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Background The presence of osteoclast-like giant cells (OGC) in hepatocellular carcinoma (HCC) is rare and literature on this topic is scarce. In this article, we report on a case of a 77-year-old male patient with HCC with OGC and provide an overview of the current literature. Methods We conducted a systematic search to find all available literature on OGC in HCC. The electronic databases PubMed, Web of Science, Embase and CENTRAL were searched from inception until October 2020. Results Thirteen articles on this topic were identified and were included in this review. Data on 14 patients were available, described in twelve case reports, one patient in a patient series and the present case. Median age of included patients was 68 years. Two patients underwent neoadjuvant therapy prior to surgery. Of the 14 cases, eight tumours with OGC arose in a cirrhotic liver. Oncological outcome in this series was unfavourable, even after surgical resection, with a median disease-free survival of 75 d. Conclusions The presence of OGC in HCC is rare. Current literature is scarce, and suggests an unfavourable outcome in regard to overall survival of HCC.

BACKGROUND Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P

Primary rhabdomyosarcoma (RMS) of the adult prostate is a very rare tumor with only 45 cases published to date. The clinical course of RMS of the prostate is very aggressive, and prognosis is very poor. Here we describe two cases of primary RMS of the prostate of adult patients and discuss the differential diagnosis of RMS with other mesenchymal tumors of prostate. The first patient was a 50-year-old man who clinically presented with urinary retention and hematuria, low serum prostate-specific antigen, moderate prostatomegaly, and multiple metastases as shown by computed tomography. Histological examination revealed a diffuse "small round blue cell" proliferation with an intermingled population of larger cells with rhabdomyoblastic differentiation that showed immunoreactivity for desmin and MYF4 (myogenin). Molecular and cytogenetic studies did not reveal recurrent chromosomal translocations associated with RMSs and other sarcomas. The patient underwent doxorubicin (adriamycin) treatment without disease progression during the whole follow-up period of 7 months. The second patient was a 39-year-old man who presented with urinary retention, an increased serum prostate-specific antigen level, extensive prostatomegaly, enlarged abdominal and inguinal lymph nodes, and skeletal metastases. Histological examination revealed a tumoral proliferation with a small round blue aspect and diffuse immunoreactivity for desmin and MYF4 (myogenin). Fluorescence in situ hybridization revealed a FOXO1 translocation, consistent with a diagnosis of alveolar-type RMS. The patient followed a multimodal treatment and died of the disease after its progression.

Background: Scoring of immunohistochemistry (IHC) staining is often done by non-pathologists, especially in large-scale tissue microarray (TMA)-based studies. Studies on the validity and reproducibility of scoring results from non-pathologists are limited. Therefore, our main aim was to assess interobserver agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localization (nucleus/membrane/cytoplasm). Methods: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyze interobserver and intraobserver agreement for 6,249 TMA cores from a colorectal cancer series. Results: Interobserver agreement between non-pathologists (independently scored) and the histopathologist was “substantial” for nuclear and membranous IHC markers (κrange = 0.67–0.75 and κrange = 0.61–0.69, respectively), and “moderate” for the cytoplasmic IHC marker (κrange = 0.43–0.57). Scores of the three non-pathologists were also combined into a “combination score” (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κnuclear = 0.74; κmembranous = 0.73; κcytopasmic = 0.57). Interobserver agreement between non-pathologists was “substantial” (κnuclear = 0.78; κmembranous = 0.72; κcytopasmic = 0.61). Intraobserver agreement of non-pathologists was “substantial” to “almost perfect” (κnuclear,range = 0.83–0.87; κmembranous,range = 0.75–0.82; κcytopasmic = 0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. Conclusions: This study shows that adequately trained non-pathologists are able to generate reproducible IHC scoring results, that are similar to those of an experienced histopathologist. A combination score of at least two non-pathologists yielded optimal results. Impact: Non-pathologists can generate reproducible IHC results after appropriate training, making analyses of large-scale molecular pathological epidemiology studies feasible within an acceptable time frame.

