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Differentiated vulvar intraepithelial neoplasia is often found in lesions
Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma
Hedwig P van de Nieuwenhof1,van cleef alhambra bracelet replica, Johan Bulten2, Harrie Hollema3, Rianne G Dommerholt4, Leon F A G Massuger1, Ate G J van der Zee5, Joanne A de Hullu1 and Leon C L T van Kempen2Received 1 June 2010; Revised 2 August 2010; Accepted 4 August 2010; Published online 5 November 2010. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past,replica vca sweet alhambra bracelet, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30 Of 60 lesions, 25 (42 were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (P Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P dyskeratosis (P hyperplasia (P and basal cellular atypia (P compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma.
There are two different pathways leading to vulvar squamous cell carcinoma with their own premalignant lesions; the most common pathway, which accounts for 80 of all squamous cell carcinomas, is HPV independent,2 but its etiology is still unknown. These, mostly differentiated keratinizing, squamous cell carcinomas often arise in lichen sclerosus, and it has therefore been suggested that lichen sclerosus is the precusor lesion of squamous cell carcinoma.3, 4, 5 Lichen sclerosus is a chronic inflammatory skin disease and mainly affects the female anogenital area.6, 7 The classical histological findings of lichen sclerosus are a thinned epidermis and the loss of rete ridges, hyperkeratosis, edema and hyalinization, as well as a chronic band like inflammatory cell infiltrate of the dermis8 (Figure 1a), but there are a lot of variations to these classical histological characteristics, leading to a myriad of lesions that may be classified as lichen sclerosus.
Figure 1.
Classical cases of lichen sclerosus. (a) Typical example of lichen sclerosus with a thinned epidermis and a loss of rete ridges, hyperkeratosis, hyalinization and a chronic band like inflammatory cell infiltrate of the dermis. (b) Lichen sclerosus with hyperkeratosis and hyperplasia. Original magnification, panels a and b: 100.
Full figure and legend (406K)
It has been hypothesized more recently that differentiated vulvar intraepithelial neoplasia (VIN) is the direct precursor of vulvar squamous cell carcinoma. Differentiated VIN (Figure 3a) is often found directly adjacent to squamous cell carcinoma and is characterized by a thickened epithelium that is typically associated with the elongation and anastomosis of rete ridges (Figure 3b). Dyskeratosis and parakeratosis are usually present (Figures 3c and d), associated with prominent intercellular bridges (Figure 3b). Basal keratinocytes are large and pleomorphic with a relatively large amount of eosinophilic cytoplasm. Keratin pearl formation within the rete ridge may be seen. The nuclear chromatin is vesicular rather than coarse, and the nuclei have prominent nucleoli (Figure 3e), usually most prominently in the basal and parabasal keratinocytes.8 Although differentiated VIN is seen adjacent to 80 of vulvar squamous cell carcinomas,2 it is seldom diagnosed as a solitary lesion,10 which may be explained by underdiagnosis due to its difficult recognition11, 12, 13 or due to its short intraepithelial phase.10 It has been hypothesized that differentiated VIN may develop from lichen sclerosus and that it carries a higher malignant potential than lichen sclerosus does,3, 13, 14, 15, 16, 17 but its role as a premalignant lesion has not been accepted by all pathologists.18 We hypothesize that of all lesions that have been diagnosed as lichen sclerosus in the past, a substantial part might currently be diagnosed as differentiated VIN.
Figure 3.
Differentiated vulvar intraepithelial neoplasia. Low power overview of differentiated VIN (a) with the five most important histopathological characteristics that can be recognized in an H stain: elongated rete ridges with anastomosis (b), disorderly basal cell layer and dyskeratosis (c), parakeratosis (d), prominent nucleoli (e) and atypical mitoses, indicated by arrows (f). Original magnifications: 50 (panel a), 100 (panels b and d), 200 (panels c and e) and 400 (panel f).
