Precursor lesions in pancreatic cancer: morphological and molecular pathology

Pancreatic cancer has a dismal prognosis and is the fourth most common cause of cancer related death in Western societies. In large part this is due to its typically late presentation, usually as locally advanced or metastatic disease. Identification of the non-invasive precursor lesions to pancreatic cancer raises the possibility of surgical treatment or chemoprevention at an early stage in the evolution of this disease, when more amenable to therapeutic interventions. Precursor lesions to pancreatic ductal adenocarcinoma, in particular pancreatic intraepithelial neoplasia (PanIN), have been recognised under a variety of synonyms for over 50 years. Over the past decade our understanding of the morphology, biological significance and molecular aberrations of these lesions has grown rapidly and there is now a widely accepted progression model integrating the accumulated morphological and molecular observations. Further progress is likely to be accelerated by improved mouse models of pancreatic cancer and by insight into the cancer genome gained by the International Cancer Genome Consortium (ICGC), in which an Australian consortium is leading the pancreatic cancer initiative. This review also outlines the morphological and molecular features of the other two precursors of pancreatic ductal adenocarcinoma, i.e., intraductal papillary mucinous neoplasms and mucinous cystic neoplasms.     

Ⅱ型子宫内膜癌的前驱病变及其发生模式

子宫内膜癌可分两型,Ⅰ型以子宫内膜样癌为代表,Ⅱ型以子宫浆液性乳头状癌为代表。本文旨在阐述Ⅱ型子宫内膜癌的前驱病变及其可能的发生发展模式。子宫浆液性乳头状癌又称子宫内膜浆液性癌,是一种侵袭性子宫内膜癌,预后不良。由于病因不清,人们一直努力试图找出该病的前驱病变,以便通过早期发现来改善其治疗效果。     

Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints

This article reviews the main molecular alterations involved in endometrial carcinoma. Five molecular features (microsatellite instability, and mutations in the PTEN, k-RAS, PIK3CA and beta-catenin genes) are characteristic of endometrioid carcinomas, whereas non-endometrioid carcinomas show alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). The review also covers the phenomenon of apoptosis resistance, as well as the results obtained from cDNA array studies, and the perspectives for targeted therapies. A group of practical applications of molecular pathology techniques are also mentioned: diagnosis of hereditary non-polyposis colon cancer syndrome in patients with endometrial carcinoma; evaluation of precursor lesions; prognosis; diagnosis, particularly for synchronous endometrioid carcinomas of the uterus and the ovaries; and targeted therapies.     

Molecular pathology of endometrial carcinoma

This review paper discusses the main molecular alterations of endometrial carcinoma, the most common cancer of the female genital tract. Two clinicopathological variants are recognized: the oestrogen‐related (type I, endometrioid carcinoma) and the non‐oestrogen‐related (type II, non‐endometrioid carcinoma). Whereas type I shows microsatellite instability and mutations in PTEN, PIK3CA, K‐RAS and CTNNB1 (beta‐catenin), type II exhibits TP53 mutations and chromosomal instability. Recent investigations regarding the role of non‐coding RNA have provided important information regarding tumour progression. Understanding pathogenesis at the molecular level is essential for identifying biomarkers of potential use in targeted therapies.     

Molecular pathology of endometrial hyperplasia and carcinoma.

Four different genetic abnormalities may occur in endometrioid adenocarcinomas of the endometrium (mircosatellite instability and mutations in the PTEN, k-RAS and beta-catenin genes), whereas nonendometrioid carcinomas of the endometrium often have p53 mutations and loss of heterozygosity on several chromosomes. Occasionally, a nonendometrioid carcinoma may develop as a result of dedifferentiation of a preexisting endometrioid carcinoma; in such a case, the tumor exhibits overlapping clinical, morphologic, immunohistochemical, and molecular features of the 2 types. The insaturation of microsatellite instability in endometrial carcinogenesis seems to occur late in the transition from complex hyperplasia to carcinoma, and it is preceded by progressive inactivation of MLH-1 by promoter hypermethylation. Moreover, the endometrioid adenocarcinomas that exhibit microsatellite instability show a stepwise progressive accumulation of secondary mutations in oncogenes and tumor suppressor genes that contain short-tandem repeats in their coding sequences. Mutations in the PTEN and k-RAS genes are also frequent in endometrioid adenocarcinomas of the endometrium, particularly in the tumors that exhibit microsatellite instability, whereas beta-catenin mutations do not seem to be associated with such a phenomenon.     

A diagnostic approach to endometrial biopsies: selected topics

Endometrial biopsies are amongst the commonest specimens received for histological assessment. Such specimens are taken from women of all ages and for a variety of reasons, and thus the histopathologist is required to consider a wide range of benign and malignant conditions, the appearances of which may be further modified by hormonal therapy. In this review we present a diagnostic approach to the common clinicopathological dilemmas which face the general surgical pathologist. The first half of the paper describes the appearances of common benign and premalignant conditions, including hypo-oestrogenic and hyper-oestrogenic states, endometritis, polyps, and the spectrum of hyperplasia and intraepithelial neoplasia. The second half of the paper deals with malignant diseases of the endometrium, including the common variants of adenocarcinoma, malignant mixed Müllerian tumours (carcinosarcomas) and stromal sarcomas.     

