recipients of solid organ transplants have an increased risk of developing certain types of malignancies as compared with that of the general population .
liver transplantation has been increased over the last two decades in korea , and its good outcome with long term survival has prompted an increase of post - transplant complications . among the neoplasms that can develop after liver transplantation , post transplant lymphoproliferative disorder ( ptld ) , lymphoma , malignant melanoma , cutaneous basal - cell and squamous cell carcinoma ( scc ) , and scc in situ of the vulva have been reported . here
we report on the first pediatric korean case of widely spread - vulvar scc in situ that developed 14 years after living - related donor liver transplantation .
the present case is unique in that the vulvar scc in situ was associated with infection by uncommon human papillomavirus ( hpv ) subtypes as well as high risk subtypes .
a 16-year - old girl presented with multiple verruocoid vulvar masses on both the labia majora and minora .
she denied any sexual intercourse history , but her hymen was torn . at the age of 18 months , she underwent living - related donor liver transplantation from her mother due to neonatal hepatitis and subsequent cirrhosis .
after that , she had been taking immunosuppressive agents , mainly tacrolimus ( fk506 , 2 mg daily ) .
two years earlier , a high fasting glucose level ( 160 mg / dl ) was noticed on the routine follow - up .
diabetes mellitus was diagnosed , and novorapid ( aspart , pen , 300 iu/3 ml per day ) therapy was taken .
she had been followed up every two months during the 14 years of the postoperative follow - up period .
the laboratory findings , including the peripheral blood cell counts and except for the hyperglycemia , were within the normal levels .
the excised specimen showed that the largest cauliflower - shaped polypoid lesion measured 3.52.00.3 cm ( fig .
some small uniform basaloid cells showed hyperchromatic and coarse nuclear chromatin , and the warty larger cells showed greater pleomorphism with koilocytotic changes near the surface ( fig .
a cervicovaginal smear showed multiple koilocytotic dysplastic cells , and this was diagnosed as low grade squamous intraepithelial lesion with hpv infection and mild dysplasia .
we also analyzed the hpv by a pcr - based dna microarray system provided by a hpv - dna chip test ( myhpvchip ; biomedlab co. ltd .
the chip contains 32 type - specific probes that consist of 18 high - risk hpv groups ( 16 , 18 , 26 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , 68 , 69 , 70 , 73 ) and 14 low - risk hpv groups ( 6 , 11 , 32 , 34 , 40 , 42 , 43 , 44 , 53 , 54 , 55 , 57 , 61 , 62 ) .
hpv types 69 and 73 and hpv types 66 , 70 , 73 , and 43 were identified in the vulvar mass and the cervicovaginal smear , respectively .
there has been no recurrence during the 3 months of follow up and her blood glucose level is under control .
liver transplantation is the standard of care for children with end - stage , irreversible liver disease . as with adults ,
the early major complications include rejection , opportunistic infection and ptld , and especially in children .
post - transplant diabetes mellitus , as shown in the present patient , is one of the frequent complications after liver transplantation , and it develops in 10% to 30% of all these patients .
the mechanism of pediatric post - transplant diabetes is likely to be a result of both insulin deficiency and the insulin resistance of immunosuppressive agents , including steroids and tacrolimus . after a long follow - up duration
, there is an increased incidence of certain malignancies developing ; the relative risk for malignancies is two to three times higher than that in the general population .
the most common malignancies in pediatric transplant recipients are lymphomas and skin and lip carcinomas , whereas skin and lip carcinomas are the most common in adults .
vulvar scc usually appears in postmenopausal women in the 7th and 8th decades of life . despite the young age , the multicentric squamous intraepithelial lesion ( vulva and uterine cervix )
post - transplant recipients demonstrated a 25- to 40-fold increased risk to develop vulvar carcinomas . about 40% of vulvar sccs
100% of the vulvar lesions in post - transplant recipients were hpv - positive compared to 21 - 57% in immunocompetent individuals .
