Search

Benign normal (NL), premalignant (endometrial intraepithelial neoplasia, EIN) and malignant (cancer, EMCA) endometria must be precisely distinguished for optimal management. EIN was objectively defined previously as a regression model incorporating manually traced histologic variables to predict clonal growth and cancer outcomes. Results from this early computational study were used to revise subjective endometrial precancer diagnostic criteria currently in use. We here use automated feature segmentation and updated machine learning algorithms to develop a new classification algorithm. Endometrial tissue from 148 patients was randomly separated into 72-patient training and 76-patient validation cohorts encompassing all 3 diagnostic classes. We applied image analysis software to keratin stained endometrial tissues to automatically segment whole-slide digital images into epithelium, cells, and nuclei and extract corresponding variables. A total of 1413 variables were culled to 75 based on random forest classification performance in a 3-group (NL, EIN, EMCA) model. This algorithm correctly classifies cases with 3-class error rates of 0.04 (training set) and 0.058 (validation set); and 2-class (NL vs. EIN+EMCA) error rate of 0.016 (training set) and 0 (validation set). The 4 most heavily weighted variables are surrogates of those previously identified in manual-segmentation machine learning studies (stromal and epithelial area percentages, and normalized epithelial surface lengths). Lesser weighted predictors include gland and lumen axis lengths and ratios, and individual cell measures. Automated image analysis and random forest classification algorithms can classify normal, premalignant, and malignant endometrial tissues. Highest predictive variables overlap with those discovered independently in early models based on manual segmentation.

Laryngeal carcinogenesis is a multistep process, characterized by an accumulation of genetic changes associated with architectural and cytologic alterations, ranging from squamous hyperplasia to carcinoma in situ and encompassed by the terminology of squamous intraepithelial lesions (SILs). The etiology, classification, genetic changes, and malignant progression of these lesions are reviewed. Tobacco remains the principal etiological factor with gastroesophageal reflux disease recently considered as a possible factor. In contrast, there is little evidence that microbiological agents, especially human papillomavirus infection, are frequently involved in laryngeal carcinogenesis and probably <10% of SILs are driven by biologically active human papillomavirus infection. Light microscopy, despite a degree of subjectivity, remains the mainstay of accurate diagnosis, prognosis, and guidance for a patient's treatment. The currently used classifications, the dysplasia system, squamous intraepithelial neoplasia, and the Ljubljana classification, reflect different standpoints on this important topic. The modified Ljubljana classification, with good interobserver agreement, could be considered as a proposal for a unified classification of laryngeal SILs. This review also briefly discusses recently discovered genetic changes, such as CDKN2A and CTNNB1 genes, and chromosome instability of chromosomes 1 and 7; however, none of these can at present improve histologic diagnosis. Malignant progression of precursor lesions varies from 2% to 74%, according to different studies. Cold-steel microinstruments, CO2 laser, and radiotherapy are used to treat the different grades of precursor lesions. There is as yet no worldwide agreement on the treatment of high-grade lesions and carcinoma in situ.

Porokeratosis is a family of several disorders characterized histologically by the presence of cornoid lamellae. The presence of cornoid lamellae represents an abnormal form of keratinization, which unifies all types of porokeratosis. A significant variation in lesional morphology can result from peculiarities involving the cornoid lamellae and changes related to epidermal hyperplasia and dermal inflammation. This diversity has led to the recognition of several unusual clinicopathological variants of porokeratosis in recent years. Cornoid lamellation, however, is not pathognomonic of porokeratosis and can be seen in some inflammatory and inherited cutaneous disorders and also as an incidental finding. Some of these conditions can be confused with an atypical presentation of porokeratosis and vice versa. An awareness of the broad morphological spectrum of porokeratosis is crucial to avoid missing the diagnosis when appearances are far from typical. This issue is critical in patient management given the potential premalignant nature of porokeratosis.

