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Pubblicazioni Dr Mario Preti

  1. Minerva Ginecol. 2016 Oct;68(5):620-1.

Nonavalent HPV vaccine (HPV-9): analysis of pre-registration data.

Mariani L , Cristoforoni P, Perino A, Stigliano CM, Preti M.


  1. J Low Genit Tract Dis. 2016 Apr;20(2):180-3. doi: 10.1097/LGT.0000000000000186.

Vulvar Lichen Sclerosus and Neoplastic Transformation: A Retrospective Study of

976 Cases.

Micheletti L , Preti M, Radici G, Boveri S, Di Pumpo O, Privitera SS,

Ghiringhello B, Benedetto C.

OBJECTIVE: The aim of the study was to estimate the neoplastic potential of

vulvar lichen sclerosus (VLS).

MATERIALS AND METHODS: This was a retrospective study of 976 women with VLS. We

recorded age at diagnosis of VLS, length of follow-up, and type of neoplasia,

categorized as the following: vulvar intraepithelial neoplasia (VIN), further

subdivided in differentiated VIN (dVIN) and high-grade squamous intraepithelial

lesion; (2) superficially invasive squamous cell carcinoma; and (3) frankly

invasive squamous cell carcinoma. Neoplasia incidence risk, neoplasia incidence

rate, and cumulative probability of progression to neoplasia according to the

Kaplan-Meier method were estimated. Log-rank test was used to compare the

progression-free survival curves by age at diagnosis of VLS.

RESULTS: The mean age at diagnosis of VLS was 60 (median = 60; range = 8-91)

years. The mean length of follow-up was 52 (median = 21; range = 1-331) months.

The following 34 patients developed a neoplasia: 8 VIN (4 dVIN, 4 high-grade

squamous intraepithelial lesions), 6 keratinizing superficially invasive squamous

cell carcinoma (5 with adjacent dVIN), and 20 keratinizing invasive squamous cell

carcinoma (1 with adjacent dVIN). The neoplasia incidence risk was 3.5%. The

neoplasia incidence rate was 8.1 per 1,000 person-years. The cumulative

probability of progression to neoplasia increased from 1.2% at 24 months to 36.8%

at 300 months. The median progression-free survival was significantly shorter in

older women (≥70 years) when compared with that in younger women (p = .003).

CONCLUSIONS: Vulvar lichen sclerosus has a nonnegligible risk of neoplastic

transformation and requires a careful and lifelong follow-up in all patients,

particularly in elderly women. Early clinical and histological detection of

preinvasive lesions is essential to reduce the risk of vulvar cancer.


  1. Obstet Gynecol. 2016 Feb;127(2):264-8. doi: 10.1097/AOG.0000000000001285.

The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD)

Terminology of Vulvar Squamous Intraepithelial Lesions.

Bornstein J , Bogliatto F, Haefner HK, Stockdale CK, Preti M, Bohl TG, Reutter

J; ISSVD Terminology Committee.

Collaborators: Bornstein J, Bogliatto F, Bohl TG, Coady D, Haefner HK, Preti M,

Reutter J, Selva-Nayagam P, Stockdale CK, Van-Beurden M.

OBJECTIVES: The impact of terminology for vulvar intraepithelial lesions has been

significant over the years, because it has affected diagnosis, treatment, and

research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in

2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of

reference to “differentiated vulvar intraepithelial neoplasia” (differentiated

VIN) could lead to its being overlooked by health care providers, despite its

malignant potential. Secondly, including the term “low-grade squamous

intraepithelial lesion” (LSIL) in LAST recreated the potential for overdiagnosis

and overtreatment for benign, self-limiting lesions.

MATERIALS AND METHODS: The International Society for the Study of Vulvovaginal

Disease (ISSVD) assigned the terminology committee the task of developing a

terminology to take these issues into consideration. The committee reviewed the

development of terminology for vulvar SILs with the previous 2 concerns in mind

and reviewed several new terminology options.

RESULTS: The final version accepted by the ISSVD contains the following: 1)

Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma or human

papillomavirus effect. 2) High-grade SIL or vulvar HSIL (which was termed “vulvar

intraepithelial neoplasia usual type” in the 2004 ISSVD terminology). 3) Vulvar

intraepithelial neoplasia, differentiated type.

CONCLUSION: The advantage of the new terminology is that it includes all types of

vulvar SILs, it provides a solution to the concerns in relation to the

application of LAST to vulvar lesion, and it is in accordance with the World

Health Organization classification as well as the LAST, creating unity among

clinicians and pathologists.


  1. J Cancer. 2016 Jan 1;7 :107-14. doi: 10.7150/jca.13503. eCollection 2016.

HPV-Testing in Follow-up of Patients Treated for CIN2+ Lesions.

Mariani L , Sandri MT(2), Preti M(3), Origoni M(4), Costa S(5), Cristoforoni

P(6), Bottari F(2), Sideri M .

Persistent positivity of HPV-DNA testing is considered a prognostic index of

recurrent disease in patients treated for CIN2+. HPV detection, and particularly

genotyping, has an adequate high rate of sensitivity and specificity (along with

an optimal reproducibility), for accurately predicting treatment failure,

allowing for an intensified monitoring activity. Conversely, women with a

negative HPV-test 6 months after therapy have a very low risk for

residual/recurrent disease, which leads to a more individualized follow-up

schedule, allowing for a gradual return to the normal screening scheme. HPV

testing should be routinely included (with or without cytology) in post-treatment

follow-up of CIN2+ patients for early detection of recurrence and cancer

progression. HPV genotyping methods, as a biological indicator of persistent

disease, could be more suitable for a predictive role and risk stratification

(particularly in the case of HPV 16/18 persistence) than pooled HPV-based

testing. However, it is necessary to be aware of the performance of the system,

adhering to strict standardization of the process and quality assurance criteria.


  1. J Low Genit Tract Dis. 2016 Jan;20 :11-4. doi: 10.1097/LGT.0000000000000169.

The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD)

Terminology of Vulvar Squamous Intraepithelial Lesions.

Bornstein J , Bogliatto F, Haefner HK, Stockdale CK, Preti M, Bohl TG, Reutter

J; ISSVD Terminology Committee.

Collaborators: Bornstein J, Bogliatto F, Bohl TG, Coady D, Haefner HK, Preti M,

Reutter J, Selva-Nayagam P, Stockdale CK, Van-Beurden M.

OBJECTIVES: The impact of terminology for vulvar intraepithelial lesions has been

significant over the years, because it has affected diagnosis, treatment, and

research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in

2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of

reference to “differentiated vulvar intraepithelial neoplasia” (differentiated

VIN) could lead to its being overlooked by health care providers, despite its

malignant potential. Secondly, including the term “low-grade squamous

intraepithelial lesion” (LSIL) in LAST recreated the potential for overdiagnosis

and overtreatment for benign, self-limiting lesions.

MATERIALS AND METHODS: The International Society for the Study of Vulvovaginal

Disease (ISSVD) assigned the terminology committee the task of developing a

terminology to take these issues into consideration. The committee reviewed the

development of terminology for vulvar SILs with the previous 2 concerns in mind

and reviewed several new terminology options.

RESULTS: The final version accepted by the ISSVD contains the

following:•Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma

or human papillomavirus effect.•High-grade SIL or vulvar HSIL (which was termed

“vulvar intraepithelial neoplasia usual type” in the 2004 ISSVD

terminology).•Vulvar intraepithelial neoplasia, differentiated type.

CONCLUSIONS: The advantage of the new terminology is that it includes all types

of vulvar SILs, it provides a solution to the concerns in relation to the

application of LAST to vulvar lesion, and it is in accordance with the World

Health Organization classification as well as the LAST, creating unity among

clinicians and pathologists.


  1. Ecancermedicalscience. 2015 Apr 29;9:533. doi: 10.3332/ecancer.2015.533.

eCollection 2015.

E6/E7 mRNA testing for human papilloma virus-induced high-grade cervical

intraepithelial disease (CIN2/CIN3): a promising perspective.

Origoni M , Cristoforoni P(2), Carminati G , Stefani C , Costa S(3), Sandri

MT(4), Mariani L(5), Preti M(6).

Since the introduction of biomolecular testing for the identification of

high-risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive

strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA

testing has been demonstrated to have better sensitivity than conventional

cytology in several settings: screening, triage of ASC-US and in follow-up after

treatment. Despite this, some limitations of these new technologies have also

been underlined: the major issue is the low specificity of the tests, which

cannot discriminate between regressive and progressive infections. Thus, recent

research has moved the attention towards novel markers of progression that could

more precisely detect cases at real risk of cancer development. In view of the

fact that progression to cancer is dependable of the E6/E7 proteins integration

and transforming action, the overexpression of E6/E7 transcripts has been seen as

a valuable marker of this risk. This review aims to summarise the literature data

on this topic and to provide a clear view of the emerging perspectives.


