Distinct spatial landscapes in clear-cell renal cell carcinoma as revealed by whole transcriptome analysis.

Background: Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of renal cancer and a paradigm of inter- and intratumor heterogeneity. We carried out an exploratory digital spatial profiling of the tumor interior and periphery of two ccRCC tumor specimens and mapped spatially the molecular and cellular composition of their tumor microenvironment and ecosystem. Materials and methods: Digital spatial profiling of the whole transcriptome of 19 regions of interest (ROIs) was carried out from two selected highly immunogenic stage pT3a/grade 3 (G3) and stage pT3a/grade 4 (G4) ccRCC. A total of 9-10 ROIs were selected from distinct areas from each tumor, including tumor interior and tumor periphery, and differences in gene expression were analyzed by RNA sequencing, pathway enrichment analysis, and cell deconvolution. Results: The distinct areas from the two locally advanced tumors displayed unique gene expression spatial patterns defining distinct biological pathways. Dimensional reduction analysis showed that the G3 ccRCC, compared to the G4 ccRCC, correlated with more variability between regions from the tumor interior and tumor periphery. Cell deconvolution analysis illustrated higher abundance of immune cells, including macrophages, myeloid dendritic cells, and CD4 T cells, and lower abundance of regulatory T cells in the tumor periphery compared to the tumor interior. Conclusions: Transcriptome spatial profiling revealed high inter- and intratumor heterogeneity in the analyzed tumors and provided information with potential clinical utility. This included the finding of less intratumor heterogeneity and more tumor-infiltrated T cells in the ccRCC tumor specimen with a higher grade.

Inverted urothelial papilloma of the upper urinary tract: description of two cases with systematic literature review.

BACKGROUND: Inverted urothelial papilloma (IUP) of the upper urinary tract is an uncommon benign tumour that occasionally presents as a polypoid mass causing urinary obstruction. Histologically, IUP is characterised by a proliferating urothelium arranged in cords and trabeculae, in continuity with overlying intact epithelium, and extending into the lamina propria in a non-invasive, endophytic manner. Cytological atypia is minimal or absent. Top differential diagnoses include urothelial carcinoma with inverted growth pattern and florid ureteritis cystica. Although urothelial carcinomas of the upper urinary tract with prominent inverted growth pattern commonly harbour microsatellite instability, the role of the mutator phenotype pathway in IUP development is still unclear. The aim of this study was to describe two additional cases of IUP of the upper urinary tract, along with an extensive literature review. CASE PRESENTATION: We observed two polypoid tumours originating in the renal pelvis and the distal ureter, respectively. Both patients, a 76-year-old woman and a 56-year-old man, underwent surgery because of the increased likelihood of malignancy. Histology was consistent with IUP and patients are alive and asymptomatic after long-term follow-up (6 years for the renal pelvis lesion and 5 years for the ureter lesion). The tumours retained the expression of the mismatch-repair protein MLH1, MSH2, and PMS2 whereas loss of MSH6 was found in both cases. CONCLUSIONS: When completely resected, IUP does not require rigorous surveillance protocols, such as those for urothelial carcinoma and exophytic urothelial papilloma. It is therefore important for the surgical pathologist to be aware of this rare entity in order to ensure correct patient management.

Drug-induced gastrointestinal injury (DIGI). Updates, reflections and key points.

The goals of this short narrative review are 1) to provide an update in recent developments in the field of drug-induced gastrointestinal injury (DIGI), and 2) to distill few key points to approach with confidence a difficult and vast area of gastrointestinal pathology. DIGI is a challenging diagnosis as it can produce almost any pattern of the injury of the gastrointestinal tract. The recognition of a pattern and the knowledge of which drugs can produce that pattern, are the first step of the diagnostic process; communication with the clinical team and a high level of suspicion are then paramount. The pathologist can be the leading clinicians of the care team in few situations in which she/he can recognize the drug at the microscope. Knowledge of the most relevant differential diagnoses of DIGI is essential to avoid significant pitfalls. Finally, several DIGIs due to recently developed immunomodulators used in oncology have shown relevance given their sometimes fatal outcome and the accumulating evidence of a common morphological appearance among them.

Discovering intratumor heterogeneity: the next frontier for pathologists.