A variety of benign and malignant endocervical glandular lesions exhibiting gastric differentiation has been described in the past decade that has resulted in the concept of an important category of cervical adenocarcinoma which is unrelated to human papillomavirus (HPV). Both minimal deviation adenocarcinoma (MDA), also known as adenoma malignum, and the benign lesion lobular endocervical glandular hyperplasia (LEGH), have been known for some time to exhibit a gastric phenotype and immunophenotype (HIK1083 and/or MUC6 positive). Accumulated evidence suggests that a subset of LEGH (atypical LEGH) exhibits a degree of cytologic and/or architectural atypia which, in some cases, may be associated with and be a precursor of adenocarcinomas exhibiting gastric differentiation, including MDA. Gastric-type adenocarcinoma (GAS), a recently described subtype of cervical adenocarcinoma, is an emerging clinicopathologic entity. These neoplasms exhibit a spectrum of differentiation, including MDA as its very well-differentiated form, are unrelated to HPV, and exhibit aggressive clinical behavior. It is proposed that a LEGH-GAS sequence exists and, from a practical point of view, the development of optimal biomarkers is awaited to assist in early detection of GAS and atypical LEGH, as current HPV-targeted screening generally does not detect these lesions and strategies employing HPV vaccination will not prevent their occurrence. Pathologists should be familiar with the morphologic spectrum of these benign, premalignant, and malignant cervical glandular lesions exhibiting gastric differentiation. They are occasionally associated with Peutz-Jeghers syndrome or are a component of "synchronous mucinous metaplasia and neoplasia of the female genital tract."

Over the past few years there have been substantial advances in our knowledge of premalignant lesions of the pancreas. Given the dismal prognosis of untreated pancreatic cancer, and the small proportion of patients who are operative candidates, an understanding of these premalignant lesions is essential for the development of strategies for early diagnosis and prevention. The 2010 WHO classification has added new entities, including intraductal tubular papillary neoplasms (ITPNs), and clarified the nomenclature and grading of previously recognised precursor lesions of pancreatic adenocarcinoma, such as intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and pancreatic intraepithelial neoplasia (PanIN). In particular, there has been an upsurge of interest in the natural history of IPMN, driven partly by improvements in imaging modalities and the consequent apparent increase in their incidence, and partly by recognition that subtypes based on location or histological appearance define groups with significantly different behaviours. In mid 2012 revised international guidelines for the classification and management of IPMNs and MCNs were published, although in several respects these guidelines represent a consensus view rather than being evidence-based. In recent years major advances in molecular technologies, including whole-exome sequencing, have significantly enhanced our knowledge of pancreatic premalignancy and have identified potentially highly specific diagnostic biomarkers such as mutations in GNAS and RNF43 that could be used to pre-operatively assess pancreatic cysts.

