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Very high risk of cancer in familial Peutz–Jeghers syndrome

      Abstract

      Background & Aims: The Peutz–Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary. Methods: We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications. Results: For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old. Conclusions: Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers.
      GASTROENTEROLOGY 2000;119:1447-1453

      Abbreviations:

      CL (confidence limits), ICD-9 (International Classification of Diseases, 9th revision), PJS (Peutz–Jeghers syndrome), RR (relative risk)
      The Peutz–Jeghers syndrome (PJS) is an autosomal dominant disease characterized by hamartomatous polyps in the gastrointestinal tract and by mucocutaneous melanin pigmentation.
      • Peutz JLA
      On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane.
      • Jeghers H
      • McKusick VA
      • Katz KH
      Generalized intestinal polyposis and melanin spots of the oral mucosa, lip and digits: a syndrome of diagnostic significance.
      Recently, investigators discovered that germline mutations of the STK 11 (serine threonine kinase 11) gene on chromosome 19p cause this disorder.
      • Hemminki A
      • Markie D
      • Tomlinson I
      • Avizienyte D
      • Roth S
      • Loukola A
      • Bignell G
      • Warren W
      • Aminoff M
      • Hoglund P
      • Jarvinen H
      • Kristo P
      • Pelin K
      • Ridanpaa M
      • Salovaara R
      • Toro T
      • Bodmer W
      • Ol-schwang S
      • Olsen AS
      • Stratton MR
      • de la Chapelle A
      • Aaltonen LA
      A serine/threonine kinase gene defect in Peutz–Jeghers syndrome.
      • Jenne DE
      • Reimann H
      • Nezu J
      • Friedel W
      • Loff S
      • Jeschke R
      • Muller O
      • Back W
      • Zimmer M.
      Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
      Patients with PJS are known to be at increased risk for common gastrointestinal and nongastrointestinal cancers.
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Hizawa K
      • Iida M
      • Matsumoto T
      • Kohrogi N
      • Kinoshita H
      • Yao T
      • Fujishima M.
      Cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      • Burdick D
      • Prior JT
      Peutz–Jeghers syndrome: a clinicopathologic study of a large family with a 27 year follow-up.
      • Utsunomiya J
      • Gocho H
      • Miyanaga T
      • Hamaguchi E
      • Kashimure A
      • Aoki N
      • Komatsu I.
      Peutz–Jeghers syndrome: its natural course and management.
      Other studies have underscored the unusual types of associated tumors, such as ovarian sex-cord tumor with annular tubules and adenoma malignum of the cervix in females.
      • Young RH
      • Welch WR
      • Dickersin GR
      • Scully RE
      Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and 4 with adenoma malignum of the cervix.
      In addition, testicular tumors of sex cord and Sertoli-cell type have been associated with sexual precocity and gynecomastia in boys with this syndrome.
      • Solh HM
      • Azoury RS
      • Najjar SS
      Peutz–Jeghers syndrome associated with precocious puberty.
      Although risk of cancer in PJS patients is considered increased, patient management has been hampered by variability in risk estimates and inconsistency in cancer screening/surveillance recommendations.
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Woolfe B.
      On estimating the relation between blood group and disease.
      Therefore, we conducted a meta-analysis of existing literature to assess risk of cancer in PJS and to better develop screening and surveillance guidelines.

      Materials and methods

       Study identification and selection

      A systematic search on the MEDLINE from January 1966 to December 1998 and the EMBASE database from 1980 to December 1998 was done to identify all literature under the MESH headings and texts words of “Peutz–Jeghers syndrome” and “melanotic pigmentation.” In addition, an extensive manual search was conducted by using references from all retrieved reports, review articles, and chapters from textbooks of gastroenterology.
      Studies included in the meta-analysis were those with confirmation of the diagnosis of PJS in affected patients, ability to calculate patient age at diagnosis of cancer, and patient follow-up time. We included studies that had a single or series of pedigrees with PJS regardless of the research question under analysis. Review articles, editorials, and letters to the editor were excluded. Also, case reports of patients with PJS and cancer that would introduce an element of publication bias by increasing estimated cancer risks were not included.

       Qualitative assessment

      We evaluated the quality of the articles with regard to (1) definition of the diagnosis of PJS, (2) ability to determine follow-up of patients, and (3) confirmation of the diagnosis of the carcinoma. We abstracted descriptive data to determine which reports could be combined from a clinical perspective. After evaluation, the authors (F.M.G., J.D.B., A.C.T., and J.A.O.) discussed the differences and achieved consensus.

       Quantitative assessment

      After qualitative assessment, we extracted the data from the literature reports. Numerical discrepancies were resolved by discussion among the authors. Data extracted included patients' sex, ethnicity, presence or absence of cancer, site of cancer, length of follow-up, and age at diagnosis of cancer. Data from each literature report were extracted together by 2 authors and converted into a common format.

       Statistical analysis

      A risk assessment using the International Classification of Diseases, 9th revision (ICD-9), was performed for all cancers (ICD-9) 140.0–208.9, esophageal carcinoma (ICD-9) 150.0–.9, stomach carcinoma (ICD-9) 151.0–.9, small intestinal carcinoma (ICD-9) 152.0–.9, colorectal carcinoma (ICD-9) 153.0–.9, pancreatic carcinoma (ICD-9) 157.0–.9, lung carcinoma (ICD-9) 162.0–.9, testicular carcinoma (ICD-9) 186.0–.9, breast carcinoma (ICD-9) 174.0–175.9, uterine carcinoma (ICD-9) 182.0–.9, ovarian carcinoma (ICD-9) 183.0–.9, and cervical carcinoma (ICD-9) 180.0–.9.
      Computation of person-years at risk for cancer started January 1, 1920. Patients were considered at risk from birth until the date of diagnosis of cancer, or the closing date of the study as mentioned in the publication. Patients were censored at age 65.
      Person-years at risk were calculated for ages 15-64 years according to sex, race, and age-specific categories during subsequent 5-year calendar time periods of observation using a computer program for cohort analysis.
      • Coleman M
      • Doublas A
      • Hermon C
      • Peto L.
      Cohort study analysis with a Fortran computer program.
      Expected cancer cases were calculated by multiplying the number of person-years for each of 5-year age groups and sex by the corresponding race, age, sex, and calendar time–specific incidence rate for the general U.S. population. For the period 1920–1964, the incidence rates from the state of Connecticut were used; for the period 1965–1998, the Surveillance, Epidemiology and End Results (SEER) data

      Surveillance, Epidemiology, and End Results (SEER) Program Public Use CD-ROM (1973–94). National Cancer Institute, DCPC, Surveillance Program, Cancer Statistics Branch, released October 1997, based on the August 1996 submission.

      for the U.S. population were used. In the risk analysis for all cancer combined, only the first cancer observed was counted for patients who developed more than one cancer. In the analysis for specific types of cancer, second and third cancers were included. The ratio of observed carcinomas over the expected number was computed with a test of significance and 95% confidence limits (CL) assuming a Poisson distribution. This ratio forms the relative risk (RR) and compares cancer risk in the study population with that in the general population. Using the absolute rates for each 5 year age group, the cumulative risk for ages 15–64 years was calculated according to cumulative risk = 1 − exp (−cumulative rate).
      • Breslow NE
      • Day NE
      The analysis of case-control studies.

