Congenital Cystic Lung Lesions: Redefining the Natural Distribution of Subtypes and Assessing the Risk of Malignancy.

Asymptomatic cystic lung lesions-congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts-are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts ≥2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions.

Histological intralesional heterogeneity of actinic keratoses relates to field cancerization.

BACKGROUND/OBJECTIVES: Histological heterogeneity within distinct actinic keratosis (AK) lesions has been described and might serve as an additional feature of AKs. We aimed to investigate and quantify the histological heterogeneity of AKs regarding different grading systems. METHODS AND MATERIAL: We assessed the histology of 3 mm biopsies of AK lesions located on the scalp or face. We documented basal proliferation (PRO I-III), histological grade (AK I-III) and determined the overall classification of each lesion. RESULTS: Of the 305 lesions included, 48 (15.7 %) lesions were classified as AK I, 152 (49.8 %) as AK II and 105 (34.4 %) as AK III. 33 AKs (10.8 %) showed no basal proliferation, 94 (30.8 %) were graded as PRO I, 99 (32.5 %) as PRO II and 79 (25.9 %) as PRO III. One histological grade and basal growth pattern per lesion was observed in 94 (30.8 %) and 104 (34.1 %) cases respectively, two grades in 170 (55.7 %) and 168 (55.1 %) cases, and three grades in 41 (13.4 %) and 33 (10.8 %) cases (Chi-squared test, p < 0.0001). CONCLUSIONS: By analogy with the clinical heterogeneity of field cancerization, AKs show a high histological grade heterogeneity even within small lesions. Variations in AK grading reflect the heterogeneity of the cancerization field and might serve as additional feature.

A comprehensive statistical classifier of foci in the cell transformation assay for carcinogenicity testing.

The identification of the carcinogenic risk of chemicals is currently mainly based on animal studies. The in vitro Cell Transformation Assays (CTAs) are a promising alternative to be considered in an integrated approach. CTAs measure the induction of foci of transformed cells. CTAs model key stages of the in vivo neoplastic process and are able to detect both genotoxic and some non-genotoxic compounds, being the only in vitro method able to deal with the latter. Despite their favorable features, CTAs can be further improved, especially reducing the possible subjectivity arising from the last phase of the protocol, namely visual scoring of foci using coded morphological features. By taking advantage of digital image analysis, the aim of our work is to translate morphological features into statistical descriptors of foci images, and to use them to mimic the classification performances of the visual scorer to discriminate between transformed and non-transformed foci. Here we present a classifier based on five descriptors trained on a dataset of 1364 foci, obtained with different compounds and concentrations. Our classifier showed accuracy, sensitivity and specificity equal to 0.77 and an area under the curve (AUC) of 0.84. The presented classifier outperforms a previously published model.

[Tumor grading of the hepatobiliary system]. / Grading der Tumoren des hepatobiliären Systems.

Tumors of the liver, intrahepatic and extrahepatic bile ducts as well as the gallbladder are very heterogeneous and show different biological behavior. The 4­stage (i.e. well, moderately, poorly and undifferentiated) grading system for hepatocellular carcinoma proposed by the WHO takes tumor size and architecture as well as the extent of cell and nuclear pleomorphism into account. In addition, the WHO defines some special forms of hepatocellular carcinoma. For carcinomas of intrahepatic bile ducts the WHO provides a 3­stage (well, moderately and poorly differentiated) grading system, which is based on architectural and cytological changes. At this localization there are also additional special histological forms that have to be dealt with outside the grading system described. The WHO proposes a 3­stage (well, moderately and poorly differentiated) grading system for carcinomas of the extrahepatic bile ducts and the gallbladder, which considers the proportion of glands contained within the adenocarcinoma. Similar to cancers of the liver and intrahepatic bile ducts there are also numerous special histological forms, which are explained in this article.

[Preneoplastic lesions and precursors of urothelial cancer]. / 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.

