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Peutz-Jeghers Syndrome

Definition

  • Mucocutaneous melanosis and gastrointestinal hamartomatous polyps

Diagnostic Criteria

  • WHO criteria for diagnosis (any one of below)
    • ≥3 hamartomatous polyps
    • ≥1 hamartomatous polyps if family history of Peutz-Jeghers Syndrome (PJS)
    • Prominent mucocutaneous melanosis if family history of PJS
    • Prominent mucocutaneous melanosis and ≥1 hamartomatous polyp
  • Mucocutaneous melanotic macules
    • Most frequently on lips and oral mucosa
    • Rarely on hands, feet and face
  • Gastrointestinal hamartomatous polyps
    • Most frequent in jejunum and ileum
      • Less frequent in large intestine, stomach and duodenum
    • Multilobated
      • May have papillary or frond-like surface
    • Arborizing smooth muscle
      • Surrounds lobules of glands
        • Glands composed of epithelial cells of same types as normally seen at site of polyp
    • Generally cytologically bland epithelium
      • Dysplasia, if present in small intestine or stomach, is only focal
        • More commonly seen in colorectal polyps
    • Epithelial misplacement (pseudoinvasion) may be seen in small intestinal polyps (Petersen 2000)
      • Entrapped mucinous glands in submucosa, muscularis propria and occasionally subserosa
      • Cytologically bland
        • Entrapment of dysplastic epithelium has been reported
      • Lacks desmoplastic response, accompanied by normal lamina propria
      • No associated high grade dysplasia
  • Sporadic non-syndromic polyps are quite rare, if they exist at all
    • Strict definitions exclude some as mucosal prolapse polyps
    • Careful clinical examination and history of associated cancers reveal nearly all others to be syndromic (Burkart 2007)
    • Even cases of solitary Peutz-Jeghers polyps appear to be associated with increased cancer risk
  • Increased incidence of a variety of cancers (see Clinical at left)

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 12/27/09, 2/12/11, 11/13/11

Supplemental Studies

Genetic studies

  • Mutations in LKB1/STK11 at 19p13.3 detectable in 50-90%

Differential Diagnosis

Cowden Disease Peutz-Jeghers Syndrome
Most have facial and oral papillomas, fibromas and skin tumors Perioral mucocutaneous hyperpigmentation
Smooth muscle not a part of polyps Prominent arborizing smooth muscle bundles in GI polyps
Lacks pseudoinvasion May have displaced mucosa with pseudoinvasion of underlying muscularis propria
PTEN mutations in 80% STK11 mutations in 30-70%

 

Juvenile Polyposis Peutz-Jeghers Syndrome
No mucocutaneous hyperpigmentation Mucocutaneous hyperpigmentation
Smooth muscle absent or only small amounts in lamina propria Prominent arborizing smooth muscle bundles in GI polyps
Frequent mucous retention cysts Lacks retention cysts
Lacks pseudoinvasion May have displaced mucosa with pseudoinvasion of underlying muscularis propria
Polyps rare in small intestine Most polyps in small intestine
MADH4 or BMPR1A mutations in 40% STK11 mutations in 50-90%

 

Cronkhite-Canada Syndrome Peutz-Jeghers Syndrome
May have facial pigmented macules but no mucosal involvement described Mucocutaneous hyperpigmentation
Hair, nail, skin pigmentation changes present Internal neoplasms and non-GI polyps may occur
Smooth muscle absent or only small amounts in lamina propria Prominent arborizing smooth muscle bundles in GI polyps
Frequent mucous retention cysts Lacks retention cysts
Lacks pseudoinvasion May have displaced mucosa with pseudoinvasion of underlying muscularis propria
Not familial Autosomal dominant

 

Mucosal Prolapse / Cloacogenic Polyp Peutz-Jeghers Polyp
Usually solitary polyp Usually multiple
Smooth muscle surrounds individual crypts Prominent arborizing smooth muscle bundles surround groups of crypts
Polyps rare in small intestine Most polyps in small intestine
Not associated with oral pigmentation Associated with oral pigmentation

 

Gastric Hyperplastic Polyp Peutz-Jeghers Polyposis
Scant smooth muscle in polyps Arborizing muscle in polyps
Frequent cystic dilation Cystic dilation not prominent
No polyps in small intestine Most polyps in small intestine
Not familial Autosomal dominant
No associated mutations LKB1/STK11 mutations in 50-90%
Histologic distinction between these two is poor; clinical findings and distribution are more important

 

Peutz-Jeghers Polyp with Misplaced Glands Small Intestinal Adenocarcinoma
Overlying typical hamartomatous polyp Overlying adenoma may be present
Usually cytologically bland Usually cytologically malignant
Glands may permeate muscle but no desmoplastic response Desmoplastic response usually present
Lamina propria may be retained around entrapped glands No retained lamina propria around infiltrating glands
Glands frequently have a mixed population of cell types - mucus, goblet, paneth cells Monomorphic population

Clinical

  • Mean age at presentation 24 years
  • 1/3 present ≤10 years
  • May cause bleeding or intussusception
  • Increased incidence of various cancers
  • Site Cumulative Lifetime Risk
    Overall 93%
    Stomach 21%
    Small intestine 13%
    Large intestine 34%
    Pancreas 36%
    Breast 54%
    Ovary 21%
    Cervix 10%
    Uterus 9%
    Testis 9%
    Data from Girardiello 2000, primarily based on familial cases
    • Mean age of diagnosis of cancer 46 years
    • Cancers only rarely appear to arise from a pre-existing hamartomatous polyps
    • Special associated neoplasms or polyps
      • Cervix – adenoma malignum
      • Ovary – sex cord tumor with annular tubules
      • Testis – multifocal intratubular large cell hyalinizing sertoli cell neoplasm
        • Some are invasive and thus designated malignant
        • No aggressive behavior has been demonstrated
      • Nose – nasal polyps
    • Miscellaneous sites of polyps
      • Bladder, renal pelvis, bronchi, biliary tract
      • Not all well described

    Bibliography

    • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010.
    • Schreibman IR, Baker M, Amos C, McGarrity TJ. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol. 2005 Feb;100(2):476-90.
    • Calva D, Howe JR. Hamartomatous polyposis syndromes. Surg Clin North Am. 2008 Aug;88(4):779-817.
    • Chen HM, Fang JY. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009 Aug;24(8):865-74.
    • 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 Aug;31(8):1209-14.
    • 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 Jan;24(1):34-9.
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