      Results

      Searches of MEDLINE, EMBASE, and referenced articles yielded 94 articles. Of these, 86 were disqualified because they were either review articles or case reports of 1 or 2 patients with PJS and cancer at young age without pedigree information. Eight publications evaluated the long-term follow-up of PJS patients. Of these 2 studies were excluded because the frequency or RR of cancer in PJS patients could not be calculated from data provided.
      The characteristics of the 6 studies included in this analysis are listed in Table 1.
      Table 1Reports on the frequency or relative risk of cancer in PJS
      StudySiteEligibilityaSample size/no. of pedigreesDesignIndices measured
      Giardiello et al.
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      MD, USA1 or (2/3) of 2,3,431/13RCSRR all CA, 18
      RR of pan CA, 100×
      Freq of CA, 48%
      Spigelman et al.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      UK1 and 272/12RCSFreq of CA, 22%
      RR of death from CA, 9 (CL, 4.2–17.3)
      RR of death GI CA, 13 (CL, 2.2–38.1)
      Westerman et al.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      Holland1 and 2 or 361/21RCSFreq of CA, 28%
      Boardman et al.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      MN, USA1 or (2/3) of 2,3,434/31RCSFreq CA, 53%
      RR all CA, 9.9 (CL, 5.7–16.2)
      RR GI CA, 50.5 (CL, 18.5–109.9)
      RR of breast and gyn CA, 20.3 (CL, 7.4–44.2)
      Foley et al.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      PA, USA2 or 1 and 312/1RCSFreq CA, 17%
      Burdick et al.
      • Burdick D
      • Prior JT
      Peutz–Jeghers syndrome: a clinicopathologic study of a large family with a 27 year follow-up.
      NY, USA1 and 38/1RCSFreq CA, 25%
      a1, Hamartomatous polyps; 2, labial melanin deposits; 3, family history of PJS; 4, small bowel polyposis.
      RCS, retrospective cohort study; CA, cancer; pan, pancreatic; Freq, frequency; CL, confidence limits; GI, gastrointestinal.
      All investigators used the usual clinical and histopathologic criteria to establish the diagnosis of PJS, and cancer diagnosis was confirmed histopathologically. Also, none of the pedigrees in this analysis were identified or recruited because of malignancy in the proband. However, variation existed in methodology and endpoints between reports. Formal RR calculations for overall cancer and for specific cancers in patients with PJS were done in 3 studies
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      (Figure 1), the rate of cancer was calculated in 1 study,
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      and no evaluation was made in 2 others.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      • Burdick D
      • Prior JT
      Peutz–Jeghers syndrome: a clinicopathologic study of a large family with a 27 year follow-up.
      Figure thumbnail gr1
      Fig. 1RR and CL of overall cancer in literature reports of patients with PJS.
      While the risk of cancer in PJS patients from multiple families was the main outcome variable in 4 of these investigations,
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      the other 2 studies
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      reported both benign and malignant events. Four studies evaluated PJS patients from multiple families,
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      and 2 studies assessed single pedigrees.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      These single pedigree studies are the only 2 such reports in the literature.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      • Foley TR
      • McGarrity TJ
      • Abt AB
      Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
      They were included in the analysis because they provided the longest term follow-up (27 and 49 years, respectively) of the 2 largest pedigrees reported and RR could be calculated from data provided.
      The study population consisted of 107 white male and 106 white female patients from 79 families with PJS. Of these, 1 male and 2 females were excluded from analysis because they were younger than 15 years by the closing date of the study. Hence, the analysis included 210 patients with PJS contributing 5059.11 person-years of follow-up. The features of the study population and follow-up times are shown in Table 2.
      Table 2Characteristics of patients with PJS
      Patients with PJS, n210
      Sex [M/F (% male)]106/104 (50)
      Race, white [n (%)]210 (100)
      Age at diagnosis of cancer (yr, mean ± SD)42.9 ± 10.2
      Age at last follow-up (yr, mean ± SD)38.7 ± 8.5
      Distribution of follow-up
      Decade(n)Person years
      0–1400
      15–242102072
      25–342051987
      35–44191742
      45–5437185
      55–651373
      Multiple cancers developed in 3 male and 7 female patients. For testicular cancer risk analysis, 106 males contributed 2552.05 person-years. For breast, cervical, uterine, and ovarian cancer, 104 females contributed 2507.05 person-years.
      The RR for all cancers in PJS patients aged 15–64 years was 15.2 (CL, 12.0%, 19.0%), and the absolute rate was 1304.6 per 100,000 person years (1.3%/yr). No difference in RR of all cancers was noted between male (RR, 15.5; 95% CL, 10.5%, 22%) and female (RR, 14.8; CL, 10%, 21%) patients. The mean age (±SD) at first diagnosis of cancer was 42.9 ±10.2 years (Figure 2).
      Figure thumbnail gr2
      Fig. 2Age of diagnosis of first cancer in patients with PJS.
      Table 3 shows the risk analysis for cancers in patients with PJS.
      Table 3Risk analysis of cancers in patients aged 15–64 years with PJS
      Site, ICD-9ObservedRR (O/E)95% CLP value, 2-sided
      All cancers 140.0–208.96615.212, 19<0.001
      Esophagus 150.0–.91572.5, 5570.036
      Stomach 151.0–.91021396, 368<0.001
      Small intestine 152.0–.96520220, 1306<0.001
      Colon 153.0–.9158447, 137<0.001
      Pancreas 157.0–.9613244, 261<0.001
      Lung 162.0–.95175.4,39<0.001
      Testes 186.0–.914.50.12, 250.396
      Breast 174.0–175.91115.27.6, 27<0.001
      Uterus 182.0–.9216.01.9, 560.014
      Ovary 183.0–.94277.3, 68<0.001
      Cervix 180.0–.931.50.31, 4.40.63
      O/E, observed/expected.
      A high statistically significant RR for all cancers—esophageal, stomach, small intestinal, colon, pancreas, lung, breast, uterine, and ovarian—was observed. No statistically significant RR for testicular or cervical cancer was found.
      The absolute rate of cancer in patients with PJS is shown in Table 4.
      Table 4Absolute rate of cancer in patients with PJS from ages 15 to 64 years
      SiteRate/100,000 person-yearsCumulative risk from age 15 to 64
      All cancers1304.693%
      Esophagus19.80.5%
      Stomach197.729%
      Small intestine118.613%
      Colon296.539%
      Pancreas118.636%
      Lung98.815%
      Testes39.29%
      Breast438.854%
      Uterus79.89%
      Ovary159.621%
      Cervix119.710%
      Risk from age 15 to 64 years for developing cancer of any site in PJS patients was 93%. Patients have the highest cumulative risks for breast (54%), colon (39%), pancreatic cancer (36%), stomach (29%), and ovarian (21%) cancer.
      Literature case reports of malignant and nonmalignant tumors not included in the meta-analysis in PJS are summarized in Table 5.