  1. Ecancermedicalscience. 2015 Apr 29;9:531. doi: 10.3332/ecancer.2015.531.

eCollection 2015.

VIN usual type-from the past to the future.

Preti M , Igidbashian S(2), Costa S(3), Cristoforoni P(4), Mariani L(5),

Origoni M(6), Sandri MT(7), Boveri S(2), Spolti N(2), Spinaci L(2), Sanvito F(2),

Preti EP(2), Falasca A(2), Radici G(2), Micheletti L(8).

Usual vulvar intraepithelial neoplasia (uVIN) is the most common VIN type,

generally related to a human papillomavirus (HPV) infection, predominantly type

  1. The incidence of uVIN has been increasing over the last decades, and a

bimodal peak is observed at the age of 40-44 and over 55 years. Almost 40% of

patients with uVIN have a past, concomitant or future HPV-associated lesion of

the lower genital tract. HPV-related malignancies are associated with a

persistent HPV infection. The host immune response is of crucial importance in

determining clearance or persistence of both HPV infections and HPV-related VIN.

About 60% of the patients present with symptoms. Clinical features of uVIN vary

in site, number, size, shape, colour, and thickness of lesions. Multicentric

disease is often present. Most uVIN lesions are positive at immunohistochemistry

to p16(ink4a) and p14(arf), but negative to p53. Irrespective of surgical

treatment used, uVIN recurrence rates are high. Positive margins do not predict

the development of invasive disease and the need to re-excide the tissue around

the scare remains to be demonstrated. Therefore, considering the low progression

rate of uVIN and psycosexual sequelae, treatments should be as conservative as

possible. Medical treatments available are mainly based on immunotherapy to

induce normalisation of immune cell count in uVIN. None are approved by the food

and drug administration (FDA) for the treatment of uVIN. If medical treatment is

performed, adequate biopsies are required to reduce the risk of unrecognised

invasive disease. Some studies suggest that failure to respond to immunotherapy

might be related to a local immunosuppressive microenvironment, but knowledge of

the uVIN microenvironment is limited. Moreover, our knowledge of the potential

mechanisms involved in the escape of HPV-induced lesions from the immune system

has many gaps. HPV vaccines have been demonstrated to be effective in preventing

uVIN, with 94.9% efficacy in the HPV-naive population, while studies on

therapeutic vaccines are limited. The low incidence of VIN requires large

multicentre studies to determine the best way to manage affected patients and to

investigate the immunological characteristics of the ‘vulvar microenviroment’

which leads to the persistence of HPV.


  1. Ecancermedicalscience. 2015 Apr 29;9:528. doi: 10.3332/ecancer.2015.528.

eCollection 2015.

Performance of HPV DNA testing in the follow-up after treatment of high-grade

cervical lesions, adenocarcinoma in situ (AIS) and microinvasive carcinoma.

Costa S , Venturoli S(2), Origoni M(3), Preti M(4), Mariani L(5), Cristoforoni

P(6), Sandri MT(4).

The Italian HPV Study Group (IHSG).

BACKGROUND: Over the last two decades it has become clear that distinct types of

human papillomavirus (HPV), the so-called high-risk types (hrHPV), are the major

cause of cervical cancer. The hrHPV-DNA testing has shown excellent performance

in several clinical applications from screening to the follow-up of

conservatively treated patients.

METHODS: We conducted a systematic review of the recent literature on the

performance of HPV DNA testing in follow-up after treatment of high-grade

cervical lesions, adenocarcinoma in situ, and microinvasive carcinoma compared to

Pap smear cytology.

RESULTS: Observational studies have demonstrated that the high risk hrHPV-DNA

test is significantly more sensitive (95%) compared to follow-up cytology(70%) in

detecting post-treatment squamous intraepithelial high-grade lesions. Moreover,

in patients treated conservatively for cervical adenocarcinoma in situ, the

hrHPV-DNA test is the most significant independent predictor of recurrent disease

or progression to invasive cancer, and the combination of viral DNA testing and

cytology reaches 90% sensitivity in detecting persistent lesions at the first

follow-up visit and 100% at the second follow-up visit. The cause of

microinvasive squamous cervical carcinoma is increasingly treated with

conservative therapies in order to preserve fertility, and an effective strategy

allowing early detection of residual or progressive disease has become more and

more important in post-treatment follow-up. Primary results seem to indicate that

the median time for viral clearance is relatively longer compared with patients

treated for CIN and suggest a prolonged surveillance for these patients. However,

the potential clinical value of HPV-DNA testing in this clinical setting needs to

be confirmed by further observations.

CONCLUSIONS: The excellent sensitivity, negative predictive value, and optimal

reproducibility of the hrHPV DNA testing, currently is considered a powerful tool

in the clinicians’ hands to better manage post-treatment follow-up either in

cervical squamous lesion or in situ adenocarcinoma.


  1. Best Pract Res Clin Obstet Gynaecol. 2014 Oct;28(7):1074-87. doi:

10.1016/j.bpobgyn.2014.07.011. Epub 2014 Jul 22.

Surgery of the vulva in vulvar cancer.

Micheletti L , Preti M(2).

The standard radical mutilating surgery for the treatment of invasive vulval

carcinoma is, today, being replaced by a conservative and individualised

approach. Surgical conservative modifications that are currently considered safe,

regarding vulval lesion, are separate skin vulval-groin incisions, drawn

according to the lesion diameter, and wide local radical excision or partial

radical vulvectomy with 1-2 cm of clinically clear surgical margins. Regarding

inguinofemoral lymph nodes management, surgical conservative modifications not

compromising patient survival are omission of groin lymphadenectomy only when

tumour stromal invasion is ≤ 1 mm, unilateral groin lymphadenectomy only in

well-lateralised early lesions and total or radical inguinofemoral

lymphadenectomy with preservation of femoral fascia when full groin resection is

needed. Sentinel lymph node dissection is a promising technique but it should not

be routinely employed outside referral centres. Pelvic nodes are better managed

by radiation. Locally advanced vulval carcinoma can be managed by ultraradical

surgery, exclusive radiotherapy or chemoradiation.


  1. Best Pract Res Clin Obstet Gynaecol. 2014 Oct;28(7):1051-62. doi:

10.1016/j.bpobgyn.2014.07.010. Epub 2014 Jul 18.

Vulvar intraepithelial neoplasia.

Preti M , Scurry J(2), Marchitelli CE(3), Micheletti L(4).

Vulvar intraepithelial neoplasia (VIN) is a high-grade intraepithelial squamous

lesion and precursor of invasive squamous cell carcinoma (SCC). The 2004

International Society for the Study of Vulvovaginal Disease (ISSVD)

classification distinguished two types of VIN: usual type (human papillomavirus

(HPV)-related) and differentiated type (not HPV-related). The incidence of

usual-type VIN is higher in younger women, while differentiated-type VIN is more

common in older patients with chronic dermatologic conditions.

Differentiated-type VIN has a greater invasive potential and shorter time between

diagnosis and SCC than usual-type VIN. The diagnosis of VIN is carried out by

identifying a lesion by visual inspection and confirming by performing a biopsy.

Screening tests are not available. Patients with usual-type VIN are at a higher

risk of developing another HPV-related malignancy of the anogenital tract;

therefore, examination from the cervix to the perianal area is mandatory. The

therapeutic approach to VIN balances the invasive potential with the need to be

as conservative as possible. Current prophylactic HPV vaccines offer protection

against usual-type VIN and related invasive carcinoma.


  1. Arch Gynecol Obstet. 2014 May;289(5):1053-60. doi: 10.1007/s00404-013-3104-5.

Epub 2013 Dec 4.

Advanced utero-vaginal prolapse and vaginal vault suspension: synthetic mesh vs

native tissue repair.

Cosma S , Menato G, Preti M, Petruzzelli P, Tin MC, Riboni F, Benedetto C.

PURPOSE: To compare prosthetic and ligament vaginal vault suspension at vaginal

hysterectomy in patients, with utero-vaginal stage III-IV pelvic organ prolapse


METHODS: A retrospective case-control study was designed to compare 61 patients

who had undergone Posterior intravaginal slingplasty (PIVS) with 61 patients in a

matched control group who had undergone uterosacral ligament suspension (ULS).

The primary outcome was to compare anatomic vaginal vault failure rate. The

secondary outcomes were subjective cure and cure without adverse events.

