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Objective: The Visiopharm artificial intelligence (AI) algorithm for oestrogen receptor (ER) immunohistochemistry (IHC) in whole slide images (WSIs) has been successfully validated in surgical pathology. This study aimed to assess its efficacy in cytology specimens., Methods: The study cohort comprised 105 consecutive cytology specimens with metastatic breast carcinoma. ER IHC WSIs were seamlessly integrated into the Visiopharm platform from the Image Management System (IMS) during our routine digital workflow, and an AI algorithm was employed for analysis. ER AI scores were compared with pathologists' manual consensus scores. Optimization steps were implemented and evaluated to reduce discordance., Results: The overall concordance between pathologists' scores and AI scores was excellent (99/105, 94.3%). Six cases exhibited discordant results, including two false-negative (FN) cases due to abundant histiocytes incorrectly counted as negatively stained tumour cells by AI, two FN cases owing to weak staining, and two false-positive (FP) cases where pigmented macrophages were erroneously counted as positively stained tumour cells by AI. The Pearson correlation coefficient of ER-positive percentages between pathologists' and AI scores was 0.8483. Optimization steps, such as lowering the cut-off threshold and additional training using higher input magnification, significantly improved accuracy., Conclusions: The automated ER AI algorithm demonstrated excellent concordance with pathologists' assessments and accurately differentiated ER-positive from ER-negative metastatic breast carcinoma cytology cases. However, precision in identifying tumour cells in cytology specimens requires further enhancement., (© 2024 John Wiley & Sons Ltd.)

Purpose: Patients with HER2-positive breast cancer commonly receive anti-HER2 neoadjuvant chemotherapy and pathologic complete response (pCR) can be achieved in up to half of the patients. HER2 protein expression detected by immunohistochemistry (IHC) can be quantified using digital imaging analysis (DIA) as a value of membranous connectivity. We aimed to investigate the association HER2 IHC DIA quantitative results with response to anti-HER2 neoadjuvant chemotherapy., Methods: Digitized HER2 IHC whole slide images were analyzed using Visiopharm HER2-CONNECT to obtain quantitative HER2 membranous connectivity from a cohort of 153 HER2+ invasive breast carcinoma cases treated with anti-HER2 neoadjuvant chemotherapy (NAC). HER2 connectivity and other factors including age, histologic grade, ER, PR, and HER2 fluorescence in situ hybridization (FISH) were analyzed for association with the response to anti-HER2 NAC., Results: Eighty-three cases (54.2%) had pCR, while 70 (45.8%) showed residual tumor. Younger age, negative ER/PR, higher HER2 DIA connectivity, higher HER2 FISH ratio and copy number were significantly associated with pCR in univariate analysis. Multivariate analysis demonstrated only age, HER2 DIA connectivity, PR negativity, and HER2 copy number was significantly associated with pCR, whereas HER2 DIA connectivity had the strongest association., Conclusions: HER2 IHC DIA connectivity is the most important factor predicting pCR to anti-HER2 neoadjuvant chemotherapy in patients with HER2-positive breast cancer.