      Table 5Case reports of malignant and nonmalignant tumors in PJS
      SiteNo. of casesSex (M/F) (% male)Age at diagnosis (mean ± SD)95% CLRangeCommentsStudy (references)
      Esophagus11/0 (100)67
      • Eng A
      • Armin A
      • Massa M
      • Gradini R.
      Peutz-Jeghers–like melanotic macules associated with esophageal adenocarcinoma.
      Stomach85/3 (63)30.1 ± 16.716.1, 44.110–61
      • Cochet B
      • Carrel J
      • Desbaillets L
      • Widgren S.
      Peutz–Jeghers syndrome associated with gastro-intestinal carcinoma. Report of two cases in a family.
      • Aideyan UO
      • Kao SC
      Gastric adenocarcinoma metastatic to the testes in Peutz–Jeghers syndrome.
      • Bujanda L
      • Beguiristain A
      • Villar VM
      • Cosme A
      • Castiella A
      • Arriola JA
      • Arenas JI
      Gastric adenocarcinoma in hamartomatous polyp in Peutz–Jeghers syndrome.
      • Achord JL
      • Proctor HD
      Malignant degeneration and metastasis in Peutz–Jeghers syndrome.
      • Horn Jr, RC
      • Payne WA
      • Fine G.
      The Peutz–Jeghers syndrome (gastrointestinal polyposis with muco-cutaneous pigmentation): report of a case terminating with disseminated gastrointestinal cancer.
      • Kopylow A
      • Bielecki M
      • Dominiczak K.
      The Peutz syndrome.
      • Payson BA
      • Moumgis B.
      Metastasizing carcinoma of the stomach in Peutz–Jeghers syndrome.
      • Reid JD
      Intestinal carcinoma in the Peutz–Jeghers syndrome.
      Small intestine167/9 (44)41.7 ± 17.532.0, 51.421–84
      • Cochet B
      • Carrel J
      • Desbaillets L
      • Widgren S.
      Peutz–Jeghers syndrome associated with gastro-intestinal carcinoma. Report of two cases in a family.
      • Payson BA
      • Moumgis B.
      Metastasizing carcinoma of the stomach in Peutz–Jeghers syndrome.
      • Reid JD
      Intestinal carcinoma in the Peutz–Jeghers syndrome.
      • Matuchansky C
      • Babin P
      • Coutrot S
      • Druart F
      • Barbier J
      • Maire P.
      Peutz–Jeghers syndrome with metastasizing carcinoma arising from a jejunal hamartoma.
      • Laughlin EH
      Benign and malignant neoplasms in a family with Peutz–Jeghers syndrome: a study of three generations.
      • Pesta J
      • Orlowska J.
      Small intestine carcinoma in Peutz–Jeghers syndrome.
      • Yoshikawa A
      • Kuramoto S
      • Mimura T
      • Kobayashi K
      • Shimoyama S
      • Yasuda H
      • Kaminishi M
      • Yamakawa M
      • Oohara T
      • Murakami T.
      Peutz–Jeghers syndrome manifesting complete intussusception of the appendix and associated with a focal cancer of the duodenum and a cystadenocarcinoma of the pancreas: report of a case.
      • Ichiyoshi Y
      • Yao T
      • Nagasaki S
      • Sugimachi K.
      Solitary Peutz–Jeghers type polyp of the duodenum containing a focus of adenocarcinoma.
      • Castro RR
      • Brant CQ
      • Ferreira LE
      • Geocze S
      • Ferrari Junior AP
      • Lanzoni VP
      • Forones NM
      Peutz–Jeghers syndrome and adenocarcinoma. Report of a case.
      • Rodriquez JM
      • Picardo A
      • Torres AJ
      • Garcia Calvo M
      • Ortega L
      • Martinez S
      • Balibrea JL
      • Ried JD
      Duodenal carcinoma in the Peutz–Jeghers syndrome.
      • Freeman JT
      • Ravdin IS
      Polyps and pigment in the Peutz–Jeghers syndrome.
      • Warren KW
      • Kune GA
      • Poulantzas JK
      Peutz–Jeghers syndrome with carcinoma of the duodenum and jejunum.
      • Williams JP
      • Knudsen A.
      Peutz–Jeghers syndrome with metastasizing duodenal carcinoma.
      • Gasser U
      • Arquint A.
      Ein fall von Peutz Jegher syndrom: Mit Maligner Entartung.
      • Mackman S
      • Perna G
      • Gossett F.
      Peutz–Jeghers syndrome with metastases to an abdominal incision.
      • Moretti G
      • Bozic C
      • Genton N.
      Polypose familiale du type Peutz–Jeghers, avec Degenerescence malingne.
      Colorectal97/2 (78)45.8 ± 17.332.4, 59.027–71
      • Tweedie JH
      • McCann BG
      Peutz–Jeghers syndrome and metastasising colonic adenocarcinoma.
      • Konishi F
      • Wyse NE
      • Muto T
      • Sawada T
      • Moioka Y
      • Sugimura H
      • Yamaguchi K.
      Peutz–Jeghers polyposis associated with carcinoma of the digestive organs: report of three cases and review of literature.
      • Hsu SD
      • Zaharopoulos P
      • May JT
      • Costanzi JJ
      Peutz–Jeghers syndrome with intestinal carcinoma: report of the association in one family.
      • Riley E
      • Swift M.
      A family with Peutz–Jeghers syndrome and bilateral breast cancer.
      • Niimi K
      • Tomoda H
      • Furusawa M
      • Hayashi I
      • Okumura Y.
      Peutz–Jeghers syndrome associated with adenocarcinoma of the cecum and focal carcinomas in hamartomatous polyps of the colon: a case report.
      • Hermann G
      • Saro A.
      Polyposis intestinalis generalisata melanoplakiaval (Peutz–Jeghers syndroma).
      • Konishi F
      • Wyse NE
      • Muto T
      • Sawada T
      • Morioka Y
      • Sugimura H
      • Yamaguchi K.
      Peutz–Jeghers polyposis associated with carcino-mas of the digestive organs. Report of three cases and review of the literature.
      Pancreas64/2 (67)40.8 ± 16.223.9, 57.816–60
      • Yoshikawa A
      • Kuramoto S
      • Mimura T
      • Kobayashi K
      • Shimoyama S
      • Yasuda H
      • Kaminishi M
      • Yamakawa M
      • Oohara T
      • Murakami T.
      Peutz–Jeghers syndrome manifesting complete intussusception of the appendix and associated with a focal cancer of the duodenum and a cystadenocarcinoma of the pancreas: report of a case.
      • Moretti G
      • Bozic C
      • Genton N.
      Polypose familiale du type Peutz–Jeghers, avec Degenerescence malingne.
      • Tweedie JH
      • McCann BG
      Peutz–Jeghers syndrome and metastasising colonic adenocarcinoma.
      • Konishi F
      • Wyse NE
      • Muto T
      • Sawada T
      • Moioka Y
      • Sugimura H
      • Yamaguchi K.
      Peutz–Jeghers polyposis associated with carcinoma of the digestive organs: report of three cases and review of literature.
      • Hsu SD
      • Zaharopoulos P
      • May JT
      • Costanzi JJ
      Peutz–Jeghers syndrome with intestinal carcinoma: report of the association in one family.
      • Riley E
      • Swift M.
      A family with Peutz–Jeghers syndrome and bilateral breast cancer.
      • Niimi K
      • Tomoda H
      • Furusawa M
      • Hayashi I
      • Okumura Y.
      Peutz–Jeghers syndrome associated with adenocarcinoma of the cecum and focal carcinomas in hamartomatous polyps of the colon: a case report.
      • Hermann G
      • Saro A.
      Polyposis intestinalis generalisata melanoplakiaval (Peutz–Jeghers syndroma).
      • Konishi F
      • Wyse NE
      • Muto T
      • Sawada T
      • Morioka Y
      • Sugimura H
      • Yamaguchi K.
      Peutz–Jeghers polyposis associated with carcino-mas of the digestive organs. Report of three cases and review of the literature.
      • Altemeier WA
      • Dozois R.
      Is there a predisposition to the development of intestinal malignancy?.
      • Bowlby LS
      Pancreatic adenocarcinoma in an adolescent male with Peutz–Jeghers syndrome.
      • Thatcher BS
      • May ES
      • Taxier MS
      • Bonta JA
      • Murthy L.