RESULTS: Follow-up mean duration for the PIVS and ULS groups was 56.2 and 57.7

months, respectively. Recurrent vault prolapse was observed more frequently in

the ULS group with pre-intervention stage IV prolapse (0 vs 14.8 %; p = 0.04),

while there was no difference in prolapse recurrence at any vaginal site.

Although the subjective cure of PIVS and ULS was superimposable (91.8 vs 86.9 %;

p = 0.25), there was a significantly higher cure rate, without adverse events, in

the ULS group (90.2 vs 100 %; p = 0.01).

CONCLUSIONS: Non-mesh vaginal vault repair should be considered the first-line

measure at vaginal hysterectomy; prosthetic repair should be used for therapeutic

purposes in patients with vaginal vault recurrence and considered at vaginal

hysterectomy only in selected subjects with complete utero-vaginal eversion.


  1. Int Urogynecol J. 2013 Dec;24(12):2125-30. doi: 10.1007/s00192-013-2134-7. Epub

2013 Jul 25.

Psychometric validation of the Italian version of the I-QoL questionnaire:

clinical and urodynamic findings.

Possavino F , Preti M, Carone R, Calabrese R, Randaccio S, D’Elia C, Allais I,

Cosma S, Benedetto C.

INTRODUCTION AND HYPOTHESIS: The aim was to validate the Italian version of the

Incontinence-Quality of Life questionnaire (I-QoL) in women with clinical and

urodynamic urinary incontinence (UI). A secondary end point was to compare the

results of women with reported UI, but negative urodynamic findings.

METHODS: The Italian translation of the I-QoL was administered to 267 Italian

women with pelvic organ prolapse < stage III, and who had undergone previous

surgical or medical therapy for UI. Cronbach’s alpha was calculated to assess

internal consistency of the I-QoL items. Reproducibility was assessed using the

intraclass correlation coefficient (ICC). Convergent validity involved comparison

of I-QoL scores and the Short Form-36 Health questionnaire.

RESULTS: One hundred and sixty-seven patients were considered for the primary end

point: 47 had a negative history of UI and a normal urodynamic test, 120

complained of UI confirmed by a urodynamic test, 59 had a positive history for UI

and a urodynamic test negative for UI, and 35 patients not reporting UI had a

positive urodynamic test. The I-QoL score revealed that the QoL was lower in

patients with reported UI, irrespective of urodynamic findings. The overall I-QoL

summary score and subscales showed high internal consistency (alpha ranges from

0.88 to 0.96). ICC ranged from 0.98 to 0.99, demonstrating the stability of the

scores. The physical domain of the I-QoL showed a 0.27 correlation with the

physical functioning subscale of the SF-36. No significant difference in I-QoL

scores was found among various types of UI.

CONCLUSION: The Italian translated version of the I-QoL is reliable, consistent

and a valid instrument for assessing impact on quality of life in Italian

speaking women with UI.



  1. J Low Genit Tract Dis. 2013 Jul;17(3):362-5. doi: 10.1097/LGT.0b013e31826f24c0.

Human papillomavirus DNA and Pap tests: the need for cotesting in opportunistic

setting during the transition time.

Mariani L, Sideri M, Costa S, Cristoforoni P, Origoni M, Preti M; Italian HPV

Study Group.


  1. Gynecol Oncol. 2012 Mar;124(3):490-5. doi: 10.1016/j.ygyno.2011.11.039. Epub 2011

Dec 1.

Factors predicting the outcome of conservatively treated adenocarcinoma in situ

of the uterine cervix: an analysis of 166 cases.

Costa S , Venturoli S, Negri G, Sideri M, Preti M, Pesaresi M, Falasca A,

Barbieri D, Zerbini M, Santini D, Sandri MT, Ghiringhello B, Caroppo Venturini N,

Syrjänen S, Syrjänen K.

OBJECTIVE: The present study assessed the clinical outcome of patients

conservatively treated for cervical adenocarcinoma in situ (AIS) and their

predictive factors using univariate and multivariate population averaged (PA)

generalized estimating equation (GEE) model in a longitudinal setting.

METHODS: A series of 166 consecutive women (mean age 39.8 yrs; range 23-63 yrs)

underwent conservative treatment of AIS as the primary treatment and were

followed-up (mean 40.9 mo) using colposcopy, PAP-smear, biopsy and HPV-testing

with Hybrid Capture 2.

RESULTS: Hysterectomy was performed as part of the primary management in 47

patients, who were excluded from the follow-up (FU) analysis. Out of 119 women

closely followed-up, additional therapeutic procedures were performed in 69. At

study conclusion, 7 patients (5.9%) showed persistent disease, while 8 (6.7%) had

progressed to invasive adenocarcinoma (AC). Positive HR-HPV test was the only

independent predictor of disease recurrence (adjusted OR=2.72; 95%CI 1.08-6.87),

and together with free cone margins (OR=0.20; 95%CI 0.04-0.92), HR-HPV positivity

was also the single most powerful predictor of disease progression to AC, with

OR=3.74; 95%CI 1.84-7.61 (p=0.0001) in multivariate PA-GEE.

CONCLUSIONS: These results suggest that testing HR-HPV positive at any time point

during FU is the most significant independent predictor of progressive disease,

while showing free margins in cone has a significant protective effect against

progression to AC. Furthermore, because 4.3% women with persistent, recurrent or

progressive disease experienced a late (5th and 6th FU) diagnosis of HG-CGIN or

microinvasive AC, a close surveillance should be scheduled for at least three

years in conservatively treated AIS patients.


  1. Int Urogynecol J. 2011 May;22(5):611-9. doi: 10.1007/s00192-010-1350-7. Epub 2011

Jan 14.

Posterior intravaginal slingplasty: efficacy and complications in a continuous

series of 118 cases.

Cosma S , Preti M, Mitidieri M, Petruzzelli P, Possavino F, Menato G.

INTRODUCTION AND HYPOTHESIS: Posterior intravaginal slingplasty (PIVS) is a

minimally invasive procedure that aims to suspend vaginal vault. Our study

evaluated efficacy and complications of PIVS at long-term follow-up.

METHODS: One hundred eighteen consecutive women underwent PIVS operation for

Pelvic Organ Prolapse Quantification stage 3 or 4 vaginal cuff prolapse (VCP; 25

patients) or utero-vaginal prolapse (UVP; 93 patients). Apical vaginal wall at

stage 0 or 1 was considered as cured.

RESULTS: Follow-up mean duration was 58.6 months (range, 24-84 months). The

success rate of PIVS was 96.6%. Some 8.5% mesh erosion (20% in patients with VCP

and 5.4% with UVP), 2.5% vaginal-perineal fistula, and 3.4% paravaginal hematoma

occurred. Neither erosion nor fistulas occurred with monofilament polypropylene


CONCLUSION: PIVS seems a safe and effective procedure for VCP and UVP. Vaginal

erosion was mainly observed in patients with VCP treated with multifilament

polypropylene mesh.


  1. J Low Genit Tract Dis. 2010 Oct;14(4):363-73. doi: 10.1097/LGT.0b013e3181d95c71.

Update on intraepithelial neoplasia of the vulva: proceedings of a Workshop at

the 2009 World Congress of the International Society for the Study of

Vulvovaginal Diseases, Edinburgh, Scotland, September 2009.

Heller DS , van Seters M, Marchitelli C, Moyal-Barracco M, Preti M, van Beurden



  1. Breast Cancer Res Treat. 2009 Sep;117 :131-40. doi: 10.1007/s10549-008-0219-7.

Epub 2008 Oct 19.

High miR-21 expression in breast cancer associated with poor disease-free

survival in early stage disease and high TGF-beta1.

Qian B , Katsaros D, Lu L, Preti M, Durando A, Arisio R, Mu L, Yu H.

MicroRNA-21 (miR-21) is considered an onco-microRNA given its abilities to

suppress the actions of several tumor suppressor genes and to promote tumor cell

growth, invasion and metastasis. Recently, transforming growth factor-beta

(TGF-beta) is found to up-regulate the expression of miR-21, and elevated miR-21

expression is seen frequently in breast cancer. To evaluate the effect of miR-21

on disease progression and its association with TGF-beta, we analyzed miR-21

expression in breast cancer. Fresh tumor samples were collected during surgery

from 344 patients diagnosed with primary breast cancer. The expression of miR-21

in tumor samples was measured with a TaqMan microRNA assay using U6 as reference.

