July 2022 – Gastroenterology Pathology

A 29-year-old man with no history of inflammatory bowel disease or malignancy undergoes a screening enteroscopy, during which multiple polyps were identified in the small bowel. Resection and retrieval of the lesions were complete, and representative histology is shown.

Image 1: Polyp 20x
Image 2: Polyp 50x

90% of individuals with this syndrome will have a mutation in which of the following genes?

  • SMAD4
  • STK11
  • MLH1
  • PTEN

The correct answer is ...


Image 3:PJS Polyp with Pseudoinvasion

The histology specimen shows a polypoid proliferation of glandular epithelium arranged in a lobular fashion. A hallmark feature is the branching smooth muscle bands in a so-called “arborizing” pattern. These are features of polyps arising in Peutz-Jeghers syndrome (PJS), an autosomal dominant cancer predisposition syndrome. A germline mutation in the STK11 tumor suppressor gene can be identified in 90% of cases. An important pitfall seen in approximately 10% of PJS polyps, particularly those arising in the small bowel, is the phenomenon of pseudoinvasion, in which traumatization of the polyp causes epithelium to be misplaced within the submucosa, muscularis propria, and even subserosa in extreme cases (see photo). Clues that pseudoinvasion is occurring include similar cytologic and architectural features between the pseudoinvasive and uninvolved components (as opposed to a higher grade of atypia typically seen in true invasive carcinoma), the presence of inflammation and/or hemorrhage, and a lack of desmoplastic response. PJS carries an increased risk of multiple types of malignancies, with up to 85% of patients developing cancer by age 70. Besides gastrointestinal sites, tumors have been documented in the breast, pancreas, and gonadal organs.

The other genes listed are all related to other cancer predisposition syndromes encountered in the GI tract. MLH1 is a mismatch repair gene mutated in Lynch syndrome and hypermethylated in sporadic MSI-high carcinomas. Polyps and tumors in Lynch syndrome do not have specifically distinguishing morphologic features, though they often display tumor-infiltrating lymphocytes and a medullary phenotype.

PTEN hamartoma tumor syndrome — also known as Cowden syndrome — is the result of mutations in the PTEN tumor suppressor gene. Patients develop multiple types of polyps across the GI tract, including hamartomas, hyperplastic polyps, adenomas, and ganglioneuromas. Mucocutaneous lesions (e.g., trichilemmomas, papillary lesions, and keratoses), however, are considered most characteristic of the disease. In addition, they are at higher risk for developing neoplasms of the breast, thyroid, and endometrium.

A mutation in the SMAD4 tumor suppressor gene is one of the most common mutations found in patients with juvenile polyposis syndrome (JPS). Juvenile polyps are characterized by edematous stroma containing cystically-dilated glands. They, too, can display a lobular architecture, but do not have the arborizing smooth muscle seen in Peutz-Jeghers polyps. Patients with this syndrome carry a higher risk for colorectal, gastric, and pancreatic malignancies. There are also reports of SMAD4 mutations resulting in a combined JPS/hereditary hemorrhagic telangiectasia phenotype.


  1. WHO Classification of Tumours Editorial Board, Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019.
  2. Shepherd NA, Bussey HJ, Jass JR. Epithelial misplacement in Peutz-Jeghers polyps. A diagnostic pitfall. Am J Surg Pathol. 1987 Oct;11(10):743-9. doi:10.1097/00000478-198710000-00001. PMID: 3661821.
  3. Hobert and Eng. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009 Oct;11(10):687-94. doi:10.1097/GIM.0b013e3181ac9aea. PMID: 19668082.
  4. Lawless ME, Toweill DL, Jewell KD, et al. Massive gastric juvenile polyposis: A clinicopathologic study using SMAD4 immunohistochemistry. Am J Clin Pathol. 2017 Apr 1;147(4):390. doi:10.1093/ajcp/aqx015. PMID: 28340255.
  5. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar 13;363(9412):852-9. doi:10.1016/S0140-6736(04)15732-2. PMID: 15031030.
Photo of Ryan W. Kendziora, M.D.

Ryan Kendziora, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic

Thomas Smyrk, M.D.
Clinical Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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