Full figure and legend (594K)
The terminology and criteria for the diagnosis of lichen sclerosus have been subjected to quite some revisions in the past 40 years,19, 20 and this has unevitably led to the diagnoses of lichen sclerosus that would currently be classified differently, including differentiated VIN.
It is currently unknown which lichen sclerosus lesion carries the risk of malignant progression. This is in part due to the wide variety of histopathological entities that have been collectively diagnosed as lichen sclerosus in the past. The first aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part would currently be diagnosed as differentiated VIN. The second aim was to determine whether, in retrospect, there are histopathological differences between lichen sclerosus lesions that did and did not progress to vulvar squamous cell carcinoma. Recognition of the lichen sclerosus at risk for squamous cell carcinoma development would greatly help to select patients who need close follow up.
Top of pagePatients and methodsPatient SelectionLichen sclerosus without progression Patients with lichen sclerosus who were not diagnosed with a subsequent vulvar squamous cell carcinoma were selected from the vulvar outpatient clinic at the Department of Obstetrics and Gynecology of the Radboud University Nijmegen Medical Centre (The Netherlands). We used the nationwide Netherlands database of Cytopathology and Histopathology (PALGA)21 to confirm that these patients did not develop a vulvar squamous cell carcinoma with a minimum follow up of 10 years.
Lichen sclerosus with progression Patients with vulvar squamous cell carcinoma who were treated at the Departments of Obstetrics and Gynecology of the Radboud University Nijmegen Medical Centre or at the University Medical Centre Groningen between 1 January 1988 and 31 December 2008 were selected for this study. Using PALGA, all previous vulvar biopsies with the diagnoses Sclerosus (et atrophicus) and dystrophy were retrieved. When multiple previous biopsies were available from different moments, the most recent biopsy was included for this study (with a minimum interval between the biopsy and vulvar squamous cell carcinoma of 3 months). In case multiple biopsies were taken at the same time, the lesion with the most severe dysplastic characteristics was selected.
The hematoxylin and eosin (H slides were retrieved and reviewed by two expert gynecopathologists (JB and HH) independently and unaware of the course of the patient. Discrepancies were resolved in a consensus meeting with these two gynecopathologists. In the analyses, we categorized the diagnoses of vulvar dystrophy and lichen sclerosus together, because in earlier days, the term dystrophy was used for the same entity as lichen sclerosus. Concordance between the original and revised diagnosis was calculated.
Collected DataPatients age, time of diagnosis of squamous cell carcinoma and time to progression were obtained from medical charts and electronic patient files. All slides were scored on the presence of hyperkeratosis, parakeratosis (Figures 1b and 3d), dyskeratosis (Figure 3c), hyperplasia (Figure 1b), basal cellular atypia (Figure 2), presence of mitotic figures (Figure 3f), edema, hyalinization (Figure 1a) and presence of subepithelial inflammation (Figure 1a). In addition, we examined the presentation of rete ridges (Figure 3b), basal cell layer (Figure 3c) and epithelial thickness.
Figure 2.
Lichen sclerosus with basal cell atypia. Lichen sclerosus with basal cell atypia (original magnification, 200), inset: magnification 400.
Full figure and legend (142K)
Statistical AnalysisCalculations were performed using Statistical Package for Social Sciences 16.0 (SPSS, Chicago, IL, USA).
Top of pageResultsLichen Sclerosus without ProgressionA total of 61 patients with lichen sclerosus without progression and a minimal follow up of 10 years were retrieved from the pathology archives of the Radboud University Nijmegen Medical Centre. The median age at the time of diagnosis was 59.5 years (range 16 years). Three biopsies did not fulfill the criteria for lichen sclerosus and were excluded,replica van cleef and arpels gold bracelet. In 58 of the 61 cases (95 the diagnosis was not changed.