Levels of miR-21 expression by disease stage, tumor grade, histology, hormone

receptor status and lymph node involvement were compared. Cox proportional

hazards regression analysis was performed to assess the association of miR-21

expression with disease-free and overall survival. The study results showed that

the expression of miR-21 was detected in all tumor samples with substantial

variation. High miR-21 expression was associated with features of aggressive

disease, including high tumor grade, negative hormone receptor status, and ductal

carcinoma. High miR-21 was also positively correlated with TGF-beta1. No

associations were found between patient survival and miR-21 expression among all

patients, but high miR-21 was associated with poor disease-free survival in early

stage patients (HR = 2.08, 95% CI: 1.08-4.00) despite no value for prognosis. The

study supports the notion that miR-21 is an onco-microRNA for breast cancer.

Elevated miR-21 expression may facilitate tumor progression, and TGF-beta may

up-regulate its expression.


  1. Eur J Cancer. 2009 Aug;45(12):2212-8. doi: 10.1016/j.ejca.2009.05.003. Epub 2009

May 26.

Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer

and their associations with disease outcomes and expression of let-7a and IGF-II.

Lu L , Katsaros D, Shaverdashvili K, Qian B, Wu Y, de la Longrais IA, Preti M,

Menato G, Yu H.

Lin-28 and lin-28B are RNA-binding proteins which can block microRNA let-7

maturation and affect the differentiation and proliferation of embryonic stem

cells. Lin-28 may also regulate the expression of insulin-like growth factor II

(IGF-II). As one of the pluripotent factors involved in making induced

pluripotent stem cells (iPS), lin-28 is considered a potential therapeutic target

for cancer treatment. To further understand the role of lin-28 in cancer, we

analysed the expression of lin-28 and its homologue lin-28B in tumour samples,

and evaluated their associations with let-7a maturation, IGF-II expression,

disease features and outcomes in 211 patients with primary epithelial ovarian

cancer. The analysis showed that both lin-28 and lin-28B were positively

correlated with primary and pre-let-7a-3; lin-28B, not lin-28, was inversely

correlated with mature let-7a. A positive correlation was also observed between

lin-28B and IGF-II expression, while no association was found between lin-28B and

IGF-I or IGFBP-3. The study further demonstrated that lin-28B expression was

associated with the risk of disease progression and death; patients with high

lin-28B had shorter progression-free and overall survival than those with low

lin-28B. These results seem to support the findings of recent in vitro

experiments, showing that lin-28 blocks the process of let-7a maturation. Our

study also suggests that lin-28B may promote ovarian cancer progression and serve

as an unfavourable prognostic marker for the disease. The correlation between

lin-28B and IGF-II indicates that the growth factor may mediate the effect of

lin-28B on tumour growth.


  1. Cancer. 2009 Jun 1;115(11):2453-63. doi: 10.1002/cncr.24282.

Stathmin and tubulin expression and survival of ovarian cancer patients receiving

platinum treatment with and without paclitaxel.

Su D , Smith SM, Preti M, Schwartz P, Rutherford TJ, Menato G, Danese S, Ma S,

Yu H, Katsaros D.

BACKGROUND: Paclitaxel interacts with microtubules to exert therapeutic effects.

Molecules that affect microtubule activity, such as betaIII-tubulin and stathmin,

may interfere with the treatment. In this study, the authors analyzed

betaIII-tubulin and stathmin expression in ovarian tumors and examined their

associations with treatment response and patient survival.

METHODS: The study included 178 patients with epithelial ovarian cancer who

underwent cytoreductive surgery followed by platinum-based chemotherapy; of these

patients, 75 also received paclitaxel. Fresh tumor samples that were collected at

surgery were analyzed for messenger RNA expression of betaIII-tubulin and

stathmin using real-time polymerase chain reaction analysis. Associations of

these molecules with treatment response, disease progression, and overall

survival were evaluated.

RESULTS: High stathmin expression was associated with worse disease

progression-free and overall survival compared with low stathmin expression. This

association was independent of patient age, disease stage, tumor grade,

histology, and residual tumor size and was observed in patients who received

platinum plus paclitaxel, but not in patients who received platinum without

paclitaxel, suggesting that stathmin expression in tumor tissue may interfere

with paclitaxel treatment. Similar effects were not observed for betaIII-tubulin,

although high betaIII-tubulin expression was associated with disease progression

among patients who received platinum without paclitaxel. No associations were

observed between treatment response and tubulin or stathmin expression.

Expression levels of betaIII-tubulin and stathmin were correlated significantly.

CONCLUSIONS: High stathmin expression predicted an unfavorable prognosis in

patients with ovarian cancer who received paclitaxel and platinum chemotherapy.

This finding supports the possibility that stathmin may interfere with paclitaxel

treatment, leading to a poor prognosis for patients with ovarian cancer.


  1. Gynecol Oncol. 2008 Jul;110 :83-6. doi: 10.1016/j.ygyno.2008.03.001. Epub 2008

Apr 24.

A suggested modification to FIGO stage III vulvar cancer.

Rouzier R , Preti M, Sideri M, Paniel BJ, Jones RW.

OBJECTIVE: FIGO Stage III vulvar cancer includes tumors that invade the lower

urethra, vagina, or anus, and/or tumors that have metastasized to the

inguino-femoral lymph nodes of one groin. We hypothesized that locally advanced

stage III vulvar cancer and regional metastatic stage III vulvar cancer (lymph

node involvement) have different prognoses.

METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) registry

public use data tapes, we identified patients diagnosed with vulvar carcinoma

from 1988 through 2004. Overall survival (OS) was measured as the time from

diagnosis to the date of death or last follow-up. We used the Kaplan-Meier method

to estimate OS and the log-rank test to assess for differences between patient

groups. The staging performance was quantified with respect to discrimination.

RESULTS: The study cohort included 895 patients. The survival difference between

stage III patients with locally advanced vulvar cancer and stage III patients

with regional metastatic node(s) disease was highly significant (P<10(-10)). The

5-year and 10-year OS of patients with locally advanced vulvar tumors without

metastatic nodes were 62% and 47%, respectively. The 5-year and 10-year OS of

patients with regional metastatic node(s) disease were 39% and 27%, respectively.

Separating locally advanced stage III and regional metastatic stage III disease

would improve discrimination (concordance index: 72% vs 69% with the actual

staging system).

CONCLUSION: Involvement of the inguinal lymph nodes in FIGO (1988) stage III

patients carries a significantly worse prognosis compared with invasion of the

lower urethra, vagina or anus alone. This difference in prognosis would favor

restaging these two entities.


  1. Eur J Gynaecol Oncol. 2008;29 :52-6.

Migrant women and cervical cancer: background of a prevention study.

Mariani L , Morrone A, Preti M, Sbiroli C, Tomao F, Tomao S.

Author information:

Department Gynecologic Oncology, Regina Elena Cancer Institute of Rome, Italy.

The study was scheduled in order to organize a program of prevention against

cervical cancer in female migrants in Rome, and therefore to facilitate access to

appropriate preventive oncological facilities for discriminated women. Moreover,

the study will also investigate the risk factors and social conditions

(HPV-subtypes, sexual behavior, smoking habits) of such women since their

migration to Italy. This is scientific and cultural background of a longitudinal,

observational study on the cervical cancer risk in Roman migrant population. By

means of a mother language questionnaire (with the presence of a cultural

mediator) it will be possible to achieve data on social conditions and the new

life-style. An HPV-testing (HC2) combined with Pap-test (with further genotype

distribution) will be performed in all women enrolled in the study. Further

diagnostic/therapeutic decisions will depend on the results of both tests.

Scientific results are expected in the next two years, but an increasing of

cancer prevention awareness among female migrant populations is expected from the

beginning of the program. The present study was aimed at culturally appropriate

intervention strategies to limit the disparities that migrants usually suffer in

most of the developed Western nations in respect to the native counterparts.


  1. Am J Surg Pathol. 2007 Sep;31(9):1452; author reply 1452–4.

Comment on the Article: Srodon M, Stoler MH, Baber GB, et al. The distribution of

low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN

and VaIN) Am J Surg Pathol. 2006;30:1513-1518.

Sideri M, Jones RW, Heller DS, Haefner H, Neill S, Preti M, Scurry J, Wilkinson

EJ, Edwards L.

Comment on

Am J Surg Pathol. 2006 Dec;30(12):1513-8.


  1. Gynecol Oncol. 2006 Oct;103 :375-6; author reply 376-7. Epub 2006 Aug 7.

Stage 1A squamous cell carcinoma of the vulva.

Preti M, Rouzier R, Mariani L.

Comment on

Gynecol Oncol. 2006 Apr;101 :172-4.