Precancerous lesions of the uterine cervix: morphology and molecular pathology

HPV-induced alterations of the uterine cervix are frequently biopsied because of suspicious findings on a Pap smear and/or colposcopy. Precancerous lesions occur at the so called transformation zone. For those representing squamous differentiation, the traditional three-tier grading system in CIN 1 to 3 is used. CIN 1 and CIN 2 represent (spontaneous) regression in 60-90% and 50%, respectively. In CIN 3 lesions progression is seen in 20-50%. For appropriate grading, improvement of inter- and intraobserver correlation as well as the exclusion of non-precancerous lesions, p16 immunohistochemistry might be helpful. The terms endocervical glandular dysplasia and low-grade glandular intraepithelial neoplasia have been suggested for glandular lesions less than adenocarcinoma in situ (AIS). Until now reproducible histological criteria have not been established. Additional studies using HPV analysis, p16 and Ki-67 immunohistochemistry have not been proved for these lesions. In accordance with international consensus meetings, these diagnostic terms are not recommended for use in practice. AIS, characterised by the replacement of glandular epithelium by cytologically malignant cells, has been established as the precancerous lesion of the endocervix. AIS is much less common than CIN 3 with a reported range of 1:50-100. But, AIS is found in association with CIN 3 with 25-75%. The differential diagnosis between AIS and non-neoplastic glandular lesion may be aided by immunohistochemistry (e.g. p16, Ki-67, bcl-2, vimentin). All specimens obtained after the clinical diagnosis of cervical precancerous lesions should be examined using step sectioning to rule out microinvasive growth. Important information for clinicians includes the quality of the specimen (cautery artefacts, transformation zone enclosed within the probe), exact grading of CIN lesions, identification of other lesions responsible for suspicious findings of a Pap smear or at colposcopy, and in the case of conisation the distance of the lesion from the resection margins (endo- and ectocervical and circumferential margin).     

Current concepts in the pathology and epigenetics of endometrial carcinoma

In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are recognised: the oestrogen-related (type I, endometrioid) and the non-oestrogen related (type II, non-endometrioid). This article reviews the epidemiology, risk factors, genetic alterations during endometrial carcinogenesis, features of tumours and precursors and early detection of the disease. Insights into the epigenetic alterations, with emphasis on DNA methylation during endometrial carcinogenesis, and their diagnostic value are also provided.     

Updates on molecular diagnostic assays in melanocytic pathology

Melanoma is the leading cause of death among cutaneous neoplasms. For the great majority of melanocytic tumors histopathologic examination can reliably distinguish nevi from melanomas; however, there is a subset of melanocytic neoplasms that defy an accurate diagnosis using histopathological criteria alone. For such tumors, additional ancillary tests would be beneficial in adjudicating a more definitive diagnosis. Conventional ancillary studies such as immunohistochemistry have only a limited utility in distinguishing an atypical nevus from melanoma. In recent years few molecular ancillary tests have been developed to help guide the diagnosis of ambiguous melanocytic proliferations. These tests are based either on the identification of genomic copy number changes or on the differential expression pattern of selected genes in nevi and melanomas. This review will present an updated overview of the major ancillary tests used in clinical practice for the diagnosis of challenging melanocytic neoplasms.     

Clinicopathological and molecular characteristics of endometrial neuroendocrine carcinomas reveal preexisting endometrial carcinoma origin

Endometrial neuroendocrine carcinoma is a rare disease with unknown clinicopathological and molecular characteristics. Therefore, we conducted the present study to elucidate the clinicopathological and molecular characteristics of endometrial neuroendocrine carcinoma, as compared to conventional endometrial carcinoma, and to determine the origin of the former. We analyzed 22 endometrial neuroendocrine carcinomas and 22 conventional endometrial neoplasia cases with respect to clinical, histological and genetic features. Of these, 21/22 neuroendocrine carcinoma cases were admixed carcinomas, with 15 admixed with endometrioid adenocarcinoma. Genetic analysis of hotspot mutations in 50 cancer-related genes revealed that the neuroendocrine carcinoma group carried mutations in PIK3CA (12/22 cases; 54%) and PTEN (8/22 cases; 36%), commonly encountered in endometrioid adenocarcinoma. Comparative statistical analysis of neuroendocrine carcinoma and conventional endometrial neoplasia cases showed a significant trend only in PIK3CA mutation. Moreover, in six mixed-type neuroendocrine carcinoma cases, macrodissection was used to separate the neuroendocrine carcinoma and endometrioid adenocarcinoma components for next-generation sequencing, which revealed several mutations common among the two. These findings suggest that endometrial neuroendocrine carcinoma could originate from conventional endometrial neoplasia, especially endometrioid adenocarcinoma.     

