Case of the Month: Sigmoid Colon

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 16, and is Peutz-Jeghers polyp.

This Peutz-Jeghers polyp (PJP) appears to be arising in the colon of a patient with Peutz-Jegher syndrome (PJS). Characteristic histologic features of PJP seen here include thick smooth muscle bundles that branch up into the head of the polyp forming a lobulated or frond-like overall architecture. The smooth muscle branches of PJP are lined by normal or hyperplastic columnar epithelium of the type native to the site of involvement. Dysplasia is present rarely (2-3% of PJP), and typically is focal. Carcinoma arising in a PJP is extremely rare.

Juvenile polyps (JP), or mucous retention polyps, are, like PJP, seen both in a syndromic and non-syndromic settings. Histologically, JP are non-dysplastic lesions in the vast majority of examples. Unlike PJP, JP lack smooth muscle supported fronds and instead, have bulbous outlines with cystically dilated crypts and an ulcerated surface composed of granulation tissue.

Inflammatory polyps (IP) more resemble JP more than PJP as they are typically bulbous and ulcerated and lack the fronds with smooth muscle cores of PJP. IP can occur sporadically in an otherwise normal colon. They can be seen in association with inflammatory bowel disease, both ulcerative colitis and Crohn’s disease, where they may be numerous, mimicking a polyposis syndrome. The IP of Crohn's disease typically are long and thin (filiform), likely related to healing fissuring ulcers.

Mucosal prolapse polyps (MPP) include solitary rectal ulcer and inflammatory cloacogenic polyps and can have similar appearance to PJP as they both have smooth muscle within the lamina propria and are non-dysplastic. MPP shows only thin strands of smooth muscle extending around individual crypts and glands, contrasted with the thick smooth muscle bands of PJP that forms a tree-like architecture. Complicating this differential diagnosis, however, is the occasional presence of prolapse changes on the surface of PJP.

Sessile serrated adenomas (SSA) are usually non-syndromic but are also seen in the syndrome of hyperplastic polyposis. Like PJP, SSA lack dysplasia in most cases, and like PJP when dysplasia is present it is typically focal (that is non-dysplastic areas of the polyp are still present). SSA are flat lesions unlike the fungating or pedunculated nature of almost all PJP. SSA completely lack lamina propria branches of smooth muscle.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant condition occurring in between 1 in 50,000-200,000 of the general population. Manifestations of PJS include gastrointestinal (GI) tract polyposis and mucocutaneous pigmented lesions. PJS carries a dual risk of polyp-related complications (intussusception and bleeding) and malignancy. It is likely that all or nearly all cases of PJS are caused by germline mutation in the STK11 (LKB1) gene located on chromosome 19p13.3. Almost all PJP occur in a syndromic setting, but rarely these polyps can be non-syndromic. The WHO criteria for PJS are: (1) three or more histologically confirmed PJP, or, (2) any number of PJP with a family history of PJS, or (3) characteristic mucocutaneous pigmentation with a family history of PJS, or (4) any number of PJP and characteristic mucocutaneous pigmentation.

PJS was initially described as a dermatologic curiosity in 1895. The eponym "Peutz-Jeghers syndrome" was coined by Andre Bruwer in 1954 giving homage to Johannes Peutz's 1921 observations first associating the pigmented lesions of PJS with gastrointestinal polyposis and Harold Jeghers who in 1949 recognized the inheritance pattern of the condition. The etiology of PJP is controversial. Initial studies of these lesions concluded that they were hamartomatous lesions; however, the etiology has since been proposed by some to be mechanical, stromal neoplasia or a form of abnormal mucosal prolapse (the latter related to the abnormal STK11 gene product).

Mucocutaneous pigmented lesions are seen in 95% of PJS patients, but are not entirely specific (similar facial macular lesions can be seen in other familial lentiginosis syndromes including Cowden disease, Bannayan-Riley-Ruvalcaba syndrome and Carney complex). These pigmented lesions are located around the mouth, oral cavity, nostrils, perianal area, fingers and toes, and the dorsal and volar aspects of the hands and feet. They arise in infancy, fade after puberty, but tend to persist in the buccal mucosa through adulthood. The histology shows increased melanin in basal cells correlating with a proposed etiology of an inflammatory block to melanin migration from melanocyte to keratinocyte. They are felt to have no risk of malignant transformation.

The polyp-related symptoms in PJS patients are common and are primarily abdominal pain secondary to recurrent intussusception and GI bleeding (manifesting as melena, blood per rectum, or anemia). These complications can lead to numerous interventions. One of Jeghers' original patients underwent 32 abdominal surgeries and more than 70 endoscopic polypectomies.