      Pancreatic adenocarcinoma in a patient with Peutz–Jeghers syndrome-a case report and literature review.
      • Pauwels M
      • Delcenserie R
      • Yzet T
      • Duchmann JC
      • Capron JP
      Pancreatic cystadenocarcinoma in Peutz–Jeghers syndrome.
      Breast90/9 (100)37.0 ± 11.428.2, 45.819–483 Cases bilateral
      • Riley E
      • Swift M.
      A family with Peutz–Jeghers syndrome and bilateral breast cancer.
      • Chen KT
      Female genital tract tumors in Peutz–Jeghers syndrome.
      • Martin-Odegard B
      • Svane S.
      Peutz–Jeghers syndrome associated with bilateral synchronous breast carcinoma in a 30-year-old woman.
      • Young RH
      • Welch WR
      • Dickersin GR
      • Scully RE
      Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix.
      Cervix280/28 (100)34.3 ± 7.830.8, 37.723–5422 Adenoma malignum
      • Konishi F
      • Wyse NE
      • Muto T
      • Sawada T
      • Morioka Y
      • Sugimura H
      • Yamaguchi K.
      Peutz–Jeghers polyposis associated with carcino-mas of the digestive organs. Report of three cases and review of the literature.
      • Chen KT
      Female genital tract tumors in Peutz–Jeghers syndrome.
      • Young RH
      • Welch WR
      • Dickersin GR
      • Scully RE
      Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix.
      • Kaku T
      • Hachisuga T
      • Toyoshima S
      • Enjoji M
      • Mori T
      • Nagaoka M.
      Extremely well differentiated adenocarcinoma (“adenoma malignum”) of the cervix in a patient with Peutz–Jeghers syndrome.
      • Costa J.
      Peutz–Jeghers syndrome: case presentation.
      • Posczaski E
      • Kaminski PF
      • Pees RC
      • Singapuri K
      • Sorosky JI
      Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
      • Young RH
      • Scully RE
      Mucinous ovarian tumors associated with mucinous adenocarcinomas of the cervix. A clinicopathological analysis of 16 cases.
      • Gilks CB
      • Young RH
      • Aguirre P
      • DeLellis RA
      • Scully RE
      Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immuno-histochemical analysis of 26 cases.
      • Choi CG
      • Kim SH
      • Kim JS
      • Chi JG
      • Song ES
      • Han MC
      Adenoma malignum of uterine cervix in Peutz–Jeghers syndrome: CT and US features.
      • Fujiwaki R
      • Takahashi K
      • Kitao M.
      Adenoma malignum of the uterine cervix associated with Peutz–Jeghers syndrome.
      • Tsuruchi N
      • Tsukamoto N
      • Kaku T
      • Kamura T
      • Nakano H.
      Adenoma malignum of the uterine cervix detected by imaging methods in a patient with Peutz–Jeghers syndrome.
      • Srivatsa PJ
      • Keeney GL
      • Podratz KC
      Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz–Jeghers syndrome.
      • Chatti S
      • Bellil K
      • Jerbi G
      • Kchir N
      • Haouet S
      • Kacem M
      • Boubaker S
      • Zouari F
      • Filali A
      • Chelli H
      • Rahal K
      • Zitouna M.
      Minimal deviation adenocarcinoma of the uterine cervix in a woman with Peutz–Jeghers syndrome. Report of a case.
      • Brand E.
      Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
      Ovarian530/53 (100)28.0 ± 12.524.4, 31.54–5749/53 Sex cord tumorsa
      • Riley E
      • Swift M.
      A family with Peutz–Jeghers syndrome and bilateral breast cancer.
      • Chen KT
      Female genital tract tumors in Peutz–Jeghers syndrome.
      • Young RH
      • Welch WR
      • Dickersin GR
      • Scully RE
      Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix.
      • Posczaski E
      • Kaminski PF
      • Pees RC
      • Singapuri K
      • Sorosky JI
      Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
      • Young RH
      • Scully RE
      Mucinous ovarian tumors associated with mucinous adenocarcinomas of the cervix. A clinicopathological analysis of 16 cases.
      • Choi CG
      • Kim SH
      • Kim JS
      • Chi JG
      • Song ES
      • Han MC
      Adenoma malignum of uterine cervix in Peutz–Jeghers syndrome: CT and US features.
      • Tsuruchi N
      • Tsukamoto N
      • Kaku T
      • Kamura T
      • Nakano H.
      Adenoma malignum of the uterine cervix detected by imaging methods in a patient with Peutz–Jeghers syndrome.
      • Brand E.
      Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
      • Herruzo AJ
      • Redondo E
      • Perez de Avila I
      • Aleman M
      • Menjon S.
      Ovarian sex cord tumor with annular tubules and Peutz–Jeghers syndrome.
      • Costa J.
      Peutz–Jeghers syndrome: case presentation.
      • Young RH
      • Dickersin GR
      • Scully RE
      A distinctive ovarian sex cord-stromal tumor causing sexual precocity in the Peutz–Jeghers syndrome.
      • Benagiano G
      • Bigotti G
      • Buzzi M
      • D'Alessandro P
      • Napolitano C.
      Endocrine and morphological study of a case of ovarian sex-cord tumor with annular tubules in a woman with Peutz–Jeghers syndrome.
      • Laughlin EH
      Benign and malignant neoplasms in a family with Peutz–Jeghers syndrome: study of three generations.
      • Shintaku M
      • Baba Y
      • Fujiwara T.
      Intra-abdominal desmoplastic small cell tumour in a patient with Peutz–Jeghers syndrome.
      • Ferry JA
      • Young RH
      • Engel G
      • Scully RE
      Oxyphilic Sertoli cell tumor of the ovary: a report of three cases, two in patients with the Peutz–Jeghers syndrome.
      • Hales SA
      • Cree IA
      • Pinion S.
      A poorly differentiated Sertoli–Leydig cell tumour associated with a ovarian sex cord tumour with annular tubules in a woman with Peutz–Jeghers syndrome.
      • Steenstrup EK
      Ovarian tumours and Peutz–Jeghers syndrome. A case of “sex cord tumour with annulartubules” (Scully).
      • Lucidarme D
      • Dridba M
      • el Khoury S
      • Vandermolen P
      • Foutrein P
      • Vandevenne P
      • Leduc M
      • Creusy C
      • Filoche B.
      Testes99/0 (100)8.6 ± 5.44.3, 12.73–20All Sertoli cell tumor
      • Cantu JM
      • Rivera H
      • Ocampo-Campos R
      • Bedolla N
      • Cortes-Gallegos V
      • Gonzalez-Mendoza A
      • Diaz M
      • Hernandez A.
      Peutz–Jeghers syndrome with feminizing Sertoli cell tumor.
      • Wilson DM
      • Pitts W
      • Hintz RL
      • Rosenfeld RG
      Testicular tumors with Peutz–Jeghers syndrome.
      • Buchino JJ
      • Uhlenhuth ER
      Large-cell calcifying Sertoli cell tumor.
      • Sharma S
      • Seam RK
      • Kapoor HL
      Malignant Sertoli cell tumor of the testis in a child.
      • Dryer L
      • Jack RK
      • du Plessis DJ
      Bilateral large cell calcifying Sertoli cell tumor of the testes with Peutz–Jeghers syndrome: a case report.
      • Niewenhuis JC
      • Wolf MC
      • Kass EJ
      Bilateral asynchronous Sertoli cell tumor in a boy with the Peutz–Jeghers syndrome.
      • Young S
      • Gooneratne S
      • Staus II, FH
      • Zeller WP
      • Bulun SE
      • Rosenthal IM
      Feminizing Sertoli cell tumors in boys with Peutz–Jeghers syndrome.
      aConcomitant breast cancer in 3 patients, breast cancer and cervical adenoma malignum in 3, breast and ovarian cancer in 1, cervical adenoma malignum in 10, ovarian adenocarcinoma in 1, ovarian and cervical adenoma malignum in 5, and Sertoli cell tumor in 3.