Previous research has suggested that the expression of proteins related to the Warburg effect may have prognostic value in colorectal cancer (CRC), but results remain inconsistent. Our objective was to investigate the relationship between Warburg‐subtypes and patient survival in a large population‐based series of CRC patients. In the present study, we investigated the expression of six proteins related to the Warburg effect (LDHA, GLUT1, MCT4, PKM2, p53, PTEN) by immunohistochemistry on tissue microarrays (TMAs) from 2,399 incident CRC patients from the prospective Netherlands Cohort Study. Expression levels of the six proteins were combined into a pathway‐based sum‐score and patients were categorised into three Warburg‐subtypes (low/moderate/high). The associations between Warburg‐subtypes and CRC‐specific and overall survival were investigated using Kaplan–Meier curves and Cox regression models. CRC patients were classified as Warburg‐low (n = 695, 29.0%), Warburg‐moderate (n = 858, 35.8%) or Warburg‐high (n = 841, 35.1%). Patients with Warburg‐high CRC had the poorest CRC‐specific [hazard ratio (HR) 1.17; 95% CI 1.00–1.38] and overall survival (HR 1.19; 95% CI 1.05–1.35), independent of known prognostic factors. In stratified analyses, this was particularly true for patients with tumour‐node‐metastasis (TNM) stage III CRC (HRCRC‐specific 1.45; 95% CI 1.10–1.92 and HRoverall 1.47; 95% CI 1.15–1.87), and cancers located in the rectum (HRoverall 1.56; 95% CI 1.15–2.13). To our knowledge, this is the first study to identify the prognostic value of immunohistochemistry‐based Warburg‐subtypes in CRC. Our data suggest that Warburg‐subtypes are related to potentially important differences in CRC survival. Further research is required to validate our findings and to investigate the potential clinical utility of these Warburg‐subtypes in CRC.

Background: Urethral stricture is a relatively frequent problem often requiring multiple surgical interventions. The objective of this study was to compare the clinicopathologic features of urethral resections from patients who underwent open end-to-end anastomotic urethroplasty and later recurred compared to those who did not.Methods: A retrospective review of the pathology files identified 36 consecutive patients who underwent urethroplasty. The histopathological analysis included evaluation of the inflammatory infiltrate based on the predominant (>50%) cell type: lymphocyte-rich, neutrophil-rich, plasma cell-rich, and mixed; length and thickness of the fibrous plaque; and the cellularity of the fibrous plaque: cellular (>40 stroma nuclei/HPF) or paucicellular (

BK polyomavirus (BKPyV) has been associated with some high-grade and special urothelial cell carcinoma (UCC) subtypes in immunosuppressed patients. Here, we evaluated the relationship of BKPyV-positive urine cytology specimens (UCS) with UCC. A large single-institution database was retrospectively searched for UCS positive for decoy cells, suggesting BKPyV infection. These were tested for the presence of BKPyV by PCR and immunohistochemistry (IHC) in urine sediments and formalin-fixed paraffin-embedded (FFPE) tissue samples of UCC. Decoy cells were reported in 30 patients out of the database with 22.867 UCS. Of these 30 patients, 16 (53.3%) had no history of UCC. Six patients out of these 16 had a history of transplantation, 4 had a history of severe chronic medical conditions, and 6 had no chronic disease. The other fourteen patients were diagnosed with either in situ or invasive UCC of the urinary bladder (14/30, 46.6%) prior to the detection of decoy cells in the urine. Nine of these UCC patients received intravesical treatment (BCG or mitomycin) after the first presentation with UCC. However, the clinical data on the treatment of the other five UCC patients was lacking. IHC identified BKPyV-positivity in the urine samples of non-UCC and UCC patients, while no BKPyV positivity was found in FFPE tissues of primary UCCs and metastases. In addition, BKPyV-PCR results revealed the presence of BKPyV DNA in the urine of the UCC cases, yet none in the UCC tissues itself. These data strongly indicate that BKPyV reactivation is not restricted to immunosuppression. It can be found in UCS of the immunocompetent patients and may be related to the intravesical BCG or mitomycin treatment of the UCC patients.

INTRODUCTION AND OBJECTIVE:Immune checkpoint inhibitors (ICIs) are frequently used in the treatment of metastatic melanoma, clear cell renal cell carcinoma, and an increasing number of other cancer...

The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities.