immunosuppression per se is a known risk factor for hpv oncogenic virus - disease , and immunosuppressive agents and hpv play synergistic roles in carcinogenesis .
hpv is widely accepted as a causative agent of anogenital cancer . to date , more than 118 hpv genotypes have been identified and sequenced , and about 40 can infect the genital tract and 12 are classified as oncogenes . by their oncogenic potential , hpv types were classified as high risk ( 16 , 18 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 68 , 73 , and 82 ) , low risk ( 6 , 11 , 40 , 42 , 43 , 44 , 54 , 61 , 70 , 72 , 81 , and cp6108 ) and probable high risk ( 26 , 53 , and 66 ) .
hpv type 16 has previously shown to be the most common type in all countries including korea
. however , hpv type 69 , which is one of the subtypes detected in our patient 's vulvar carcinoma , is previously unknown in genital scc .
a recent world - wide assessment of hpv genotypes has shown that the previously unknown hpv types , which were identified as type 26 , 30 , 61 , 67 , 69 , 82 , and 91 , comprise 1% of all the studied invasive cervical carcinomas .
the biological behaviors of the rare and uncommon hpv types have only been investigated in a few studies , and mostly included lesions that were cervical intraepithelial neoplasms and a few cases of invasive cervical cancer .
little is known about the exact mechanism of hpv - associated vulvar carcinogenesis of these rare hpv types because of the insufficient epidemiological evidence .
hpv vaccination is prophylactic , and it is assumed that maximum effectiveness will be achieved by administration before exposure to hpv or viral reactivation because hpv vaccination may offer a boosting effect of previously acquired natural immunity . two recent vaccines , the recombinant quadrivalent hpv vaccine ( merck , gardasil ) and the bivalent hpv recombinant vaccine ( galxosmithkline , cervarix ) , can mainly prevent the hpv targeting types 16 , 18 , 6 , 11 , 31 , and 9 for gardasil and types 16 , 18 , 45 , and 31 for cervarix .
however , these vaccines are not effective in protecting against other high - risk hpv types , including the above mentioned uncommon types , which were also found in the present case . in conclusion ,
the present case is the first reported korean case of vulvar scc that developed in an adolescent who was taking immunosuppressive drugs after liver transplantation .
specialized vaccination programs may be required in post - transplant recipients because uncommonly found hpv subtypes may be ascribed to the carcinogenesis of vulvar scc , especially in immunocompromised patients . this case is the first to show that uncommon hpv subtypes are related to pediatric post - transplant vulvar scc . albeit the incidence of pediatric vulvar scc is rare , physicians should carefully perform more regular periodic genital examinations in children and adolescent transplant recipients because of their long - term follow - up and improved survival .
 here we report the first korean case of a girl who developed noninvasive squamous cell carcinoma of the vulva at the age of 16 years . 
 she was taking tacrolimus , an immunosuppressive agent , after living - related liver transplantation . 
 the vulvar masses were microscopically proved as vulvar intraepithelial neoplasm ii and iii , even squamous cell carcinoma in situ . 
 human papillomavirus subtypes ( 69 and 73 ) and human papillomavirus types ( 66 , 70 , 73 , and 43 ) were detected in the vulvar mass and the cervicovaginal smear , respectively . 
 the outcome of liver transplantation for children has been markedly improved during the last several decades . 
 however , the present case highlights the need to perform periodic genital examinations for the adolescents after liver transplantation . 
 in addition to the high risk and probable high subtypes , uncommonly found human papillomavirus subtypes were extracted from her vulvar cancer . 
 the present case is the first to show the possible relationship between previously unknown and uncommon human papillomavirus subtypes and pediatric post - transplant vulvar squamous cell carcinoma . 
 more attention should be paid to the vulvar and cervical surveillance of pediatric transplant recipients by both medical specialists and general physicians . 
INTRODUCTION
CASE REPORT
DISCUSSION