      Discussion

      This meta-analysis agrees with the high increased RR and young age of onset of cancer in patients with PJS previously described.
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      The magnitude of cancer risk in this study was similar to that recently reported.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      However, unlike Boardman et al.,
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      this investigation found no significant difference in overall cancer risk between genders. RR was increased for a wide variety of gastrointestinal and nongastrointestinal malignancies in PJS patients over the general population. Of note, this study confirms the previously reported increased risk of pancreatic cancer, particularly in men and the risk of breast and gynecological tumors noted in women.
      • Boardman LA
      • Thibodeau SN
      • Schaid DJ
      • Lindor NM
      • McDonnell SK
      • Burgart LJ
      • Ahlquist DA
      • Podratz KC
      • Pittelkow M
      • Hartmann LC
      Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
      We found an overall cumulative risk for cancer of >90% in patients with PJS. Of concern, the absolute risk of breast cancer is similar to the magnitude of risk noted in hereditary forms of that tumor caused by germline mutations of BRCA1 or BRCA2 (genes associated with hereditary breast cancer).
      The findings in this investigation are limited by the small number of families analyzed. Also, because we evaluated patients with familial PJS, the data may not be applicable to sporadic cases. This highlights the need for a more extensive cohort study using data from multiple Peutz–Jeghers registries to better estimate cancer risk. Although mutation of STK 11 gene has been identified in most PJS families evaluated, differences may exist between site and type of mutation and cancer risk. The pedigrees in this study were not recruited because of malignancy in the proband, but preferential publication of families with high cancer rates, causing exaggeration of the estimated risk, cannot be eliminated. However, even if this factor elevated the risk, it seems unlikely to fully account for the magnitude of cumulative risk noted; these patients would still merit attention to surveillance and close follow-up even if the risks were substantially lower than those reported by us.
      Germline mutations in the STK 11 gene were described in patients with PJS by 2 independent groups.
      • Hemminki A
      • Markie D
      • Tomlinson I
      • Avizienyte D
      • Roth S
      • Loukola A
      • Bignell G
      • Warren W
      • Aminoff M
      • Hoglund P
      • Jarvinen H
      • Kristo P
      • Pelin K
      • Ridanpaa M
      • Salovaara R
      • Toro T
      • Bodmer W
      • Ol-schwang S
      • Olsen AS
      • Stratton MR
      • de la Chapelle A
      • Aaltonen LA
      A serine/threonine kinase gene defect in Peutz–Jeghers syndrome.
      • Jenne DE
      • Reimann H
      • Nezu J
      • Friedel W
      • Loff S
      • Jeschke R
      • Muller O
      • Back W
      • Zimmer M.
      Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
      Investigators found that truncating germline mutations in the STK 11 gene appear necessary and sufficient to cause PJS.
      • Hemminki A
      • Markie D
      • Tomlinson I
      • Avizienyte D
      • Roth S
      • Loukola A
      • Bignell G
      • Warren W
      • Aminoff M
      • Hoglund P
      • Jarvinen H
      • Kristo P
      • Pelin K
      • Ridanpaa M
      • Salovaara R
      • Toro T
      • Bodmer W
      • Ol-schwang S
      • Olsen AS
      • Stratton MR
      • de la Chapelle A
      • Aaltonen LA
      A serine/threonine kinase gene defect in Peutz–Jeghers syndrome.
      • Jenne DE
      • Reimann H
      • Nezu J
      • Friedel W
      • Loff S
      • Jeschke R
      • Muller O
      • Back W
      • Zimmer M.
      Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
      • Gruber 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 GJA
      • Giardiello FM
      Pathogenesis of adenocarcinoma in Peutz–Jeghers syndrome.
      Gruber et al.
      • Gruber 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 GJA
      • Giardiello FM
      Pathogenesis of adenocarcinoma in Peutz–Jeghers syndrome.
      reported evidence in PJS that STK 11 acts as a tumor-suppressor gene potentially involved in the earliest steps of pathogenesis of hamartomas into adenocarcinomas. The confirmation of the wide variety and striking risk of malignancy in PJS should stimulate research into the molecular mechanism and role of STK11 gene mutations in carcinogenesis of sporadic cancer. Of note, STK11 mutations were found in sporadic pancreatic cancers.
      • Su GH
      • Hruban RH
      • Bansal RV
      • Bova GS
      • Tang DJ
      • Shekher MC
      • Westerman AM
      • Entius MM
      • Goggins M
      • Yeo CJ
      • Kern SE
      Germline and somatic mutations of STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers.
      Also, genotype/phenotypic studies are needed to attempt to stratify risk in PJS patients.
      Several investigators have made suggestions for cancer surveillance in patients with PJS.
      • Giardiello FM
      • Welsh SB
      • Offerhaus GJA
      • Booker SV
      • Krush AJ
      • Hamilton SR
      • Yardley JH
      • Luk GD
      Increased risk of cancer in Peutz–Jeghers syndrome.
      • Spigelman AD
      • Murday V
      • Phillips RKS
      Cancer and the Peutz–Jeghers syndrome.
      • Westerman AM
      • Entius MM
      • van Velthuysen MLF
      • Coebergh JWW
      • Lindhout D
      • Offerhaus GJA
      • Wilson JHP
      Cancer risk in Peutz–Jeghers syndrome (abstr).
      • Woolfe B.
      On estimating the relation between blood group and disease.
      However, patient management has been impeded by variability in risk estimates by individual reports. The results of this study place the risk of breast, gynecological, colorectal, stomach, and pancreatic cancer in the range of risk at which surveillance programs have been advocated in other conditions. Recommendations for cancer surveillance in PJS might be modeled after guidelines developed for disorders with similar cancer risks. Future studies based on pooled registry data are needed to confirm the risk estimates cited in the present study. In addition, formal evaluation will be necessary to assess the impact of surveillance regimens on morbidity and mortality in patients with PJS.

