Präneoplastische Läsionen und Vorstufen des Urothelkarzinoms

As even a mere thickening of the urothelium can harbor genetic changes identical to that of low grade papillary urothelial tumors, it is not always possible to clearly recognize a precursor lesion of urothelial carcinoma by routine histological diagnostics. Complementary immunohistochemical and molecular diagnostic methods assist the recognition of these entities. These methods especially help to identify clinically important genetically unstable cells as the hallmark of carcinoma in situ (CIS). Little is known about the clinical significance of the morphological subtypes of CIS, which range from large cell to micropapillary variants. For a better understanding of special types of bladder cancer (e.g. adenocarcinoma and squamous cell carcinoma), it seems to be important to define the phenotype and the molecular pattern of non-urothelial lesions, such as intestinal metaplasia and squamous metaplasia, better and more precisely.     

Pulmonary preinvasive neoplasia

Advances in molecular biology have increased our knowledge of the biology of preneoplastic lesions in the human lung. The recently published WHO lung tumour classification defines three separate lesions that are regarded as preinvasive neoplasia. These are (1) squamous dysplasia and carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIP-NECH). SD/CIS is graded in four stages (mild, moderate, severe, and CIS), based upon the distribution of atypical cells and mitotic figures. Most airways showing SD/CIS demonstrate a range of grades; many epithelia are hard to assess and the reproducibility of this complex system remains to be established. Detailed criteria are, however, welcome and provide an objective framework on which to compare various molecular changes. Alterations in gene expression and chromosome structure known to be associated with malignant transformation can be demonstrated in CIS, less so in dysplasias, but also in morphologically normal epithelium. The changes might be sequential, and their frequency and number increase with atypia. Less is known of the "risk of progression" of SD/CIS to invasive "central" bronchial carcinoma. It may take between one and 10 years for invasion to occur, yet the lesion(s) may be reversible if carcinogen exposure ceases. AAH may be an important precursor lesion for peripheral "parenchymal" adenocarcinoma of the lung: the "adenoma" in an adenoma-carcinoma sequence. There is good morphological evidence that AAH may progress from low to high grade to bronchioloalveolar carcinoma (BAC; a non-invasive lesion by definition). Invasion then develops within BAC and peripheral lung adenocarcinoma evolves. The molecular events associated with this progression are not well understood and studies are hampered by a lack of clear criteria to distinguish high grade AAH from BAC. Nonetheless, as with SD/CIS, the patterns of expression of tumour associated genes are consistent with neoplastic progression. We have little idea of the incidence of AAH in the normal or "smoking" populations. It is found more frequently in cancer bearing lungs, especially in those with adenocarcinoma, and is more common in women. No data are available on the risk of progression of AAH. DIPNECH is an exceptionally rare lesion associated with the development of multiple carcinoid tumours. Almost nothing is known of its biology. Knowledge of these lesions will be crucial in the design and understanding of lung cancer screening programmes, where it is likely that the morphological and, more importantly perhaps, the molecular characteristics of these lesions will provide useful targets for detection and possibly even treatment.     

Monoclonality of Atypical Adenomatous Hyperplasia of the Lung

Atypical adenomatous hyperplasia (AAH) of the lung has been postulated as a possible precursor lesion of bronchioloalveolar carcinoma (BAC). The clonality of AAHs from seven female patients was analyzed to determine whether AAH is a monoclonal expansion. All AAHs were identified in lungs surgically resected for BAC. The clonality of the BAC and bronchiolar metaplasia in each case was also analyzed. Approximately 500 cells in each lesion were precisely microdissected from methanol-fixed sections. Adjacent normal lung tissue was collected as a normal control. DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor gene (HUMARA). HUMARA was found to be amplified with or without previous digestion by the methylation-sensitive restriction endonuclease HpaII. Five cases were informative. All 10 AAHs and 7 BACs obtained from the informative cases showed monoclonality, whereas the control cells showed polyclonality. Three different AAH lesions in a single case showed both possible patterns of monoclonality. BAC and contiguous AAH showed identical monoclonality in two cases. Two lesions of bronchiolar metaplasia, which was considered reactive, were polyclonal. Our results demonstrated the monoclonal nature of AAH, and this finding suggests that AAH is a precursor of BAC or a preneoplastic condition.     