Colorectal carcinoma: diagnostic, prognostic, and molecular features.

Surgical resection is the primary treatment modality for colorectal cancer, and the pathologic assessment of the resection specimen provides data that is essential for patient management, including the estimation of postoperative outcome and the rationale for adjuvant therapy. The essential elements of the pathological assessment of colorectal cancer resection specimens include the pathologic determination of TNM stage, tumor type, histologic grade, status of resection margins, and vascular invasion. The prognostic and/or predictive value of these elements, as well as guidelines for their derivation and interpretation, are reviewed in detail. Other tissue-based prognostic factors that are strongly suggested by existing data to have stage-independent prognostic value or to predict response to adjuvant therapy but that have not yet been validated for routine patient care are also reviewed. These include perineural invasion, tumor border configuration, host immune response to tumor, and molecular features such as microsatellite instability or loss of heterozygosity of chromosome 18. The need for high-quality, reproducible pathologic data in the care of the colorectal cancer patient, and the dependence of that data on standardization of all aspects of pathological assessment, is emphasized.     

Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology

The following is a proposition for a simple histopathological classification system to measure inflammation in synovial tissue. This synovitis-score is employed in conventionally stained routine sections, and is applicable to every kind of synovitis, irrespective of etiology and including the following relevant morphological alterations. First: hyperplasia/enlargement of synovial lining cell layer. Second: activation of resident cells/synovial stroma. Third: inflammatory infiltration. All defined histopathological qualities are graded from absent (0), slight (1) and moderate (2) to strong (3), with summaries ranging from 0 to 9. 0 to 1 corresponds to no synovitis (inflammatory grade = 0), 2 to 3 to a slight synovitis (inflammatory grade 1), 4 to 6 to a moderate synovitis (inflammatory grade 2), and 7 to 9 to a strong synovitis (inflammatory grade 3). Using this score, we analyzed 308 random specimens of synovial tissue from degenerative (osteoarthritis (OA)) and inflammatory joint diseases - reactive arthritis (ReA), psoriasis arthritis (PA) and rheumatoid arthritis (RA) - as well as synovial tissue from healthy individuals. The mean grade given to synovitis of RA turned out to be significantly higher than the mean grade of OA (p < 0.0005) and of healthy controls (p < 0.0005). On the contrary, no significant differences could be found between the mean grades of synovitis scores from patients with RA and those with PA and ReA. Another comparison between RA-synovitis types I and II according to the Stiehl classification resulted in type I (p < 0.0005), showing significantly higher values of inflammatory infiltration, and type II (p = 0.037), showing significantly higher values of stroma activation. Since in OA, synovitis is regarded as a result of degenerative cartilage destruction whereas in inflammatory joint diseases (RA, PA, ReA), synovitis is regarded to be the cause of cartilage destruction, it can be concluded that scores with considerable high values indicate the pathogenetic potential of synovitis and that the inflammatory score may be helpful in estimating the destructive potential of synovitis at the same time. Furthermore, the comparison of the score data with the Stiehl RA-synovitis types shows that the score enables us to discriminate the morphological peculiarities of the synovitis types. In experimental pathology, it could provide standardized information on molecular synovial tissue analyses where a correlation of molecular with morphological data is essential. In diagnostic pathology, this synovitis score (in combination with other typing systems) could provide basic and standardized information concerning the degree of inflammatory alterations in synovial tissue.     

Palpable lesions as a diagnostic tool in patients with thoracic pathology

Palpable lesion(s) noticed in a patient with thoracic disease may be a useful diagnostic tool and it often gives a clue for further management. In this study, we searched the diagnostic value of palpable lesions in patients with thoracic pathology suspected clinically and/or radiologically. We prospectively examined the correlations of clinical/radiologic and pathologic findings of 72 palpable lesions from 68 patients who presented with suspect for a thoracic disease from two tertiary medical centers. Thirty‐two lesions (44.4%) were diagnosed as malignant either by fine‐needle aspiration (FNA) only or FNA with confirmatory biopsy. The most common malignancy was non‐small‐cell carcinoma (10) followed by adenocarcinoma (6), and small‐cell carcinoma (5). The most common localization of the palpable lesions was cervical region (20.8%) followed by left supraclavicular (13.8%) and anterior chest wall (13.8%). FNA was effective in obtaining an accurate diagnosis in 66.6% of the patients. Tissue confirmation of FNA was performed in 54 patients. The sensitivity, specificity, negative predictive value, and positive predictive value of FNA in distinguishing a malignant lesion from a benign disease for these palpable lesions were 75, 97, 96, and 80, respectively. One false negativity and one false positivity were also found. Abnormal radiologic features were not correlated with having a malignant palpable lesion. Evaluation of the palpable lesions by FNA and tissue biopsy together is effective for initial triage of the patients with suspect for a thoracic pathology. FNA alone is a convenient and easy method for this purpose especially when the material is immediately assessed for specimen adequacy. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.