      Acknowledgements

      The authors thank Linda Welch for technical support.

      References

        • Peutz JLA
        On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane.
        Ned Tijdschr Geneeskd. 1921; 10: 134-146
        • Jeghers H
        • McKusick VA
        • Katz KH
        Generalized intestinal polyposis and melanin spots of the oral mucosa, lip and digits: a syndrome of diagnostic significance.
        N Engl J Med. 1949; 241: 1031-1036
        • Hemminki A
        • Markie D
        • Tomlinson I
        • Avizienyte D
        • Roth S
        • Loukola A
        • Bignell G
        • Warren W
        • Aminoff M
        • Hoglund P
        • Jarvinen H
        • Kristo P
        • Pelin K
        • Ridanpaa M
        • Salovaara R
        • Toro T
        • Bodmer W
        • Ol-schwang S
        • Olsen AS
        • Stratton MR
        • de la Chapelle A
        • Aaltonen LA
        A serine/threonine kinase gene defect in Peutz–Jeghers syndrome.
        Nature. 1998; 391: 184-187
        • Jenne DE
        • Reimann H
        • Nezu J
        • Friedel W
        • Loff S
        • Jeschke R
        • Muller O
        • Back W
        • Zimmer M.
        Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
        Nat Genet. 1998; 18: 38-43
        • Giardiello FM
        • Welsh SB
        • Offerhaus GJA
        • Booker SV
        • Krush AJ
        • Hamilton SR
        • Yardley JH
        • Luk GD
        Increased risk of cancer in Peutz–Jeghers syndrome.
        N Engl J Med. 1987; 316: 1511-1514
        • Hizawa K
        • Iida M
        • Matsumoto T
        • Kohrogi N
        • Kinoshita H
        • Yao T
        • Fujishima M.
        Cancer in Peutz–Jeghers syndrome.
        Cancer. 1993; 72: 2777-2781
        • Spigelman AD
        • Murday V
        • Phillips RKS
        Cancer and the Peutz–Jeghers syndrome.
        Gut. 1989; 30: 1588-1590
        • Westerman AM
        • Entius MM
        • van Velthuysen MLF
        • Coebergh JWW
        • Lindhout D
        • Offerhaus GJA
        • Wilson JHP
        Cancer risk in Peutz–Jeghers syndrome (abstr).
        Eur J Hepatogastroenterol. 1998; 10: A42
        • Boardman LA
        • Thibodeau SN
        • Schaid DJ
        • Lindor NM
        • McDonnell SK
        • Burgart LJ
        • Ahlquist DA
        • Podratz KC
        • Pittelkow M
        • Hartmann LC
        Increased risk for cancer in patients with the Peutz–Jeghers syndrome.
        Annal Intern Med. 1998; 128: 896-899
        • Foley TR
        • McGarrity TJ
        • Abt AB
        Peutz–Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up.
        Gastroenterology. 1988; 95: 1535-1540
        • Burdick D
        • Prior JT
        Peutz–Jeghers syndrome: a clinicopathologic study of a large family with a 27 year follow-up.
        Cancer. 1982; 50: 2139-2146
        • Utsunomiya J
        • Gocho H
        • Miyanaga T
        • Hamaguchi E
        • Kashimure A
        • Aoki N
        • Komatsu I.
        Peutz–Jeghers syndrome: its natural course and management.
        Johns Hopkins Med J. 1975; 136: 71-82
        • Young RH
        • Welch WR
        • Dickersin GR
        • Scully RE
        Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and 4 with adenoma malignum of the cervix.
        Cancer. 1982; 50: 1384-1402
        • Solh HM
        • Azoury RS
        • Najjar SS
        Peutz–Jeghers syndrome associated with precocious puberty.
        J Pediatr. 1983; 103: 593-595
        • Woolfe B.
        On estimating the relation between blood group and disease.
        Ann Hum Genet. 1955; 10: 251-253
        • Coleman M
        • Doublas A
        • Hermon C
        • Peto L.
        Cohort study analysis with a Fortran computer program.
        Int J Epidemiol. 1986; 15: 698-703
      1. Surveillance, Epidemiology, and End Results (SEER) Program Public Use CD-ROM (1973–94). National Cancer Institute, DCPC, Surveillance Program, Cancer Statistics Branch, released October 1997, based on the August 1996 submission.

