Microscopic description:

On low power, the H&E slides show multiple polyps with villous/papillary architecture. Muscularis mucosa is seen in an arborizing pattern throughout the lamina propria giving rise to a nodular/lobular appearance. The epithelium is benign and resembles normal colonic epithelium in the majority of the polyp. Areas of both low and high-grade adenoma like dysplasia are identified in some polyps. Poorly differentiated adenocarcinoma characterized by infiltrative nests and cords of tumor cells is seen arising from one polyp. The tumor cells are large, hyperchromatic, show prominent nucleoli and increased mitotic activity. Tumor invaded into muscularis propria.

The polyps are multiple, hamartomatous, and show arborizing muscularis mucosa, and given the history of polyps in childhood, these findings are consistent with a diagnosis of Peutz-Jeghers syndrome. Some of the polyps demonstrated dysplasia, with one polyp showing invasive, poorly differentiated adenocarcinoma.

Discussion:

Peutz-Jeghers polyps (PJP) are hamartomatous polyps that are more commonly syndromic and very rarely sporadic.

Peutz-Jeghers syndrome (PJS) is an inherited, autosomal dominant condition and consists of gastrointestinal polyposis, muco-cutaneous pigmentation and increased cancer predisposition.

Incidence: 1 in 25,000 to 300,000; Males=Females, affects all ethnic groups.

In PJS polyps occur most commonly in small intestine (64%), colon (53%), stomach (49%) and rectum (32%). In small intestine, jejunum is most commonly affected followed ileum and duodenum.

>95% individuals have pigmented dark blue black macules, can occur in lips, peri-oral region, buccal mucosa, eyes, nostrils, fingertips, palms, soles and perianal areas.`

Clinically, the presenting complaints are intestinal obstruction (43%), abdominal pain (23%), blood in the stool (14%) and anal extrusion of polyp (7%).

Hyperpigmentation is the most common presenting symptom (95%) in childhood, decreases during puberty and adulthood.

Polyps can be sessile or pedunculated and range from 1 to 100’s and can vary in size from few mm to several cm.

Complications include bowel obstruction due to intussusception from polyps, chronic bleeding, anemia.

The clinical diagnosis of PJS is established in an individual with at least one of the following World Health Organization criteria: 1) Detection of ≥3 PJPs. 2) Any number of PJPs with a family history of PJS. 3) Characteristic mucocutaneous pigmentation with a family history of PJS. 4)Any number of PJPs with characteristic mucocutaneous pigmentation.

 Germline mutation in STK11 (LKB1) is identified in up to 96% of individuals with the clinical diagnosis of PJS.

STK11/LKB1 tumor suppressor gene on chromosome 19p13.3 is involved- germline STK11 mutation is accompanied by acquired defect in second STK11 allele in somatic cells.

Histologically, PJP usually has distinctive interdigitating smooth muscle bundles in a characteristic arborizing (branching tree) appearance throughout lamina propria giving rise to lobular or nodular configuration. The larger lobules can show dilated crypts at the center, while smaller crypts can be at the periphery. The outermost crypts can be associated with a few mitotic figures and, when present, Paneth cells. The epithelium is benign looking and shows polarity with nuclei arranged at the base and cytoplasm facing the lumen.

Dysplasia can be present and is usually focal.

In cases without apparent lobular organization, Desmin and SMA stains can highlight muscularis mucosa and can help uncover lobular or nodular configuration.

In stomach, PJPs can resemble hyperplastic/juvenile polyps.

In colon, PJPs can resemble mucosal prolapse polyps (especially polyps <1 cm) and the distinctive arborization pattern may be less prominent or entirely absent.

Mucosal prolapse usually occurs in left colon and rectum, shows increased lamina propria inflammation, edema, congestion, fibromuscular hyperplasia and interdigitating smooth muscle bundles between crypts. Usually no dysplasia is present. In contrast, colonic PJPs can occur throughout colon and rectum and show lobular configuration of crypts, arborizing smooth muscle, normal lamina propria and can have dysplasia.

Lifetime risk: 45% to 50% for breast carcinoma, 39% for colorectal carcinoma, 29% for gastric carcinoma, 13% for small intestinal carcinoma, 11% to 36% for pancreatic carcinoma, and 15% to 17% for lung carcinoma

Females with PJS at increased risk of sex cord tumor with annular tubules (SCTAT) and mucinous tumors of ovaries and fallopian tubes and adenoma malignum of the uterine cervix.

Males with PJS are at increased risk of Sertoli cell tumors

PJS patients require increased surveillance. Surveillance protocols in PJS have two main purposes. One is to detect sizeable gastroenterological polyps which could cause intussusception/obstruction or bleeding/anemia. The other is the detection of cancer at an early stage. The indication for screening is therefore age dependent: polyp-related complications may arise in childhood, whereas the cancer risk largely pertains to the adult population.

American College of Gastroenterology recommends surveillance in at-risk or affected patients with PJ syndrome for tumors of colon, stomach, small bowel, pancreas, breast, ovary, uterus, cervix and testes. Upper gastrointestinal endoscopy and colonoscopy should be performed every 3 years, starting at 8 years in patients with polyps or 18 years without polyps.

References:

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Pai RK. When to suspect and how to diagnose syndromic polyps and carcinomas of the gastrointestinal tract: focus on Lynch syndrome and colonic hamartomatous polyposis. Diagn Histopathol. 2020 Jan;26(1):8-14.

Wu M, Krishnamurthy K. Peutz-Jeghers Syndrome. 2021 Jul 23. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 30570978.

Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, Bertario L, Blanco I, Bülow S, Burn J, Capella G, Colas C, Friedl W, Møller P, Hes FJ, Järvinen H, Mecklin JP, Nagengast FM, Parc Y, Phillips RK, Hyer W, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen JT, Clark SK, Hodgson SV. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010 Jul;59(7):975-86. doi: 10.1136/gut.2009.198499. PMID: 20581245.

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