The Bethesda System for Reporting Thyroid Cytopathology is a standardized reporting system for classifying thyroid fine-needle aspiration results comprising of 6 diagnostic categories with unique risks of malignancy and recommendations for clinical management. The majority of thyroid nodules are benign; however, up to 30% of fine-needle aspiration of thyroid nodule results are equivocal. Until 2007, various diagnostic terms were used to classify such cases, including "atypical," "indeterminate," and rule-out or cannot exclude malignancy. A literature review of 13 original studies was conducted to evaluate whether utilization of the Bethesda System for Reporting Thyroid Cytopathology nomenclature represent an improvement over thyroid cytopathology reporting schemes used before 2007 in diagnosing thyroid malignancy. The sensitivity and specificity of thyroid fine-needle aspiration was high in the studies that assessed the measures. However, a selection bias exists and most studies do not include indeterminate diagnosis in their calculations. Although the Bethesda System for Reporting Thyroid Cytopathology recommends a repeat fine-needle aspiration to follow-up nondiagnostic specimens, in the majority of studies, an appreciable number of cases underwent follow-up surgical biopsy or thyroidectomy. The diagnostic category of atypia/follicular lesion of undetermined significance remains heterogenous in terms of usage and clinical outcome. The majority of the studies that utilize the Bethesda System for Reporting Thyroid Cytopathology in this literature review retrospectively reclassified thyroid fine-needle aspiration into the Bethesda System for Reporting Thyroid Cytopathology nomenclature with reported malignancy rates that are similar between cases reclassified as atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Aims: Columnar cell lesions (CCLs) of the breast have been increasingly recognised in biopsies taken to investigate mammographic screen detected microcalcification. The aim of this study was to identify distinct CCL subtypes by systematic analysis of histopathology., Methods: Hierarchical cluster analysis was performed based on the profile of histopathological features in 102 screen detected CCLs. Features assessed included nuclear morphology, acinar dilatation, epithelial cell hyperplasia, cell crowding, apical snout formation and intraluminal secretion. The stability of this classification was tested in an independent cohort of 32 cases., Results: The histopathology of screen detected CCLs was extremely variable. Hierarchical cluster analysis identified two subclasses: Class 1 (34/102, 33%) characterised by absence of nuclear atypia and less pronounced hyperplasia; and Class 2 (68/102, 67%) that were generally more atypical. Ki-67 scores were significantly lower for Class 1 CCLs (p < 0.001). In the independent cohort of 32 cases, Class 1 cases were clearly distinguished from Class 2, indicating that these were stable phenotypes amongst screen detected CCLs., Conclusions: The histopathological features of CCLs diagnosed at screening are extremely heterogeneous. Using a systematic approach, we have devised a broad classification system that delineates a category of less atypical CCLs that could form a basis for future studies.

Consumption of the epidermis (COE), defined as thinning of the epidermis with attenuation of basal and suprabasal layers and loss of rete ridges adjacent to collections of melanocytes, is a recently coined term encompassing changes of the epidermal architecture associated with melanoma. To evaluate this feature as an additional diagnostic criterion for melanoma, we examined COE in 453 melanocytic lesions, including 213 invasive melanomas from a population-based series and 240 suspicious pigmented lesions from a clinic-based series, excluding halo and Spitz nevi. In the population-based series, COE was identified in 92/213 (43%) invasive melanomas and became progressively more frequent with increasing Breslow depth (P < 0.0001) and Clark level (P = 0.0002). COE was more frequent when mitotic figures (P < 0.0001), ulceration (P = 0.005), or vertical growth phase (P = 0.009) were present, but it was not significantly associated with age, gender, site, regression, or tumor-infiltrating lymphocytes. In the clinic-based series of pigmented lesions, COE was present in 2/25 (8%) in situ melanomas, 1/29 (3%) lesions classified as melanoma in situ/high-grade dysplastic nevi, and 1/40 (2.5%) high-grade dysplastic nevi. COE was not identified in 146 low-grade dysplastic, congenital, or common nevi. In the combined datasets, 94/96 (98%) lesions exhibiting COE were classified as melanoma. This study demonstrates that COE is frequently present in invasive melanomas, is associated with more aggressive histopathologic features (including increased Breslow depth and ulceration) and may be a useful supplementary diagnostic criterion for melanoma. Furthermore, the process leading to COE may be the first step in a progression to ulceration.

The classification of cervical precancers has evolved over the past 40 years as knowledge concerning the pathogenesis of these human papillomavirus-related lesions has expanded. This commentary reviews the current classification scheme in light of (1) the historical classification systems and (2) the ability of the target epithelium, that is the transformation zone to exhibit varied morphology depending on the cell type that is infected with human papillomavirus. The evolution in our understanding of preinvasive glandular neoplasia is also summarized, with particular attention to so-called superficial (or early) adenocarcinoma in situ. In addition, practical issues in the diagnosis and management of squamous epithelial lesions, particularly the recognition of nonconventional variants and the application of biomarkers, are discussed.

