonine kinase STK11 (LKB1), is located on chromosome 19p (19p13.3 – although there is some evidence suggesting locus variability), and loss of heterozygosity at this locus has been demonstrated in the majority of PJPs and associated intestinal cancers. [5] Predisposition to cancer of multiple organ systems is a critical feature of PJS. Well-documented extra-intestinal neoplasms associated with PJS include sex cord tumors with annular tubules (SCTAT) of the ovary, adenoma malignum of the uterine cervix, Sertoli cell tumors of the testis, carcinoma of the stomach, carcinoma of the pancreas, adenocarcinoma of the breast, and, rarely, adenocarcinomas of the esophagus, appendix, biliary tract and gallbladder. Exceptionally, PJPs may also occur in the nasopharynx and urinary tract.

Prognosis

Although intussusception is a major source of mortality in PJS kindreds, this can be effectively treated with surgery. Thus, the prognosis of affected individuals is mainly related to their risk of malignancy. Unfortunately, the rarity of the syndrome prohibits accurate assessment of the prognosis related to malignancy, but at least one report suggests that PJS-associated cancers are especially aggressive. [6] Cancer is more likely in patients with familial PJS.

Management
This patient's management is two-fold:
  • Confirming the diagnosis PJS
    Extensive evaluation of the upper GI tract, especially the small intestine is paramount. This can be carried out by one or more of the following: imaging studies; upper, lower and capsule endoscopy; a complete physical exam looking for melanin spots, and a careful, detailed family history involving as many cooperative family members as possible. Genetic testing and is now available for patients of PJS and their families and can be readily accessed through Gene Tests-GeneClinics on the Internet at www.genetests.org or GeneDx. In familial cases with a known genetic linkage to STK11, genetic testing carries a sensitivity of 70%. In sporadic cases of PJS, testing has a sensitivity ranging from 30% to 67%. [7] It is recommended that genetic testing only be done where genetic counseling is available.

  • Follow-up and treatment of PJS
    Follow-up guidelines that have been proposed for the GI tract include EGD (beginning at age 10) with an interval of two years, colonoscopy (beginning at age 10) with an interval of two years; and upper GI series with follow through (beginning at age 10) with an interval of two years. More recent publications advocate the use of capsule endoscopy to fully evaluate the small intestine for polyps, both for diagnostic and surveillance purposes. [8, 9] . Regarding recommendations for surveillance of non-gastrointestinal malignancies, for the breast a physician's breast exam and mammography (beginning at age 25) with an interval of one to three years; for the testis, examination (beginning at age 10) with an interval of one year; for the ovary/uterus, pelvic examination (beginning at age 20) with an interval of one year; and for the pancreas endoscopic ultrasound (beginning at age 30) with an interval of one to two years. [1, 10, 11] Treatment of PJS involves complete excision of all polyps greater than 1 cm. Some patients undergo laparotomy for small bowel obstruction or when the number and size of polyps are too great for safe endoscopic removal. Subtotal colectomy may also be warranted if there is rapid recurrence or growth of polyps. There is no current evidence to justify prophylactic colectomy in patients with PJS. [12]

References

  1. Hamilton SR, Aaltonen LA (eds) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press:Lyon 2000; pp. 74-76.

  2. Doxy BW, Kuwada SK, Burt RW. Inherited polyposis syndromes: Molecular mechanisms, Clinicopathology and genetic testing. Clinical Gastroenterol and Hepatol 2005;3:633-641.

  3. Shepard NA, Bussey HJR, Jass JR. Epithelial misplacement in Peutz-Jeghers polyps. A diagnostic pitfall. Am J Surg Pathol 1987;11:743-749.

  4. Bruber SB, Entius MM, Petersen GM, Laken SJ, Longo PA, Boyer R, Levin AM, Mujumdar UJ, Trent JM, Kinzler KW, Vogelstein B, Hamilton SR, Polymeropoulos MH, Offerhaus GJ, Giardiello FM. Pathogenesis of adenocarcinoma in Peutz-Jeghers Syndrome. Cancer Res 1998;58:5267-5270.

  5. Flageole H, Raptis S. Trudel JL, Lough JO. Progression toward malignancy of hamartomas in a patient with Peutz-Jeghers syndrome: Case report and literature review. Can J Surg 1994;37:231-236.

  6. Perin KH, Bridge MF. Adenomatous and carcinomatous changes in hamartomatous polyps of the small intestine (Peutz-Jeghers syndrome): Report of a case and review of the literature. Cancer 1994;73:971-983.

  7. Spigelman AD, Murday V, Phillips RK. Cancer and Peutz-Jeghers syndrome. Gut 1989;30:1588-1590.

  8. Soares J, Lopes L, Vilas Boas G, Pinho C. Wireless capsule endoscopy for evaluation of phenotypic expression of small-bowel polyps in patients with Peutz-Jeghers syndrome and in symptomatic first-degree relatives. Endoscopy 2004;36:1060-1066.

  9. Burke CA, Santisi J, Church J, Levinthal G. The utility of capsule endoscopy small bowel surveillance in patients with polyposis. Am J Gastroenterol 2005;100:1498-1502;

  10. Bronner MP. Gastrointestinal inherited polyposis syndromes. Mod Pathol 2003;16:359-365.

  11. Soravia C, Berk T, Cohen Z. Genetic testing and surgical decision making in hereditary colorectal cancer. Int J Colorectal Dis 2000;15:21-28.

  12. Luk GD. Diagnosis and therapy of hereditary polyposis syndromes. The Gastroenterologist 1995;3:153-167.
Another excellent review article:
Schreibman IR, Baker M, Amos C, McGarrity TJ. The hamartomatous polyposis syndromes: A clinical and molecular review. Am J Gastroenterol 2005;100:476-490.