        • Breslow NE
        • Day NE
        The analysis of case-control studies.
        Statistical methods in cancer research. Volume I. International Agency for Research on Cancer, Lyon, France1980 (IARC scientific publication no.32)
        • Gruber 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 GJA
        • Giardiello FM
        Pathogenesis of adenocarcinoma in Peutz–Jeghers syndrome.
        Cancer Res. 1998; 58: 5267-5270
        • Su GH
        • Hruban RH
        • Bansal RV
        • Bova GS
        • Tang DJ
        • Shekher MC
        • Westerman AM
        • Entius MM
        • Goggins M
        • Yeo CJ
        • Kern SE
        Germline and somatic mutations of STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers.
        Am J Pathol. 1999; 154: 1835-1840
        • Eng A
        • Armin A
        • Massa M
        • Gradini R.
        Peutz-Jeghers–like melanotic macules associated with esophageal adenocarcinoma.
        Am J Dermatopathol. 1991; 13: 152-157
        • Cochet B
        • Carrel J
        • Desbaillets L
        • Widgren S.
        Peutz–Jeghers syndrome associated with gastro-intestinal carcinoma. Report of two cases in a family.
        Gut. 1979; 20: 169-175
        • Aideyan UO
        • Kao SC
        Gastric adenocarcinoma metastatic to the testes in Peutz–Jeghers syndrome.
        Pediatr Radiol. 1994; 24: 496-497
        • Bujanda L
        • Beguiristain A
        • Villar VM
        • Cosme A
        • Castiella A
        • Arriola JA
        • Arenas JI
        Gastric adenocarcinoma in hamartomatous polyp in Peutz–Jeghers syndrome.
        Gastroenterol Hepatol. 1996; 19: 452-455
        • Achord JL
        • Proctor HD
        Malignant degeneration and metastasis in Peutz–Jeghers syndrome.
        Arch Intern Med. 1963; 111: 498-502
        • Horn Jr, RC
        • Payne WA
        • Fine G.
        The Peutz–Jeghers syndrome (gastrointestinal polyposis with muco-cutaneous pigmentation): report of a case terminating with disseminated gastrointestinal cancer.
        Arch Pathol. 1963; 76: 29-37
        • Kopylow A
        • Bielecki M
        • Dominiczak K.
        The Peutz syndrome.
        Pol Rev Radiol Nucl Med. 1963; 76: 29-37
        • Payson BA
        • Moumgis B.
        Metastasizing carcinoma of the stomach in Peutz–Jeghers syndrome.
        Ann Surg. 1967; 165: 145-151
        • Reid JD
        Intestinal carcinoma in the Peutz–Jeghers syndrome.
        JAMA. 1974; 229: 833-834
        • Matuchansky C
        • Babin P
        • Coutrot S
        • Druart F
        • Barbier J
        • Maire P.
        Peutz–Jeghers syndrome with metastasizing carcinoma arising from a jejunal hamartoma.
        Gastroenterology. 1979; 77: 1311-1315
        • Laughlin EH
        Benign and malignant neoplasms in a family with Peutz–Jeghers syndrome: a study of three generations.
        South Med J. 1991; 84: 1205-1209
        • Pesta J
        • Orlowska J.
        Small intestine carcinoma in Peutz–Jeghers syndrome.
        Mater Med Pol. 1989; 21: 43-47
        • Yoshikawa A
        • Kuramoto S
        • Mimura T
        • Kobayashi K
        • Shimoyama S
        • Yasuda H
        • Kaminishi M
        • Yamakawa M
        • Oohara T
        • Murakami T.
        Peutz–Jeghers syndrome manifesting complete intussusception of the appendix and associated with a focal cancer of the duodenum and a cystadenocarcinoma of the pancreas: report of a case.
        Dis Colon Rectum. 1998; 41: 517-521
        • Ichiyoshi Y
        • Yao T
        • Nagasaki S
        • Sugimachi K.
        Solitary Peutz–Jeghers type polyp of the duodenum containing a focus of adenocarcinoma.
        Ital J Gastroenterol. 1996; 28: 95-97
        • Castro RR
        • Brant CQ
        • Ferreira LE
        • Geocze S
        • Ferrari Junior AP
        • Lanzoni VP
        • Forones NM
        Peutz–Jeghers syndrome and adenocarcinoma. Report of a case.
        Arq Gastroenterol. 1994; 31: 145-148
        • Rodriquez JM
        • Picardo A
        • Torres AJ
        • Garcia Calvo M
        • Ortega L
        • Martinez S
        • Balibrea JL
        Rev Esp Enferm Dig. 1993; 84: 56-59
        • Ried JD
        Duodenal carcinoma in the Peutz–Jeghers syndrome.
        Cancer. 1965; 18: 970-977
        • Freeman JT
        • Ravdin IS
        Polyps and pigment in the Peutz–Jeghers syndrome.
        N Engl J Med. 1955; 253: 958-1861
        • Warren KW
        • Kune GA
        • Poulantzas JK
        Peutz–Jeghers syndrome with carcinoma of the duodenum and jejunum.
        Lahey Clin Found Bull. 1965; 14: 97-102
        • Williams JP
        • Knudsen A.
        Peutz–Jeghers syndrome with metastasizing duodenal carcinoma.
        Gut. 1965; : 179-184
        • Gasser U
        • Arquint A.
        Ein fall von Peutz Jegher syndrom: Mit Maligner Entartung.
        Schweiz Med Wochenschr. 1969; 99: 1894-1895
        • Mackman S
        • Perna G
        • Gossett F.
        Peutz–Jeghers syndrome with metastases to an abdominal incision.
        Arch Surg. 1969; 98: 99-102
        • Moretti G
        • Bozic C
        • Genton N.
        Polypose familiale du type Peutz–Jeghers, avec Degenerescence malingne.
        Arch Chir Infant. 1969; 10: 243-248
        • Tweedie JH
        • McCann BG
        Peutz–Jeghers syndrome and metastasising colonic adenocarcinoma.
        Gut. 1984; 25: 1118-1123
        • Konishi F
        • Wyse NE
        • Muto T
        • Sawada T
        • Moioka Y
        • Sugimura H
        • Yamaguchi K.
        Peutz–Jeghers polyposis associated with carcinoma of the digestive organs: report of three cases and review of literature.
        Dis Colon Rectum. 1987; 30: 790-799
        • Hsu SD
        • Zaharopoulos P
        • May JT
        • Costanzi JJ
        Peutz–Jeghers syndrome with intestinal carcinoma: report of the association in one family.
        Cancer. 1979; 44: 1527-1532
        • Riley E
        • Swift M.
        A family with Peutz–Jeghers syndrome and bilateral breast cancer.
        Cancer. 1980; 46: 815-817
        • Niimi K
        • Tomoda H
        • Furusawa M
        • Hayashi I
        • Okumura Y.
        Peutz–Jeghers syndrome associated with adenocarcinoma of the cecum and focal carcinomas in hamartomatous polyps of the colon: a case report.
        Jpn J Surg. 1991; 21: 220-223
        • Hermann G
        • Saro A.
        Polyposis intestinalis generalisata melanoplakiaval (Peutz–Jeghers syndroma).
        Orv Hetil. 1961; 102: 129-130
        • Konishi F
        • Wyse NE
        • Muto T
        • Sawada T
        • Morioka Y
        • Sugimura H
        • Yamaguchi K.
        Peutz–Jeghers polyposis associated with carcino-mas of the digestive organs. Report of three cases and review of the literature.
        Dis Colon Rectum. 1987; 30: 790-799
        • Altemeier WA
        • Dozois R.
        Is there a predisposition to the development of intestinal malignancy?.
        Arch Surg. 1969; 98: 517
        • Bowlby LS