The most common location of PJP is the small bowel (jejunum > ileum > duodenum), with nearly all PJS patients having small bowel polyps. A quarter of PJS patients have polyps in the colon, rectum, and stomach. Small bowel and colon PJP are typically pedunculated and large (thus their association with intussusception), while stomach PJP tend to be sessile and histologically more subtle (smooth muscle fronds are less developed). About 10% of small bowel PJP show expansion into the submucosa, muscularis propria, and even subserosa, mimicking invasive carcinoma; this phenomenon has been referred to as "epithelial displacement" or "enteritis cystica profunda". This displacement is more common in larger polyps (> 3 cm) and possibly is secondary to polyp torsion and/or infarction.

There is strong predisposition for cancer development in PJS; it appears that the cancer risk is not directly related to the polyps themselves. The cumulative lifetime cancer risk in PJS patients is 93% (18 times that of the general population) with onset at an earlier median age. The largest risk is for cancers of the GI tract (including stomach, small bowel, colorectum, and pancreas) and breast. Increased cancer risk is also present, but to a lesser degree, for carcinomas of the endometrium and cervix (including adenoma malignum). PJS is strongly associated with unusual tumors of the ovaries (sex cord stromal tumor with annular tubules) and testes (large cell calcifying Sertoli cell tumors), both of which tend to be small, bilateral, and benign when presenting in this syndromic setting. When the same lesions present in a sporadic setting, they are typically larger, unilateral, and have a 20% risk of malignant behavior).

Clinical management of PJS is complicated given the myriad clinical manifestations and early age of onset. The most important aspect of management in PJS is GI tract surveillance which has two roles: (1) to prevent polyp- related complications (intussusception and GI bleeding) and (2) detect GI cancers. Given the rarity of PJS, guidelines for GI tract surveillance are largely consensus-based rather than evidence-based. Below is one suggested set of recommendations:

• Baseline endoscopy, colonoscopy and video capsule endoscopy (VCE) starting at age 8 (if polyps present repeat every 3 years).
• Polyp complications and cancer surveillance starts at age 18 with every 3 year EGD, colonoscopy and VCE/ barium follow-through or with symptoms.
• At age 50 increase intervals to 1-2 years due to rapid increase of cancer risk at this age.

Routine screening for non-GI cancers is less rigorous than the GI surveillance. Female PJS patients have a breast cancer risk that approaches that of patients with BRCA mutations, some authorities have suggested following the breast surveillance program recommended for BRCA mutations. Surveillance for pancreatic cancer is not routinely done, despite its significantly increased risk in PJS, due to the absence of a good surveillance method. Routine screening for genital tract malignancies in PJS is generally not recommended beyond participation in standard cervical screening (adding a high index of suspicion for adenoma malignum).

1. Which combination of findings meets WHO diagnostic criteria for Peutz-Jeghers syndrome?
   
   1. Three or more histologically confirmed Peutz-Jeghers polyps
   2. Any number of Peutz-Jeghers polyps and characteristic mucocutaneous pigmentation.
   3. Any number of PJP with a family history of Peutz-Jeghers syndrome
   4. Characteristic mucocutaneous pigmentation with a family history of Peutz-Jeghers syndrome
   5. All of the above
2. Most Peutz-Jeghers polyps are sporadic lesions not associated with Peutz-Jeghers syndrome
   
   1. True
   2. False
3. What is the lifetime cancer risk in Peutz-Jeghers syndrome?
   
   1. 5%
   2. 18%
   3. 53%
   4. 93%

1. Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: A systematic review and recommendations for management. Gut. 2010;59(7):975-986.
2. Brosens LA, van Hattem WA, Jansen M, de Leng WW, Giardiello FM, Offerhaus GJ. Gastrointestinal polyposis syndromes. Curr Mol Med. 2007;7(1):29-46.
3. Burkart AL, Sheridan T, Lewin M, Fenton H, Ali NJ, Montgomery E. Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital. Am J Surg Pathol. 2007;31(8):1209-1214.
4. Dormandy TL. Gastrointestinal polyposis with mucocutaneous pigmentation (Peutz-Jeghers syndrome). N Engl J Med. 1957;256(25):1186-1190.
5. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209-3215.
6. McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol. 2000;95(3):596-604.
7. Petersen VC, Sheehan AL, Bryan RL, Armstrong CP, Shepherd NA. Misplacement of dysplastic epithelium in Peutz-Jeghers polyps: the ultimate diagnostic pitfall? Am J Surg Pathol. 2000;24(1):34-39.

2012
H. Parry Dilworth, MD
Surgical Pathology Committee
Hospital Pathology Associates
Minneapolis, MN

1. All of the above (e). 
2. False (b). 
3. 93% (d).