Discovering intratumor heterogeneity is a crucial issue in modern oncologic medicine. Highly sophisticated technology such as high-throughput DNA sequencing has demonstrated the real dimension of the problem. The overwhelming majority of malignant tumors show high levels of intratumor heterogeneity when thoroughly studied. Intratumor heterogeneity develops both in temporal and spatial domains and its distribution is not deterministic making each case truly unique and unrepeatable. Pathologists are main actors in intratumor heterogeneity detection since they are the medical specialists who sample the tumors. Recent evidences have shown that currently applied sampling protocols are insufficient for a reliable intratumor heterogeneity detection. Pathologists must adapt classic sampling to the new times thus continuing being key pieces in the multidisciplinary approach to neoplasia that modern medicine demands.

Transperineal biopsies of MRI-detected aggressive index lesions in low- and intermediate-risk prostate cancer patients: Implications for treatment decision.

PURPOSE: Multiparametric MRI (mpMRI) has a potential role for the identification of aggressive cancer that can be targeted for biopsy. We report the incidence and severity of discordant information between the pathology found on the transrectal ultrasound (TRUS)-guided biopsy and the mpMRI findings in patients with favorable or intermediate-risk prostate cancer referred for brachytherapy. METHODS AND MATERIALS: From March 2014 to September 2015, 10/44 consecutive patients with low- or intermediate-risk prostate cancer referred for brachytherapy presented an aggressive lesion on mpMRI and underwent an MRI-TRUS fusion-guided transperineal biopsy of the index lesion. RESULTS: A median of two intraprostatic lesions were detected by mpMRI for each patient. Three patients had bilateral disease, and seven had unilateral disease on mpMRI. The median number of cores obtained by MRI-TRUS-guided fusion of the index lesion was 3 (range 2-4). As a result of the re-evaluation consequent to additional information becoming available after the transperineal biopsy, upgrading of Gleason score occurred in 8 of the 10 patients, which changed the risk group in 9 patients. These changes resulted in modification of the proposed treatment in 8 patients. CONCLUSIONS: MpMRI-US fusion-targeted biopsy sampling allows detection and characterization of otherwise undetected aggressive disease, often placing men in higher risk groups and altering the treatment approach.

Revealing the production process of Joaquín Albarrán's Les Tumeurs de la Vessie 125 years after its writing. / Desvelando el proceso de producción de Les Tumeurs de la Vessie de Joaquín Albarrán 125 años después de su escritura.

OBJECTIVE: Investigate how in 1891 Joaquín Albarrán organised and wrote his Les Tumeurs de la Vessie, a manuscript printed by Georges Steinheil in 1892. MATERIAL AND METHODS: An analysis was conducted of the manuscript that compiles the casuistry set forth in the work, which helps us understand his production process. The contents of the text are analysed, revealing the originality and value of the text in the manuscript. RESULTS: The book describes the author's personal histopathology findings from surgical and autopsied cases in Necker Hospital between 1868 and 1891: 28 numbered autopsy specimens and 67 identified by the patient's name (or, in lieu thereof, the physician's name, bed, ward and date of surgery). The notebook also contains the preliminary design of a number of photomicrographs printed in the book. Histopathology data are provided on the classification of bladder cancer, the pathway of lymphocytic spread, the genesis of cancer, tumoural heterogeneity and a number of original descriptions (squamous cell carcinoma, Von Brunn nests). Other notable clinical concepts include diagnostic symptomatology, prognosis assessment, extirpation by vesical height (with primary closure of the bladder and abdominal wall), the role of nascent endoscopic tumour extirpation and the experimental development of radical cystectomy with urinary diversion. CONCLUSIONS: Joaquín Albarrán analysed his experience and that of professors Reverdin, Guyon and Horteloup. He reviewed autopsies and surgical specimens from patients and performed the histopathology study in each case. The main original observations from the work are discussed.

Cadmium, copper, lead and zinc concentrations in female and embryonic Pacific sharpnose shark (Rhizoprionodon longurio) tissues.

In this work we compared the cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) contents of muscle, liver and placenta of gestating females of the viviparous shark Rhizoprionodon longurio and of muscle, liver and umbilical cord of their respective embryos. The higher values of the essential Cu and Zn were in embryonic or embryo-related tissues (placenta and umbilical cord). Maternal muscle and liver had the highest values of Pb and Cd, respectively. There were significant direct correlations between the Zn and Cd concentrations of placenta and umbilical cord, as well as between maternal muscle and embryonic livers for Pb and Cd, but the relation between these tissues was inverse in the case of Zn. All correlations between the metal content of embryonic tissues and size of the embryos were negative, suggesting an inverse relation between the rate of mother-to-embryo metal transfer and embryonic growth.