        Pancreatic adenocarcinoma in an adolescent male with Peutz–Jeghers syndrome.
        Hum Pathol. 1986; 17: 97-99
        • Thatcher BS
        • May ES
        • Taxier MS
        • Bonta JA
        • Murthy L.
        Pancreatic adenocarcinoma in a patient with Peutz–Jeghers syndrome-a case report and literature review.
        Am J Gastroenterol. 1986; 81: 594-597
        • Pauwels M
        • Delcenserie R
        • Yzet T
        • Duchmann JC
        • Capron JP
        Pancreatic cystadenocarcinoma in Peutz–Jeghers syndrome.
        J Clin Gastroenterol. 1997; 25: 485-486
        • Chen KT
        Female genital tract tumors in Peutz–Jeghers syndrome.
        Hum Pathol. 1986; 17: 858-861
        • Martin-Odegard B
        • Svane S.
        Peutz–Jeghers syndrome associated with bilateral synchronous breast carcinoma in a 30-year-old woman.
        Eur J Surg. 1994; 160: 511-512
        • Young RH
        • Welch WR
        • Dickersin GR
        • Scully RE
        Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix.
        Cancer. 1982; 7: 1384-1402
        • Kaku T
        • Hachisuga T
        • Toyoshima S
        • Enjoji M
        • Mori T
        • Nagaoka M.
        Extremely well differentiated adenocarcinoma (“adenoma malignum”) of the cervix in a patient with Peutz–Jeghers syndrome.
        Int J Gynecol Pathol. 1985; 4: 266-273
        • Costa J.
        Peutz–Jeghers syndrome: case presentation.
        Obstet Gynecol. 1977; 50: 15S-17S
        • Posczaski E
        • Kaminski PF
        • Pees RC
        • Singapuri K
        • Sorosky JI
        Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
        Gynecol Oncol. 1991; 42: 74-78
        • Young RH
        • Scully RE
        Mucinous ovarian tumors associated with mucinous adenocarcinomas of the cervix. A clinicopathological analysis of 16 cases.
        Int J Gynecol Pathol. 1988; 7: 99-111
        • Gilks CB
        • Young RH
        • Aguirre P
        • DeLellis RA
        • Scully RE
        Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immuno-histochemical analysis of 26 cases.
        Am J Surg Pathol. 1989; 13: 717-729
        • Choi CG
        • Kim SH
        • Kim JS
        • Chi JG
        • Song ES
        • Han MC
        Adenoma malignum of uterine cervix in Peutz–Jeghers syndrome: CT and US features.
        J Comput Assist Tomogr. 1993; 17: 819-821
        • Fujiwaki R
        • Takahashi K
        • Kitao M.
        Adenoma malignum of the uterine cervix associated with Peutz–Jeghers syndrome.
        Int J Gynaecol Obstet. 1996; 53: 171-172
        • Tsuruchi N
        • Tsukamoto N
        • Kaku T
        • Kamura T
        • Nakano H.
        Adenoma malignum of the uterine cervix detected by imaging methods in a patient with Peutz–Jeghers syndrome.
        Gynecol Oncol. 1994; 54: 232-236
        • Srivatsa PJ
        • Keeney GL
        • Podratz KC
        Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz–Jeghers syndrome.
        Gynecol Oncol. 1994; 53: 256-264
        • Chatti S
        • Bellil K
        • Jerbi G
        • Kchir N
        • Haouet S
        • Kacem M
        • Boubaker S
        • Zouari F
        • Filali A
        • Chelli H
        • Rahal K
        • Zitouna M.
        Minimal deviation adenocarcinoma of the uterine cervix in a woman with Peutz–Jeghers syndrome. Report of a case.
        Ann Pathol. 1997; 17: 193-195
        • Brand E.
        Peutz–Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum.
        Gynecol Oncol. 1992; 45: 334-335
        • Herruzo AJ
        • Redondo E
        • Perez de Avila I
        • Aleman M
        • Menjon S.
        Ovarian sex cord tumor with annular tubules and Peutz–Jeghers syndrome.
        Eur J Gynaecol Oncol. 1990; 11: 141-144
        • Costa J.
        Peutz–Jeghers syndrome: case presentation.
        Obstet Gynecol. 1977; 50: 15S-17S
        • Young RH
        • Dickersin GR
        • Scully RE
        A distinctive ovarian sex cord-stromal tumor causing sexual precocity in the Peutz–Jeghers syndrome.
        Am J Surg Pathol. 1983; 7: 233-243
        • Benagiano G
        • Bigotti G
        • Buzzi M
        • D'Alessandro P
        • Napolitano C.
        Endocrine and morphological study of a case of ovarian sex-cord tumor with annular tubules in a woman with Peutz–Jeghers syndrome.
        Int J Gynaecol Obstet. 1988; 26: 441-452
        • Laughlin EH
        Benign and malignant neoplasms in a family with Peutz–Jeghers syndrome: study of three generations.
        South Med J. 1991; 84: 1205-1209
        • Shintaku M
        • Baba Y
        • Fujiwara T.
        Intra-abdominal desmoplastic small cell tumour in a patient with Peutz–Jeghers syndrome.
        Virchows Arch. 1994; 425: 211-215
        • Ferry JA
        • Young RH
        • Engel G
        • Scully RE
        Oxyphilic Sertoli cell tumor of the ovary: a report of three cases, two in patients with the Peutz–Jeghers syndrome.
        Int J Gynecol Pathol. 1994; 13: 259-266
        • Hales SA
        • Cree IA
        • Pinion S.
        A poorly differentiated Sertoli–Leydig cell tumour associated with a ovarian sex cord tumour with annular tubules in a woman with Peutz–Jeghers syndrome.
        His-topathology. 1994; 25: 391-393
        • Steenstrup EK
        Ovarian tumours and Peutz–Jeghers syndrome. A case of “sex cord tumour with annulartubules” (Scully).
        Acta Obstet Gynecol Scand. 1972; 51: 237-240
        • Lucidarme D
        • Dridba M
        • el Khoury S
        • Vandermolen P
        • Foutrein P
        • Vandevenne P
        • Leduc M
        • Creusy C
        • Filoche B.
        Gastroenterol Clin Biol. 1990; 14: 1015-1018
        • Cantu JM
        • Rivera H
        • Ocampo-Campos R
        • Bedolla N
        • Cortes-Gallegos V
        • Gonzalez-Mendoza A
        • Diaz M
        • Hernandez A.
        Peutz–Jeghers syndrome with feminizing Sertoli cell tumor.
        Cancer. 1980; 46: 223-228
        • Wilson DM
        • Pitts W
        • Hintz RL
        • Rosenfeld RG
        Testicular tumors with Peutz–Jeghers syndrome.
        Cancer. 1986; 57: 2238-2240
        • Buchino JJ
        • Uhlenhuth ER
        Large-cell calcifying Sertoli cell tumor.
        J Urol. 1989; 141: 953-954
        • Sharma S
        • Seam RK
        • Kapoor HL
        Malignant Sertoli cell tumor of the testis in a child.
        J Surg Oncol. 1990; 44: 129-131
        • Dryer L
        • Jack RK
        • du Plessis DJ
        Bilateral large cell calcifying Sertoli cell tumor of the testes with Peutz–Jeghers syndrome: a case report.
        Pediatr Dermatol. 1994; 11: 335-337
        • Niewenhuis JC
        • Wolf MC
        • Kass EJ
        Bilateral asynchronous Sertoli cell tumor in a boy with the Peutz–Jeghers syndrome.
        J Urol. 1994; 152: 1246-1248
        • Young S
        • Gooneratne S
        • Staus II, FH
        • Zeller WP
        • Bulun SE
        • Rosenthal IM
        Feminizing Sertoli cell tumors in boys with Peutz–Jeghers syndrome.
        Am J Surg Pathol. 1995; 19: 50-58