PATHOLOGICAL AND BIOLOGICAL CHARACTERISTICS OF INTERVAL BREAST CANCER

INTRODUCTION: Protocols for excision of mammographically detected lesions following core biopsy include all diagnoses of atypical ductal hyperplasia (ADH) or intraductal atypia of uncertain significance (AUS). The aims of this study were to look at: i) the prevalence of reporting ADH and AUS, ii) the proportion of cases where excision revealed breast carcinoma, iii) whether any cases could be downgraded to hyperplasia on review.
METHODS: Breast core biopsy reports from the SCGH Breast Centre for the years 1999–2000 were retrieved. The results of excision biopsy were obtained and slides reviewed.
RESULTS: There were 1048 core biopsies from 911 women. Breast carcinoma was diagnosed in 197 samples (18.8%) including 88 with invasive carcinoma (8.4%), 109 with ductal carcinoma in situ (10.4%) and 3 samples (2.9%) suspicious of invasive carcinoma. The suspicious cases all proved to be invasive carcinomas. There were 53 samples (5.1%) with a diagnosis of ADH or AUS. 46 were excised, showing 7 invasive carcinomas 15 DCIS, 11 ADH, 2 lobular carcinoma in situ (LCIS), 1 mucocoele-like lesion, 1 fibroadenoma and 9 fibrocystic change (FCC). The 22 malignancies represented 47.8% of the excised lesions. At review, 8 of the 53 original diagnoses were downgraded to benign hyperplasia; 5 underwent excision; 2 showed 'incidental' invasive carcinomas, 1 'incidental' LCIS, 1 ADH and 1 FCC.
CONCLUSIONS: There was a low prevalence of reporting of ADH and AUS in core biopsies (5.1%) and a high rate of carcinoma (47.8%) in subsequent excision biopsies. Very few diagnoses of ADH/AUS were downgraded at review. Current protocols for excision of lesions with a core biopsy diagnosis of ADH/AUS appear to be justified.     

Bracken fern-induced bladder tumors in guinea pigs. A model for human neoplasia.

We have induced tumors by feeding guinea pigs with a diet containing 25 or 30% dried bracken fern for 100 or 150 days. A high incidence of bladder tumors was obtained. All but one animal had preneoplastic or neoplastic lesions after 4 months; after one year, 24 or 25 exposed animals had carcinoma. Bladder tumors obtained were essentially pure transitional cell carcinomas, although 4 cases (7% of the exposed animals and 10% of the 39 transitional cell carcinoma observed) showed areas of focal squamous metaplasia. Immunohistological detection of cytokeratins 10, 13, and 18 confirmed the transitional nature of these tumors. Tumor development can be followed by ultrasonography and cytology. Bladder tumors arose through several steps. Dysplasia and preneoplastic hyperplasia were seen after 4 months and papillary carcinomas appeared after 6 months, whereas muscle-invasive carcinomas required 1 year. Thus this model reproduces the full spectrum of preneoplastic and neoplastic bladder lesions observed in humans. Interestingly, when tumors were induced in older guinea pigs, none of them progressed to a muscle-invasive stage. This phenomenon should provide the opportunity to study the molecular mechanisms associated with these two different growth patterns, a major issue in understanding human bladder tumor progression.     

Preneoplastic non-papillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation

BACKGROUND AND AIMS: This paper summarizes the work done by the members of the Committee no. 2 at the International Consultation on the Diagnosis of Non-Invasive Urothelial Neoplasms held in Ancona, Italy (11-12 May 2001). The committee members discussed and reached consensus regarding the optimal contemporary diagnosis and classification of the preneoplastic non-papillary lesions of the urothelium. An important objective was to promote a precise terminology and to use it consistently in daily practice in pathology and urology. RESULTS AND CONCLUSIONS: The result of the meeting is represented by a refined classification of the non-papillary intraepithelial lesions and conditions of the urothelium. This classification includes epithelial abnormalities (reactive urothelial atypia and flat urothelial hyperplasia), presumed preneoplastic lesions and conditions (keratinizing squamous and glandular metaplasia, and malignancy-associated cellular changes), as well as preneoplastic (dysplasia) and neoplastic non-invasive (carcinoma in situ) lesions. Each of these lesions is defined with strict morphological criteria in order to provide more accurate information to urologists in managing patients.     

