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ABSTRACT: OBJECTIVE: Over 10% of women who undergo conization for cervical intraepithelial neoplasia (CIN) show no lesion in the surgical specimen. We aimed to determine whether these patients can be identified before conization using clinical, virological and/or cyto-histological characteristics, to avoid unnecessary treatment. METHODS: Of 687 women with CIN treated by conization in the Hospital Clinic of Barcelona between 2008 and 2011, all patients (n=110, 16%) showing no lesion in the surgical specimen were included as the study group. The control group included a series of randomly selected women with CIN in the cone specimen (n=220). Pre-conization clinical characteristics as well as high-risk human papillomavirus (hr-HPV) status determined by Hybrid Capture 2 were analyzed as possible predictors of absence of lesion. RESULTS: A negative pre-conization hr-HPV test or a low viral load (< 10 relative light units) significantly increased the probability of absence of CIN in the conization specimen (75.0%, and 52% respectively) compared with patients with a high viral load, (26.7%, p<0.001). This association was confirmed in the multivariate analysis (p<0.001). The risk of developing persistent/recurrent disease after treatment was significantly lower in patients with negative hr-HPV test or a low viral load (16.1% CIN1, 0% CIN2-3), than in patients with a high viral load (27.6% CIN1, 4.1% CIN2-3, p=0.031). CONCLUSION: Women with negative pre-conization hr-HPV test results or a low viral load have a high probability of having no lesion in the conization specimen. These patients should be excluded from immediate surgical excision and considered for follow-up.
Gynecologic Oncology 10/2012; · 3.89 Impact Factor
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ABSTRACT: Vulvar squamous cell carcinoma (VSCC) accounts for >90% of the malignant tumours of the vulva. Most VSCCs originate in intraepithelial lesions, named vulvar intraepithelial neoplasia (VIN), that precede the development of VSCC by a variable period of time. Strong evidence has accumulated showing that there are two different aetiopathogenic pathways for the development of VSCC and VIN, one associated with infection by human papillomavirus (HPV), and a second independent of HPV infection. These two different types of VSCC have different epidemiological, pathological and clinical characteristics, and should therefore be considered as two separate entities. Histologically, HPV-associated VSCCs are of the basaloid or warty type, and arise from VIN of the usual type. Inactivation of p53 and the retinoblastoma tumour suppressor gene product by the viral gene products E6 and E7 is involved in the process of malignant transformation. HPV-independent VSCCs are histologically keratinizing, are associated with differentiated VIN and lichen sclerosus, and frequently show mutations of p53. p16(INK4a) and p53 immunostaining can be useful for classifying VSCC into HPV-associated or HPV-independent. Although large, multicentre studies are needed to definitively assess the involvement of HPV in the prognosis of VSCC, most studies have not found clear differences in survival between HPV-associated and HPV-independent tumours.
Histopathology 09/2012; · 3.08 Impact Factor
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ABSTRACT: Recent evidence has confirmed two independent pathways in the development of vaginal squamous cell carcinoma (VaSCC): one related to and the other independent of human papillomavirus (HPV). The aim of our study was to evaluate whether HPV status has prognostic significance in this neoplasm.
All confirmed primary VaSCCs diagnosed and treated from 1995 to 2009 in two institutions were retrospectively evaluated (n=57). HPV infection was detected by PCR using SPF-10 primers and typed with the INNO-LIPA HPV assay and p16(INK4a) expression by immunohistochemistry. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model.
HR-HPV DNA was detected in 70.2% patients. HPV16 was the most prevalent genotype (67.5% of cases). p16(INK4a) was positive in 97.5% HPV-positive and 17.6% HPV-negative tumors (p<.001). FIGO stage was associated with DFS (p=.042) and OS (p=.008). HPV-positive tumors showed better DFS (p=.042) and OS (p=.035) than HPV-negative tumors. Multivariate analysis confirmed better DFS and OS of HPV-positive patients independent of age and stage. This reduced risk of progression and mortality in HPV-positive patients was limited to women with FIGO stages I and II tumors (HR=0.26; 95% CI 0.10-0.69; p=0.006).