Objective: To propose a cholangiographic classification for intraductal growth type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor, collectively termed intraductal papillary mucinous neoplasm of the bile ducts (IPMN-B)., Summary Background Data: For the extensive clinicopathologic variations of IPMN-B, a detailed characterization of cholangiography for IPMN-B is beneficial for determining the optimal therapeutic strategy., Methods: A total of 124 patients with cholangiography-available and pathologically proven IPMN-B were retrospectively studied. Numbers of IPMN-B type 1, type 2, type 3, and type 4 were 33, 17, 15, and 59, respectively. A cholangiographic classification was proposed based on the presence of hepatolithiasis, mucobilia, neoplasia localization, and concomitant malignancies. The demographics, histologic grading, management, and survival were also analyzed., Results: All 33 IPMN-B type 1 and 12 of 17 IPMN-B type 2 displayed cholangiographic pattern IA demonstrating hepatolithiasis-related biliary stricture. The remaining 5 IPMN-B type 2 displayed cholangiographic pattern IB or IC, which demonstrated mucobilia without discernible neoplasia. Seven of 15 IPMN-B type 3 and 52 of the 59 IPMN-B type 4 displayed cholangiographic pattern IIA or IIB, which demonstrated overt intraductal neoplasia. Seven IPMN-B type 3 or 4 displayed cholangiographic pattern IIIA or IIIB, which demonstrated IPMN-B and concomitant malignancies. For those presenting with cholangiographic pattern IA, IC, IIA, IIB, and IIIA, straightforward hepatectomies for the diseased lobes were performed. For those with pattern IB, surgical resections were performed only when there was emergence of mucin-producing neoplasia. For those with IIIB, the concomitant malignancies were considered inoperable. No disease-related death occurred in IPMN-B type 1and 2. The mean survival rates of IPMN-B type 3 and type 4 were 55.5 +/- 17.1 months and 36.9 +/- 6.3 months, respectively., Conclusion: The presented cholangiographic classification facilitates the management for IPMN-B. Significant survival discrepancy at the various stages warrants a more aggressive surgical strategy.

The popular term for vulvar squamous cell carcinoma in situ/dysplasia is vulvar intraepithelial neoplasia (VIN). VIN is a histological diagnosis based on loss of squamous epithelial maturation associated with enlarged, hyperchromatic, pleomorphic nuclei and increased, usually atypical mitoses. There are two types of VIN: the usual (not otherwise specified) type, also known as warty-basaloid, and the differentiated type. There are 3 grading systems for warty-basaloid VIN: the traditional 3-grade system of VIN 1-3, a low-grade/high grade Bethesda-like system and the International Society for the Study of Vulvovaginal Disease's proposal for only 1 grade. The ISSVD system eliminates VIN 1 and combines VIN 2 and 3 on the grounds that VIN 1 has not been shown to be a reproducible diagnosis and VIN 2 and 3 are not reliably separated. The evidence supports the ISSVD proposal. Warty basaloid VIN may be sub-typed into warty and basaloid VIN. Sub-typing has clinical relevance but its reproducibility is not proven. Warty-basaloid VIN may regress. Differentiated VIN has been typically diagnosed co-incident with squamous cell carcinoma. With increased frequency of performance of biopsy of hyperplastic lesions, differentiated VIN should be diagnosed more commonly before squamous carcinoma occurs.

Numerous variants of melanocytic naevi have been described. Their main pathological significance lies in their distinction from melanoma, as well as being precursors and risk markers for melanoma. Various degrees of atypia such as cytological atypia, architectural disorder and pagetoid spread (pagetoid melanocytosis) may be present in naevi and need to be recognised as appropriate for the subtype. As well as the distinction from melanoma, naevi must be differentiated from atypical lesions, such as atypical Spitz tumours, which do not fulfil all the criteria of melanoma, may be benign or malignant and have been called 'melanocytic tumours of unknown malignant potential'. The diagnostic grey area also includes a group of benign atypical naevi which are difficult to subclassify into specific entities. In this paper naevi are divided into: firstly, the common acquired group with a brief discussion of junctional, compound and intradermal naevi, minor variants such as halo and balloon naevi and the major variants that may cause problems -- dysplastic naevi, naevi of special sites, recurrent naevi and Spitz naevi; secondly, congenital naevi; thirdly, blue naevi and related lesions (dermal melanocytoses); and finally, combined naevi. The emphasis is on diagnostic pathological features and the differential diagnosis with melanoma.