[Apocrine poroma. A relatively little known skin tumor with multilineage differentiation]. / Das apokrine Porom. Ein wenig bekannter Hauttumor mit adnexieller Mischdifferenzierung.

Poromas were originally classified as eccrine tumors which predominantly consist of poroid ductal cells and differentiate in the direction of sweat gland ducts. However, there have now been many reports on poromas with additional differential characteristics differentiating in the direction of sebaceous and/or apocrine glands and/or hair follicles. These tumors have been termed apocrine poromas. Multilineage differentiation within a poroma can be explained by the embryological association of the sweat duct with the so-called folliculo-sebaceous-apocrine unit. The clinical and histopathological features of apocrine poromas are reviewed in comparison to classical eccrine poromas by taking into account seven own cases of apocrine poroma and a review of the literature. It is important for histopathologists not to confuse apocrine poroma with other tumors with multilineage differentiation. Apocrine poroma needs to be distinguished from sebaceoma and from basal cell carcinoma with sebaceous differentiation, in particular, because these tumors have therapeutic consequences for the patient. The main histopathological differences between apocrine poroma, sebaceoma and basal cell carcinoma with sebaceous differentiation are explained.

[Skin adnexal tumors with follicular differentiation]. / Hautadnextumoren mit Haarfollikeldifferenzierung.

Skin adnexal tumors with predominantly follicular differentiation represent a clinicopathological heterogeneous group of neoplasms and are classified according to the cytologically achieved differentiation of the follicular compartment. Given the complex structure of non-neoplastic hair follicles it is not surprising to find varying differentiations in neoplasms and there are overlapping clinicopathological features between the established entities. The use of immunohistochemical staining has only a limited value in the diagnosis of follicular neoplasms.

[Endocrine mucin-producing sweat gland carcinoma. three case reports with a brief review of the literature]. / Endokrines muzinproduzierendes Schweißdrüsenkarzinom. Drei Fallberichte mit kurzer Literaturübersicht.

Endocrine mucin-producing sweat gland carcinoma (EMPS) is a rare low-grade sweat gland carcinoma with an infiltrating growth pattern. It occurs mostly in women and shows a predilection for the periorbital region. Histopathologically, the tumor shows analogous features to endocrine ductal carcinoma/solid papillary carcinoma of the breast and shares some clinical and morphological similarities with primary mucinous carcinoma of the skin. The tumor is characterized by large monomorphous epithelial cells with little nuclear pleomorphism and only a few mitotic figures. The solid cystic tumor shows mucin-filled small cystic spaces, cribriform areas and expresses the neuroendocrine markers synaptophysin, chromogranin and neuron-specific enolase with varying staining intensities. The tumor cells are also positive for estrogen and progesterone receptors. We present three cases of this rare tumor with typical clinical, histopathological and immunohistochemical findings, give a short summary of the literature and discuss the most relevant differential diagnoses.

[Cutaneous adnexal and salivary gland tumours. Similarities and differences]. / Hautadnex- vs. Speicheldrüsentumoren. Analoges und Divergentes.

Despite major discrepancies in basic microscopic anatomy, remarkable similarities are manifest within the wide spectrum of cutaneous adnexal and salivary gland tumors. In this study salivary gland and adnexal tumors were identified and investigated with respect to similarities in histology, terminology and pathogenesis. Histological similarities of certain types of salivary gland tumors relate to eccrine, apocrine and rarely sebaceous (but not trichofollicular) types of adnexal tumors. The most striking similarity was found with salivary gland pleomorphic adenoma and cutaneous mixed tumor. Multistep carcinogenesis starting with intraductal carcinoma, identified in carcinoma ex pleomorphic adenoma is identical to that found in cutaneous carcinoma ex spiradenoma. Further histological and terminological similarities are shown for mucinous and mucoepidermoid carcinoma, for lymphadenoma and lymphoepithelial carcinoma, for sebaceous adenoma and carcinoma, for adenoid-cystic carcinoma, as well as for salivary gland basal cell adenoma versus cutaneous spiradenoma. Manifest diagnostic problems related to histologically similar salivary gland and adnexal tumors are rare and are topographically limited to the parotid and oral areas.