HPV-positive early stage (FIGO I and II) VaSCCs have a better prognosis than early HPV-negative tumors. HPV detection and/or p16(INK4a) immunostaining can be easily implemented in routine pathology and should be considered as valuable prognostic biomarkers in the study of patients with VaSCC.
Gynecologic Oncology 01/2012; 125(1):194-9. · 3.89 Impact Factor
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ABSTRACT: Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy.
All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated (n=98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16(INK4a) expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model.
HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16(INK4a) stained 100% HPV-positive and 1.3% HPV-negative tumors (p<.001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p=.831), or OS (67.2% vs. 71.4% at 5 years; p=.791). No differences in survival were observed between HPV-positive and -negative patients requiring radiotherapy (hazard ratio [HR] 1.04, 95% confidence interval [CI] .45 to 2.41). FIGO stages III-IV (p=.002), lymph node metastasis (p=.030), size ≥ 20 mm (p=.023), invasion depth (p=.020) and ulceration (p=.032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61).
HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women.
Gynecologic Oncology 06/2011; 122(3):509-14. · 3.89 Impact Factor
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ABSTRACT: Less than 5% of women with cervical or vaginal biopsy proven high-grade squamous intraepithelial lesions (HG-SIL) show a negative Hybrid Capture 2 (HC2) result. We analyzed 1) human papillomavirus (HPV) genotypes by PCR in order to determine whether these cases represent infections by common or unusual types, and 2) the clinical, colposcopic and pathological differential characteristics of these patients.
646 women with a histological diagnosis of HG-SIL and a HC2 test collected within 6 months prior to the diagnosis were identified. Patients with a negative HC2 result were selected. HPV was typed in the biopsy specimen in all by PCR using SPF10 and GP5+/6+ primers, and p16(INK4a) immunostaining was performed. The clinical and colposcopy findings of these women were compared with a control group of HG-SIL with positive HC2 result.
20 women (3.1%) with HG-SIL had a negative HC2. All biopsies were positive for p16(INK4). PCR analysis detected HPV types included in HC2 test in 55% of the cases, with an identical percentage of common viruses between women with relative light unit values above or below 0.40 (p=.361). False negative HC2 tests increased with age (p=.002) and were more frequent in patients with non satisfactory colposcopy or small sized lesions (p<.001).
A negative HC2 test is an infrequent event in women with HG-SIL. Common HPV types are identified in over half of the cases. Older women and patients with small lesions or non satisfactory colposcopy have a higher rate of HC2 negative results.
Gynecologic Oncology 05/2011; 122(3):515-20. · 3.89 Impact Factor
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ABSTRACT: To evaluate the risk of progression to cervical intraepithelial neoplasia (CIN) grade 2 or 3 in women with positive human papillomavirus (HPV) testing and low-grade (low-grade squamous intraepithelial lesions), borderline (atypical squamous cells of undetermined significance), or no cervical lesions, and to determine the accuracy of initial colposcopy to predict progression.
Women with HPV infection and low-grade squamous intraepithelial lesions, atypical squamous cells, or normal cytology were recruited and grouped according to cytologic or histologic diagnosis. Exclusion criteria were histologic CIN 2 or 3, previous cervical cancer and HPV infection, cervical disease, or treatment for CIN 2 or 3 in the past 3 years. Four-hundred sixty-five women were included and monitored by cytology, Hybrid Capture-2 test, and colposcopy every 6 months. Colposcopy results were described as normal, with minor or major changes, and lesion size was recorded in quadrants.
Forty-three women (9.3%) had progression to CIN 2 or 3. No significant differences were found in rate of progression between women with low-grade squamous intraepithelial lesions, atypical squamous cells, or negative results (8.2%, 13.4%, and 9.8%, respectively; P=.679). Neither colposcopy pattern (P=.284) nor lesion size (P=.170) at recruitment provided any information on the risk of progression. History of cervical lesion and worsening of the colposcopy pattern during follow-up were associated with progression (P<.001).
Initial colposcopy findings do not provide relevant information on the risk of progression in HPV-positive women with minor or no cervical lesions. These women have a similar risk of progression and should benefit from the same follow-up strategies.