In the gastrointestinal tract, the term 'dysplasia' is used to refer to non-invasive neoplastic epithelium. Although we recognise adenomas of the gut as dysplastic, we don't use the term 'dysplasia' in reporting them. The use of the term 'dysplasia' for pre-invasive epithelium gradually came to replace other terms in studies attempting to identify epithelial changes that were cancer precursors in surveillance biopsies of patients with chronic colitides. The two-tier system of classification, dividing dysplasias into low-grade or high-grade lesions is conceptually straightforward; however, difficulties exist in the distinction of regenerative epithelium from low-grade dysplasia, of low-grade from high-grade dysplasia, and in identifying superficially invasive carcinoma in a dysplastic mucosa. The category 'indefinite for dysplasia' is an honest recognition of the difficulties in distinguishing reactive or regenerative epithelium from low-grade dysplasia, since these epithelia share many cytological features. In surveillance biopsies in ulcerative colitis and Barrett's mucosa, for each epithelial category from non-dysplastic through indefinite, low-grade and high-grade dysplasia, there are specific management recommendations that vary from no change in surveillance to increased surveillance to definitive therapy that is often a major resection. The recommendation for referral of high-grade dysplasias to consultants reflects the concern pathologists have about making such clinically significant diagnoses with limited experience. Pathologists should use the accepted terminology, share cases to expand their experience, and seek consultation in selected cases. This paper follows the evolution of the dysplasia concept, details the difficult areas of diagnosis, and discusses the importance of interaction between clinicians and pathologists in dealing with dysplasias.

Aim: Apply the statistical classification strategy (SCS) to magnetic resonance spectroscopy (MRS) data from liver biopsies and test its potential to discriminate between normal liver, cirrhotic nodules and nodules of hepatocellular carcinoma with a high degree of accuracy., Methods: Liver tissue specimens from 54 patients undergoing either partial (hemi) or total hepatectomy were analysed by one-dimensional proton MRS at 8.5 Tesla. Histologically, these specimens were confirmed as normal (n=31), cirrhotic (n=59), and hepatocellular carcinoma (HCC, n=32). Diagnostic correlation was performed between the MR spectra and histopathology. An SCS was applied consisting of pre-processing MR magnitude spectra to identify spectral regions of maximal discriminatory value, and cross-validated linear discriminant analysis., Results: SCS applied to MRS data distinguished normal liver tissue from HCC with an accuracy of 100%. Normal liver tissue was distinguished from cirrhotic liver with an accuracy of 92% and cirrhotic liver was distinguished from HCC with an accuracy of 98%., Conclusions: SCS applied to proton MRS of liver biopsies provides a robust method to distinguish, with a high degree of accuracy, HCC from both cirrhotic and normal liver.

