Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma

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.     

Early gastric neoplasia: diagnosis and implications

Early gastric neoplasia, which includes dysplasia and adenocarcinoma invading no more than the submucosa have been the subject of numerous studies in recent years. For example, different dysplastic phenotypes have been identified, in addition to the traditional adenomatous type, foveolar, pyloric, and tubule-neck dysplasia (associated with diffuse type carcinoma) have been recognized. Each subtype of dysplasia shows a different immunohistochemical profile, and may vary in their risk of progression to adenocarcinoma. With regard to early gastric cancer the emergence of better diagnostic techniques allowed the development of endoscopic techniques such as endoscopic mucosal resection and endoscopic submucosal resection that nowadays allow optimal nonsurgical management. The purpose of this review is to discuss the current concepts in gastric dysplasia and early gastric cancer as they relate to diagnosis and management.     

Presence and type of oncogenic human papillomavirus in classic and in differentiated vulvar intraepithelial neoplasia and keratinizing vulvar squamous cell carcinoma

The presence and type of oncogenic papillomavirus (HPV) in classic warty/basaloid vulvar intraepithelial neoplasia and in differentiated vulvar intraepithelial neoplasia and keratinizing vulvar squamous cell carcinoma was investigated using three techniques, that is, histology, in situ hybridization, and PCR-ELISA. HPV typing was performed using in situ hybridization and PCR-ELISA. Differentiated vulvar intraepithelial neoplasia and invasive keratinizing vulvar squamous cell carcinoma proved completely negative for HPV by PCR-ELISA, in situ hybridization, and histologic examination, while in classic vulvar intraepithelial neoplasia, a HPV positivity of 66.1% was found. HPV 16 was the predominant type, with HPV 35, 33, and 52 types found rarely and sometimes together with HPV 16. PCR-ELISA proved to be the most suitable method to detect and type mucosal oncogenic HPVs. The absolute absence of HPV DNA in differentiated vulvar intraepithelial neoplasias and in keratinizing vulvar squamous cell carcinoma suggests a strong HPV-independent pathway of malignant progression to invasive carcinoma.     

Hodgkin's disease: classification and differential diagnosis.

During the past decade, there have been many advances in our understanding of Hodgkin's disease. Among the most important is the discovery that the Reed-Sternberg cell is a lymphoid cell, in most cases a B cell, and that it is clonal. Hodgkin's disease is thus a true lymphoma, deserving of a name change to Hodgkin's lymphoma (HL). On the basis of a combination of immunophenotype and morphologic features, the Revised European-American classification system recognizes two main types of HL: classical types (nodular sclerosis, mixed cellularity, lymphocyte-rich classical HL, and lymphocyte depletion) and nodular lymphocyte-predominant type. These two types probably are distinct biologic entities. The immunophenotype and genetic features of the classical HL and the nodular lymphocyte-predominant type have been defined. These are useful in the subclassification of HL and in distinguishing HL from two recently described, aggressive lymphomas that were in the past often diagnosed as HL, i.e., anaplastic large-cell lymphoma, T-cell type, and T-cell/histiocyte-rich large B-cell lymphoma. Epstein-Barr virus has been detected in approximately 40% of the cases of classical HL, and it is clonal; this suggests that this virus might play a role in the pathogenesis of at least some types of HL. Alternatively, its presence might simply reflect the prevalence of Epstein-Barr virus-infected B cells in the individual. Despite the advances of the past 10 years, many questions remain to be answered; these will provide the challenges of the next decade.     

Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development

van de Nieuwenhof H P, Hebeda K M, Bulten J, Otte‐Holler I, Massuger L F A G, de Hullu J A & van Kempen L C L T
(2010) Histopathology 57, 351–362
Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development Aims: The aetiology of vulvar squamous cell carcinomas (SCC) that are not causally associated with high‐risk human papillomavirus remains largely elusive. The aim of this study was to analyse the inflammatory response in its presumed precursor lesions, lichen sclerosus (LS) and differentiated vulvar intraepithelial neoplasia (dVIN), and provide evidence that dVIN is a likely precursor of vulvar SCC. Methods and results: Immunohistochemical analyses for CD4+, CD8+, CD20+, CD68+, S100+ and tryptase‐positive immune cells were performed and quantified in LS (n = 7), dVIN (n = 19), SCC (n = 11), and normal vulvar tissue (n = 8). The subepithelial inflammatory response in dVIN and SCC was comparable, but absent in LS. Abundant intraepithelial mast cells were observed in dVIN only, and confirmed by electron microscopy, toluidine blue staining and cKIT expression. Adjacent keratinocytes displayed increased proliferation as determined by MIB‐1 positivity. Electron microscopy revealed intraepithelial mast cell degranulation. Intraepithelial mast cells were not or infrequently observed in vulvar hyperplasia (n = 13), condylomata acuminata (n = 5), keratinocytic intraepidermal neoplasia of sun‐exposed skin (n = 15), epidermal hyperplasia of head and neck (n = 12), and psoriasis (n = 3). Conclusions: These data indicate that dVIN can be recognized by intraepithelial mast cells and that they might promote the progression of dVIN to SCC.     

Sporadic adenoma and colitis-associated intraepithelial neoplasia: a difficult differential diagnosis

The differential diagnosis between sporadic adenoma and colitis-associated neoplasia is difficult. Clinical, histological and molecular genetic methods are available to recognise a difference between these two entities. The aim of the present analysis was to check known criteria in a large series of patients and 352 patients with ulcerative colitis and concomitant intraepithelial neoplastic lesions [149 adenomas (A), 123 colitis-associated intraepithelial neoplasias (N), 80 carcinomas (K)] were investigated. Clinical history helped to identify patients with sporadic adenoma since patients with colitis-associated neoplastic lesions presented with different data such as age (A: 61.3+/-13 years, N: 48.4+/-16.4 years, K: 53.9+/-16.9 years), duration of disease (A: 6.9+/-8.1 years, N: 11.9+/-10 years, K: 13.6+/-9.6 years), frequency of pancolitis (A: 28.6%, N: 56.3%, K: 48.3%) and frequency of solitary lesions (A: 83.7%, N: 23.1%, K: 51.9%). The differential diagnosis between adenoma and colitis-associated neoplasia in patients with ulcerative colitis appears to be possible but the diagnosis should only be made in the remission phase. Furthermore the patients need a careful endoscopic and bioptic follow-up. If in doubt one should consider colitis-associated neoplasia especially when there are multiple intraepithelial neoplastic lesions. Long-term follow-up studies are urgently needed.     

Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias.

Squamous neoplasms of the female genital tract, including vulvar intraepithelial neoplasia, presumably are derived from a single cell. This study addressed this hypothesis and determined the clonal status of other squamous epithelial alterations associated with vulvar carcinoma, including hyperplasia and lichen sclerosis. X chromosome inactivation patterns of 22 epithelial lesions and matched normal epithelium were determined using a polymerase chain reaction (PCR)-based assay targeting the X-linked human androgen receptor gene (HUMARA). Clonality was inferred by comparing matched lesional and control tissues as follows: 1) monoclonal, if intensity of either PCR product was skewed relative to normal reference epithelium (control), 2) polyclonal, if both lesional and control were unskewed, and 3) unknown, if both lesion and control tissues were skewed toward the same allele. Two cases were excluded because of noninformative homozygous HUMARA alleles. Of 8 vulvar intraepithelial neoplasias analyzed, 7 were scored monoclonal and 1 polyclonal. Of 12 hyperplasias, 6 were monoclonal, including one with lichen sclerosis, 2 were polyclonal, and in 4, the clonal status could not be determined. The PCR-based clonal assay supports a monoclonal derivation for vulvar intraepithelial neoplasia and, in some cases, vulvar hyperplasia, and lichen sclerosis. The finding of monoclonal hyperplasia and lichen sclerosis suggests that clonal expansion may evolve before the development of morphological atypia in these epithelia.     