  1. Obstet Gynecol. 2006 Mar;107(3):672-7.

Development and validation of a nomogram for predicting outcome of patients with

vulvar cancer.

Rouzier R , Preti M, Haddad B, Martin M, Micheletti L, Paniel BJ.

OBJECTIVE: To construct and validate a nomogram to predict relapse-free survival

of patients treated for vulvar cancer.

METHODS: Data from 244 patients treated for vulvar cancer at a single institution

(Creteil, France) were used as a training set to develop and calibrate a nomogram

for predicting relapse-free survival and local relapse-free survival. We used

bootstrap resampling for the internal validation and we tested the nomogram on an

independent validation set of patients (Torino, Italy) for the external


RESULTS: The nomograms were based on a Cox proportional hazards regression model.

Covariates for the relapse-free survival model included age, T stage, number of

metastatic nodes, bilateral lymph node involvement, omission of the

lymphadenectomy, margin status, lymphovascular space invasion, and depth of

invasion. The concordance indices were 0.85 and 0.83 in the training set before

and after bootstrapping, respectively, and 0.83 in the validation set. The

predictions of our nomogram discriminated better than did the International

Federation of Gynecology and Obstetrics stage (0.83 compared with 0.78, P = .01).

The calibration of our nomogram was good. In the validation set, 2-year and

5-year relapse-free survival were well predicted with less than 5% difference

between the predicted and observed survivals for each quartile. A nomogram for

predicting local relapse was also developed.

CONCLUSION: We have developed nomograms for predicting distant and local relapse

of vulvar cancer at 2 and 5 years and validated them both internally and

externally. These nomograms will be freely available on the International Society

for the Study of Vulvovaginal Disease Web site.


  1. Clin Obstet Gynecol. 2005 Dec;48(4):862-8.

Superficially invasive carcinoma of the vulva: diagnosis and treatment.

Preti M , Rouzier R, Mariani L, Wilkinson EJ.


  1. Clin Obstet Gynecol. 2005 Dec;48(4):845-61.

Squamous vulvar intraepithelial neoplasia.

Preti M , Van Seters M, Sideri M, Van Beurden M.


  1. J Reprod Med. 2005 Nov;50(11):807-10.

Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD

Vulvar Oncology Subcommittee.

Sideri M , Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H,

Neill S.

In the current classification, squamous vulvar intraepithelial neoplasia (VIN) is

categorized as VIN 1, 2 and 3 according to the degree of abnormality. There is

neither evidence that the VIN 1-3 morphologic spectrum reflects a biologic

continuum nor that VIN 1 is a cancer precursor. The VIN 2 and 3 category includes

2 types of lesion, which differ in morphology, biology and clinical features.

VIN, usual type (warty, basaloid and mixed), is HPV related in most cases.

Invasive squamous carcinomas of warty or basaloid type is associated with VIN,

usual type. VIN, differentiated type, is seen particularly in older women with

lichen sclerosus and/or squamous cell hyperplasia in some cases. Neither VIN,

differentiated type, nor associated keratinizing squamous cell carcinoma is HPV

related. The term VIN should apply only to histologically high grade squamous

lesions (former terms, VIN 2 and VIN 3 and differentiated VIN 3). The term VIN 1

will no longer be used. Two categories should describe squamous VIN: VIN, usual

type (encompassing former VIN 2 and 3 of warty, basaloid and mixed types) and

VIN, differentiated type (VIN 3, differentiated type).


  1. J Low Genit Tract Dis. 2003 Apr;7(2):122-35.

Vulvar Paget disease: one century after first reported.

Preti M , Micheletti L, Massobrio M, Ansai S, Wilkinson EJ.

OBJECTIVES.: To provide a critical assessment of the published literature on

vulvar Paget disease and to allow individualized approaches to affected patients.

MATERIALS AND METHODS.: A computerized search for studies published in the

literature up to June 2002 was carried out using Ovid(c) and Medline databases.

We excluded single case reports, letters to editors, and abstracts. RESULTS.:

Historical and epidemiological aspects of vulvar Paget disease are summarized.

Clinical and histopathological data support a recent proposal to classify vulvar

Paget disease into two categories, primary and secondary, with significant

clinical and prognostic implications. The treatment for primary vulvar Paget

disease is wide and deep surgical excision. Inguinofemoral lymphadenectomy is

added in the management of invasive neoplasms. In the presence of secondary Paget

disease, therapy must be directed toward treatment of associated carcinoma.

CONCLUSIONS.: The subclassification of vulvar Paget disease is essential for

correct clinical management and treatment. Immunohistochemistry may assist in

this important distinction.


  1. J Reprod Med. 2002 Sep;47(9):715-7.

Vulvology. A proposal for a multidisciplinary subspecialty.

Micheletti L , Preti M, Bogliatto F, Lynch PJ.

Author information:

Department of Gynecology and Obstetrics, University of Turin, Turin, Italy.

OBJECTIVE: To underline the usefulness of a new multidisciplinary subspecialty

devoted entirely to vulvar diseases, to be termed vulvology.

STUDY DESIGN: Disorders of the vulva present a wide spectrum of clinical

appearance, rendering clinical diagnosis difficult, if not impossible. The three

types of physicians usually involved in treating the vulva (generalists,

dermatologists and gynecologists) receive little training in and have little

experience with vulvar problems. The end result is that women today are receiving

far less than optimal care for vulvar disorders.

RESULTS: This situation can be much improved through the establishment of

vulvology as a new multidisciplinary subspecialty. Vulvology can become a neutral

field for research and debate and can provide a point of consolidation for all

clinical care (infectious, metabolic, oncologic, neurologic, psychological, etc.)

of vulvar disorders. The interdisciplinary nature of this new subspecialty will

also facilitate the standardization and systematization of the currently

confusing terminology and classification applicable to vulvar disorders.

CONCLUSION: Vulvology, as a new, well-defined, multidisciplinary subspecialty,

will improve the care of women with vulvar problems through the delineation of

vulvologists as physicians with special expertise in this area, the establishment

of clinics devoted specifically to the care of vulvar problems and the provision

of education for physicians, other health care providers and the public.


  1. J Surg Oncol. 2002 Sep;81 :19-24.

Rationale and definition of the lateral extension of the inguinal lymphadenectomy

for vulvar cancer derived from an embryological and anatomical study.

Micheletti L , Levi AC, Bogliatto F, Preti M, Massobrio M.

BACKGROUND AND OBJECTIVES: The objective of the present study was to define the

location of the most lateral superficial inguinal node lying along the inguinal

ligament, through an embryological and anatomotopographical study, in order to

rationalize the lateral extension of the groin lymphadenectomy in vulvar cancer.

METHODS: Sections of the upper portion of the femoral triangle belonging to three

human fetuses, whose crown-rump (CR) length ranged from 70 to 310 mm,

corresponding to a developmental age of 11 and 35 weeks, were studied. In

addition, for an objective topographical evaluation of the disposition of the

superficial inguinal lymph nodes, adult cadavers photographs of dissected

Scarpa’s triangle, reported in anatomical atlases, were analyzed.

RESULTS: Both the embryological investigation and the anatomotopographical

evaluation on cadavers photographs demonstrate that the most lateral superficial

inguinal lymph node does not rise above the medial margin of the sartorius

muscle, nor far lateral to the point where the superficial circumflex iliac

vessels cross the inguinal ligament.

CONCLUSIONS: On the basis of the present study, the authors believe that the

superficial circumflex iliac vessels could represent the lateral surgical

landmark, easily detectable, at which the inguinal lymphadenectomy should cease.

Therefore, there is no need to extend the lateral excision to the anterior

superior iliac spine. Finally, leaving the fatty tissue laterally to these

vessels, some lymphatic channels could be preserved, decreasing the incidence and

the entity of wound seroma and lymphedema.


  1. Br J Dermatol. 2000 Dec;143(6):1349-50.

Vulval lichen planus in the practice of a vulval clinic.

Micheletti L, Preti M, Bogliatto F, Zanotto-Valentino MC, Ghiringhello B,

Massobrio M.


  1. Minerva Ginecol. 2000 Dec;52(12 Suppl 1):87-91.

[Vestibular papillomatosis].

[Article in Italian]

Micheletti L , Preti M, Bogliatto F, Chieppa P.

Author information:

Dipartimento di Discipline Ginecologiche ed Ostetriche, Università di Torino.