Nephrogenic rests are the consequence of residual metanephric tissue in a fully developed kidney. They usually occur along the perimeter of a mature renal lobe (i.e., perilobar), within the lobe itself (i.e., intralobar), or both (i.e., combined). Nephrogenic rests can be grossly obvious or microscopically discrete. Nephroblastomatosis designates nephrogenic rests that are multifocal or diffuse, and implies more extensive disease. Universal (panlobar) nephroblastomatosis denotes complete replacement of the renal lobe by nephrogenic tissue. The fate of nephrogenic rests and nephroblastomatosis varies and includes obsolescence, sclerosis, dormancy, hyperplasia, or neoplasia. Evidence strongly suggests that neoplastic transformation of nephrogenic rests results in Wilms' tumor (nephroblastoma). Nephrogenic rests almost always occur in the setting of Wilms' tumor; perilobar rests show a strong association with synchronous bilateral Wilms' tumors, whereas intralobar rests are more strongly associated with metachronous tumors. Genetic studies have shown that nephrogenic rests often share many of the same chromosomal defects as Wilms' tumor, which provides further evidence that they are precursors to nephroblastoma. Thus, nephrogenic rests are recognized as clinically significant entities requiring adequate detection and close surveillance. Heightened awareness regarding the clinical relevance of nephrogenic rests and nephroblastomatosis (1) has led to improved detection of these precancerous lesions, (2) fostered more intensive investigation into their biologic behavior, and (3) initiated in-depth discussions about potentially new treatment regimens. The pathologists' ability to identify and detect nephrogenic rests has benefited from the more efficient Beckwith classification. Radiologists have deployed high-resolution radiologic/imaging modalities to improve detection of nephrogenic rests in situ. Clinicians and surgeons are more aware of the impact that nephrogenic rests have upon patient management. Despite this progress, more data is needed to further define these lesions.

There is no internationally accepted classification of epithelial hyperplastic laryngeal lesions (EHLL). The majority of current classifications follow criteria similar to those commonly used for cervical epithelial lesions. However, the different etiology of laryngeal cancer and its particular clinical and histologic features necessitate a grading system more appropriate to this region. The Ljubljana classification of EHLL was devised in 1971 to cater to this requirement. Detailed criteria for histologic grading in this classification were formulated by a working group on EHLL of the European Society of Pathology in 1999. The system recognizes four grades: simple and abnormal hyperplasia are benign categories; atypical hyperplasia ("risky" epithelium) is potentially malignant, and carcinoma in situ actually malignant. The main features by which the proposed grading system differs from other classifications are: 1. the distinction between benign and potentially malignant lesions; 2. the positive separation of carcinoma in situ from atypical hyperplasia; 3. the lack of prognostic significance for any surface keratin layer. The eventual outcome of EHLL patients so graded justifies the proposal for separating the lesions into a benign group, showing malignant transformation in only 0.9% of cases, from a potentially malignant group showing malignant transformation in 11% of cases. For diagnostically difficult cases, supplementary techniques such as those using morphometry, immunohistochemical and molecular biology are advised to improve the accuracy of diagnosis and predictions of their biological behavior.

Microscopic examination of stained smears and tissue sections remains the standard method for definitive diagnosis and classification of lung cancer. However, the morphology of lung cancer is complex, and consensus classifications such as those prepared by a panel World Health Organization (WHO) are required for the sake of consistency and clinical relevance. In the most recent (1999) WHO classification, the diagnostic categories of greatest clinical importance, small cell lung carcinoma and non-small cell lung carcinoma, remain fundamentally unchanged. However, application of immunohistochemistry and electron microscopy has revealed expression of neuroendocrine markers in a wide variety of tumors. Expression of these markers is not taken into account in current treatment protocols, and additional correlative studies will be required to determine the clinical relevance of neuroendocrine differentiation in lung carcinoma. In addition to histological classification, microscopic analysis can provide in situ evidence of response to chemotherapy, as well as information on precursor lesions and multistep carcinogenesis in the airways. Finally, it is likely that morphological assessment of lung carcinoma and preneoplastic lesions will continue to be refined as new diagnostic modalities such as spiral computed tomography and fluorescence bronchoscopy provide previously inaccessible specimens for morphological and correlative molecular studies.

The purpose of this paper is to summarize the author's views on precancerous lesions of the epithelium of the uterine cervix. It is pointed out that the pathologist's ability to prognosticate the outcome of any such lesion is limited. The names attached to these lesions, ranging from mild dysplasia to carcinoma in situ do not necessarily reflect their true biologic potential in terms of disappearance, persistence, or progression. It is suggested that a unified nomenclature of these lesions may be helpful in clarifying the issue at hand. Comments on the accomplishments and failures of the cytologic methods of diagnosis of these lesions are appended.