Hemorrhage of cerebral cavernous malformation in third trimester of pregnancy.

Cerebral cavernous malformation is a rare but important cause of cerebral hemorrhage in pregnancy and puerperium. In pregnancy, cavernomas can more easily bleed as a result of increased female hormones and growth factors such as vascular endothelial growth factor. We present the case of a pregnant woman who had been diagnosed with a cerebral cavernoma about ten years previously, after repeated headache episodes; at the 28th week of pregnancy the woman was hospitalized for epileptic seizures and active bleeding from the anterior cerebral artery. We describe the management of the case, the decision for a preterm delivery and for a resolutive neurosurgical procedure.

Pediatric Hemangiomas in the Female Genital Tract: A Literature Review.

BACKGROUND: Hemangiomas are aberrant proliferations of blood vessels and the most frequent benign pediatric soft tissue tumors. Although they are common, genital localization is rare. This study aimed to assist doctors in the diagnosis, management, and treatment of pediatric vulvovaginal hemangiomas by conducting a review of the literature. METHODS: We conducted a literature review including papers published between August 2009 and May 2023. RESULTS: While most hemangiomas are usually indolent and resolve with time, in some cases, especially cervicovaginal and uterine ones, they might present with severe symptoms like heavy bleeding and need further instrumental investigation for diagnosis, like CT or MRI. As for the treatment, many options are available, with medical therapy or expectant management being the first choice. CONCLUSIONS: Vulvovaginal pediatric hemangiomas are rare and require more research on how to detect and manage these lesions, especially the symptomatic and the psychologically impacting ones. For the time being, treatment should be personalized based on the patient's situation and clinician's expertise.

Lipschütz Ulcer and SARS-CoV-2: What We Currently Know?

BACKGROUND: In recent years, several interesting case reports have been published which describe the possible role of SARS-CoV-2 infection or vaccination in the etiopathogenesis of Lipschütz ulcer. Our aim is to analyze this association and provide a rapid algorithm that is of support to gynecologists and dermatologists both in the diagnosis and in setting up the therapy. To do so, in this paper, we describe an interesting case of acute vulvar ulcer triggered by SARS-CoV-2 infection and review the related literature. METHODS: We conducted a literature review including papers published between October 2021 and April 2023, and we described the case of a patient referred to our clinic with Lipschütz ulcer and SARS-CoV-2 infection. RESULTS: In almost all cases analyzed, a correlation with SARS-CoV-2 infection or vaccination was found; ulcers usually manifest after 2 to 4 weeks and are associated with flu-like symptoms. A concordance in review papers, as well as in our case report, was also found about the treatment, which is mainly symptomatic. CONCLUSIONS: Previous infection or vaccination for SARS-CoV-2 should be included as possible etiopathogenetic factors in the onset of Lipschütz ulcer.

Therapeutic Choices for Genitourinary Syndrome of Menopause (GSM) in Breast Cancer Survivors: A Systematic Review and Update.

(1) Background: Genitourinary syndrome of menopause (GSM) is a medical condition that can affect breast cancer survivors (BCS). This is a complication that often can occur as a result of breast cancer treatment, causing symptoms such as vaginal dryness, itching, burning, dyspareunia, dysuria, pain, discomfort, and impairment of sexual function. BCS who experience these symptoms negatively impact multiple aspects of their quality of life to the point that some of them fail to complete adjuvant hormonal treatment; (2) Methods: In this systematic review of the literature, we have analyzed possible pharmacological and non-pharmacological treatments for GSM in BCS. We reviewed systemic hormone therapy, local hormone treatment with estrogens and androgens, the use of vaginal moisturizers and lubricants, ospemifene, and physical therapies such as radiofrequency, electroporation, and vaginal laser; (3) Results: The data available to date demonstrate that the aforementioned treatments are effective for the therapy of GSM and, in particular, vulvovaginal atrophy in BCS. Where possible, combination therapy often appears more useful than using a single line of treatment; (4) Conclusions: We analyzed the efficacy and safety data of each of these options for the treatment of GSM in BCS, emphasizing how often larger clinical trials with longer follow-ups are needed.

Efficacy of N-Acetylcysteine on Endometriosis-Related Pain, Size Reduction of Ovarian Endometriomas, and Fertility Outcomes.