The aim of the present study is to re-update the clinical significance of

vestibular papillomatosis. At the beginning of the eighties this condition has

been related to HPV infection based on histological and/or molecular evidence of

the virus presence and considered responsible of many cases of pruritus and/or

vulvodynia. Based upon these findings a lot of clinicians have been treating this

condition by laser ablation or by topical application of podophyllin or

trichloroacetic acid. At present the majority of the authors believes that

vestibular papillomatosis should be considered an anatomical variant of the

vestibular mucosa not HPV related. Therefore HPV-DNA presence should be

considered a causal rather than a causal agent. This evidence is important in

defining the management of vestibular papillomatosis: the papillae are usually

distinguishable from condylomata acuminata by clinical examination and biopsies

or HPV testing are not necessary. According to the studies considering vestibular

papillomatosis a non HPV related condition and on the bases of a series of 252

women examined, the Authors share the opinion that this clinical entity should be

considered a normal vestibular findings. As a consequence no ablative treatment

is usually required even if in presence of symptomatology or HPV molecular



  1. BJOG. 2000 May;107(5):594-9.

Inter-observer variation in histopathological diagnosis and grading of vulvar

intraepithelial neoplasia: results of an European collaborative study.

Preti M , Mezzetti M, Robertson C, Sideri M.

Author information:

Department of Obstetrics and Gynaecology, University of Turin, Italy.

OBJECTIVE: To evaluate the inter-observer variability of vulvar intraepithelial

neoplasia diagnosis and grading system.

DESIGN: Prospective study.

SAMPLE: Histological sections of 66 vulvar biopsies.

METHODS: Six consultant pathologists working at different European institutions

independently reviewed 66 vulvar biopsies. The following variables were

investigated: specimen adequacy, gross categorisation into benign or neoplastic

changes, presence of atypical cytological pattern, presence of neoplastic

architectural pattern, grade of vulvar intraepithelial neoplasia, presence of

histopathologic associated findings for human papillomavirus infection.

MAIN OUTCOME MEASURES: The degree of inter-observer variation for each

histopathologic parameter was assessed by Kappa (kappa) statistics. The frequency

and the degree of disagreement were calculated by a symmetrical agreement matrix

showing the number paired classifications.

RESULTS: A good agreement (overall weighted kappa = 0.65, unweighted kappa =

0.46) was observed for grading vulvar intraepithelial neoplasia. Human

papillomavirus infection associated findings and specimen adequacy were the

variables with less inter-observer agreement (overall weighted kappa 0.26 and

0.22, respectively). Exact agreement between two pathologists for grade of vulvar

intraepithelial neoplasia was observed in 63.6% of paired readings; the rate of

paired agreement reached 73.9% considering vulvar intraepithelial neoplasia 2 and

3 as a single class. Conversely, only 5.0% of vulvar intraepithelial neoplasia 1

diagnoses were concordant in paired analysis.

CONCLUSIONS: Current terminology offers a reproducible tool in the hands of

expert pathologists. While on the diagnosis of ‘high grade’ vulvar

intraepithelial neoplasia (vulvar intraepithelial neoplasia 2 and 3) there is

good agreement, the diagnostic category of vulvar intraepithelial neoplasia 1 is

not reproducible.


  1. Minerva Ginecol. 2000 May;52(5):203-11.

[Vulvar Paget’s disease. Clinico-pathologic review of the literature].

[Article in Italian]

Preti M , Micheletti L, Ghiringhello B, Privitera S, Condello V, Chieppa P,

Massobrio M.

In 1986 the International Society For the Study of Vulvar Disease classified

vulvar Paget’s disease (VPD) as a non-squamous intraepithelial lesion of the

vulva. The clinical multiform aspect of VPD, similar to other dermatological

lesions, often delays the execution of a biopsy. Paget’s cells could be instead

easily identified at histological examination and with histochemical reactions.

Underlying adenocarcinomas or stromal invasion are present in about 10% of

intraepithelial VPD. Patients with VPD are at risk for a second synchronous or

metachronous neoplasia: colo-rectal adenocarcinoma (more frequent in perianal

localization of VPD), cervical adenocarcinoma, carcinoma of the transitional

epithelium from the renal pelvis to urethra and mammary carcinoma. A wide

spectrum of frequency of these associations is reported in the literature

(0-45%). Therapy for intraepithelial VPD is wide and deep surgical resection

comprising all the skin appendages. However VPD has a high frequency of

recurrences (15-62%), often irrespective for radicality of surgical excision.

When association with underlying invasive adenocarcinoma or stromal invasion is

histologically confirmed, vulvar surgical approach must be integrated with

inguino-femoral lymphadenectomy. The role of chemotherapy and radiotherapy in the

multimodal approach to extensive or recurring VPD is still controversial.

Recurrences or progression of intraepithelal VPD are reported more than 10 years

from first surgical resection so that long term follow-up is mandatory.


  1. Minerva Ginecol. 2000 May;52(5):197-201.

[Vulvar lesions caused by HPV].

[Article in Italian]

Micheletti L , Preti M, Bocci C, Bogliatto F, Condello V, Chieppa P.

Human papillomavirus subclinical lesions are well known on the cervix and are

identified by colposcopy after acetic acid staining. The transfer of this

technique from the cervix to the vulva has led to the identification of areas of

white epithelial changes which have been defined by similarity as vulvar

subclinical HPV (VSHPV) lesions. A critical revision of the different clinical

VSHPV lesions classifications, the vulvar diagnostic role of acetic acid

staining, the natural history of HPV infection and the histological-biomolecular

diagnostic techniques has the authors to the conclusions that the majority of the

“so called” VSHPV lesions should not be considered a real disease. The presence

of HPV-DNA in these subclinical lesions should be considered causal and not

causal. To avoid overtreatments in women with proven HPV-DNA positivity without

macroscopic clinical lesions, the authors recommend to abandon the acetic acid

staining on the vulva and invite to consider the VSHPV lesions a faked diagnosis

and not a clinical entity.


  1. Cancer. 2000 Apr 15;88(8):1869-76.

Recurrent squamous cell carcinoma of the vulva: clinicopathologic determinants

identifying low risk patients.

Preti M , Ronco G, Ghiringhello B, Micheletti L.

BACKGROUND: The identification of prognostic factors in the recurrence of vulvar

squamous cell carcinoma is crucial for less invasive treatments.

METHODS: The authors studied 101 patients treated for primary invasive squamous

cell carcinoma of the vulva. Selected pathologic variables were observed in a

standardized manner during treatment, and their association with disease free

survival was investigated using the Cox model. Independent prognostic factors

were selected by a stepwise procedure. The absolute survival of patient groups

determined on the basis of such factors was computed by the product limit method.

RESULTS: The median follow-up was 3.1 years (range, 56 days to 15.5 years).

Recurrences developed in 33 patients. The independent recurrence predictors were

as follows: International Federation of Gynecology and Obstetrics (FIGO) Stage

IVA (vs. IB, II, or III) (risk ratio [RR]adjusted for other independent factors,

7.39), tumor multifocality (RR, 4.10), lymphovascular space involvement (LVSI)

(RR, 2.96), the presence of associated vulvar intraepithelial neoplasia (VIN)

Grade 2 or 3 (RR, 3.34), and the involvement of resection margins (RR, 4.88). By

ignoring the FIGO stage and lymph node status, the independent predictors were

then as follows: greatest tumor dimension < 2.5 cm, 2.5-4 cm (RR, 2.86), or > 4

cm (RR, 5.98); tumor multifocality (RR, 3.36); LVSI (RR, 4.19); the presence of

VIN 2 or 3 (RR, 3.06); and the involvement of surgical margins (RR, 2.78). No

recurrences were observed in 119 at-risk years among patients with unifocal

tumors < 2.5 cm in greatest dimension, free surgical margins, no LVSI, and no

associated VIN 2 or 3.

CONCLUSIONS: The presence of associated VIN 2 or 3 was revealed to be a

previously unidentified independent prognostic factor for recurrence. Subjects at

low risk of recurrence could be identified even without consideration of lymph

node status.


  1. Cancer. 1998 Oct 1;83(7):1369-75.

A proposed glossary of terminology related to the surgical treatment of vulvar


Micheletti L , Preti M, Zola P, Zanotto Valentino MC, Bocci C, Bogliatto F.

BACKGROUND: The authors’ objective was to provide a glossary of terminology

related to the surgical treatment of invasive vulvar carcinoma. There is

currently no consensus in the literature regarding the names of the surgical

procedures used to treat this disease.

METHODS: A surgical glossary should be supported by clear definitions and

acceptance of notions related to topographic anatomy that are specific to the

surgical practice. A critical review of the classic, chiefly used Italian,

French, German, and English textbooks of anatomy revealed some discrepancies and

lack of uniformity in descriptions of vulvar and inguinal fascial structures and

lymph nodes, which represent the principal landmarks of surgical treatment. In

the proposed glossary, the descriptions of these anatomic landmarks integrate

classic anatomic knowledge, data from recent gynecologic studies of inguinal

anatomy, and the clinical experiences of the authors.