Langerhans cells in vulvar lichen sclerosus and vulvar squamous cell carcinoma

Introduction: Langerhans cells (LCs), specializing in antigen presentation, are a very important part of the skin immune system (SIS). Materials and Methods: Skin biopsies from 22 women with vulvar lichen sclerosus (LS): 15 patients with early and 7 with the late stage of the disease, were evaluated. Five women with vulvar squamous cell carcinoma (SCC) were also examined. The control group consisted of 9 women who underwent plastic surgery of the vulvar region. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissues samples using antihuman CD1a antibody (NCL-CD1a-235, Novocastra). Results: Increased numbers of LC stainings were present in early LS, whereas decreased numbers of these cells were present in late LS and in SCC compared with the control group. Conclusions: This study showed that dysregulation of the SIS may lead to suppression of LCs in the vulvar epithelium and may be one of the reasons for a higher tendency for carcinogenesis in the vulvar region.     

乳腺小叶肿瘤组织学亚型及其分子病理学研究进展

第5版WHO乳腺肿瘤分类(2019), 将小叶瘤变定义为"起源于终末导管小叶单位(terminal ductal lobular units)失黏附上皮细胞的不典型增生, 伴或不伴有终末导管的派杰样播散"。小叶瘤变包括不典型小叶增生(atypical lobular hyperplasia)和小叶原位癌(lobular carcinoma in situ)。根据细胞形态将小叶原位癌细分为经典型小叶原位癌、旺炽型小叶原位癌和多形性小叶原位癌3种组织学亚型。近年来, 随着分子病理学不断发展, 对组织学形态特征的认识不断深入, 加深了对小叶瘤变及其亚型的研究和分析。本文将对小叶肿瘤各组织学亚型的临床病理学特征和分子病理学等方面进行综述。     

乳腺小叶肿瘤组织学亚型及其分子病理学研究进展

第5版WHO乳腺肿瘤分类(2019), 将小叶瘤变定义为"起源于终末导管小叶单位(terminal ductal lobular units)失黏附上皮细胞的不典型增生, 伴或不伴有终末导管的派杰样播散"。小叶瘤变包括不典型小叶增生(atypical lobular hyperplasia)和小叶原位癌(lobular carcinoma in situ)。根据细胞形态将小叶原位癌细分为经典型小叶原位癌、旺炽型小叶原位癌和多形性小叶原位癌3种组织学亚型。近年来, 随着分子病理学不断发展, 对组织学形态特征的认识不断深入, 加深了对小叶瘤变及其亚型的研究和分析。本文将对小叶肿瘤各组织学亚型的临床病理学特征和分子病理学等方面进行综述。     

The importance of multiple endocrine neoplasia syndromes in differential diagnosis

Summary In the differential diagnosis of endocrine symptoms, the autosomal dominant multiple endocrine neoplasia (MEN) syndromes are rare but important. We found seven index cases of MEN-I in 176 patients with adenomas of the anterior pituitary and 26 patients with primary hyperparathyroidism. Of 23 cases of medullary thyroid carcinoma and eight cases of pheochromocytoma, 14 patients are classified as MEN-IIa and one as MEN-IIb. Family screening identified six MEN-I and seven MEN-II cases among 32 individuals examined. Because of autosomal dominant inheritance and sometimes-delayed manifestation of the complete syndrome, screening of healthy and affected family members should be repeated at least every other year.     

Early diagnosis of multiple endocrine neoplasia type IIa

Summary We report on incidental findings during family screening of two kindreds with multiple endocrine neoplasia type IIa. Pheochromocytoma and medullary thyroid carcinoma of considerable size were detected. The results underline the importance of early diagnosis of the syndrome, since the afflicted may be almost or wholly asymptomatic. High resolution chromosome banding studies were carried out in both families, but no abnormality was found. Linkage analysis using DNA markers closely related to the chromosomal locus at chromosome 10 was carried out and was positive in two asymptomatic offspring of one family, whereas the markers were not informative in a second family. We recommend early linkage analysis for establishing the genetic status in offspring of multiple endocrine neoplasia type IIa families to identify for further screening those who are predicted to be gene carrier.Abbreviations MEN Multiple endocrine neoplasia - Q-Banding=QFQ-Banding Q-bands labeled by quinacrine florescence using quinacrine staining - R-Banding=RBA-Banding R-bands labeled by BrdU incorporation and acridine-orange staining - BrdU Bromodeoxyuridine - RFLP Restriction fragment length polymorphism - MIBG Metaiodobenzylguanidine     