Aims: Scoring of immunohistochemical (IHC) staining is often done by non-pathologists, especially in large-scale Tissue MicroArray (TMA)-based studies. Studies on the validity of scoring results from non-pathologists are very limited. Therefore, our main aim was to assess inter-observer agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localisation (nucleus/membrane/cytoplasm). Methods and results: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyse inter- and intra-observer agreement for 6249 TMA cores from a colorectal cancer (CRC) series. Inter-observer agreement between non-pathologists (independently scored) and the histopathologist was “substantial” for nuclear and membranous IHC markers (κrange=0.67-0.75 and κrange=0.61-0.69, respectively), and “moderate” for the cytoplasmic IHC marker (κrange=0.43-0.57). Scores of the three non-pathologists were also combined into a combination score (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κnuclear=0.74; κmembranous=0.73; κcytopasmic=0.56). Inter-observer agreement between non-pathologists was “substantial” (κnuclear=0.78; κmembranous=0.72; κcytopasmic=0.61). Intra-observer agreement of non-pathologists was “substantial” to “almost perfect” (κnuclear,range=0.83-0.87; κmembranous,range=0.75-0.82; κcytopasmic,range=0.69-0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. Conclusions: This study shows that adequately trained non-pathologists are able to produce similar IHC scoring results as an experienced histopathologist. Considering the histopathologist's score as the golden standard, we can conclude that trained non-pathologists can produce valid IHC results on TMA sections. A combination score of at least two non-pathologists yielded optimal results. Citation Format: Kelly Offermans, Josien C. Jenniskens, Iryna Samarska, Gregorio E. Fazzi, Colinda C. Simons, Kim M. Smits, Leo J. Schouten, Matty P. Weijenberg, Piet A. van den Brandt, Heike I. Grabsch. Validity and reproducibility of immunohistochemical scoring by trained non-pathologists on Tissue MicroArrays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 830.

Condyloma acuminatum rarely occurs in the urinary bladder and is considered to be a risk factor for squamous cell carcinoma, although there are only a few publications with limited cases. We studied 51 cases of condyloma acuminatum of the urinary bladder from transurethral resections of the urinary bladder of 38 patients from the consult files of one of the authors. Transurethral resections of the urinary bladder were obtained from 25 males with a median age of 73 years (range: 41 to 87 y) and 13 females with a median age of 68 years (range: 30 to 86 y). The follow-up period ranged from 15 months to 20 years (median: 6 y). Bladder lesions were accompanied by urethral lesions in 4 men. Eight patients (8/38; 21.0%) had a history of immunosuppression. Seven patients (7/8; 87.5%) from this group had multiple and/or recurrent condylomas. One patient (1/38; 2.6%) with renal transplantation had 10 separate bladder condylomas over time. One patient (1/38; 2.6%) had extensive anogenital condylomas and anal intraepithelial neoplasia grade 3. One patient (1/8; 12.5%) with renal transplantation presented with a solitary condyloma with synchronous squamous cell carcinoma in situ. Three female patients (3/38; 7.9%) had a history of premalignant vagina/cervix lesions. In total, 17 patients (17/38; 44.7%) had squamous cell carcinoma of the bladder, either invasive or in situ. In all cases, the squamous cell carcinoma (either in situ or invasive) was diagnosed either concurrent with the diagnosis of bladder condyloma or within 1 year of the condyloma diagnosis). In total, 9 of 38 (23.7%) patients had invasive squamous cell carcinoma with or without in situ squamous cell carcinoma. Eight of 38 (21.0%) patients had squamous cell carcinoma in situ only (without a definitive invasive component-in 3 cases invasive squamous cell carcinoma could not be excluded with certainty). In total, 19 patients (19/38; 50%) were positive for either low-risk human papillomavirus (LR-HPV) or high-risk human papillomavirus (HR-HPV) or both (3 were positive for both LR-HPV and HR-HPV, 12 patients for only LR-HPV, and 4 for only HR-HPV). Of the 19 patients that were negative for both LR-HPV and HR-HPV, 9 of 19 (47.4%) patients had associated squamous cell carcinoma. Of the 12 patients with only LR-HPV, 4 (33.3%) had associated squamous cell carcinoma (either invasive or in situ). Of the 7 patients with HR-HPV (with or without LR-HPV), 4 (57.1%) has associated squamous cell carcinoma. In summary, condyloma acuminatum of the urinary bladder shows a strong association with squamous cell carcinoma of the bladder, regardless of the condyloma's HPV in situ hybridization results. Immunosuppression is associated with condylomas of the bladder. It is important to distinguish bladder condylomas from papillary urothelial carcinoma, given their different risks for panurothelial disease and risk of squamous cell carcinoma. Recognition of bladder condylomas histologically is often challenging given their rarity, and that they can be negative for both LR-HPV and HR-HPV. The lack of a history of other anogenital human papillomavirus-related lesions further increases the difficulty in establishing the correct diagnosis.

