Aberrant E-cadherin staining patterns in invasive mammary carcinoma

BACKGROUND: E-cadherin, a cell surface protein involved in cell adhesion, is present in normal breast epithelium, benign breast lesions, and in breast carcinoma. Alterations in the gene CDH1 on chromosome 16q22 are associated with changes in E-cadherin protein expression and function. Inactivation of E-cadherin in lobular carcinomas and certain diffuse gastric carcinomas may play a role in the dispersed, discohesive "single cell" growth patterns seen in these tumors. The molecular "signature" of mammary lobular carcinomas is the loss of E-cadherin protein expression as evidenced by immunohistochemistry, whereas ductal carcinomas are typically E-cadherin positive. PATIENTS AND METHODS: We report on E-cadherin immunostaining patterns in five cases of invasive mammary carcinoma RESULTS: These were five exceptional instances in which the E-cadherin immunophenotype did not correspond to the apparent histologic classification of the lesion. These cases which are exceedingly rare in our experience are the subject of this report. CONCLUSION: Findings such as those illustrated in this study occur in virtually all biologic phenomena and they do not invalidate the very high degree of correlation between the expression of E-cadherin and the classification of breast carcinomas as ductal or lobular type on the basis of conventional histologic criteria

Mitochondrial DNA copy number variation across human cancers.

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities

The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "Blue Book"), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section "essential and desirable diagnostic criteria" included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term "germ cell neoplasia in situ" (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term "primitive neuroectodermal tumour" by "embryonic neuroectodermal tumour" to separate these tumours clearly from Ewing sarcoma. The term "carcinoid" has been changed to "neuroendocrine tumour", with most examples in the testis now classified as "prepubertal type testicular neuroendocrine tumour"

Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer

The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting

Reappraisal of Morphological Differences between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase-Deficient Renal Cell Carcinoma

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations

CT of renal cell carcinoma: assessment of collecting system invasion

OBJECTIVE. Although renal collecting system invasion is not considered in the current TNM staging system, this finding may be relevant in terms of treatment planning and prognosis. The objective of this study was to investigate the frequency of collecting system invasion in renal cell carcinoma (RCC) and to assess the diagnostic performance of excretory phase CT for the assessment of collecting system invasion. MATERIALS AND METHODS. We conducted a retrospective study of 261 patients (171 men and 90 women; average age, 61 years; age range, 32-86 years) who underwent CT before nephrectomy for RCC between November 2008 and July 2011 at a single institution. On excretory phase contrast-enhanced CT images, two radiologists independently determined whether RCC components caused a filling defect within the collecting system and whether the RCC was in contact to the collecting system wall or separated from it. Histopathology served as the standard of reference. Interreader agreement and diagnostic performance tests for the detection of collecting system invasion were calculated. RESULTS. Histopathology identified collecting system invasion exclusively in clear cell RCC that showed a filling defect within the collecting system on excretory phase CT images (5.4%, 14/261). Tumors separated from or in contact with the collecting system on imaging (both readers; 94.6%, 247/261) did not show collecting system invasion on histopathology (sensitivity, 100%; specificity, 100%). Interreader agreement was excellent (κ, 0.965; 95% CI, 0.93-0.99). CONCLUSION. CT provides reliable assessment of collecting system invasion in patients with RCC, with excellent sensitivity and specificity

Role of CT in the assessment of muscular venous branch invasion in patients with renal cell carcinoma

OBJECTIVE: The purpose of this article is to determine whether the relationship between a renal cell carcinoma and the renal sinus fat on contrast-enhanced CT could predict muscular venous branch invasion and the type of surgery needed. MATERIALS AND METHODS: A total of 115 consecutive patients underwent pre-operative contrast-enhanced CT between August 2011 and December 2011. Without access to histopathologic information, on nephrographic phase contrast-enhanced CT images, two radiologists independently determined whether the renal tumor was in contact with the renal sinus fat or separated from the renal sinus fat. Interreader agreements and performance characteristics of imaging tests were calculated, and histopathologic analysis served as the standard of reference. RESULTS: Histopathologic analysis identified 115 renal tumors, 90% (103/115) of which were renal cell carcinomas. Thirty-nine percent (31/80) of renal cell carcinomas that abutted the renal sinus fat on CT displayed muscular venous branch invasion on histopathologic analysis. Patients with renal cell carcinomas separated from the renal sinus fat were more likely to undergo partial nephrectomies (96% [22/23]; p = 0.013). Sensitivity and specificity for the identification of muscular venous branch invasion on CT were 94% (95% CI, 80-99%) and 30% (20-42%), respectively. Interreader agreement of visual assessment was excellent (κ = 0.87; 95% CI, 0.81-0.92). CONCLUSION: If a renal cell carcinoma was separated from the renal sinus fat on CT, the likelihood of muscular venous branch invasion being identified by histopathologic analysis was significantly decreased, and the patient was more likely to undergo a partial nephrectomy

Differentiation of Clear Cell Renal Cell Carcinoma From Other Renal Cortical Tumors by Use of a Quantitative Multiparametric MRI Approach

OBJECTIVE The purpose of this study was to develop a quantitative multiparametric MRI approach to differentiating clear cell renal cell carcinoma (RCC) from other renal cortical tumors. MATERIALS AND METHODS This retrospective study included 119 patients with 124 histopathologically confirmed renal cortical tumors who underwent preoperative MRI including DWI, contrast-enhanced, and chemical-shift sequences before nephrectomy. Two radiologists independently assessed each tumor volumetrically, and apparent diffusion coefficient values, parameters from multiphasic contrast-enhanced MRI (peak enhancement, upslope, downslope, AUC), and chemical-shift indexes were calculated. Univariate and multivariable logistic regression analyses were performed to identify parameters associated with clear cell RCC. RESULTS Interreader agreement was excellent (intraclass correlation coefficient, 0.815-0.994). The parameters apparent diffusion coefficient (reader 1 AUC, 0.804; reader 2, 0.807), peak enhancement (reader 1 AUC, 0.629; reader 2, 0.606), and downslope (reader 1 AUC, 0.575; reader 2, 0.561) were significantly associated with discriminating clear cell RCC from other renal cortical tumors. The combination of all three parameters further increased diagnostic accuracy (reader 1 AUC, 0.889; reader 2, 0.907; both p ≤ 0.001), yielding sensitivities of 0.897 for reader 1 and 0.897 for reader 2, and specificities of 0.762 for reader 1 and 0.738 for reader 2 in the identification of clear cell RCC. With maximized sensitivity, specificities of 0.429 and 0.262 were reached for readers 1 and 2, respectively. CONCLUSION A quantitative multiparametric approach statistically significantly improves diagnostic performance in differentiating clear cell RCC from other renal cortical tumors