DNA repair genes and prognosis in sporadic forms of urothelial carcinoma of the upper urinary tract.

INTRODUCTION: Lynch syndrome or hereditary nonpolyposis colorectal cancer is caused by mutations in DNA repair genes, known as mismatch repair (MMR) genes, and is associated with microsatellite instability. Urothelial carcinoma of the renal pelvis is also associated with this syndrome. These genetic abnormalities have been described in sporadic forms of upper tract urothelial carcinoma (UTUC). MATERIAL AND METHOD: This was a descriptive study and survival analysis of a series of 80 patients with sporadic UTUC with no metastases at diagnosis (N0/Nx M0) treated exclusively with nephroureterectomy. We evaluated the expression of MMR genes (hMLH1, hPMS2, hMSH2 and hMSH6) in sections performed with tissue microarray (TMA) and their association with clinical-pathological parameters. We analyzed the prognostic value of the loss of expression of these genes in UTUC. RESULTS: We detected no loss of MSH2 or of MSH6, but there was a loss of MLH1 in 11 cases (13.8%) and of PMS2 in 21 cases (26.3%). The expression of hMLH1 and hPMS2 were strongly associated (P<.0001), and this phenotype expression entails significant clinical implications. The loss of MLH1 was associated with a low grade (P=.02). Loss of PMS2 was associated with a lower stage (P=.05), a pushing pattern with no invasive edges (P=.008) and less angiogenesis (P=.008). The inactivation of hPMS2 or hMLH1 is an independent protective factor (HR, 0.309) and, along with the histologic grade (HR, 5.561), defines the patients' prognosis. CONCLUSION: In our experience, the inactivation of hPMS2 or hMLH1 is an independent marker of good prognosis and occurs in a quarter of sporadic UTUC cases. The immunohistochemical study of these patients can be used to assess the screening of hidden forms of Lynch syndrome.

Prostate anatomy in motheaten viable (me(v)) mice with mutations in the protein tyrosine phosphatase SHP-1.

OBJECTIVE: To study prostate and seminal vesicle anatomy in viable motheaten (mev) with mutations in PTPN6 gene leading to a severe reduction in the activity of protein tyrosine phosphatase SHP-1. Homozygous mev mice exhibit multiple anomalies that include immunodeficiencies, increased proliferation of macrophage, neutrophil, and erythrocyte progenitors, decreased bone density and sterility. MATERIAL AND METHOD: We analyzed macro- and microscopic anatomy of the seminal vesicle and prostate macro- and microscopic anatomy of 5 mev/mev and 8 wt/wt adult 7 week old mice. Computerized morphometric analysis was performed to measure the relative changes appearing in the epithelial volume of the different prostatic lobes. RESULTS: All mice studied revealed normal genital organs (penis, testis, epididymis, vas deferens) and bladder. The seminal vesicle was absent in all mev/mev individuals analyzed, being normal and very noticeable in wt/wt mice. The different glands that compose the prostatic complex (anterior, ventral and dorso-lateral prostate) were atrophied in mev/mev mice: anterior prostate 0.4 times, ventral 0.19 times, dorsal 0.35 times and lateral 0.28 times those of the respective regions in wt/wt mice. Microscopically, mev/mev mice revealed scarce and large prostatic ducts, acini severely atrophic with empty lumen and scarce loose epithelial component forming tufts and infoldings, and hyperplastic changes in fibromuscular stroma. CONCLUSIONS: The prostate of mev/mev mice exhibits signs of aberrant differentiation and the resulting phenotype may be related to the loss of function of SHP-1. Prostatic anomalies in these mice affect, together with defects in sperm maduration, for their sterility. These data suggest SHP-1 plays an important role in prostate epithelial morphogenesis.

Diagnostic usefulness of the cytological study of the transport buffer in transrectal prostate core biopsies.