Background: Immune reaction with tumor-infiltrating lymphocytes (TILs) has been extensively investigated in breast cancer. Programmed cell death 1 and its ligand (PD-L1) are key physiologic suppressors of cytotoxic immune reaction. However, the combination of TILs with PD-L1 expression has not been well studied in breast cancer., Patients and Methods: A multi-color immunohistochemical multiplex assay simultaneously detecting PD-L1, CD8, and CD163 was performed on biopsy whole sections from 123 HER2-positive (HER2 + ) breast cancers, including 64 treated with anti-HER2 neoadjuvant therapy and subsequent resection., Results: PD-L1 expression was identified in 88 cases (72%) including 21 (17%) in tumor cells and 67 (55%) in immune cells. PD-L1 expression was positively associated with high Nottingham grade, high nuclear grade, and a high level of CD8 + and CD163 + cells. Among the 64 patients who received neoadjuvant therapy, 39 had pathologic complete remission (pCR) and 25 had incomplete response. Multivariate analysis showed progesterone receptor negativity, HER2/chromosome 17 centromere (CEN17) ratio and intratumoral CD8 + cells were significantly associated with pCR. Furthermore, all patients with intratumoral CD8 + cells but no PD-L1 expression achieved pCR., Conclusion: Our data have shown that examination of intratumoral CD8 + cells together with PD-L1 expression proves useful in predicting response to anti-HER2 targeted therapy in patients with HER2 + breast cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Distinguishing urothelial carcinoma (UC) from prostate carcinoma (PC) is important due to potential therapeutic and prognostic implications. However, this can be a diagnostic challenge when there is limited tissue and in poorly differentiated tumors. We evaluated the diagnostic utility of a dual immunohistochemical stain comprising p63 and P501S (prostein), applied sequentially on a single slide and visualized by double chromogen reaction, in differentiating these two cancers. Thus far, there have been no previous studies assessing the diagnostic utility of p63 and P501S combined together as a dual immunostain in distinguishing between these two cancers., Methods: p63/P501S dual-color sequential immunohistochemical staining was performed on archival material from 132 patients with high-grade UC and 23 patients with PC, and evaluated for p63 (brown nuclear) and P501S (red cytoplasmic) expression. Both the staining intensity and percentage of positive tumor cells were assessed., Results: p63 was positive in 119/132 of UC and negative in PC. P501S was positive in 22/23 of PC and negative in UC. The p63+/P501S- immunoprofile had 90% sensitivity and 100% specificity for UC. The p63-/P501S+ immunoprofile had 96% sensitivity and 100% specificity for PC., Conclusion: Our results indicate that double sequential immunohistochemical staining with p63 and P501S is highly specific and can be a useful tool in distinguishing UC from PC especially when there is limited diagnostic tissue as it can be performed on a single slide.

Background. Spindle cell/sclerosing rhabdomyosarcoma is a rare neoplasm and has an aggressive clinical course. Because of its rarity, we performed a multi-institutional collaboration to comprehend the overarching clinical, histopathological, and immunohistochemical characteristics of a cohort of spindle cell/sclerosing rhabdomyosarcoma. Materials and Methods. Forty-five patients with spindle cell/sclerosing rhabdomyosarcoma were identified. Demographics, clinical, histopathological, and immunohistochemistry data were reviewed and recorded. Results. The patients' age ranged from 1 to 85 years with a male to female ratio of 1.2:1. There were 15 children/adolescents and 30 adults. Eighteen (40%) tumors were located in the head and neck region. Twenty-four (53%) tumors displayed a bimorphic cellular arrangement with hypercellular areas having short, long, and sweeping fascicular and herringbone pattern, and hypocellular areas with stromal sclerosis and associated hyalinized and/or chondromyxoid matrix. Histomorphological differentials considered were leiomyosarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma, nodular fasciitis, liposarcoma, synovial sarcoma, sarcomatoid carcinoma, solitary fibrous tumor, dermatofibrosarcoma protuberans, and schwannoma. Six tumors exhibited marked stromal sclerosis. The myogenic nature was confirmed by immunohistochemistry. Positivity for at least one skeletal muscle-associated marker (MyoD1 and/or myogenin) was observed. Conclusion. Spindle cell/sclerosing rhabdomyosarcoma diagnosis can be challenging as a number of malignant spindle cell neoplasm mimic this entity. Thus a correct diagnosis requires immunohistochemical work up with a broad panel of antibodies. In view of rarity of this neoplasm, further studies on a large cohort of patients with clinical follow-up data are needed for a better understanding of this tumor. [ABSTRACT FROM AUTHOR]