Carcinoma in situ (CIS) is difficult to visualize with white light cystoscopy (WLC), whereas blue light cystoscopy (BLC) using photosensitizing agents improves detection rates. We retrospectively reviewed transurethral biopsies of bladder tumors in which both WLC and BLC evaluations were performed (n = 135 samples from 79 patients). Biopsies were classified based on the presence/absence of fluorescence under BLC and the final pathological report (CIS/benign/atypical). Forty-one (30%) cases were diagnosed as CIS; of those, 38 (93%) were BLC(+), including 23 that were WLC(-). Conversely, 51 (38%) lesions were BLC(+) but classified as non-CIS. Eleven BLC(+) cases were diagnosed as "atypical." These cases were anonymized and reviewed by 7 pathologists for concordance and then immunostained for CK20, p53, and Ki-67. Immunohistochemistry results were interpreted as consistent with CIS if there was full thickness staining of CK20, more than 50% p53-positive cells, and more than 50% Ki-67 positive cells. Review of BLC(+)/atypical cases showed a mean agreement of 79%, and none of the cases showed staining pattern consistent with CIS. Therefore, all 11 cases of BLC(+)/atypical were considered non-CIS for the final analysis. All patients with BLC(+)/atypical lesions had a history of intravesical Bacillus Calmette-Guerin and/or mitomycin. Using final pathology as the reference, sensitivity, specificity, and negative predictive value of BLC were 93% (confidence interval [CI], 80.1%-98.5%), 46% (CI, 35.4%-56.3%), and 94% (CI, 82.5%-97.8%), respectively. The low specificity of BLC leads to BLC(+) lesions with atypical diagnosis. Morphological classification of these lesions is fairly consistent among different pathologists. Immunohistochemistry for p53/CK20/Ki-67 in this setting is only helpful to potentially avoid overcalling CIS. (C) 2019 Elsevier Inc. All rights reserved.

This cohort study examines the potential association of the use of immune checkpoint inhibitors with testicular histopathologic conditions.

A new prostate cancer grading system was proposed in 2013 and endorsed by major journals and societies in 2014, in part because of anecdotal evidence that Gleason scores (GSs) were incorrectly combined in the literature.To examine how published studies categorized GSs in current practice.A PubMed search was conducted on articles published in 2016-2017 using the search terms "Gleason" and "prostate". This literature review included 1576 articles after exclusions.(1) Separating GS 7: pathology journals were more likely than non-pathology journals to grade GS 7 separately (56.9% vs 40.0%, p0.05). Articles co-authored by a pathologist separated GS 7 more than those without a pathologist (53.2% vs 32.9%, p0.001). North American and European studies separated GS 7 more than Asian studies (47.6% and 44.1% vs 24.1%, p0.001). Clinical articles separated GS 7 more than research articles (43.7% vs 32.9%, p0.001). (2) Separating GS 8 from GS 9-10: pathology journals separated GS 8 from GS 9-10 more than non-pathology journals (55.2% vs 34.4%, p=0.001). Articles co-authored by a pathologist separated GS 8 from GS 9-10 more often than those without a pathologist (44.9% vs 29.5%, p0.001). (3) Using grade groups as "ideal" with all other groupings "non-ideal": pathology journals used ideal more than non-pathology journals (32.2% vs 15.9%, p0.001). Ideal grouping is more likely in articles co-authored by a pathologist than in those without a pathologist (20.6% vs 11.0%, p0.001). North American and European studies used ideal grouping more than Asian studies (17.6% and 14.0% vs 9.1%, p0.05). (4) Arranging groupings in decreasing order from ideal to non-ideal: pathology journals were closer to ideal than non-pathology journals (p=0.002). Articles co-authored by a pathologist were classified closer to ideal than those without a pathologist (p0.001). North American (p0.001) and European (p=0.02) studies were closer to ideal than Asian studies.There is still wide variation in how GSs are grouped world-wide. Only a minority of published articles group GSs accurately.In this report, we looked at how GSs were grouped world-wide. We found that only a minority of published articles on prostate cancer were grouping GSs accurately, which could lead to inaccurate results and affect patient care with different prostate cancer grades. Our study calls for more widespread adoption of the new prostate cancer grading system composed of five grade groups to minimize incorrect grouping for future studies.

Our case report describes the strong ability of noninvasive diagnostic techniques to detect cardiac involvement in advanced systemic amyloid light chain amyloidosis, which was confirmed at autopsy.