[Differential diagnostics of sebaceous tumors]. / Differenzialdiagnostik der Talgdrüsentumoren.

Sebaceous tumors are epithelial tumors with a differentiation towards sebaceous adnexal structures of the skin. They imitate the epithelial cells of mature sebaceous glands, sebaceous ducts, immature (embryonic) sebaceous structures or sebaceous glands that are not stimulated by hormones (mantle structures). This article explains the classification of sebaceous tumors on the basis of the normal histology of sebaceous glands. Clinical and histopathological criteria are given for the most important sebaceous tumors. The differential diagnosis of sebaceoma, sebaceous adenoma and various types of sebaceous carcinoma is emphasized. The importance of a specific diagnosis of adnexal tumors is demonstrated by tumor-associated syndromes with involvement of other organs (e.g., Muir-Torre syndrome and Birt-Hogg-Dubé syndrome). Furthermore, conceptional controversies, problems in differential diagnosis and the impact of immunohistochemical staining in the assessment of sebaceous tumors are considered.

[Histological grading of epithelial ovarian cancer. Review and recommendation]. / Histologische Malignitätsgraduierung des Ovarialkarzinoms. Überblick und Empfehlung.

Histological grading of ovarian cancer has prognostic relevance and implications for treatment decisions. No standardized grading system has been established so far. Several grading systems are currently being used, including the FIGO, WHO, and Silverberg grading systems which cannot be directly translated into each other. Furthermore, individual grading criteria are not uniformly applicable to different histological subtypes. For serous ovarian cancer a binary grading system is now in use as the distinction between low-grade versus high-grade carcinomas reflects the different pathogenesis of these entities. Uniform guidelines for grading ovarian cancer are necessary and should ideally reflect the prognosis. This article provides an overview of commonly used grading systems and their prognostic value. The article demonstrates that a type-specific grading of ovarian cancer should be performed and recommendations for grading the various histological subtypes are given.

[Invasive breast cancer: the current WHO classification]. / Invasive Mammakarzinome: Die aktuelle WHO-Klassifikation.

The World Health Organization (WHO) classification of tumors of the breast defines the international standards for tumor categorization and nomenclature. The fourth edition, published in 2012, provides an update on the current knowledge concerning the classification, immunohistology profile, differential diagnosis and genetics of these lesions. Compared to the previous edition, some terms have been modified, some entities were reclassified and some current molecular data have been added. This article focuses on invasive carcinomas. Definitions for histological diagnosis are supplemented by clinical, macroscopic and molecular characteristics as well as prognostic and predictive features.

Diagnostic aids for detection of oral precancerous conditions.

Oral cancer has a tendency to be detected at late stage which is detrimental to the patients because of its high mortality and morbidity rates. Early detection of oral cancer is therefore important to reduce the burden of this devastating disease. In this review article, the most common oral precancerous lesions are discussed and the importance of early diagnosis is emphasized. In addition, the most common non-invasive oral cancer devices that can aid the general practitioners in early diagnosis are also discussed.

The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma.