RESULTS: The glossary is composed of 16 surgical definitions, which are divided

into 3 main sections of terminology describing the surgical treatment of the: 1)

vulva, 2) inguinal lymph nodes, and 3) pelvic lymph nodes. The fundamental

objective behind the glossary is to describe the area and the depth of the

surgical procedure. Three determinants of the area (local, partial, and total)

and three determinants of the depth of surgery (superficial, simple, and deep)

were used to arrive at the fully articulated definitions in the glossary.

CONCLUSIONS: The authors are aware that the proposed glossary should not be

considered a definitive one; however, it could serve as a good basis for further

debate. The terms employed in the glossary are accompanied by anatomic and

descriptive references to help avoid confusion and promote better understanding

among gynecologic oncologists who are involved in the treatment of vulvar



  1. Minerva Ginecol. 1995 Jun;47(6):269-75.

[Terminology and classification problems in relation to vulvar pathology].

[Article in Italian]

Micheletti L , Nicolaci P, Barbero M, Zanotto Valentino MC, Preti M.

The aim of this paper is to update the physicians (gynecologists, dermatologists

and pathologists) on the evolution of vulvar disease terminologies. In doing that

the authors illustrate briefly the fundamental steps which led to present

classifications of the International Society for the Study of Vulvar Disease

(ISSVD). The classification of “non neoplastic epithelial disorders” together

with that of “intraepithelial alterations” are illustrated and compared with the

terminologies previously employed. The last ISSVD definition of “superficially

invasive carcinoma” of the vulva is also presented and discussed. The authors

concluded that even if all these ISSVD classifications represent an important

effort for reaching a common language for a better international exchange of

different experiences, nevertheless an improvement of these terminologies is

still requested.


  1. J Reprod Med. 1994 Dec;39(12):961-3.

Psychological distress in women with nonneoplastic epithelial disorders of the


Preti M , Micheletti L, Barbero M, Piccioni V, Valentino MC, Nicolaci P, Borgno


The aim of this study was to evaluate psychological distress in 44 women with

vulvar squamous cell hyperplasia and 21 with vulvar lichen sclerosus in order to

examine the presence of psychological factors in these dermatologic disorders.

Two psychometric tests were used to evaluate depressive status and various

aspects of anger. No significant depressive status was diagnosed with the former

test either in patients with vulvar squamous cell hyperplasia or in patients with

vulvar lichen sclerosus. Patients with squamous cell hyperplasia had two

components of anger (state and internal anger) that were significantly higher and

three components (trait anger, exteriorization and control of anger)

significantly lower than did the controls. In patients with lichen sclerosus all

the components of anger were within the normal range. These findings suggest that

psychological factors may be associated with vulvar conditions, such as squamous

cell hyperplasia, and may have some therapeutic implications in cases resistant

to standard treatment.


  1. J Reprod Med. 1994 Dec;39(12):949-52.

Membranous hypertrophy of the posterior fourchette as a cause of dyspareunia and


Barbero M , Micheletti L, Valentino MC, Preti M, Nicolaci P, Ghiringhello B,

Borgno G.

Author information:

Institute of Gynaecology and Obstetrics, University of Torino, Italy.

Twenty-one women were treated surgically for entry dyspareunia and vulvodynia.

The ages of the patients ranged from 18 to 39 years (mean, 24.5). Physical

examination showed the presence of membranous hypertrophy of the posterior

fourchette with consequent stricture of the vaginal introitus in all the

patients. Eighty percent of the patients had erythema and tenderness of the

vestibule, particularly in the posterior part. The histologic findings were

somewhat enigmatic and quite unimpressive, frequently suggestive of chronic

nonspecific inflammation; in only two cases were histologic changes suggestive of

human papillomavirus infection observed. All the patients underwent excision of

the posterior part of the vestibule with vaginal advancement under general

anesthesia. Follow-up showed elimination of the symptoms in 19 patients and an

improvement in the symptoms in the remaining 2.


  1. Minerva Ginecol. 1994 Apr;46(4):195-204.

[Current knowledge about the natural history of intraepithelial neoplasms of the


[Article in Italian]

Micheletti L , Zanotto Valentino MC, Barbero M, Preti M, Nicolaci P, Canni M.

The data on the natural history of vaginal intraepithelial neoplasia (VaIN)

available in the literature are scarce and incomplete. As a matter of fact the

majority of the Authors report series with a small number of cases, which are

predominantly represented by VaIN III and usually already treated. Nevertheless

from the review of the literature it seems that VaIN, particularly those of low

grade (I-II), tend to show a high rate of spontaneous regression. The lesions are

frequently multifocal, associated with papilloma virus (HPV) infection and

arising in young women. On the contrary, the VaIN showing a more aggressive

behaviour are usually represented by single lesions, arising in older women.

Those patients are also frequently immunosuppressed, with a history of preceding

genital neoplasia and a previous exposure to radiation and/or chemotherapy.


  1. Eur J Gynaecol Oncol. 1994;15 :70-4.

Vulvar intraepithelial neoplasia of low grade: a challenging diagnosis.

Micheletti L , Barbero M, Preti M, Zanotto Valentino MC, Chiringhello B,

Pippione M.

The authors reviewed 21 cases of “mild vulvar atypia” diagnosed from 1981 to

  1. The first 16 cases were diagnosed as hyperplastic dystrophy with mild

atypia according to the 1976 ISSVD Classification of Vulvar Disease, while the

last five cases were diagnosed as vulvar intraepithelial neoplasia grade I (VIN

I). The review of the specimens was made by the same pathologist who gave the

initial diagnosis and by a dermatopathologist unaware of the initial diagnosis.

Both reviewers used the 1986 and 1989 ISSVD terminologies. The presence of “mild

atypia” was confirmed in only four of the 21 specimens, that is in 19% of the

cases, and two of them were found in the context of patients suffering from a

lichen planus. These findings show that the diagnosis of mild atypia in vulvar

tissues is a challenge and that mild vulvar atypia cannot be automatically

considered a VIN I.


  1. J Reprod Med. 1993 Feb;38(2):108-12.

Biologic behavior of vulvar intraepithelial neoplasia. Histologic and clinical


Barbero M , Micheletti L, Preti M, Valentino MC, Nicolaci P, Canní M,

Ghiringhello B, Borgno G.

The aim of this study was to evaluate the role by which different factors, such

as human papillomavirus (HPV) infection, age, dystrophic alterations, focal

nature and size of the lesion, influence the biologic behavior of vulvar

intraepithelial neoplasia (VIN). Sixty-nine cases of VIN were investigated (28

VIN 1, 9 VIN 2, 32 VIN 3). Follow-up was possible in 58 cases, with a mean of 31

months; no treatment was given to 3 patients, while 55 were treated either

medically or surgically. Eighty-four percent of the patients were cured,

recurrences were found in 11%, and 5% of the patients showed progression of the

disease to carcinoma. The ratio between medical and surgical treatment was the

same among the cured, recurred and progressed groups of patients. No differences

with regard to focal nature of the lesion, presence of HPV infection or

dystrophic alterations were observed between the three groups of patients. Only

the mean age was higher in patients who showed progression of the lesion to



  1. J Reprod Med. 1993 Jan;38 :28-32.

Histologic parameters of vulvar invasive carcinoma and lymph node metastases.

Preti M , Micheletti L, Barbero M, Ghiringhello B, Valentino MC, Nicolaci P,

Canni M, Borgno G, Segnan N, Ronco G.

Author information:

Institute of Gynaecology and Obstetrics, University of Torino, Italy.

We evaluated seven histologic parameters (tumor diameter, histologic grading,

depth of stromal invasion, vascular invasion, pattern of invasion,

lymphoplasmocytic infiltration and amount of necrosis) of 50 cases of vulvar

invasive carcinoma to assess their correlation with groin lymph node metastases.

Of 50 patients, 25 had groin lymph node metastases. No lymph node metastasis was

found in four cases with depth of invasion < or = 2.0 mm. Among the 31 patients

with vascular invasion, 23 (74%) had positive nodes, whereas lymph nodes were

metastatic only in two of the 19 patients (10%) without vascular invasion. At

univariate analysis, performed with Fisher’s exact method, all the parameters

considered, except pattern of invasion and amount of necrosis, were significantly

associated (P < .05) with lymph node metastases. However, after adjustment by

multiple logistic regression for the variables statistically significant at

univariate level, only the presence of vascular invasion was significantly

associated with nodal involvement and tumor diameter was borderline, whereas the

effect of the other variables was almost completely explained by confounding.