BACKGROUND: To evaluate the diagnostic usefulness of the cytological study of the transport buffer in the diagnosis of prostate adenocarcinoma in transrectal core biopsies. METHODS: A total of 256 consecutively biopsied patients have been included in the analysis, 100 of them diagnosed of prostate adenocarcinoma. The procedure included the cytological analysis of the transport buffer and conventional histology. Cytological evaluation was performed in a blind way by the same pathologist. RESULTS: Overall sensitivity, specificity, and positive and negative predictive values to detect malignancy in the cytological slides were 54%, 98%, 94% and 76%, respectively. When restricted the analysis to cases with Gleason score higher than 8, sensitivity and negative predictive value increased to 85% and 97%, respectively. Similarly, when the analysis focused exclusively to cases with more than 5mm of cancer in the biopsy, sensitivity and positive predictive value increased to 66% and 96%, respectively. CONCLUSIONS: This study shows that whilst specificity was maintained in 98%, sensitivity, and positive and negative predictive values significantly improved in high grade and high volume adenocarcinomas. Our findings confirm that the cytological study of the transport buffer may complement the histology in the diagnosis of prostate adenocarcinoma.

Impact of p53, MIB-1 and PECAM-1 expression on the prognosis of urothelial carcinoma of the renal pelvis.

OBJECTIVE: Determine whether the overexpression p53, MIB-1 and PECAM-1 of protein levels is of interest in predicting the prognosis of transitional cell carcinoma of the upper urinary tract (TCC-UUT) with the primary seat in the renal pelvis. MATERIAL AND METHOD: A univariate and multivariate analysis was conducted for prognosis prediction in a series of 82 patients with TCC-UUT of the renal pelvis who had no metastases at diagnosis (N0/Nx M0) and were treated exclusively with nephroureterectomy. We assessed clinicopathological parameters (age, gender, tumor grade and extent, histological variety, growth pattern, vascular invasion, infiltration of the renal parenchyma, tumor necrosis) and the immunohistochemical expression of p53, MIB-1 (ki-67) and PECAM-1 (CD31) in sections performed with tissue microarray (TMA). RESULTS: A total of 47.6% of the patients had high-grade lesions according to the USIP-WHO classification. The growth pattern was flat in 15.85%. The distribution by T category was: 3.7% pTa, 51.2% pT1, 11% pT2, 29.3% pT3 and 4.9% pT4. The mean follow-up was 46.8+38.5 (range, 4-172) months. The median survival was reached at 57 (95% CI 44-63) months. The univariate analysis revealed that survival in these patients is associated with tumor size (P=.028), histological variety (P<.0001), growth pattern (P<.0001), grade (P<.0001), pT (P=.01), vascular invasion (P=.025), necrosis (P=.004) and overexpression of p53 (P=.0006), PECAM-1 (P=.0036) and MIB-1 (P=.0038). The Cox regression model showed that high-grade (HR, 4.2; 95% CI 1.28-13.79; P=.018), flat growth pattern (HR, 2.52; 95% CI 1.05-6.03; P=.038) and p53 overexpression (HR, 2.8; 95% CI 1.22-6.44; P=.015) were independent predictors. CONCLUSION: Histological grade, tumor growth pattern and p53 overexpression were established as the primary predictors of prognosis for primary TCC-UUT of the renal pelvis. The independent value of MIB-1 observed in other studies was not reproduced in this study.

Concurrent solitary fibrous tumor and low-grade fibrillary astrocytoma of the cerebellum.

OBJECTIVE: We report the clinicopathologic features of a solitary fibrous tumor (SFT) having undergone malignant transformation and being intimately associated with a WHO Grade II astrocytoma. CLINICAL PRESENTATION: A 7-month old patient presented with delayed motor development and hydrocephalus. INTERVENTION: Histologic and immunocytologic methods were applied in the study of the tumors. Resection was initially employed and the SIOP protocol employing vincristine and carboplatin was applied upon tumor recurrence. CONCLUSION: The biologic basis for the association of SFT and astrocytoma is unknown. The complex lesion differs substantially from WHO Grade IV gliosarcoma and from gliofibroma, lesions in which the disparate elements are linked by metaplasia. Indeed, it may represent a collision tumor. Lastly, induction of the glioma by the solitary fibrous tumor, a mechanism invoked to explain the poorly understood "sarcoglioma," deserves consideration.

Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain--results of the LEARN Study.

Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice.

[Papillary renal cell carcinoma spectrum]. / El espectro del carcinoma renal papilar.

