a 61-year - old woman visited our hospital for alleged colon polyps found during a colonoscopy examination as part of a routine health examination .
abdominopelvic computed tomography ( ct ) showed an approximately 4-cm - sized , well - enhancing soft tissue lesion in the right perianal area ( fig . 1a ) and a well - enhancing enlarged lymph node in both inguinal areas , suggesting hypervascular tumor metastasis such as melanoma in those lymph nodes ( fig .
, however , a widespread erythematous lichenified skin lesion , measuring 129.7 cm , was noted in the perianal and vulvar area ( fig .
2a ) , which had developed over the previous 3 years according to the patient .
she had no history of anal fissure , fistula , or change in bowel habit .
skin biopsy was taken from the perianal and vulvar area , which showed infiltrating pagetoid cells and srcc cells .
the preoperative carcinoembryonic antigen ( cea ) level was elevated to 39.75 ng / ml ( reference , 0 to 5 ng / ml ) .
inguinal lymph node dissection with an extended miles operation was performed ; traditional miles operation with extended resection around bilateral labium majora , followed by skin reconstruction with gluteal flap , was performed .
the resected specimen was composed of the anal canal and rectum with skin and soft tissue of the perianal region and vulva ( fig .
upon sectioning , the anal canal showed an ulcerative firm mass measuring 4.03.02.7 cm , which invaded the perianal sphincter muscle and subcutaneous fat of the anal skin ( fig . 2c ) .
light microscopy showed that the anal canal was totally replaced by singly scattered intracytoplasmic mucin - containing signet ring cells and some extracellular mucin ( fig .
focally , well - formed glands were also found in less than 5% of the tumor .
the erythematous skin around the anus and labium majora showed linear infiltration of pagetoid cells as well as infiltration of signet ring cells in the dermis and subcutis ( fig .
immunohistochemically , both signet ring cells and pagetoid cells were positive for cytokeratin ( ck ) 20 , cea , moc-31 , and ck19 .
paget s cells were positive for epidermal growth factor receptor and weakly positive for ck5/6 .
they were negative for ck7 , human melanoma black 45 , s-100 protein , caudal - related homeobox gene nuclear transcription factor ( cdx2 ) , p53 , synaptophysin , chromogranin , and cd56 .
these results are shown in table 1 . a mutation study of the kras gene ( codon 12 and codon 13 ) was performed by means of the peptide nucleic acid - mediated real - time polymerase chain reaction clamping method using genomic dna isolated from formalin fixed paraffin - embedded tissue .
microsatellite instability ( msi ) was tested using five bethesda markers ( d2s123 , d5s346 , d17s250 , bat25 , and bat26 ) .
msi - high ( msi - h ) was defined if they differed in at least two of the five markers and msi - low was defined if they differed in only one of the five markers .
the case was diagnosed as anal canal srcc with pagetoid spread in perianal and vulva skin , stage iiib according to the tnm staging system of the american joint committee on cancer .
the patient was scheduled to undergo chemotherapy with mitomycin - c and 5-fluorouracil ( 5-fu ) and subsequent radiotherapy .
colorectal srcc is a rare histologic subtype of adenocarcinoma , accounting for 0.1% to 2.4% of all colorectal malignancies .
anal canal srcc is even rarer ; only two cases of anal canal srccs have been reported in the english literature .
seven additional cases have been retrieved from the japanese literature [ 3,7 - 12 ] .
anal canal carcinoma is histologically and pathogenetically divided into squamous cell carcinoma , cloacogenic ( basaloid or transitional cell ) carcinoma and adenocarcinoma .
anal canal squamous cell carcinoma originates from the non - keratinizing squamous epithelium below the dentate line of the anal canal , while anal canal adenocarcinoma is regarded as arising from the upper part lined by the columnar epithelium .
, anal canal adenocarcinomas are subclassified according to adenocarcinoma arising from anal mucosa and extramucosa , and adenocarcinoma arising from anorectal fistula or adenocarcinoma of anal glands .
no description of in situ lesion was found in the previously reported cases of anal canal srccs .
based on the findings of the overlying ulcerated anal surface mucosa , remnants of anal gland adenocarcinoma in situ without continuity to srcc portion , the present anal canal srcc belongs to extramucosal perianal adenocarcinoma with wide pagetoid spread along the perianal soft tissues and skin .
similar to the current case , eight out of 10 anal canal srccs ( 80% ) were accompanied by perianal or vulvar pagetoid spread [ 3 - 5,7 - 12 ] .
extramammary perianal paget s disease is a rare and heterogeneous neoplasm , which is frequently combined with underlying hidden adenocarcinoma .