Obstetrics and Gynecology 12/2010; 116(6):1324-31. · 4.73 Impact Factor
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ABSTRACT: To determine the role of human papillomavirus (HPV) in the pathogenesis of primary squamous cell carcinoma of the vagina (SCCVa), and to evaluate its clinicopathological significance.
All cases of SCCVa diagnosed over a 15-year period from two hospitals in Barcelona, Spain (n=32) were retrieved. Patients with a history of carcinoma of the cervix diagnosed <5 years before were excluded. HPV was detected and typed by polymerase chain reaction (PCR) using SPF10 primers. Immunohistochemistry was performed for p16 and p53. HPV was detected in 25 cases (78.1%). HPV16 was the most prevalent type. Patients with HPV-positive tumours were associated frequently with a history of carcinoma or intraepithelial neoplasia of the cervix or vulva diagnosed more than 5 years before (56% versus 0%; P=0.01). HPV-positive tumours were more frequently of non-keratinizing, basaloid or warty type than HPV-negative neoplasms (84% versus 14.3%; P<0.001), and showed diffuse positive immunoreactivity for p16(INK4a) (96%, versus 14.3%; P<0.001). The sensitivity and specificity of p16 to identify HPV-positive tumours were 96% and 85.7%, respectively.
A high number of SCCVs are related to HPV infection and may be identified by immunohistochemistry for p16. HPV-positive tumours tend to affect women with history of cervical neoplasia.
Histopathology 12/2010; 57(6):907-16. · 3.08 Impact Factor
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ABSTRACT: Fuste V, del Pino M, Perez A, Garcia A, Torne A, Pahisa J & Ordi J (2010) Histopathology57, 907–916Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16INK4Aoverexpression and clinicopathological correlationsAim: To determine the role of human papillomavirus (HPV) in the pathogenesis of primary squamous cell carcinoma of the vagina (SCCVa), and to evaluate its clinicopathological significance.Methods and results: All cases of SCCVa diagnosed over a 15-year period from two hospitals in Barcelona, Spain (n = 32) were retrieved. Patients with a history of carcinoma of the cervix diagnosed <5 years before were excluded. HPV was detected and typed by polymerase chain reaction (PCR) using SPF10 primers. Immunohistochemistry was performed for p16 and p53. HPV was detected in 25 cases (78.1%). HPV16 was the most prevalent type. Patients with HPV-positive tumours were associated frequently with a history of carcinoma or intraepithelial neoplasia of the cervix or vulva diagnosed more than 5 years before (56% versus 0%; P = 0.01). HPV-positive tumours were more frequently of non-keratinizing, basaloid or warty type than HPV-negative neoplasms (84% versus 14.3%; P < 0.001), and showed diffuse positive immunoreactivity for p16INK4a (96%, versus 14.3%; P < 0.001). The sensitivity and specificity of p16 to identify HPV-positive tumours were 96% and 85.7%, respectively.Conclusions: A high number of SCCVs are related to HPV infection and may be identified by immunohistochemistry for p16. HPV-positive tumours tend to affect women with history of cervical neoplasia.
Histopathology 11/2010; 57(6):907 - 916. · 3.08 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the usefulness of p16(INK4a) staining to classify cervical intraepithelial neoplasia grade 1 according to its progression/regression risk.
Patients with a histologic diagnosis of cervical intraepithelial neoplasia grade 1 were prospectively recruited (n = 138). Simultaneous detection of high-risk human papillomaviruses and p16(INK4a) evaluation were performed. Follow-up was conducted every 6 months by cytology and colposcopy and annually by high-risk human papillomavirus testing, for at least 12 months (mean, 29.0). Progression was defined as a histologic diagnosis of cervical intraepithelial neoplasia grades 2-3, regression as a negative cytology and high-risk human papillomaviruses, and persistence as a cytologic result of low-grade squamous intraepithelial lesions and/or a positive test for high-risk human papillomaviruses.