Precursor lesions of the urinary bladder

The classification of neoplastic precursor lesions in the urinary tract has evolved slowly with the gradual accumulation of clinicopathological data. Current nomenclature was codified most recently by the 2016 WHO classification, which is based on primary data with clinical outcome, consensus group statements and considerations of practical utility in routine diagnosis. This review discusses precursor lesions of urothelial, squamous and glandular lineage. For urothelial neoplasia, both flat lesions with atypia and early ‘difficult‐to‐classify’ proliferations are considered. Subtypes of squamous metaplasia, florid non‐invasive squamous proliferations and frank squamous dysplasia are also addressed. Finally, rare glandular precursors of adenocarcinoma are reviewed, to include intestinal metaplasia, glandular dysplasia and villous adenoma. For each category, morphology (including differential diagnostic considerations), immunohistochemistry and any known molecular correlates are detailed. The goal is to provide a concise, practical up‐to‐date overview of this complex topic.     

So-called "superficial" bladder tumors. Which classification in 2003? Part 2: Flat urothelial lesions

Flat urothelial lesions of the urinary bladder have been recently discussed by the International Society of Urological Pathology (ISUP) in 1998 and more recently redefined by an international consultation held in Ancona, Italy in 2001. This paper summarizes and illustrates the recent literature about non-papillary lesions of the urinary bladder. Flat urothelial lesions include: epithelial abnormalities (reactive urothelial atypia and flat hyperplasia), preneoplastic lesion (dysplasia) and neoplastic non invasive carcinoma (carcinoma in situ) and a new category of presumed neoplastic lesions and conditions; the latter points out to a notion of tumor biology, which may help to the understanding of urothelial carcinogenesis.     

Pulmonary preneoplasia – sequential molecular carcinogenetic events

Bronchial and bronchioloalveolar carcinogenesis is a multicentric and multistep process, leading to a sequential accumulation of molecular and genetic abnormalities, mainly due to exposure to tobacco carcinogens. Concomitantly, a series of morphological alterations of normal bronchial or bronchioloalveolar epithelium occur, resulting in preneoplastic and then neoplastic lesions. The three pulmonary preneoplastic changes recognized to date in the lung include bronchial squamous dysplasia and in situ carcinoma, preceding invasive squamous cell carcinoma and basaloid carcinoma, atypical adenomatous hyperplasia, a preneoplastic condition of bronchioloalveolar carcinoma, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a proposed precursor for carcinoid tumours. Although the gradual accumulation of molecular alterations has been widely investigated in bronchial carcinogenesis, with the aim of determining new biomarkers for early lung cancer detection in high-risk patients and targeted chemoprevention, lung adenocarcinoma pathogenesis has been only recently highlighted, with the recent discovery of epidermal growth factor receptor mutation pathway in non-smokers. This review focuses on the current status of molecular pathology in lung cancer and pulmonary preneoplastic conditions.     

Prognostic significance of atypical papillary urothelial hyperplasia

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.     

Identification of chromosome 9 alterations and p53 accumulation in isolated carcinoma in situ of the urinary bladder versus carcinoma in situ associated with carcinoma

Carcinoma in situ (CIS) of the urinary bladder is a flat, aggressive lesion and may be the most common precursor of invasive bladder cancer. Although chromosome 9 alterations are among the earliest and most prevalent genetic alterations in bladder cancer, discrepancy exists about the frequency of chromosome 9 losses in CIS. We analyzed 22 patients with CIS of the bladder (15 patients with isolated CIS, 7 patients combined with synchronous pTa or pT1 carcinomas) for gains and losses of chromosome (peri)centromere loci 1q12, 7p11-q11, 9p11-q12, and 9p21 harboring the INK4A/ARF locus (p16(INK4A)/p14(ARF)) and INK4B (p15(INK4B)) by multiple-target fluorescence in situ hybridization, and for p53 protein accumulation by immunohistochemistry. In 15 of 20 (75%) CIS lesions analyzed p53 overexpression was detected, whereas aneusomy for chromosomes 1 and 7 was identified in 20 of 22 (91%) CIS. In 13 of 22 (60%) CIS cases analyzed, 12 of which were not associated with a synchronous pTa or pT1 carcinoma, no numerical losses for chromosome 9 (p11-q12 and 9p21) were detected as compared with chromosomes 1 and 7. Furthermore 6 of 12 (50%) patients showed a metachronous invasive carcinoma within 2 years. In the remaining nine biopsies CIS lesions (40%) were recognized that showed losses of chromosome 9p11-q12 and 9p21, six of these were associated with a synchronous pTa or pT1 carcinoma. Three of these carcinomas were pTa and exhibited loss of 9q12 as well as a homozygous deletion of 9p21. The others were invasive carcinomas in which CIS lesions were also recognized that showed no numerical loss of chromosome 9, but did show an accumulation of p53. In conclusion our data demonstrate that predominantly isolated CIS lesions contained cells with no specific loss of chromosome 9, as opposed to CIS lesions with synchronous carcinomas that showed evidence of chromosome 9 loss. Furthermore our data strengthen the proposition that p53 mutations (p53 overexpression) precede loss of chromosomes 9 and 9p21 in CIS as precursor for invasive bladder cancer, as opposed to noninvasive carcinomas where chromosome 9 (9p11-q12) losses are early and frequently combined with homozygous deletions of 9p21.     

Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett's metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.     

Salivary gland hyperplasia

Thirteen cases of adenomatous ductal hyperplasia (ADH) of the major salivary glands coexisting with salivary gland tumors or chronic parotitis are reported. The proliferating ducts have the morphology and immunohistochemistry similar to intercalated duct epithelium. Adenomatous ductal hyperplasia is compared to adenomatoid acinar hyperplasia (AAH), a lesion found predominantly in intraoral salivary glands and histologically composed of hyperplastic acinar cells. The exact nature of both lesions is not clear. However, ADH may be a precursor lesion of salivary gland tumors (especially epithelial-myoepithelial carcinomas), whereas AAH may represent a reactive process of idiopathic nature.     

Molecular cytogenetic comparison of apocrine hyperplasia and apocrine carcinoma of the breast

The relationship of apocrine metaplasia to invasive breast cancer is controversial. Different authors have reported that apocrine differentiation in proliferative lesions may be a risk factor, a precursor lesion, or have no association with malignancy. The aim of this study was to compare the genetic alterations in benign apocrine hyperplasia with apocrine ductal carcinoma in situ (DCIS) and invasive apocrine carcinomas of the breast using comparative genomic hybridization. The mean number of alterations in apocrine hyperplasia was 4.1 (n = 10) compared to 10.2 in apocrine DCIS (n = 10) and 14.8 (n = 4) in invasive carcinoma. The most common alterations in apocrine hyperplasia were gains of 2q, 13q, and 1p and losses of 1p, 17q, 22q, 2p, 10q, and 16q. Apocrine DCIS and invasive carcinomas showed gains of 1q, 2q, 1p, and losses of 1p, 22q, 17q, 12q, and 16q as their most common DNA copy number changes. Apocrine hyperplasia is considered to be a benign lesion and its relationship to invasive carcinoma remains unclear. Our data suggest that some apocrine hyperplasias may be clonal proliferations. The mean number of alterations are lower in apocrine hyperplasia, however the changes show considerable overlap with those identified in in situ and invasive apocrine carcinoma. These alterations are also commonly seen in nonapocrine breast cancer. The data are consistent with apocrine hyperplasia as a putative nonobligate precursor of apocrine carcinoma.     

Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis

Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.     

Papillary lesions of the breast

Papillary lesions include benign and malignant lesions. As this array of papillary lesions cannot be differentiated by clinical and imaging means, the diagnosis relies on pathologic examination. Intraductal papillomas are benign, and often complicated by superimposed epithelial metaplasia or hyperplasia. When they are involved by atypical duct hyperplasia, the prevailing practice is to upgrade the diagnosis to ductal carcinoma in situ when the extent of involvement is ≥3 mm. Intraductal papillary carcinomas has low grade malignant epithelial changes, retaining an outer myoepithelial layer but lost the myoepithelial cells within the lesion around fibrovascular cores. Encapsulated papillary carcinomas and solid papillary carcinomas have distinctive morphology, but both are characterized by frequent loss of myoepithelial cells surrounding the lesion, although the current classification still consider these to be in situ lesions. Invasion is used for irregular groups, tongues and nests of tumor cells extending into the stroma beyond the rounded boundary. Immunohistochemistry is useful in differentiating papillary lesions, with positivity of myoepithelial markers, high molecular weight cytokeratins and heterogeneous staining of ER denoting benignity and vice versa. Core needle biopsy is frequently used in diagnosing papillary lesions: both under- and over-diagnoses may occur, the former being more frequent. Genetically papillary carcinomas are grouped mostly into luminal cancers, further attesting to the generally low grade nature of all subtypes of papillary carcinomas.     