BACKGROUND: Endometriosis is a chronic, estrogen-dependent, inflammatory disease, whose pivotal symptoms are dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Besides the usual medical treatments, recent evidence suggests there are potential benefits of oral N-acetylcysteine (NAC) on endometriotic lesions and pain. The primary objective of this prospective single-cohort study was to confirm the effectiveness of NAC in reducing endometriosis-related pain and the size of ovarian endometriomas. The secondary objective was to assess if NAC may play a role in improving fertility and reducing the Ca125 serum levels. METHODS: Patients aged between 18-45 years old with a clinical/histological diagnosis of endometriosis and no current hormonal treatment or pregnancy were included in the study. All patients received quarterly oral NAC 600 mg, 3 tablets/day for 3 consecutive days of the week for 3 months. At baseline and after 3 months, dysmenorrhea, dyspareunia and CPP were assessed using the Visual Analog Scale score (VAS), while the size of the endometriomas was estimated through a transvaginal ultrasound. Analgesics (NSAIDs) intake, the serum levels of Ca125 and the desire for pregnancy were also investigated. Finally, the pregnancy rate of patients with reproductive desire was evaluated. RESULTS: One hundred and twenty patients were recruited. The intensity of dysmenorrhea, dyspareunia and CPP significantly improved (p < 0.0001). The use of NSAIDs (p = 0.001), the size of the endometriomas (p < 0.0001) and the serum levels of Ca125 (p < 0.0001) significantly decreased. Among the 52 patients with reproductive desire, 39 successfully achieved pregnancy within 6 months of starting therapy (p = 0.001). CONCLUSIONS: Oral NAC improves endometriosis-related pain and the size of endometriomas. Furthermore, it decreases Ca125 serum levels and may improve fertility in patients with endometriosis.

Case Series of Acute Meconium Peritonitis Secondary to Perforation of the Ileum in the Antepartum Period.

Perforation of the ileum in the antepartum period resulting in meconial peritonitis is a condition that, although rare, is burdened by several complications. In 80-90% of cases, meconial ileus is the first manifestation of a disease, cystic fibrosis. In the remaining 10-20% of cases, it is caused by other situations, such as prematurity. In most cases, the diagnosis of meconial ileus occurs after birth, although in some cases it can be suspected prenatally, with the finding of a hyperechoic intestine on second trimester ultrasound. The prognosis depends on the gestational age, the location of the obstruction and the presence of fetal abnormalities. Mortality is very high and the recovery of intestinal function in the postoperative course is very high risk. In this case series, we describe two meconial peritonitis and our experience at the center.

Vulvodynia: Pain Management Strategies.

Background: Vulvodynia is defined in this international consensus as persistent vulvar pain that occurs for >3 months without an identifiable cause and with several potential associated factors. At present there is no univocal consensus in the therapeutic treatment of vulvodynia. The methods of intervention are based on various aspects including, above all, the management of painful symptoms. Methods: a research on scientific database such as "Pubmed", "Medline Plus", "Medscape" was conducted, using the words "women's genital pain" and "vulvodynia" for the review of the scientific evidence on the assessment and treatment of women's genital pain. Results: Among the drugs with pain-relieving action, the most effective in the treatment of vulvodynia would seem to be those with antidepressant and anticonvulsant action, even if their mechanisms of action are not known and there are still insufficient studies able to demonstrate their real validity. Among the least effective are non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. However, the ideal would seem to use a combined treatment with multiple types of drugs. Conclusions: Future studies are needed to draw up a unique therapeutic action plan that considers the stratification of patients with vulvodynia and the variability of the symptom.

Does Lung Ultrasound Have a Role in the Clinical Management of Pregnant Women with SARS COV2 Infection?

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection is a major health threat. Pregnancy can lead to an increased susceptibility to viral infections. Although chest computed tomography (CT) represents the gold standard for the diagnosis of SARS-CoV-2 pneumonia, lung ultrasound (LUS) could be a valid alternative in pregnancy. The objectives of this prospective study were to assess the role of LUS in the diagnosis of lung involvement and in helping the physicians in the management of affected patients. Thirty pregnant women with SARS-CoV-2 infection were admitted at the obstetrical ward of our Hospital. Mean age was 31.2 years, mean gestational age 33.8 weeks. Several LUS were performed during hospitalization. The management of the patients was decided according to the LUS score and the clinical conditions. Mean gestational age at delivery was at 37.7 weeks, preterm birth was induced in 20% of cases for a worsening of the clinical conditions. No neonatal complications occurred. In 9 cases with a high LUS score, a chest CT was performed after delivery. CT confirmed the results of LUS, showing a significant positive correlation between the two techniques. LUS seems a safe alternative to CT in pregnancy and may help in the management of these patients.