Progression was observed in 14 women (10.1%), 66 (47.6%) regressed, and 58 (42.0%) had a persistent disease. p16(INK4a) was positive in 77 (55.8%) initial biopsy specimens. Progression to cervical intraepithelial neoplasia grades 2-3 was identified in 14 of 77 (18.2%) women with positive and none of 61 (0.00%) women with negative p16(INK4a) immunostaining (P < .001).
p16(INK4a) negative cervical intraepithelial neoplasia grade 1 lesions rarely progress and may benefit from a less intensive follow-up.
American journal of obstetrics and gynecology 09/2009; 201(5):488.e1-7. · 3.28 Impact Factor
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ABSTRACT: This report considers a highly exceptional case of ovarian hyperstimulation syndrome due to a gonadotroph adenoma secreting LH in a 31-year-old patient who presented with amenorrhoea and galactorrhoea syndrome and a complex bilateral ovarian mass. Magnetic resonance imaging revealed a pituitary adenoma, and laboratory tests corroborated the hyperprolactinaemia without other hormonal pituitary abnormalities. Ovarian hyperstimulation syndrome due to a gonadotroph adenoma with normal gonadotrophins is extremely rare. Most of the described cases are caused by FSH adenomas. Due to the originality of the case, it was considered useful for understanding the management of this entity, and it is proposed that LH adenomas should also be considered in the differential diagnosis of patients with spontaneous ovarian hyperstimulation syndrome.
Reproductive biomedicine online 09/2009; 19(2):153-5. · 2.04 Impact Factor
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ABSTRACT: Vulvar intraepithelial neoplasia (VIN) is classified into 2 clinicopathologic subtypes, classic, related to human papillomavirus (HPV) infection and affecting relatively young women, and simplex (differentiated), negative for HPV and affecting elderly women. Histologically, classic VIN may be basaloid and characterized by a replacement of the whole epidermis by a homogeneous population of small, "undifferentiated" keratinocytes, which are diffusely positive for p16(INK4a) and negative for p53. Simplex VIN is characterized by atypia of the basal layer with high degree of cellular differentiation and shows negative staining for p16(INK4a) and frequent positivity for p53. Simplex VIN is frequently associated with squamous cell hyperplasia and lichen sclerosus. From a series of 110 invasive squamous cell carcinomas of the vulva negative for HPV by highly sensitive polymerase chain reaction, 51 had VIN lesions located at least 1 cm away from the tumor. In 4 (7.8%) cases, the VIN had basaloid histologic features. All cases showed obvious architectural disorganization with a homogeneous population of basaloid, undifferentiated keratinocytes with scanty cytoplasm replacing the whole epidermis. Immunohistochemically, all cases were negative for p16(INK4a) and strongly positive for p53 with suprabasilar extension of positive cells. All patients were postmenopausal (median age 61.0 y; range, 45-76). Squamous cell hyperplasia was identified in 1 case and lichen sclerosus in 1 case. The invasive squamous cell carcinoma was of keratinizing type in 3 cases and basaloid in 1 case. In conclusion, simplex, HPV-negative VIN may occasionally have basaloid morphology. Immunostaining for p16(INK4a) and p53 protein may be helpful in the identification of these lesions and the differential diagnosis with classic, HPV-positive basaloid VIN.
The American journal of surgical pathology 09/2009; 33(11):1659-65. · 4.06 Impact Factor
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ABSTRACT: The nonsteroidal antiandrogenic drug flutamide is a safe and generally well-tolerated drug used for the treatment of prostate cancer and female hyperandrogenism.
We describe the case of a 26-year-old girl with amenorrhea and severe hirsutism who was treated with flutamide 250 mg/day and developed liver toxicity during therapy.
Other causes of liver toxicity were appropriately ruled out. The use of the standard Council for International Organization of Medical Sciences (CIOMS) scale and the Maria & Vitorino (M&V) scale indicated a highly probable relationship between the development of liver toxicity and flutamide therapy. Severe liver dysfunction has been rarely documented in women with hirsutism treated with flutamide, even though cases of fulminant liver failure have been described. The mechanisms responsible for the occurrence of hepatotoxicity during treatment with flutamide are unknown, but mitochondrial dysfunction seems to be implicated.