Lichen Sclerosus with ProgressionDuring the study period 1988 273 patients with vulvar squamous cell carcinoma were treated in Nijmegen and 548 patients were treated in Groningen. In Nijmegen, 33 cases that met the criteria of a previous biopsy with Sclerosus (et atrophicus) or dystrophy were identified and 72 in Groningen. Of these 105 cases, a total of 60 biopsies were received from the pathology archives of the Radboud University Nijmegen Medical Centre Medical Centre Groningen and from the referring hospitals in the surrounding areas. We did not receive the 35 biopsies that we requested from the hospitals where the biopsies were taken, and 10 biopsies were excluded from analyses for different reasons (poor quality H staining (n or slides with too little tissue to review (n study population consisted of 60 lichen sclerosus patients with progression to vulvar squamous cell carcinoma. The median age at the time of diagnosis of lichen sclerosus was 64.6 years (range 30 years). In total, diagnoses of 42 biopsies were changed by the two expert gynecopathologists (70 Of the 60 (42 lesions, 25 were previously diagnosed as lichen sclerosus, but that did progress to squamous cell carcinoma, were reclassified as differentiated VIN (Figure 3). The biopsies that were changed into differentiated VIN mainly came from the original diagnosis categories of lichen sclerosus with an associated lesion such as an HPV induced lesion (VIN I, III, Morbus Bowen, Buschke L or from lichen sclerosus with hyperplasia,van cleef rose gold bracelet replica, atypia or both. The highest percentage of concordance between the original and changed diagnoses was achieved for lichen sclerosus without an associated lesion (43 The original and revised diagnoses are given in Table 1. Of all biopsies, six were not classified as lichen sclerosus VIN. A total of 29 biopsies were diagnosed as lichen sclerosus, of which 1 was classified as early lichen sclerosus (categorized as lichen sclerosus),22 and 3 were classified as lichen sclerosus with hyperplasia (Figure 1b). Five lichen sclerosus biopsies had basal cellular atypia (Figure 2), and two biopsies were classified as lichen sclerosus with hyperplasia and basal cellular atypia. These seven biopsies did not comply with other criteria for differentiated VIN.
Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma
Hedwig P van de Nieuwenhof1,van cleef alhambra bracelet replica, Johan Bulten2, Harrie Hollema3, Rianne G Dommerholt4, Leon F A G Massuger1, Ate G J van der Zee5, Joanne A de Hullu1 and Leon C L T van Kempen2Received 1 June 2010; Revised 2 August 2010; Accepted 4 August 2010; Published online 5 November 2010. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past,replica vca sweet alhambra bracelet, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30 Of 60 lesions, 25 (42 were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (P Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P dyskeratosis (P hyperplasia (P and basal cellular atypia (P compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma.
There are two different pathways leading to vulvar squamous cell carcinoma with their own premalignant lesions; the most common pathway, which accounts for 80 of all squamous cell carcinomas, is HPV independent,2 but its etiology is still unknown. These, mostly differentiated keratinizing, squamous cell carcinomas often arise in lichen sclerosus, and it has therefore been suggested that lichen sclerosus is the precusor lesion of squamous cell carcinoma.3, 4, 5 Lichen sclerosus is a chronic inflammatory skin disease and mainly affects the female anogenital area.6, 7 The classical histological findings of lichen sclerosus are a thinned epidermis and the loss of rete ridges, hyperkeratosis, edema and hyalinization, as well as a chronic band like inflammatory cell infiltrate of the dermis8 (Figure 1a), but there are a lot of variations to these classical histological characteristics, leading to a myriad of lesions that may be classified as lichen sclerosus.
Figure 1.
Classical cases of lichen sclerosus. (a) Typical example of lichen sclerosus with a thinned epidermis and a loss of rete ridges, hyperkeratosis, hyalinization and a chronic band like inflammatory cell infiltrate of the dermis. (b) Lichen sclerosus with hyperkeratosis and hyperplasia. Original magnification, panels a and b: 100.
