lynch syndrome ( ls ) , also known as hereditary non - polyposis colorectal cancer ( hnpcc ) , is an uncommon , but not rare , autosomal dominant familial cancer syndrome ( barrow et al . , 2013 ) .
this condition predisposes individuals to colorectal carcinoma ( crc ) as well as various extra - colonic tumours including cancer of the endometrium , ovaries , small bowel , stomach and urothelium ( barrow et al . , 2013 ) .
tumours arise as a result of inactivating mutations in genes encoding essential proteins in the dna mismatch repair ( mmr ) pathway ( barrow et al . , 2013 ,
this pathway is principally involved in the repair of replication errors , such as base mismatches and small insertions or deletions , in highly repetitive base sequences known as microsatellites ( masuda et al . ,
accumulation of these mutations , in genes involved in carcinogenesis , predisposes cellular malignant transformation ; hence individuals with ls have an increased incidence of specific tumours ( barrow et al . , 2013 , masuda et al . , 2011 )
. four human mmr genes have been implicated in this condition ; mlh1 , msh2 , msh6 and psm2 ( masuda et al . ,
mutations icbun mlh1 and msh2 account for approximately 90% of all ls cases ( barrow et al . , 2013 ) .
in women with ls there is an increased risk of developing both endometrial carcinoma and ovarian carcinoma ; indeed , endometrial carcinoma is seen as commonly as crc in these individuals and is often the sentinel malignancy .
in contrast , predisposition to cervical cancer is not a feature of ls ( barrow et al . , 2013 ) .
there have been only occasional cases of cervical cancer reported in the literature in patients with ls ; one patient with a germline - mutation in msh2 , in which the tumour was immunohistochemically deficient for msh2 and msh6 with high levels of msi ( mongiat - artus et al . , 2006 ) and the other with the muir 
torre variant of ls , where individuals have defects in either msh2 or mlh1 ( mongiat - artus et al .
, there was no mention of the tumour morphology ( mongiat - artus et al . , 2006 ) while in the second the neoplasm was described as an adenocarcinoma with focal serous papillary features ( nair et al . , 2012 ) .
in the second case , there was no mention of testing the tumour for msi or undertaking immunohistochemistry for mismatch repair proteins . in this case report , we describe a case of gastric - type cervical adenocarcinoma in a patient with ls secondary to an msh6 mutation .
we discuss the possibility that ls may be associated with rare non - hpv related cervical adenocarcinomas .
a 50  year - old female underwent a supracervical abdominal hysterectomy and bilateral salpingo - oophorectomy as a prophylactic procedure for previously diagnosed ls .
eight years previously , a family history of early onset colonic cancer led to genetic testing , which subsequently revealed a germline mutation in the msh6 gene on chromosome 2 , consistent with the diagnosis of ls .
the patient had no history of malignancy , with the last colonoscopy for colonic cancer surveillance undertaken 2  years ago and reported as normal .
cervical smears were up - to - date and normal with no evidence of a squamous or glandular abnormality .
gross pathological examination revealed no abnormality in the uterus , cervix , ovaries or fallopian tubes .
the cervix was incompletely excised without representation of the ectocervix or the transformation zone . within the endocervix ,
these measured 8  mm and 3  mm in their maximum horizontal dimension and both had a depth of invasion of 1.5  mm . both areas comprised moderately differentiated adenocarcinomas composed of tumour cells with atypical nuclei , clear cytoplasm and prominent cell membranes .
there was an associated brisk inflammatory infiltrate , mainly consisting of lymphocytes ( fig .  1 ) .
immunohistochemically , both foci were largely negative for p16 and were negative for oestrogen receptor ( er ) , progesterone receptor ( pr ) and carcinoembryonic antigen ( cea ) .
linear array hpv genotyping ( roche molecular diagnostics , pleasanton , california , usa ) was performed on paraffin blocks of the areas containing the abnormal cervical glandular proliferation .
linear array hpv genotyping involves pcr amplification of target dna followed by hybridization for the detection of 37 hpv types ; 18 high risk types ( 16 , 18 , 26 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 53 , 56 , 58 , 59 , 66 , 68 , 73 , 82 ) and 19 low risk types ( 6 , 11 , 40 , 42 , 54,55 , 61 , 62 , 64 , 67 , 69 , 70 , 71 , 72 , 81 , 83 , 84 , is39 , cp108 ) .
hpv testing was negative . given the morphology , immunohistochemistry and the absence of hpv , a diagnosis of primary cervical gastric - type adenocarcinoma was made .
immunohistochemistry for mismatch repair proteins was performed and this demonstrated normal nuclear staining with mlh1 , pms2 and msh2 .