immunohistochemical panels such as ck7 , ck20 , cea , gross cystic disease fluid protein-15 ( gcdfp-15 ) , muc1 , muc2 , muc5ac , and cdx2 have been used to distinguish primary from secondary paget s disease . in anal srccs with pagetoid spread , i.e. , not primary extramammary paget s disease ,
the tumor cells were positive for ck20 , muc1 , or moc-31 , while they were negative for gcdfp-15 , and negative for ck7 , whereas primary paget s disease is commonly positive for ck7 .
however , none of these were a specific and confirmative diagnostic clue ; further accumulative data may be needed .
srcc is most commonly encountered in the stomach , but it can also arise in various organs , such as breast , urinary bladder , or colon .
immunohistochemical profiles for ck7 and ck20 have also been used to differentiate the sites of origin for srccs ; ck20 is normally expressed in the gastrointestinal epithelium , urothelium , and in merkel s cells .
while ck7 is uncommonly expressed in the lower gastrointestinal tract , it is commonly expressed in lung , ovary , endometrium , and breast . as the term  signetring cells 
implies , the tumor cells have intracellular mucin vacuoles displacing the nucleus to one side of the cells scattered as single cells or in loose clusters .
this is caused by disrupted cell - to - cell adhesion and diffuse spreading , and results in more frequent lymphovascular invasion and node metastasis of srcc as compared with other mucinous adenocarcinoma . in view of the clinical aspects ,
colorectal srcc has a very high mortality rate compared to mucinous carcinoma and nonmucinous colorectal adenocarcinomas .
even a minor signet - ring cell component , i.e. , 50% or less , in colorectal carcinomas was independently associated with a high mortality rate , regardless of molecular or other clinicopathological factors .
anal canal srcc grows insidiously underneath the mucosa , and thus it may not be found before the late advanced stage .
it is uncertain whether anal srccs have an adverse prognosis like that of colorectal srcc .
inguinal nodes should be examined for anal cancer staging . in a review of 10 cases of anal canal srccs , the ages ranged from 46 to 87 years ( mean , 63.4 years ) [ 3 - 5,7 - 12 ] .
srcc has a shorter patient survival . during the follow - up period , ranging from 4 to 25 months , death caused by lymphatic or peritoneal carcinomatosis or distant metastases occurred in 50% of cases ( 5/10 ) .
the five remaining cases were alive with a follow - up period ranging from 2 months to 6 years .
for the past decade , molecular prognostic markers in colorectal carcinoma have been studied ; msi - h is a well - established reliable predictive marker for chemotherapeutic efficacy in colorectal carcinoma .
however , contrary to colorectal srccs that take an aggressive course , colorectal mucinous carcinoma takes a favorable course , although both are associated with msi - h .
data on anal canal srcc concerning msi - h as a predictive factor is lacking .
due to the rarity of anal canal srccs , the msi status of anal canal srcc relating to prognosis has not been determined .
traditional treatment of anal canal carcinoma is surgery including abdominopelvic resection with or without chemoradiotherapy .
radiation therapy for anal canal carcinoma reaches a cure rate of up to 70% in selected low - stage patients .
however , there is no general agreement regarding the treatment of anal canal srcc due to the extremely rare incidence and limited data on cancer treatment , as shown in table 2 . in a case reported by yoshitani et al .
, a patient with distant metastatic foci achieved complete remission after chemotherapy using bevacizumab / mfolfox6 , folfiri .
.   reported on a long - survived stage ii patient with no recurrent tumor who underwent chemoradiotherapy using 5-fu for a 6-year follow - up period . in summary ,
if there is perianal paget s disease raising the possibility of underlying hidden adenocarcinoma , careful evaluation is necessary for early diagnosis of anal canal srcc .
 a 61-year - old woman was referred to surgery for incidentally found colonic polyps during a health examination . 
 physical examination revealed widespread eczematous skin lesion without pruritus in the perianal and vulvar area . 
 abdominopelvic computed tomography showed an approximately 4-cm - sized , soft tissue lesion in the right perianal area . 
 inguinal lymph node dissection and mils operation extended to perianal and perivulvar skin was performed . 
 histologically , the anal canal lesion was composed of mucin - containing signet ring cells , which were similar to those found in pagetoid skin lesions . 
 it was diagnosed as an anal canal signet ring cell carcinoma ( srcc ) with perianal and vulvar pagetoid spread and bilateral inguinal lymph node metastasis . 
 anal canal srcc is rare , and the current case is the third reported case in the english literature . 
 seven additional cases were retrieved from the world literature . here , we describe this rare case of anal canal srcc with perianal pagetoid spread and provide a literature review . 
CASE REPORT
DISCUSSION