Full figure and legend (406K)
It has been hypothesized more recently that differentiated vulvar intraepithelial neoplasia (VIN) is the direct precursor of vulvar squamous cell carcinoma. Differentiated VIN (Figure 3a) is often found directly adjacent to squamous cell carcinoma and is characterized by a thickened epithelium that is typically associated with the elongation and anastomosis of rete ridges (Figure 3b). Dyskeratosis and parakeratosis are usually present (Figures 3c and d), associated with prominent intercellular bridges (Figure 3b). Basal keratinocytes are large and pleomorphic with a relatively large amount of eosinophilic cytoplasm. Keratin pearl formation within the rete ridge may be seen. The nuclear chromatin is vesicular rather than coarse, and the nuclei have prominent nucleoli (Figure 3e), usually most prominently in the basal and parabasal keratinocytes.8 Although differentiated VIN is seen adjacent to 80 of vulvar squamous cell carcinomas,2 it is seldom diagnosed as a solitary lesion,10 which may be explained by underdiagnosis due to its difficult recognition11, 12, 13 or due to its short intraepithelial phase.10 It has been hypothesized that differentiated VIN may develop from lichen sclerosus and that it carries a higher malignant potential than lichen sclerosus does,3, 13, 14, 15, 16, 17 but its role as a premalignant lesion has not been accepted by all pathologists.18 We hypothesize that of all lesions that have been diagnosed as lichen sclerosus in the past, a substantial part might currently be diagnosed as differentiated VIN.
Figure 3.
Differentiated vulvar intraepithelial neoplasia. Low power overview of differentiated VIN (a) with the five most important histopathological characteristics that can be recognized in an H stain: elongated rete ridges with anastomosis (b), disorderly basal cell layer and dyskeratosis (c), parakeratosis (d), prominent nucleoli (e) and atypical mitoses, indicated by arrows (f). Original magnifications: 50 (panel a), 100 (panels b and d), 200 (panels c and e) and 400 (panel f).
Full figure and legend (594K)
The terminology and criteria for the diagnosis of lichen sclerosus have been subjected to quite some revisions in the past 40 years,19, 20 and this has unevitably led to the diagnoses of lichen sclerosus that would currently be classified differently, including differentiated VIN.
It is currently unknown which lichen sclerosus lesion carries the risk of malignant progression. This is in part due to the wide variety of histopathological entities that have been collectively diagnosed as lichen sclerosus in the past. The first aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part would currently be diagnosed as differentiated VIN. The second aim was to determine whether, in retrospect, there are histopathological differences between lichen sclerosus lesions that did and did not progress to vulvar squamous cell carcinoma. Recognition of the lichen sclerosus at risk for squamous cell carcinoma development would greatly help to select patients who need close follow up.
Top of pagePatients and methodsPatient SelectionLichen sclerosus without progression Patients with lichen sclerosus who were not diagnosed with a subsequent vulvar squamous cell carcinoma were selected from the vulvar outpatient clinic at the Department of Obstetrics and Gynecology of the Radboud University Nijmegen Medical Centre (The Netherlands). We used the nationwide Netherlands database of Cytopathology and Histopathology (PALGA)21 to confirm that these patients did not develop a vulvar squamous cell carcinoma with a minimum follow up of 10 years.
Lichen sclerosus with progression Patients with vulvar squamous cell carcinoma who were treated at the Departments of Obstetrics and Gynecology of the Radboud University Nijmegen Medical Centre or at the University Medical Centre Groningen between 1 January 1988 and 31 December 2008 were selected for this study. Using PALGA, all previous vulvar biopsies with the diagnoses Sclerosus (et atrophicus) and dystrophy were retrieved. When multiple previous biopsies were available from different moments, the most recent biopsy was included for this study (with a minimum interval between the biopsy and vulvar squamous cell carcinoma of 3 months). In case multiple biopsies were taken at the same time, the lesion with the most severe dysplastic characteristics was selected.