OBJECTIVES: Significant conceptual expansion of renal cancer continues to increase. The key point to this phenomenon is based on the combination of morphology and molecular data. The result is the new 2004 WHO classification of renal tumors in adults. The apparently never ending advance in molecular genetics is constantly pushing to update recently proposed listings. MATERIAL AND METHODS: Papillary renal cell carcinoma, considered the term in the broader sense, is the subject of this study. This histological phenotype in renal cancer, with an accelerated growth in the last times, is a good example of the never ending evolution of pathology as a clinical discipline. RESULTS: The genetic background and the phenotype of all renal neoplasms with papillary or tubulo-papillary phenotype, or with its genetic background, some of them being very recently described entities even now under discussion is wide and heterogenous: conventional sporadic papillary carcinoma, papillary carcinomas linked to genetic syndromes (hereditary papillary carcinoma, papillary carcinoma associated to hereditary leiomyomatosis, papillary carcinoma associated to hereditary papillary thyroid carcinoma, Birt-Hogg-Dubé syndrome) or to specific genetic disorders (Xp11.2 associated papillary carcinoma), papillary carcinoma with distinct morphology (micropapillary carcinoma, inverted papillary carcinoma, papillary carcinoma with spindle cells and angulated tubules) and new renal carcinomas included within the group of papillary carcinoma (tubulo-cystic carcinoma and tubular, mucinous and spindle cell carcinoma). CONCLUSION: Aside from the classically known histological variants, several new entities, some of them still badly delineated, are progressively enlarging the group of renal carcinomas with papillary phenotype. This growth will continue in the next times on the light of the new findings and pathologists will be main actors in this fact.

[Plasmacytoid urothelial carcinoma of the urinary bladder. A study of 7 cases]. / Carcinoma urotelial plasmocitoide de vejiga urinaria. Estudio de 7 casos.

OBJECTIVE: Plasmacytoid urothelial carcinoma is a rare and aggressive variant of bladder cancer that mimics plasmacytoma histologically and that can be confused with hemolymphoid neoplasms secondarily affecting the urinary bladder. Only single cases and short series have been described so far. PATIENTS AND METHODS: Seven cases of plasmacytoid urothelial carcinoma have been found among 720 high grade urothelial carcinomas of the urinary bladder. RESULTS: In our series, 0.97% of high grade urothelial carcinomas of the urinary bladder show plasmacytoid phenotype. All the cases were smoking males between 58 and 75 years old. Histologically, two cases showed pure plasmacytoid features, while in the other five cases the plasmacytoid phenotype was mixed with conventional transitional cell or glandular histologies. By immunohistochemistry, all the plasmacytoid areas showed fair epithelial differentiation. The clinical behaviour was aggressive in all the cases, with distant metastases at diagnosis in three cases and early tumor recurrence after chemotherapy in four of them. CONCLUSIONS: In our experience, the plasmacytoid urothelial carcinoma of the urinary bladder is a rare tumor that can also be detected in association with areas of conventional urothelial carcinoma. It is mandatory to recognize this histological subtype due to the clinical and prognostic implications of this diagnosis.

Biomechanical regulation of cell orientation and fate.

Biomechanical regulation of tumor phenotypes have been noted for several decades, yet the function of mechanics in the co-evolution of the tumor epithelium and altered cancer extracellular matrix has not been appreciated until fairly recently. In this review, we examine the dynamic interaction between the developing epithelia and the extracellular matrix, and discuss how similar interactions are exploited by the genetically modified epithelium during tumor progression. We emphasize the process of mechanoreciprocity, which is a phenomenon observed during epithelial transformation, in which tension generated within the extracellular microenvironment induce and cooperate with opposing reactive forces within transformed epithelium to drive tumor progression and metastasis. We highlight the importance of matrix remodeling, and present a new, emerging paradigm that underscores the importance of tissue morphology as a key regulator of epithelial cell invasion and metastasis.

Primary pure squamous cell carcinoma of the breast diagnosed by fine-needle aspiration cytology: a case study using liquid-based cytology.

Pure primary squamous cell carcinoma (SCC) is an extremely rare type of breast tumor. We report one of such cases in a 32-year-old woman, diagnosed by fine-needle aspiration cytology (FNAC). Aspiration smears were characterized by squamous cells, both isolated and in aggregates, at various stages of maturation. The tumor was excised, and the histologic sections confirmed the cytologic diagnosis. Pure primary SCC of the breast has a distinctive cytomorphologic appearance, and diagnosis of this tumor by FNAC is possible. For its diagnosis, the exclusion of SCC of local cutaneous structures and metastasis of distant squamous carcinoma are mandatory.