PURPOSE: We investigated the clinicopathological outcomes of patients treated with cystectomy for pure urothelial carcinoma vs urothelial carcinoma, and squamous and/or glandular differentiation. MATERIALS AND METHODS: We reviewed the records of 1,013 patients who underwent radical cystectomy, including 827 (72%) with pure urothelial carcinoma and 186 (18%) with urothelial carcinoma, and squamous and/or glandular differentiation. Of patients with variant histology 132 had squamous differentiation, 41 had glandular features and 13 had each type. Cancer specific survival was estimated using the Kaplan-Meier method. The association of histological differentiation with death from bladder cancer was evaluated using multivariate Cox proportional hazard regression analysis. RESULTS: Patients with urothelial carcinoma, and squamous and/or glandular differentiation were more likely to have pT3-T4 tumors (70% vs 38%, p <0.0001) and pN+ disease (20% vs 15%, p = 0.05) than those with pure urothelial carcinoma. Median followup was 11.4 years. A total of 432 patients died of bladder cancer, including 77 with histological differentiation and 355 with pure urothelial carcinoma. Ten-year cancer specific survival did not significantly differ between patients with urothelial carcinoma and histological differentiation, and those with pure urothelial carcinoma (52% vs 51%, p = 0.71). After adjusting for clinicopathological features squamous and/or glandular differentiation was not significantly associated with the risk of death from bladder cancer (HR 0.79, p = 0.10). CONCLUSIONS: Patients with urothelial carcinoma, and squamous and/or glandular differentiation were more likely to have extravesical tumors and node positive disease. Nevertheless, they did not have adverse survival compared to patients with pure urothelial carcinoma. Additional studies are needed to further define prognostic factors in such patients.

[Bethesda classification of fine needle punctures of the thyroid. Much ado about nothing really new?]. / Bethesda-Klassifikation der Feinnadelpunktion der Schilddrüse. Viel Lärm um wenig Neues?

The Bethesda system for reporting thyroid cytopathology was published in 2008 (Baloch et al. 2008, Cytojournal 5:6; Baloch et al. 2008, Diagn Cytopathol 36:425-437) offering a classification system which is closely related to clinical data. The aim was to ensure adequate terminology without risk of errors in understanding, to advise clinicians concerning therapeutic options in relationship to cytological diagnoses as well as to facilitate the comparison of cytology data at national and international levels. However, mainly due to specific US American (both medical and legal) demands, this classification system is not yet fully appreciated in most European countries. The reasons are various: (a) Criteria for representative material are much more restrictive than those commonly used and in Germany a higher number of (unnecessary) repunctures would be the consequence. (b) It remains doubtful whether the introduction of a new and rather heterogeneous category of "atypia of undetermined significance or follicular lesion of undetermined significance" would contribute to a substantial decrease of findings classified as "follicular neoplasia". Furthermore it is unlikely that clinicians would be willing to accept the recommended conservative approach with repuncture if a new diagnostic category is associated with a calculated risk of malignancy in 5-15% cases. (c) Until now an integration of new developments in molecular markers into the Bethesda system is missing. Thus, for experienced cytologists the Bethesda system for reporting thyroid cytopathology offers very limited benefits in comparison to the currently used, established and highly accepted classification systems. However, a positive argument remains the fact that an internationally accepted classification system may improve the comparability of the results of national and international studies on thyroid findings.

Identifying malignant transformations in recurrent low grade gliomas using high resolution magic angle spinning spectroscopy.