The hematoxylin and eosin (H slides were retrieved and reviewed by two expert gynecopathologists (JB and HH) independently and unaware of the course of the patient. Discrepancies were resolved in a consensus meeting with these two gynecopathologists. In the analyses, we categorized the diagnoses of vulvar dystrophy and lichen sclerosus together, because in earlier days, the term dystrophy was used for the same entity as lichen sclerosus. Concordance between the original and revised diagnosis was calculated.
Collected DataPatients age, time of diagnosis of squamous cell carcinoma and time to progression were obtained from medical charts and electronic patient files. All slides were scored on the presence of hyperkeratosis, parakeratosis (Figures 1b and 3d), dyskeratosis (Figure 3c), hyperplasia (Figure 1b), basal cellular atypia (Figure 2), presence of mitotic figures (Figure 3f), edema, hyalinization (Figure 1a) and presence of subepithelial inflammation (Figure 1a). In addition, we examined the presentation of rete ridges (Figure 3b), basal cell layer (Figure 3c) and epithelial thickness.
Figure 2.
Lichen sclerosus with basal cell atypia. Lichen sclerosus with basal cell atypia (original magnification, 200), inset: magnification 400.
Full figure and legend (142K)
Statistical AnalysisCalculations were performed using Statistical Package for Social Sciences 16.0 (SPSS, Chicago, IL, USA).
Top of pageResultsLichen Sclerosus without ProgressionA total of 61 patients with lichen sclerosus without progression and a minimal follow up of 10 years were retrieved from the pathology archives of the Radboud University Nijmegen Medical Centre. The median age at the time of diagnosis was 59.5 years (range 16 years). Three biopsies did not fulfill the criteria for lichen sclerosus and were excluded,replica van cleef and arpels gold bracelet. In 58 of the 61 cases (95 the diagnosis was not changed.
Lichen Sclerosus with ProgressionDuring the study period 1988 273 patients with vulvar squamous cell carcinoma were treated in Nijmegen and 548 patients were treated in Groningen. In Nijmegen, 33 cases that met the criteria of a previous biopsy with Sclerosus (et atrophicus) or dystrophy were identified and 72 in Groningen. Of these 105 cases, a total of 60 biopsies were received from the pathology archives of the Radboud University Nijmegen Medical Centre Medical Centre Groningen and from the referring hospitals in the surrounding areas. We did not receive the 35 biopsies that we requested from the hospitals where the biopsies were taken, and 10 biopsies were excluded from analyses for different reasons (poor quality H staining (n or slides with too little tissue to review (n study population consisted of 60 lichen sclerosus patients with progression to vulvar squamous cell carcinoma. The median age at the time of diagnosis of lichen sclerosus was 64.6 years (range 30 years). In total, diagnoses of 42 biopsies were changed by the two expert gynecopathologists (70 Of the 60 (42 lesions, 25 were previously diagnosed as lichen sclerosus, but that did progress to squamous cell carcinoma, were reclassified as differentiated VIN (Figure 3). The biopsies that were changed into differentiated VIN mainly came from the original diagnosis categories of lichen sclerosus with an associated lesion such as an HPV induced lesion (VIN I, III, Morbus Bowen, Buschke L or from lichen sclerosus with hyperplasia,van cleef rose gold bracelet replica, atypia or both. The highest percentage of concordance between the original and changed diagnoses was achieved for lichen sclerosus without an associated lesion (43 The original and revised diagnoses are given in Table 1. Of all biopsies, six were not classified as lichen sclerosus VIN. A total of 29 biopsies were diagnosed as lichen sclerosus, of which 1 was classified as early lichen sclerosus (categorized as lichen sclerosus),22 and 3 were classified as lichen sclerosus with hyperplasia (Figure 1b). Five lichen sclerosus biopsies had basal cellular atypia (Figure 2), and two biopsies were classified as lichen sclerosus with hyperplasia and basal cellular atypia. These seven biopsies did not comply with other criteria for differentiated VIN.
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