Fatal Takotsubo syndrome in critical COVID-19 related pneumonia.

COVID-19 can involve several organs and systems, often with indirect and poorly clarified mechanisms. Different presentations of myocardial injury have been reported, with variable degrees of severity, often impacting on the prognosis of COVID-19 patients. The pathogenic mechanisms underlying cardiac damage in SARS-CoV-2 infection are under active investigation. We report the clinical and autopsy findings of a fatal case of Takotsubo Syndrome occurring in an 83-year-old patient with COVID-19 pneumonia. The patient was admitted to Emergency Department with dyspnea, fever and diarrhea. A naso-pharyngeal swab test for SARS-CoV-2 was positive. In the following week his conditions worsened, requiring intubation and deep sedation. While in the ICU, the patient suddenly showed ST segment elevation. Left ventricular angiography showed decreased with hypercontractile ventricular bases and mid-apical ballooning, consistent with diagnosis of Takotsubo syndrome. Shortly after the patient was pulseless. After extensive resuscitation maneuvers, the patient was declared dead. Autopsy revealed a subepicardial hematoma, in absence of myocardial rupture. On histology, the myocardium showed diffuse edema, multiple foci of contraction band necrosis in both ventricles and occasional coagulative necrosis of single cardiac myocytes. Abundant macrophages CD68+ were detected in the myocardial interstitium. The finding of diffuse contraction band necrosis supports the pathogenic role of increased catecholamine levels; the presence of a significant interstitial inflammatory infiltrate, made up by macrophages, remains of uncertain significance.

Cerebral cavernous malformation: Management and outcome during pregnancy and puerperium. A systematic review of literature.

INTRODUCTION: Cerebral cavernomas malformations (CCMs) are vascular malformations that occur with an incidence of 0,4-0,8 % in general population. The most feared complication is cerebral hemorrhage. Currently there are no guidelines for pregnant women with CCMs. Some authors claimed that many physiological changes related to pregnancy could be linked to an high risk of rupture and bleeding of the cerebral cavernoma. However, more recent studies highlight that the presence of cerebral cavernomatosis is not a contraindication for pregnancy and that the risk of bleeding is similar in pregnant and in non-pregnant women. AIM OF THE STUDY: The purpose of our work is to analyze, through the study of controversial findings in literature, all the information currently available trying to establish a common approach for management of women with cerebral cavernomatosis in pregnancy, during childbirth and in the puerperium. FINDINGS: In accordance with existing literature, pregnancy does not appear to be a significant risk factor for the worsening of clinical manifestations associated with the presence of CCMs. Vaginal delivery is not contraindicated in patients with CCMs and there is no indication to perform cesarean section to reduce the incidence of hemorrhage. The only indication for neurosurgery of CCMs in pregnancy is the presence of rapidly progressive symptoms and should be postponed to the puerperium if arises after 30 weeks. The puerperium is a critical time for the woman with cavernomas for the possibility of bleeding and clinical observation must be continued. CONCLUSION: The patients with a diagnosis of a CCMs can have a pregnancy without any particular risk to themselves and the fetus but should be addressed to highly specialized obstetrics center to assesses the initial individual risk related to their pathology and to follow the pregnancy.

Structural Variations of Vaginal and Endometrial Microbiota: Hints on Female Infertility.

Microbiota are microorganismal communities colonizing human tissues exposed to the external environment, including the urogenital tract. The bacterial composition of the vaginal microbiota has been established and is partially related to obstetric outcome, while the uterine microbiota, considered to be a sterile environment for years, is now the focus of more extensive studies and debates. The characterization of the microbiota contained in the reproductive tract (RT) of asymptomatic and infertile women, could define a specific RT microbiota associated with implantation failure. In this pilot study, 34 women undergoing personalized hormonal stimulation were recruited and the biological samples of each patient, vaginal fluid, and endometrial biopsy, were collected immediately prior to oocyte-pick up, and sequenced. Women were subsequently divided into groups according to fertilization outcome. Analysis of the 16s rRNA V4-V5 region revealed a significant difference between vaginal and endometrial microbiota. The vaginal microbiota of pregnant women corroborated previous data, exhibiting a lactobacilli-dominant habitat compared to non-pregnant cases, while the endometrial bacterial colonization was characterized by a polymicrobial ecosystem in which lactobacilli were exclusively detected in the group that displayed unsuccessful in vitro fertilization. Overall, these preliminary results revisit our knowledge of the genitourinary microbiota, and highlight a putative relationship between vaginal/endometrial microbiota and reproductive success.