  1. Minerva Ginecol. 1992 Jun;44(6):329-34.

[Intra-lesion administration of beta-interferon in the treatment of CIN

associated with HPV infection].

[Article in Italian]

Micheletti L , Barbero M, Preti M, Zanotto Valentino MC, Nicolaci P, Corbella

L, Borgno G.

Thirty-two women with histologically confirmed cervical intraepithelial neoplasia

(CIN) associated with human papillomavirus (HPV) infection were treated with

intralesional beta-interferon. At 12 months from the end of the treatment, 60% of

the patients showed complete regression, histologically assessed, of CIN.

Considering separately the different CIN grades, the regression for CIN I was

71%, 64% for CIN II and 45% for CIN III. Side-effects were rather frequent (84%)

but they did not require discontinuation of the treatment. On the basis of these

data the Authors believe that intralesional beta-interferon, in selected cases,

can play a role, as a conservative modality, among the different techniques of

CIN therapy.


  1. J Reprod Med. 1990 Dec;35(12):1130-3.

Deep femoral lymphadenectomy with preservation of the fascia lata. Preliminary

report on 42 invasive vulvar carcinomas.

Micheletti L , Borgno G, Barbero M, Preti M, Cavanna L, Nicolaci P, Benedetto

C, Ghiringhello B, Bocci A.

Forty-two patients with primary invasive vulvar carcinoma were treated with

radical vulvectomy and deep femoral lymphadenectomy with preservation of the

fascia lata and cribriform fascia. The rationale for using this technique was

based on anatomic knowledge of the topographic distribution of groin lymph nodes,

which was confirmed by the study of 50 cadavers. The preliminary data show that

the number of superficial and deep femoral lymph nodes removed from the 42

patients (mean number of nodes, 20; range, 8-32) was similar to the number

reported in anatomy books. In addition, the five-year actuarial survival rate,

70%, was comparable to that in the literature. These preliminary results suggest

that the surgical technique used in this study is as radical an oncologic

procedure as Way’s classic groin lymphadenectomy, which consists of removing the

fascia lata and cribriform fascia.


  1. J Reprod Med. 1990 Dec;35(12):1127-9.

Topographic distribution of groin lymph nodes. A study of 50 female cadavers.

Borgno G , Micheletti L, Barbero M, Cavanna L, Preti M, Valentino MC,

Ghiringhello B, Bocci A.

There is a discrepancy between anatomy textbooks’ description of groin node

position and Way’s technique of lymphadenectomy. On the one hand, anatomic

studies have demonstrated that the deep femoral nodes are on the medial side of

the femoral vein, lying on the deep portion of the fascia lata, and can be seen

easily through the opening of the fossa ovalis. On the other hand, the standard

technique of deep femoral lymphadenectomy consists of removing the fat lying

lateral to the femoral artery through the incision and detachment of the fascia

lata from the sartorius to adductor longus muscle. With the aim of demonstrating

that a correct deep femoral lymphadenectomy does not require removal of the

fascia lata, we dissected Scarpa’s triangles in 50 female cadavers. The

examination of 100 specimens demonstrated that the deep femoral nodes are always

situated within the opening of the fossa ovalis, and no lymph nodes are distal to

the lower margin of the fossa ovalis, under the fascia cribrosa. These findings

suggest that deep femoral lymphadenectomy can be performed without removing the

fascia lata.


  1. J Reprod Med. 1990 Nov;35(11):1023-8.

Vulvar intraepithelial neoplasia. A clinicopathologic study of 60 cases.

Barbero M , Micheletti L, Preti M, Cavanna L, Boselli F, Garuti G, Valentino

MC, Nicolaci P, Ghiringhello B, Borgno G.

Sixty cases of vulvar intraepithelial neoplasia (VIN) were analyzed

clinicopathologically (24 VIN I, 9 VIN II, 27 VIN III). The ages of the patients

ranged from 21 to 83 years (mean, 53.7). Colposcopic examinations showed the

presence of white areas in 29 cases, red areas in 9, acetowhite areas in 6 and

other alterations in 13. One-third of the lesions were multifocal. Pruritus and

burning were present in 65% of the cases. Fifty-one percent of the cases showed

histologic changes suggestive of human papillomavirus (HPV) infection; the mean

age of those patients was significantly lower than that of patients without HPV

infection. In 15 cases of VIN, HPV DNA testing was performed with Southern blot

hybridization; in three (20%) of those specimens HPV 16 episomal DNA was

identified. Epithelial alterations surrounding the areas of VIN were found in 24

cases (40%)-23 squamous cellular hyperplasias and 1 lichen sclerosus. Different

types of treatment were performed according to the different grades of VIN:

medical therapy, diathermocoagulation, local excision, hemivulvectomy and total

vulvectomy. Follow-up was possible in 52 cases, with a mean of 33 months (range,

3-98). Two cases of VIN I showed progression of disease over 12-24 months.


  1. Minerva Ginecol. 1988 Dec;40(12):743-7.

[Condylomata acuminata and vulvar intraepithelial neoplasms (VIN)].

[Article in Italian]

Barbero M, Micheletti L, Cavanna L, Preti M, Zanotto Valentino MC, Ghiringhello

B, Borgno G.


  1. Minerva Ginecol. 1988 Oct;40(10):603-6.

[Cervical intraepithelial neoplasia caused by human papillomavirus infection.

Cytomorphologic, colposcopic and immunohistochemical correlations].

[Article in Italian]

Preti M, Micheletti L, Barbero M, Cavanna L, Ghiringhello B, Borgno G.

PMID: 2851756 [PubMed – indexed for MEDLINE]


  1. J Reprod Med. 1988 Jun;33(6):555-8.

Vulvar dystrophies in young and premenopausal women.

Barbero M , Micheletti L, Borgno G, Cavanna L, Preti M, Ghiringhello B.

Eighty-six cases of vulvar dystrophy in young and premenopausal women (age range,

6-53 years) were studied clinically and histopathologically. The most frequent

symptom was pruritus associated with burning. Clinical examination showed the

presence of white areas in 73% of the patients, red areas in 9% and other signs

(such as melanosis) in 18%. Hyperplastic dystrophy was the most frequent type of

dystrophy in these patients and was observed in 63% of cases. Cellular atypia was

observed in 9.8% of the cases and was found almost exclusively in hyperplastic

dystrophy. Epithelial changes suggestive of human papillomavirus infection were

found in 4 of the 86 cases of dystrophy, and they were observed only in atypical



  1. J Reprod Med. 1988 Jun;33(6):539-41.

Cellular atypia in vulvar dystrophies.

Micheletti L , Borgno G, Barbero M, Preti M, Cavanna L, Benedetto C,

Ghiringhello B.

Author information:

Institute of Gynecology and Obstetrics, University of Turin, Italy.

We studied the frequency and distribution of cellular atypia in 448 cases of

vulvar dystrophy. The total frequency was 9.4%. Atypia was found almost

exclusively in hyperplastic areas. Epithelial changes suggestive of human

papillomavirus infection were found in 14.2% of the atypical dystrophies. During

the follow-up of 78 patients with typical dystrophy, mild atypia developed in

three cases, but with the continuation of medical treatment it disappeared in two

cases. Eleven cases of atypical dystrophy were followed for 3-48 months; three

patients with severe atypia underwent surgical treatment, and eight with mild

atypia underwent medical treatment. Among the last patients, six showed

regression and two, progression of the atypia.


  1. J Reprod Med. 1988 Jun;33(6):500-2.

Epithelial alterations adjacent to 111 vulvar carcinomas.

Borgno G , Micheletti L, Barbero M, Preti M, Cavanna L, Ghiringhello B.

Material from 111 invasive primary vulvar carcinomas was reviewed in order to

study the histopathologic changes adjacent to the neoplasia. The histopathologic

characteristics of the adjacent tissue were divided into categories. Dystrophic

lesions were adjacent to invasive cancer in 57.6% of the cases, carcinoma in situ

(CIS) in 21.6% and epithelial changes suggestive of human papillomavirus

infection in 18.9%. A spectrum of epithelial changes, ranging from hyperplastic

dystrophy without atypia to CIS, was found adjacent to nine cases of invasive

carcinoma (8.1%). In 40.5% of the vulvar carcinomas there were no specific

alterations surrounding the neoplasia. These data show that dystrophies and CIS

were adjacent to invasive carcinomas in nearly 60% and 20% of cases,