msh6 was difficult to interpret due to cytoplasmic immunoreactivity but there was loss of nuclear staining with a positive internal control in the form of nuclear staining of some lymphoid and stromal cells .
the ovaries and fallopian tubes showed no histological abnormality . following the histological results , the residual cervix was assessed by examination under anaesthesia ( eua ) , cystoscopy and pelvic mri scan .
no cervical abnormality was detected on mri and the 3  cm cervical stump was mobile on eua , with no evidence of parametrial , bladder or rectal involvement .
the tumour was provisionally staged as figo 1b1 ( based on the histological measurements ) .
both surgery , in the form of a radical hysterectomy with lymphadenectomy , and chemoradiation were considered as equally effective treatment options ( landoni et al . , 1997 ) .
after discussion with the patient , laparotomy with excision of the cervical stump and vaginal cuff with bilateral pelvic node dissection was undertaken along with omentectomy , given the high rate of intraabdominal dissemination described with cervical gastric - type adenocarcinoma ( to be discussed later ) ( kojima et al .
, 2007 ) . there was no evidence of macroscopic disease at laparotomy and histological assessment of all resected specimens , including the cervical stump , parametria , vaginal cuff , omentum , infundibular pelvic ligaments , pelvic nodes and common iliac nodes , was unremarkable with no evidence of residual or metastatic adenocarcinoma .
no adjuvant therapy was recommended and routine follow was arranged with the surgical gynaecological team .
she has now been in follow up for 18  months with no evidence of disease .
a 50  year - old female underwent a supracervical abdominal hysterectomy and bilateral salpingo - oophorectomy as a prophylactic procedure for previously diagnosed ls .
eight years previously , a family history of early onset colonic cancer led to genetic testing , which subsequently revealed a germline mutation in the msh6 gene on chromosome 2 , consistent with the diagnosis of ls .
the patient had no history of malignancy , with the last colonoscopy for colonic cancer surveillance undertaken 2  years ago and reported as normal .
cervical smears were up - to - date and normal with no evidence of a squamous or glandular abnormality .
gross pathological examination revealed no abnormality in the uterus , cervix , ovaries or fallopian tubes .
the cervix was incompletely excised without representation of the ectocervix or the transformation zone . within the endocervix ,
these measured 8  mm and 3  mm in their maximum horizontal dimension and both had a depth of invasion of 1.5  mm . both areas comprised moderately differentiated adenocarcinomas composed of tumour cells with atypical nuclei , clear cytoplasm and prominent cell membranes .
there was an associated brisk inflammatory infiltrate , mainly consisting of lymphocytes ( fig .  1 ) .
immunohistochemically , both foci were largely negative for p16 and were negative for oestrogen receptor ( er ) , progesterone receptor ( pr ) and carcinoembryonic antigen ( cea ) .
linear array hpv genotyping ( roche molecular diagnostics , pleasanton , california , usa ) was performed on paraffin blocks of the areas containing the abnormal cervical glandular proliferation .
linear array hpv genotyping involves pcr amplification of target dna followed by hybridization for the detection of 37 hpv types ; 18 high risk types ( 16 , 18 , 26 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 53 , 56 , 58 , 59 , 66 , 68 , 73 , 82 ) and 19 low risk types ( 6 , 11 , 40 , 42 , 54,55 , 61 , 62 , 64 , 67 , 69 , 70 , 71 , 72 , 81 , 83 , 84 , is39 , cp108 ) .
hpv testing was negative . given the morphology , immunohistochemistry and the absence of hpv , a diagnosis of primary cervical gastric - type adenocarcinoma was made .
immunohistochemistry for mismatch repair proteins was performed and this demonstrated normal nuclear staining with mlh1 , pms2 and msh2 .
msh6 was difficult to interpret due to cytoplasmic immunoreactivity but there was loss of nuclear staining with a positive internal control in the form of nuclear staining of some lymphoid and stromal cells .
following the histological results , the residual cervix was assessed by examination under anaesthesia ( eua ) , cystoscopy and pelvic mri scan .
no cervical abnormality was detected on mri and the 3  cm cervical stump was mobile on eua , with no evidence of parametrial , bladder or rectal involvement .
the tumour was provisionally staged as figo 1b1 ( based on the histological measurements ) .
both surgery , in the form of a radical hysterectomy with lymphadenectomy , and chemoradiation were considered as equally effective treatment options ( landoni et al . , 1997 ) .
after discussion with the patient , laparotomy with excision of the cervical stump and vaginal cuff with bilateral pelvic node dissection was undertaken along with omentectomy , given the high rate of intraabdominal dissemination described with cervical gastric - type adenocarcinoma ( to be discussed later ) ( kojima et al .