Recent advances in the diagnosis,classification and molecular pathogenesis of cutaneous mesenchymal neoplasms

The diagnosis of cutaneous mesenchymal neoplasms remains challenging, due to a combination of overlapping histological features, the rarity of some diagnoses and often inadequate sampling in superficial biopsies. Here, we describe recent advances in cutaneous mesenchymal neoplasms. We discuss improvements in our understanding of the molecular pathogenesis of non-neural granular cell tumour, epithelioid fibrous histiocytoma, composite and retiform haemangioendothelioma and dermatofibrosarcoma protuberans. We also discuss recently described tumour types, including some discovered via molecular testing: EWSR1::SMAD3-rearranged fibroblastic tumour, clear cell neoplasm with MITF::CREM rearrangement and melanocytoma with CRCT1::TRIM11 rearrangement, and some discovered via traditional histopathology: superficial CD34-positive fibroblastic tumour, plexiform myofibroblastoma and clear cell neoplasm with melanocytic differentiation and ACTIN::MITF translocation.     

Global DNA methylation evaluation: potential complementary marker in differential diagnosis of thyroid neoplasia

The implications of global DNA hypomethylation were recently reported in several models of tumorigenesis. Little is known about this epigenetic event in thyroid neoplasia. The study aimed to evaluate the status of global DNA methylation in several types of thyroid tumors using a monoclonal antibody specific for 5-methylcytidine (5-mc) and to define the diagnosis potential of this marker. 5-mc immunostaining scores were calculated in 17 papillary thyroid carcinomas (PTC), 6 follicular thyroid carcinomas (FTC), 16 follicular adenomas (FA), 19 nodular goiters (NG) and ten Hürthle cells adenomas (HCA). The expression of galectin-3 was also evaluated. Computerized image analysis showed a significant lower level of 5-mc immunostaining in thyroid carcinoma when compared with benign tumors or adjacent normal thyroid parenchyma (P<0.0001). Overall, 5-mc accuracy to distinguish malign from benign thyroid tumors was similar to that of galectin-3 (89% versus 87%, P>0.05). The combination of 5-mc with galectin-3 led to an excellent accuracy level of 96%. Among follicular neoplasia 5-mc accuracy to differentiate malign tumors trends to be higher than galectin-3 one (90% versus 66%, P=0.06). These data stress the necessity of epigenetic events evaluation among thyroid nodules and propose global DNA methylation assessment as a potential diagnostic tool to combine with other valuable markers.     

Alterations of the p16/Rb/cyclin-D1 pathway in vulvar carcinoma,vulvar intraepithelial neoplasia,and lichen sclerosus

Three different alterations in the p16/pRb/cyclin-D1 pathway (p16(INK4a)-promoter hypermethylation and expression of pRb and cyclin-D1) were investigated in a series of 38 cases of vulvar carcinoma (VC), 13 cases of vulvar intraepithelial neoplasia (VIN), and 21 cases of lichen sclerosus (LS). Paraffin blocks from 72 patients were selected for investigation of DNA methylation patterns in the CpG island of p16(INK4a) by methylation-specific polymerase chain reaction. Immunohistochemical studies for pRb and cyclin-D1 were performed using the standard avidin-biotin-peroxidase complex method. Epigenetic silencing of p16(INK4a) was detected in 68% of VC, 69.2% of VIN, and 42.8% of LS cases. Lack of pRb protein was found in 21% of VC, 0% of VIN, and 0% of LS cases. Overexpression of cyclin-D1 was found in 21% of VC, 30.8% of VIN, and 0% of LS cases. We conclude (1) that p16(INK4a) epigenetic inactivation most likely represents an early event, insufficient for malignant transformation, that may occur in clinically benign lesions such as LS; (2) that lack of pRb was only detected in fewer than one quarter of the carcinomas and could be considered a late secondary event; and (3) that cyclin-D1, which was overexpressed in VC and VIN, could contribute to the malignant transformation in association with p16 hypermethylation.