BRCA1/2 genes mutations, ovarian reserve and female reproductive outcomes: a systematic review of the literature.

INTRODUCTION: BRCA1 and BRCA2 genes mutations seems to impact female fertility, in addition to increasing the risk of ovarian and breast cancer. Several studies had investigated this issue but data available are still controversial. In order to clarify the role of BRCA1 and BRCA2 mutations in female fertility and ovarian function we carried out a systematic review of the literature with the aim to establish a possible management's strategy of these patients. EVIDENCE ACQUISITION: A review of current literature regarding BRCA mutation (BRCAm) and fertility was conducted using the PubMed tool to select remarkable articles with the keywords "BRCA1/2 gene," "BRCA1/2 mutation," "anti-Müllerian hormone," "female fertility," "ovarian reserve" and "premature ovarian failure." EVIDENCE SYNTHESIS: In current literature there are controversial findings about the relation between BRCA genes mutations and lifespan of female reproductive age. Several studies showed an higher risk of premature ovarian insufficiency of BRCAs mutations carriers, according to lower serum AMH level, primordial follicle count, or fewer oocyte yield after ovarian stimulation; on the other hand more recent studies reported not significant differences in serum AMH level or in reproductive outcomes between mutated and non-mutated BRCA patients. For this reason, currently there is not a strict recommendation for routine evaluation of fertility in female carriers of BRCA mutations. Nevertheless, the strong advice to complete childbearing by age 40 and then to undergo a risk-reducing salpingo-oophorectomy and the increased risk of infertility as a result of anticancer treatment in breast cancer BRCAm patients, make the issue of fertility and pregnancy planning in these women worthy of consideration. CONCLUSIONS: A dedicated counseling to discuss these issues, eventually associated with a personalized assessment of serum AMH or antral follicle count in order to have a panoramic view of ovarian reserve, may be useful in the management of these patients.

Could art cycles have a detrimental effect on ovarian reserve? A retrospective case control study.

BACKGROUND: Even if it is supposed damage of repeated ART (assisted reproductive technology) cycles on oocyte pool, there is still no evidence in literature. Aim of the study is to investigate whether infertile women who undergo to several ART cycles can show a lower ovarian reserve measured by AMH (Anti-Mullerian hormone) levels. METHODS: The study includes 282 infertile women, between 18 and 42 years, and allocated into two groups: 159 women previously submitted to two or more ART cycles (group A) and 123 women never submitted naïve to-ART cycles (group B). We tested whether AMH, FSH, LH and E2 levels were significantly different between the two groups, stratifying according to age. RESULTS: Regardless to the age ranges bands, the AMH in group A was statistically significant lower than in group B with a statistical significance (P=0.047). In particular women aged over 35 previously submitted to one or more ART cycles showed lower AMH levels, than those paired with age, which had never been treated with ART. CONCLUSIONS: Despite the limitations of the study, our data demonstrate a reduced AMH levels in women aged over 35 previously submitted to two or more repeated ART-cycles compared to patients never treated before. The strength of this study is the actuality of the topic that has not been discussed before in detail.

Behcet's disease and pregnancy: a systematic review.

INTRODUCTION: Behcet's disease (BD) is a rare inflammatory, multisystemic, autoimmune disorder with unknown origin. BD is included in vasculitic disorders with a more frequent onset characterized by oral and genital ulcers associated with eye inflammation. However, BD has several clinical manifestations, and the most fearful complication is thrombotic involvement. BD occurs mainly in women of childbearing age, therefore it is important to identify the potential risks of pregnancy on the mother and fetus. EVIDENCE ACQUISITION: The aim of our review is to identify, through the study of existing literature, the possible consequences of pregnancy on the course of this disease, the potential risks for the mother and fetus in gestation period and in puerperium, in order to identify a correct pregnancy management in patient affected by BD. EVIDENCE SYNTHESIS: Currently, there are few studies that have analyzed the consequences of the disease on the course of pregnancy and pregnancy on the activity of the pathology. Some authors believe that pregnancy may worsen the symptoms of the disease, while others may even improve the course. Many authors believe that thromboembolic events are the main problems for which focus attention on these patients, both in pregnancy and in puerperium. Different opinions exist about pregnancy complications and neonatal outcomes, although events such as abortion, intrauterine growth restriction and C-section appear to have a higher incidence in BD patients. CONCLUSIONS: There are no contraindications for the onset of pregnancy in BD patients. In most cases pregnancy can improve the course of the disease. However, in view of the potential adverse events, a thorough follow-up of the pregnancy is necessary in order to minimize any risks to the mother and fetus.