, 2007 ) . there was no evidence of macroscopic disease at laparotomy and histological assessment of all resected specimens , including the cervical stump , parametria , vaginal cuff , omentum , infundibular pelvic ligaments , pelvic nodes and common iliac nodes , was unremarkable with no evidence of residual or metastatic adenocarcinoma .
no adjuvant therapy was recommended and routine follow was arranged with the surgical gynaecological team .
she has now been in follow up for 18  months with no evidence of disease .
we report a rare case of gastric - type adenocarcinoma of the cervix in a patient with ls secondary to a germline mutation in the msh6 mmr gene . as this patient had coexisting endometrial atypical hyperplasia , initially it was considered whether the cervical glandular proliferation could have represented spread from the endometrium .
however , a thorough histological examination of the entire endometrium was performed and no evidence of invasive endometrial carcinoma was identified . moreover ,
the morphology and immunophenotype ( hormone receptor negative ) were not that of an endometrioid adenocarcinoma of the endometrium .
this subtype is an uncommon variant of primary cervical adenocarcinoma which exhibits gastric differentiation ( on the basis of mucin histochemistry and immunohistochemistry ) and , in contrast to the majority of cervical cancers , is not associated with hpv infection .
histologically , gastric type adenocarcinoma is characterised by tumour cells with atypical nuclei and abundant clear or eosinophilic cytoplasm , typically with distinct cell borders .
there is sometimes a marked associated inflammatory infiltrate , including lymphocytes , neutrophils and eosinophils .
p16 is usually negative or only focally positive , in contrast to hpv associated adenocarcinomas where diffuse positive staining is seen .
although the clinical features have not been extensively studied , it is thought that cervical gastric type adenocarcinoma is associated with aggressive behaviour and a poor prognosis , including a possible propensity for peritoneal , omental and adnexal dissemination ( kojima et al . , 2007 ) .
kojima et al . found that gastric type adenocarcinomas had a 5  year disease free survival of 30% compared to 74% for usual endocervical - type adenocarcinomas ( kojima et al . , 2007 ) .
in this case , the tumour exhibited loss of nuclear expression of msh6 thus supporting the association of this adenocarcinoma to the patient 's known msh6 germline mutation , rather than representing a sporadic tumour . this is somewhat unusual as cervical adenocarcinoma is not one of the tumours typically considered to be associated with ls .
indeed , a recent study undertaken by mills et al . demonstrated intact mmr protein in 60 cervical adenocarcinomas ( mills et al . , 2012 ) .
the mutations in the mmr genes vary between ls patients and are often family - specific .
it is plausible that certain mutations confer a susceptibility to the development of unusual tumours .
indeed , this theory has been suggested in a separate case report describing an unusual spectrum of tumours in a family of patients with ls ( yu et al . , 2009 ) .
another recent study described the occurrence of four unusual tumours in patients with ls , suggesting that the spectrum of tumours associated with this syndrome may be wider than is currently appreciated ( karamurzin et al . , 2012 ) .
germane to the current case , it is interesting that ls associated endometrial carcinomas have been reported to more frequently having a lower uterine segment ( lus ) location ( westin , 2008 ) . given that non - hpv related cervical adenocarcinomas , including gastric - type , may arise proximal to the transformation zone and extend to involve the lus , it is possible that some of the lus carcinomas reported in patients with ls represent non - hpv related cervical adenocarcinomas .
our usual practice would be to always carry out a total hysterectomy for patients with ls but this patient was initially treated at a referring hospital by a non gynaecological oncology surgeon and thus underwent a supracervical hysterectomy .
this case highlights the fact that unusual tumour types may occur in patients with ls .
mmr immunohistochemistry is a useful screening tool in unusual tumours when ls is suspected and loss of immunoreactivity with 1 or more of the mmr proteins may direct further investigations to confirm or exclude ls .
mmr immunohistochemistry also has the advantage of suggesting which mmr gene is likely to be mutated and thus focusing further molecular tests .
. further study of unusual non - hpv related variants of cervical adenocarcinoma are warranted to ascertain if there is an association with ls .
 highlightslynch syndrome ( ls ) is an uncommon , genetic disorder which predisposes affected individuals to colorectal , endometrial and ovarian malignancies.we report a case of cervical gastric - type adenocarcinoma in a patient with ls.immunohistochemistry for mismatch repair proteins is a useful screening tool in tumours suspected to be associated with ls . 
Introduction
Case report
Discussion
Conclusion
Conflict of interest statement