The potential of flutamide to act as a potent hepatotoxin should be kept in mind when treatment with this drug is being planned. This case reminds us that patients who are receiving flutamide should be regularly monitored for liver function. If drug-induced liver injury is suspected, flutamide must be discontinued promptly to avoid progression of liver injury.
Gynecological Endocrinology 07/2009; 25(7):419-22. · 1.58 Impact Factor
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José Muñoz,
Oriol Coll,
Teresa Juncosa,
Mireia Vergés, Marta del Pino,
Victoria Fumado,
Jordi Bosch,
Elizabeth J Posada,
Sara Hernandez,
Roser Fisa,
Josep Maria Boguña,
Montserrat Gállego,
Sergi Sanz,
Montserrat Portús,
Joaquim Gascón
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ABSTRACT: We performed a prospective screening for Trypanosoma cruzi infection in 1350 Latin American pregnant women and their offspring in Barcelona, Spain. The rate of seroprevalence was 3.4%, and 7.3% of the newborns were infected. Routine screening and management programs in maternity wards may be warranted.
Clinical Infectious Diseases 06/2009; 48(12):1736-40. · 9.15 Impact Factor
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ABSTRACT: To evaluate whether p16 staining could help to recognize underestimated cervical intraepithelial neoplasia (CIN) in women positive for high-risk human papillomavirus (HR-HPV) with negative biopsy. Out of 1,259 women undergoing a histologic study and a simultaneous HR-HPV detection using the Hybrid Capture 2 test, we selected all patients testing positive for HR-HPV and having a negative biopsy (n=139), as well as all women testing negative for HR-HPV with a biopsy of either CIN 1 (26 cases) or CIN 2 to 3 (11 cases). Of the remaining 1,083 women, we randomly selected for the purpose of controls, 50 cases negative for HR-HPV with negative biopsy and 100 cases positive for HR-HPV and with biopsy of CIN (50 CIN 1, 50 CIN 2-3). In all cases, immunohistochemical staining for p16 and a second evaluation of the initial biopsy was carried out. Thirty-four out of 139 biopsies (24.5%) testing positive for HR-HPV but having a negative biopsy were positive for p16. Thirty of these cases (21.6%) were classified as harboring a CIN (11 CIN 1, 19 CIN 2/3) after reevaluation. Both the number of cases reclassified as CIN of any grade, or as CIN 2/3, were significantly higher for cases with HR-HPV load above 100 relative light unit (P<0.005). Particular attention should be paid to biopsies from patients having positive Hybrid Capture 2. The risk of harboring undetected CIN of any type or CIN 2/3 is significantly higher for patients with high HR-HPV load. Immunostaining with p16 should be considered as a highly desirable addition to the histologic evaluation of cervical biopsy specimens in HR-HPV-positive women.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 12/2008; 28(1):90-7. · 2.07 Impact Factor
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ABSTRACT: Surgical treatment has modest efficacy for the treatment of infertility associated with early-stage endometriosis. Immunomodulation with pentoxifylline is considered as a new strategy potentially useful in treating endometriosis. Thus, this study investigated the usefulness of combined laparoscopic surgery and pentoxifylline therapy in the treatment of infertility associated with minimal to mild endometriosis.
A prospective, randomized, controlled blind trial was conducted. Patients entered the study immediately after laparoscopic surgery and were randomly assigned to the treatment with either oral pentoxifylline (800 mg/day) (pentoxifylline group, n = 51) or an oral placebo (placebo group, n = 53). Patients were then observed for pregnancy for 6 months.
Among 98 patients finally considered in the evaluation of the results, the 6 month overall pregnancy rates were 28 and 14% in the pentoxifylline and placebo groups, respectively. Thus, an absolute difference of 14% (95% CI -2 to 30) (Chi-squared test, P = 0.1) in the cumulative probability of pregnancy in 6 months after laparoscopic surgery in patients receiving pentoxifylline versus placebo post-operatively was observed.
Our findings provide preliminary clinical evidence to suggest the new experimental treatment approaches, toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute our results.
Human Reproduction 09/2008; 23(8):1910-6. · 4.47 Impact Factor