The impact of primary Sjogren's syndrome on female sexual function.

INTRODUCTION: Sjogren syndrome (SS) is a chronic autoimmune disease that usually affects women more than man with a 9:1 ratio. It leads to a progressive functional impairment of exocrine glands. Tipically, its clinical presentation is characterized by xerostomia and xerophtalmia, but it can also affect, among others, female genital apparatus, causing vaginal dryness and dyspareunia. EVIDENCE ACQUISITION: PubMed and Google Scholar were searched for articles in English indexed from January 1995 to November 2019 to assess evidence on the impact of primary Sjogren's syndrome on female sexual function. Our attention was directed specifically on the quality of sexual life of patients affected by primary SS. EVIDENCE SYNTHESIS: SS is associated with sexual dysfunction and it can significantly worsen patient's quality of life. CONCLUSIONS: The genital disorders secondary to SS can strongly alter the quality of female life both physically and psychologically as they alter sexuality. However, the observation of certain behavioral norms and the use of appropriate local substances can alleviate the symptoms and effectively contribute to reducing the discomfort.

Does hysterosalpingo-foam sonography have any therapeutic effect? A systematic review.

INTRODUCTION: Tubal patency is one of the mandatory and necessary conditions to be granted in order to guarantee a good pregnancy rate. Numerous studies have been conducted to compare the various testing techniques for tubal evaluation in order to optimize the diagnostic-therapeutic process. Aim of this review is to clarify if hysterosalpingo-foam sonography could be considered as a useful tool not only in the diagnostic procedure, but also in treatment of infertility. EVIDENCE ACQUISITION: We performed a comprehensive search of relevant studies from January 2010 to December 2019 to ensure all possible studies were captured. A systematic search of PubMed databases was conducted. EVIDENCE SYNTHESIS: Over the years, increasingly less invasive approaches have been used to test tubal patency. For many years Laparoscopic with chromopertubation (DLS) has been considered the reference standard, then less invasive procedures have been introduced, such as hysterosalpingography (HSG). Sonohysterosalpingography (HyCoSy) represents a non-invasive procedure with accuracy comparable to HSG. Several studies have been made on different contrast agents that could be used on this procedure and recent studies considered hysterosalpingo-foam sonography (HyFoSy) procedure as a new technique used for the study of tubal function performed on unfertile women. Nowadays, HyFoSy is largely used in the study of tubal patency, but it is not completely clear the role of this technique as treatment of imperviousness of Fallopian tubes, leading to an increase in pregnancy rate after its use. CONCLUSIONS: As described in the literature for other procedures, similarly with HyFoSy, the tubal flushing improves the chance of an embryo implanting and establishing a spontaneous pregnancy. More prospective studies should be taken to better analyze the singular maternal risk fators, hoping to offer more complete indications to recommend HyFoSy.

Diagnosis & management of imported malaria in pregnant women in non-endemic countries.

Malaria in pregnancy is an important cause of maternal and foetal morbidity and is a potentially life-threatening infection. With ever-growing global exchanges, imported malaria in pregnancy is becoming an issue of concern in non-endemic countries where women, because of low immunity, have higher risk of severe diseases and death. Malaria in pregnancy is a dangerous condition which can be associated with important consequences for both mother and child such as stillbirth, low birth weight, maternal anaemia. In non-endemic-countries it is more frequent in its severe form which can lead to maternal death if not treated adequately. Specific anti-malarial interventions such as the use of repellents and insecticide treated bed nets in addition to chemoprophylaxis should be used by pregnant women if they are travelling to endemic areas. In cases of confirmed infection, specific treatment regimens vary according to gestational age and the presence of complications. Malaria should be considered a global health problem, increasingly involving western countries. Clinicians all over the world need to be prepared for this emerging disease both in terms of prevention and therapy.

Fetus morphology changes by second-trimester ultrasound in pregnant women drinking alcohol.