Endometrial metaplasias and reactive changes: a spectrum of altered differentiation

Endometrial metaplasias and changes (EMCs) are conditions frequently overlooked and misdiagnosed. The aim of this review is to update current issues and provide a classification with a practical clinicopathological approach. Hormonal or irritative stimuli are the main inducing factors of EMCs, although some metaplasias have a mutational origin. EMCs vary from reactive, degenerative lesions to those able to associate with malignancy or those having a preneoplastic potential. The most common types of EMCs are ciliated tubal metaplasia (CTM) and mucinous metaplasia (MM), which occur in simple and complex glands, and possibly these architectural changes hold the same prognostic significance as they do in hyperplastic endometrioid lesions. Immunohistochemically, CTM is positive for LhS28, bcl-2, PAX2 and p16(INK4A). Complex CTM is likely to be a precursor of ciliated endometrioid-type carcinomas. MMs should be evaluated architecturally, taking into account that their atypicality is minimal. The differentiation between complex MM and mucinous carcinoma may be extremely difficult. Surface complex, papillary MM in endometrial polyps can be considered as benign. Intestinal-type endometrial MM is rare and its presence should prompt further investigation of associated lesions in the endocervix. Endometrial squamous metaplasia (ESS) is often linked to chronic irritative situations. It should be differentiated from secondary involvement by a human papilomavirus-related cervical lesion. Morular metaplasia is a mutational phenomenon with a distinct phenotype that helps to differentiate it from ESS. Morules are benign, hormonally inert structures that are often markers of complex endometrioid glandular architecture, and they are associated with an attenuated malignancy. Endometrial reactive changes are commonly associated with desquamation or hormonal imbalance. The frequent, p16(INK4A) positive, benign surface papillary syncytial change may be misdiagnosed, in some cases, as surface serous adenocarcinoma. Eosinophilic, oxyphilic, oncocytic and clear cell changes are non-specific. Rare stromal metaplasias have little clinical significance and should be differentiated from implanted fetal or embryonal tissues.     

EGFR/erB-1, HER2/erB-2, CK7, LP34, Ki67 and P53 expression in preneoplastic lesions of bronchial epithelium: an immunohistochemical and genetic study

A prognostic interpretation of preneoplastic lesions would have impact in bronchial carcinoma early diagnosis and through the study of Erb-B family receptors as they have an important role in lung carcinogenesis. The existence of drugs as tyrosine kinase inhibitors stressed the importance of studying gene alterations for selected chemoprevention schemes and characterization of carcinogenesis. Bronchial preneoplastic lesions were characterized by immunohistochemistry using the antibodies LP34 (high weigh molecular cytokeratin), CK7, chromogranin A, Ki67, p53, C-erbB-2 and EGFR. HER2 and EGFR gene copy number was also evaluated by fluorescent in situ hybridization in those lesions. The expected results defined the origin cell for basal cell hyperplasia and squamous metaplasia as adaptative lesions and dysplasia. By known experiences and published data, beyond the stem cell, the spectral evolution of bronchial preneoplastic lesions was demonstrated by characterizing basal cells (LP34) and their neoplastic potentiality. Dysplasias showed a higher expression of EGFR, Ki67 and p53 with a stepwise increase with the gravity of the respective grading. C-erbB-2 immunohistochemical overexpression was a rare event in preneoplastic lesions. Polysomy was the main mechanism for EGFR and HER2/neu higher gene copy number and together with increased proliferation index (Ki67) will account to preview bronchial carcinogenesis.     

Morphological classification and definition of benign, preneoplastic and non-invasive neoplastic lesions of the urinary bladder

The morphological classification used in this essay has been based on the most recent World Health Organization (WHO) classification of tumours of the urinary system (i.e. 2004 WHO classification). It includes epithelial abnormalities and metaplasias as well as dysplasias and carcinomas in situ. The lesions are broadly subdivided into two major groups: benign, preneoplastic and non-invasive neoplastic lesions of the urothelium; and benign, preneoplastic and non-invasive neoplastic bladder lesions other than urothelial. Each of these lesions is defined with strict morphological criteria to provide more accurate information to urologists and oncologists in managing patients. There is still debate in the literature as to whether the 2004 WHO system should be the only one to be used and whether the 1973 WHO system should be abandoned.     

High-grade prostatic intraepithelial neoplasia: the only accepted prostate cancer precursor lesion

For many tumors the early detection of precursor lesions of invasive cancer has an impact on the clinical course. The high-grade prostatic intraepithelial neoplasia (HG-PIN) is the only accepted facultative precursor lesion for acinar prostate cancer. While HG-PIN shows many similarities to prostate cancer it is most probably not a precursor of every prostate cancer variant. However, the detection of HG-PIN in needle biopsies is a significant risk factor for the subsequent diagnosis of invasive prostate cancer. Low-grade PIN (LG-PIN), proliferative inflammatory atrophy (PIA), and atypical adenomatous hyperplasia are no longer considered to be true precursor lesions.