Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz–Jeghers syndrome due to a germline mutation of STK11

Abstract

Lobular endocervical glandular hyperplasia (LEGH) is a recently recognized disease concept proposed by Nucci et al. in 1999 [1.Nucci M.R. Clement P.B. Young R.H. Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum.Am J Surg Pathol. 1999; 23: 886-891doi:10.1097/00000478-199908000-00005Crossref PubMed Scopus (151) Google Scholar]. LEGH is a benign pseudoneoplastic glandular lesion, and mimics minimal deviation adenocarcinoma (MDA or adenoma malignum), which is a subtype of cervical adenocarcinoma and is frequently associated with Peutz–Jeghers syndrome (PJS). The relationship between PJS and LEGH is, however, uncertain. Only a few reports have focused on a possible link between LEGH and PJS without gene testing [2.Hahn H.S. Maeng L.S. Ro D.Y. et al.Lobular endocervical glandular hyperplasia in a woman with Peutz–Jeghers syndrome: a case report.Eur J Obstet Gynecol Reprod Biol. 2012; 160: 117-118doi:10.1016/j.ejogrb.2011.09.043Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar].A 42-year-old woman consulted our genetic clinic with her son. She had been diagnosed with PJS during childhood. She noticed that her 7-year-old son had pigmentation of the lips, oral cavity, and fingers similar to hers, raising concern that the son might also have PJS. The pedigree is shown in Figure 1 (panel A). She and her child met the diagnostic criteria for PJS (supplementary material S1, available at Annals of Oncology online). She had undergone a total of six laparotomies for repeated intussusception due to small-intestinal polyps since childhood, but had never sought detailed genetic counseling or undergone genetic examination. To date, only mutations in STK11, serine/threonine kinase, have been identified as a cause of PJS [3.Jenne D.E. Reimann H. Nezu J. et al.Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Nat Genet. 1998; 18: 38-43doi:10.1038/ng0198-38Crossref PubMed Scopus (972) Google Scholar]. After obtaining informed consent, mutation analysis of the STK11 gene was carried out only for mother. A four-base deletion of codon263 (exon 6) of the gene was identified employing exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR)-direct sequencing (Supplement Table S2, Supplement Table S3) . Genotype–phenotype correlations related to STK11 mutations are not yet established, and this mutation site was not previously reported. Mehenni et al. indicated that mutations in exon 6 associate with increased risk of cancer [4.Mehenni H. Resta N. Guanti G. et al.Molecular and clinical characteristics in 46 families affected with Peutz–Jeghers syndrome.Dig Dis Sci. 2007; 52: 1924-1933doi:10.1007/s10620-006-9435-3Crossref PubMed Scopus (62) Google Scholar].She had already been kept under strict surveillance for breast, colon, and intestine, but she had not done cervical screening for 6 years. We, therefore, explained at genetic counseling that the mother should be screened for uterine cervix as well as gastrointestinal cancers because PJS is frequently associated with cervical neoplastic lesion. Gynecological physical examination revealed excessive watery vaginal discharge and a polycystic mass of the uterine cervix was also detected. Magnetic resonance imaging revealed a multi-lobular cystic mass on the uterine cervix (Figure 1, panel B). Pap smear was negative and serum CA-125, CEA, and CA19-9 levels were within the normal ranges. The patient underwent a punch biopsy and diagnostic laser conization of the cervix, and LEGH was pathologically diagnosed.The patient underwent modified radical hysterectomy and bilateral salpingo-oophorectomy. A pathological examination of the cervical specimen revealed LEGH (Figure 1, panels C and D).In operation, peritoneal melanosis the color of Indian ink was also observed on the peritoneal surface (Figure 1, panel E). This pigmentation appeared to be melanin (Figure 1, panel F), and was thought to related to PJS. Benign peritoneal melanosis is very rare, with only 12 cases having been reported to date [5.Kim S.S. Nam J.H. Kim S.M. et al.Peritoneal melanosis associated with mucinous cystadenoma of the ovary and adenocarcinoma of the colon.Int J Gynecol Pathol. 2010; 29: 113-116doi:10.1097/PGP.0b013e3181bb4182Crossref PubMed Scopus (10) Google Scholar]. They have never been reported in association with PJS or STK11 mutations.PJS is characterized by pigmentation and the development of gastrointestinal hamartomas, and an elevated cancer risk with cancers in particular affecting the GI tract in addition to gynecological tumors and breast cancer. This case highlights the importance of not only periodic intensive observation of the intestinal tract but also surveillance of the uterine cervix in women with PJS, keeping in mind the possibility of cervical LEGH or MDA. Screening and assessing these lesions are often very difficult.This is the first report of PJS patient who also had LEGH and peritoneal melanosis and was found to be positive for STK11 mutation.fundingThis work was supported in part by Foundation for Promotion of Cancer Research in Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan, a Grant-in-Aid for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare, Japan, and by the National Cancer Center Research and Development Fund ( 21bunshi-9- ② and 23-A-2 ).disclosureThe authors have declared no conflicts of interest. Lobular endocervical glandular hyperplasia (LEGH) is a recently recognized disease concept proposed by Nucci et al. in 1999 [1.Nucci M.R. Clement P.B. Young R.H. Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum.Am J Surg Pathol. 1999; 23: 886-891doi:10.1097/00000478-199908000-00005Crossref PubMed Scopus (151) Google Scholar]. LEGH is a benign pseudoneoplastic glandular lesion, and mimics minimal deviation adenocarcinoma (MDA or adenoma malignum), which is a subtype of cervical adenocarcinoma and is frequently associated with Peutz–Jeghers syndrome (PJS). The relationship between PJS and LEGH is, however, uncertain. Only a few reports have focused on a possible link between LEGH and PJS without gene testing [2.Hahn H.S. Maeng L.S. Ro D.Y. et al.Lobular endocervical glandular hyperplasia in a woman with Peutz–Jeghers syndrome: a case report.Eur J Obstet Gynecol Reprod Biol. 2012; 160: 117-118doi:10.1016/j.ejogrb.2011.09.043Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. A 42-year-old woman consulted our genetic clinic with her son. She had been diagnosed with PJS during childhood. She noticed that her 7-year-old son had pigmentation of the lips, oral cavity, and fingers similar to hers, raising concern that the son might also have PJS. The pedigree is shown in Figure 1 (panel A). She and her child met the diagnostic criteria for PJS (supplementary material S1, available at Annals of Oncology online). She had undergone a total of six laparotomies for repeated intussusception due to small-intestinal polyps since childhood, but had never sought detailed genetic counseling or undergone genetic examination. To date, only mutations in STK11, serine/threonine kinase, have been identified as a cause of PJS [3.Jenne D.E. Reimann H. Nezu J. et al.Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Nat Genet. 1998; 18: 38-43doi:10.1038/ng0198-38Crossref PubMed Scopus (972) Google Scholar]. After obtaining informed consent, mutation analysis of the STK11 gene was carried out only for mother. A four-base deletion of codon263 (exon 6) of the gene was identified employing exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR)-direct sequencing (Supplement Table S2, Supplement Table S3) . Genotype–phenotype correlations related to STK11 mutations are not yet established, and this mutation site was not previously reported. Mehenni et al. indicated that mutations in exon 6 associate with increased risk of cancer [4.Mehenni H. Resta N. Guanti G. et al.Molecular and clinical characteristics in 46 families affected with Peutz–Jeghers syndrome.Dig Dis Sci. 2007; 52: 1924-1933doi:10.1007/s10620-006-9435-3Crossref PubMed Scopus (62) Google Scholar]. She had already been kept under strict surveillance for breast, colon, and intestine, but she had not done cervical screening for 6 years. We, therefore, explained at genetic counseling that the mother should be screened for uterine cervix as well as gastrointestinal cancers because PJS is frequently associated with cervical neoplastic lesion. Gynecological physical examination revealed excessive watery vaginal discharge and a polycystic mass of the uterine cervix was also detected. Magnetic resonance imaging revealed a multi-lobular cystic mass on the uterine cervix (Figure 1, panel B). Pap smear was negative and serum CA-125, CEA, and CA19-9 levels were within the normal ranges. The patient underwent a punch biopsy and diagnostic laser conization of the cervix, and LEGH was pathologically diagnosed. The patient underwent modified radical hysterectomy and bilateral salpingo-oophorectomy. A pathological examination of the cervical specimen revealed LEGH (Figure 1, panels C and D). In operation, peritoneal melanosis the color of Indian ink was also observed on the peritoneal surface (Figure 1, panel E). This pigmentation appeared to be melanin (Figure 1, panel F), and was thought to related to PJS. Benign peritoneal melanosis is very rare, with only 12 cases having been reported to date [5.Kim S.S. Nam J.H. Kim S.M. et al.Peritoneal melanosis associated with mucinous cystadenoma of the ovary and adenocarcinoma of the colon.Int J Gynecol Pathol. 2010; 29: 113-116doi:10.1097/PGP.0b013e3181bb4182Crossref PubMed Scopus (10) Google Scholar]. They have never been reported in association with PJS or STK11 mutations. PJS is characterized by pigmentation and the development of gastrointestinal hamartomas, and an elevated cancer risk with cancers in particular affecting the GI tract in addition to gynecological tumors and breast cancer. This case highlights the importance of not only periodic intensive observation of the intestinal tract but also surveillance of the uterine cervix in women with PJS, keeping in mind the possibility of cervical LEGH or MDA. Screening and assessing these lesions are often very difficult. This is the first report of PJS patient who also had LEGH and peritoneal melanosis and was found to be positive for STK11 mutation. fundingThis work was supported in part by Foundation for Promotion of Cancer Research in Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan, a Grant-in-Aid for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare, Japan, and by the National Cancer Center Research and Development Fund ( 21bunshi-9- ② and 23-A-2 ).