Extending Human Papillomavirus (HPV) vaccination beyond female adolescents and after treatment for high grade CIN: the Italian HPV Study Group (IHSG) review and position paper.

OBJECTIVE: Human PapillomaVirus (HPV) vaccination has been introduced in recent years in clinical practice as the most effective primary prevention strategy for cervical cancer and HPV-induced lesions, either pre-malignant or benign. Since its introduction, HPV vaccination has been progressively demonstrated as extremely effective in preventing extra-genital and male diseases also; furthermore, non only adolescents but adult subjects have been investigated and reported as positively responding to vaccine immunostimulation. More recently, effectiveness of post-treatment vaccine administration has been preliminarily investigated with very promising results in terms of decreased recurrences. On this basis, we report an Italian-focused picture of the state of the art and take a position in favour of the extension of HPV vaccination to male adolescents, to older age groups and to already treated subjects.

TGF-beta1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival.

Transforming growth factor-beta (TGF-beta)-mediated signals play complicated roles in the development and progression of breast tumour. The purposes of this study were to analyse the genotype of TGF-beta1 at T29C and TGF-beta1 phenotype in breast tumours, and to evaluate their associations with IGFs and clinical characteristics of breast cancer. Fresh tumour samples were collected from 348 breast cancer patients. TGF-beta1 genotype and phenotype were analysed with TaqMan and ELISA, respectively. Members of the IGF family in tumour tissue were measured with ELISA. Cox proportional hazards regression analysis was performed to assess the association of TGF-beta1 and disease outcomes. Patients with the T/T (29%) genotype at T29C had the highest TGF-beta1, 707.9 pg mg(-1), followed by the T/C (49%), 657.8 pg mg(-1), and C/C (22%) genotypes, 640.8 pg mg(-1), (P=0.210, T/T vs C/C and C/T). TGF-beta1 concentrations were positively correlated with levels of oestrogen receptor, IGF-I, IGF-II and IGFBP-3. Survival analysis showed TGF-beta1 associated with disease progression, but the association differed by disease stage. For early-stage disease, patients with the T/T genotype or high TGF-beta1 had shorter overall survival compared to those without T/T or with low TGF-beta1; the hazard ratios (HR) were 3.54 (95% CI: 1.21-10.40) for genotype and 2.54 (95% CI: 1.10-5.89) for phenotype after adjusting for age, grade, histotype and receptor status. For late-stage disease, however, the association was different. The T/T genotype was associated with lower risk of disease recurrence (HR=0.13, 95% CI: 0.02-1.00), whereas no association was found between TGF-beta1 phenotype and survival outcomes. The study suggests a complex role of TGF-beta1 in breast cancer progression, which supports the finding of in vitro studies that TGF-beta1 has conflicting effects on tumour growth and metastasis.

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

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.

[Vulvar lesions caused by HPV]. / Lesioni vulvari da HPV.

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.

[Vulvar Paget's disease. Clinico-pathologic review of the literature]. / La malattia di Paget vulvare. Revisione clinico-patologica della letteratura.

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.

Inter-observer variation in histopathological diagnosis and grading of vulvar intraepithelial neoplasia: results of an European collaborative study.

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.

Recurrent squamous cell carcinoma of the vulva: clinicopathologic determinants identifying low risk patients.

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.

[Vestibular papillomatosis]. / La papillomatosi vestibolare.

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 infection.

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

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 carcinoma.

Multichannel cochlear implant in a deaf-blind patient.

In this work, a case study of the first deaf-blind patient implanted with the Combi-40 cochlear implant is analyzed. The patient is a 69-year-old man who has been blind since the age of 25 and deaf since the age of 51. Before surgery, his wife used Braille and finger-spelling on his hand to communicate with him. In this study, we intend to show how the rehabilitation program was applied to his particular characteristics and to describe the problems we faced throughout the process. Significant improvements in the dynamic ranges of perception and comprehension of segmental features of speech were observed within two weeks after the setting up. Within four weeks, the patient was able to maintain a simple conversation through the cochlear implant alone, and he abandoned the use of tactile communication. Nowadays, he is able to speak over the phone. A battery of tests was performed 2, 4 and 6 months after the switch-on. The results obtained for this patient, whose scores are among the best in our experience, suggest that deaf-blind individuals may benefit from a multichannel cochlear implant as an auditory substitute.

[Terminology and classification problems in relation to vulvar pathology]. / Problematiche classificativo-terminologiche relative alla patologia vulvare.

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.

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

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.

[Current knowledge about the natural history of intraepithelial neoplasms of the vagina]. / Attuali conoscenze sulla storia naturale delle neoplasie intraepiteliali della vagina.

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.

Vulvar intraepithelial neoplasia of low grade: a challenging diagnosis.

The authors reviewed 21 cases of "mild vulvar atypia" diagnosed from 1981 to 1990. 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.

Biologic behavior of vulvar intraepithelial neoplasia. Histologic and clinical parameters.

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 carcinoma.

Histologic parameters of vulvar invasive carcinoma and lymph node metastases.

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.

[Intra-lesion administration of beta-interferon in the treatment of CIN associated with HPV infection]. / Il beta-interferone intralesionale nel trattamento delle CIN associate ad infezione da HPV.

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.

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

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.

Deep femoral lymphadenectomy with preservation of the fascia lata. Preliminary report on 42 invasive vulvar carcinomas.

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.