OBJECTIVE: The objective of this study was to determine whether metabolic parameters derived from ex vivo analysis of tissue samples are predictive of biologic characteristics of recurrent low grade gliomas (LGGs). This was achieved by exploring the use of multivariate pattern recognition methods to generate statistical models of the metabolic characteristics of recurrent LGGs that correlate with aggressive biology and poor clinical outcome. METHODS: Statistical models were constructed to distinguish between patients with recurrent gliomas that had undergone malignant transformation to a higher grade and those that remained grade 2. The pattern recognition methods explored in this paper include three filter-based feature selection methods (chi-square, gain ratio, and two-way conditional probability), a genetic search wrapper-based feature subset selection algorithm, and five classification algorithms (linear discriminant analysis, logistic regression, functional trees, support vector machines, and decision stump logit boost). The accuracy of each pattern recognition framework was evaluated using leave-one-out cross-validation and bootstrapping. MATERIALS: The population studied included fifty-three patients with recurrent grade 2 gliomas. Among these patients, seven had tumors that transformed to grade 4, twenty-four had tumors that transformed to grade 3, and twenty-two had tumors that remained grade 2. Image-guided tissue samples were obtained from these patients using surgical navigation software. Part of each tissue sample was examined by a pathologist for histological features and for consistency with the tumor grade diagnosis. The other part of the tissue sample was analyzed with ex vivo nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Distinguishing between recurrent low grade gliomas that transformed to a higher grade and those that remained grade 2 was achieved with 96% accuracy, using areas of the ex vivo NMR spectrum corresponding to myoinositol, 2-hydroxyglutarate, hypo-taurine, choline, glycerophosphocholine, phosphocholine, glutathione, and lipid. Logistic regression and decision stump boosting models were able to distinguish between recurrent gliomas that transformed to a higher grade and those that did not with 100% training accuracy (95% confidence interval [93-100%]), 96% leave-one-out cross-validation accuracy (95% confidence interval [87-100%]), and 96% bootstrapping accuracy (95% confidence interval [95-97%]). Linear discriminant analysis, functional trees, and support vector machines were able to achieve leave-one-out cross-validation accuracy above 90% and bootstrapping accuracy above 85%. The three feature ranking methods were comparable in performance. CONCLUSIONS: This study demonstrates the feasibility of using quantitative pattern recognition methods for the analysis of metabolic data from brain tissue obtained during the surgical resection of gliomas. All pattern recognition techniques provided good diagnostic accuracies, though logistic regression and decision stump boosting slightly outperform the other classifiers. These methods identified biomarkers that can be used to detect malignant transformations in individual low grade gliomas, and can lead to a timely change in treatment for each patient.

[Gastrointestinal mixed adenoneuroendocrine carcinomas. An attempt at classification of mixed cancers]. / Gastrointestinale gemischte adenoneuroendokrine Karzinome. Versuch einer Ordnung des Gemischten.

Mixed adenoneuroendocrine carcinomas (MANECs) are a challenge for the diagnostics and the concept of a histogenetic tumor typing. They are classified into three malignant subgroups: high grade malignant MANECs combine an adenoma or adenocarcinoma with a small cell or large cell neuroendocrine carcinoma, intermediate grade malignant MANECs consist of a neuroendocrine tumor (NET grade 1 or 2), often a globlet cell carcinoid and a poorly differentiated adenocarcinoma or diffuse carcinoma of signet ring cell type. The prototype of a low grade malignant MANEC is the globlet cell carcinoid. Molecular analysis indicates a common clonal origin of the different components in MANECs. The prognosis is determined by the most aggressive tumor component. The pathogenesis of MANECs is apparently a sequence of increasing malignant transformation which leads either from an adenoma/adenocarcinoma to a small or large cell neuroendocrine carcinoma or from a neuroendocrine tumor (NET), often a globlet cell carcinoid to a poorly differentiated adenocarcinoma or a diffuse carcinoma of signet ring cell type.

[WHO classification 2010 for the lower gastrointestinal tract: what is new?]. / WHO-Klassifikation 2010 für den unteren Gastrointestinaltrakt: Was ist neu?

The new WHO classification of tumors of the digestive system not only redefines common diagnostic terms, such as intraepithelial neoplasia and dysplasia but also introduces changes in the nomenclature and diagnostics of colorectal tumors which will be important in daily practice. Changes in nomenclature and classification include the introduction of serrated adenocarcinoma, cribriform comedo type adenocarcinoma and micropapillary adenocarcinoma as new distinct histological subtypes of colorectal cancer. The grading of mucinous and signet ring carcinomas, which were previously invariably graded as G3/high grade, is now dependent on the microsatellite instability (MSI) status as a high MSI (MSI-H) indicates a better and low or no MSI (MSI-L/MSS) a worse prognosis. Thus, analysis of microsatellite instability via immunohistochemistry or fragment length analysis must be included in the pathological report of these tumors. Serrated polyps/adenomas and their potential of progression into colorectal cancer via the alternative pathway of colorectal carcinogenesis will be discussed as well as new insights into prognostic and predictive markers of colorectal cancer. This manuscript will give an overview of the most important changes within the new WHO classification of colorectal tumors.