Fetal alcohol spectrum disorders (FASDs) are a group of negative conditions occurring in children exposed to alcohol during gestation. The early discovery of FASD is crucial for mother and infant follow-ups. In this study, we investigated in pregnant women the association between urine ethylglucuronide (EtG-a biomarker of alcohol drinking) and indicators of the physical characteristics of FASD by prenatal ultrasound in the second trimester of gestation. We also correlated these data with the AUDIT-C, T-ACE/TACER-3, TWEAK, and food habit diary, screening questionnaires used to disclose alcohol drinking during pregnancy. Forty-four pregnant women were randomly enrolled and examined for ultrasound investigation during the second trimester of gestation. Urine samples were provided by pregnant women immediately after the routine interviews. EtG determinations were performed with a cutoff established at 100 ng/mL, a value indicating occasional alcohol drinking. Fifteen of the enrolled pregnant women overcame the EtG cutoff (34.09%). Analysis of variance (ANOVA) revealed that the fetuses of the positive EtG pregnant women had significantly longer interorbital distance and also significantly increased frontothalamic distance (P's < 0.02). Quite interestingly, no direct correlation was found between EtG data and both food diary and AUDIT-C. However, a significant correlation was observed between urinary EtG and T-ACE (r = 0.375; P = 0.012) and between urinary EtG and TWEAK (r = 0.512; P < 0.001) and a concordance with all questionnaire for EtG values higher than 500 ng/mL. This study provides clinical evidence that the diagnosis of maternal alcohol consumption during pregnancy by urine EtG may disclose FASD-related damage in the fetus.

Ultrasonography reappraisal of tubal patency in assisted reproduction technology patients: comparison between 2D and 3D-sonohysterosalpingography. A pilot study.

BACKGROUND: The aim of this study was to compare 2D and 3D-sonohysterosalpingography (2D-3D-HyFoSy) with previous diagnostic laparoscopy in the diagnosis of tubal patency, and compare each procedure in terms of procedure's time, perceived pain and complication rate. METHODS: We prospectively recruited infertile women, previously submitted to laparoscopy and randomly allocated into 2D-HyFoSy (group I) and 3D-HyFoSy (group II). We analyzed the results in term of sensitivity, specificity, positive predictive value and negative predictive value in tubal patency evaluation of both procedures in comparison with laparoscopy. RESULTS: We enrolled 50 women, 25 in group I and 25 in group II. 2D-HyFoSy findings obtained in group I, were concordant with laparoscopy in 81% of cases, with a sensitivity of 80% and a specificity of 92%. In group II, a correspondence was present in 88% of examinations, with a sensitivity and specificity of 98% and 91.4% respectively. 3D-HyFoSy was found to be faster and less painful than 2D (P<0.001). CONCLUSIONS: In the diagnosis of tubal occlusion, in the high-risk population, it seems advisable to us using the 3D-HyFoSy as the first-level examination, while, in low-risk patients, if the tubes appear obstructed in 2D-HyFoSy, the 3D-HyFoSy should be indicated before submitting patients to operative laparoscopy.

HPV-related vulvar diseases and perspectives of p16INK4a immunochemistry: a review of the literature.

INTRODUCTION: Two different types of vulvar intraepithelial neoplasia (VIN), HPV-related and HPV-unrelated, should be considered as two separate entities with different management options. The incidence of HPV-related VIN is increasing worldwide and is implicated in carcinogenesis. Our objective is to investigate the use of p16INK4a immunostaining or p16INK4a/p53 double staining for the detection of HPV-related disease to overcome the problem that histological criteria often have significant overlap. METHODS: A systematic literature search was carried out in the online databases PubMed, EMBASE, Cochrane Library, Clincaltrials.gov and Scopus. The key search terms were HPV, VIN, p16INK4a immunochemistry and p53. RESULTS: We found that nuclear and cytoplasmic immunostaining for p16INK4a was intense and diffuse in HPV-associated lesions and weak and focal in normal vulvar epithelium, nondysplastic lesions, lichen sclerosus and keratinizing vulvar squamous cell carcinoma. p53 nuclear immunostaining was always negative in HPV-related disease. CONCLUSIONS: Our findings indicated that p16INK4a or p16INK4a/p53 immunoreactivity, along with histological diagnosis, could be a convenient means to adequately classify VIN and its connection to HPV infection. Therefore, the clear recognition of HPV-associated VIN would lead to an appropriate strategy of treatment and follow-up.