Papillary renal neoplasm with reverse nuclear polarity (PRNRP) is an emerging oncocytic renal tumor. Cytomorphologic features of this tumor have not been described in the literature before. Thee objective of this study was to review the cytomorphology of a case PRNRP and compare with cytomorphologic features of papillary renal cell carcinomas (pRCCs) reported in the literature. 1 case of core needle biopsy (CNB) with touch preparation (TP) of a renal mass diagnosed as PRNRP was reviewed retrospectively. Clinical presentation, cytomorphologic features, ancillary tests and histopathology results were analyzed. The touch preparation was cellular and showed tight 3-D clusters of cuboidal epithelial cells with variable presence of fibrovascular cores (FC), granular eosinophilic cytoplasm, round apically located grade 1 nuclei compared to cases of pRCC that consistently showed presence of FCs lined by cuboidal to columnar epithelial cells with variable degree of cytologic atypia. Features characteristic of pRCC like foamy macrophages, hemosiderin laden macrophages, nuclear grooves or psammoma bodies were not present. No necrosis or mitosis were identified. By immunohistochemistry (IHC) the tumor cells were positive for cytokeratin 7, GATA-3 and AMACR (focal) and negative for CA-IX, CD117 and vimentin. Cytomorphologic features of PRNRP are unique and characterized by tight 3-D clusters (with or without FCs) of cuboidal cells with small round apically located nuclei and finely granular oncocytic cytoplasm. Specific diagnosis of PRNRP on cytology or CNB is feasible along with use of ancillary tests IHC and /or molecular tests. [ABSTRACT FROM AUTHOR]

Background: SOX17 (SRY‐box transcription factor 17) was recently identified as a highly sensitive and specific marker for ovarian and endometrial carcinomas in surgical specimens. In this study, validation of the utility of SOX17 immunohistochemistry (IHC) in diagnosing metastatic gynecologic carcinomas in cytology specimens was sought. Methods: The study cohort included 84 cases of metastatic carcinomas that included 29 metastatic gynecologic carcinomas (24 ovarian high‐grade serous carcinomas, two endometrial serous carcinomas, one low‐grade serous carcinoma, one ovarian clear cell carcinoma, and one endometrial endometrioid carcinoma) and 55 cases of metastatic nongynecologic carcinomas (10 clear cell renal cell carcinomas, 10 papillary thyroid carcinomas, 11 gastrointestinal adenocarcinomas, 10 breast carcinomas, 10 lung adenocarcinomas, and four urothelial carcinomas). Cytology specimen types included peritoneal fluid (n = 44), pleural fluid (n = 25), and fine‐needle aspiration (n = 15). SOX17 IHC was performed on the cell block sections. The intensity of staining and percent positivity of the tumor cells were evaluated. Results: SOX17 was highly expressed in all tested metastatic gynecologic carcinomas with diffuse and strong nuclear expression (29 of 29; 100%). SOX17 was negative in other metastatic nongynecologic carcinomas (54 of 55; 98.18%) except for one papillary thyroid carcinoma that showed low positivity (<10%). Conclusions: SOX17 is a highly sensitive (100%) and specific (98.2%) marker for the differential diagnosis of metastatic gynecologic carcinomas in cytology specimens. Therefore, SOX17 IHC should be included in the workup of differential diagnosis of metastatic gynecologic carcinomas in cytology specimens. The results of this study showed that SOX17 was highly expressed in all tested metastatic gynecologic carcinomas with diffuse (100%) and strong nuclear expression (29 of 29) and was negative in 54 of 55 metastatic nongynecologic carcinomas. SOX17 is a highly sensitive (100%) and specific (98.2%) marker for the diagnosis of metastatic gynecologic carcinomas in cytology specimens. [ABSTRACT FROM AUTHOR]

Background: The Visiopharm human epidermal growth factor receptor 2 (HER2) digital imaging analysis (DIA) algorithm assesses digitized HER2 immunohistochemistry (IHC) by measuring cell membrane connectivity. We aimed to validate this algorithm for clinical use by comparing with pathologists' scoring and correlating with HER2 fluorescence in situ hybridization (FISH) results. Materials and Methods: The study cohort consisted of 612 consecutive invasive breast carcinoma specimens including 395 biopsies and 217 resections. HER2 IHC slides were scanned using Philips IntelliSite Scanners, and the digital images were analyzed using Visiopharm HER2-CONNECT App to obtain the connectivity values (0-1) and scores (0, 1+, 2+, and 3+). HER2 DIA scores were compared with Pathologists' manual scores, and HER2 connectivity values were correlated with HER2 FISH results. Results: The concordance between HER2 DIA scores and pathologists' scores was 87.3% (534/612). All discordant cases (n = 78) were only one-step discordant (negative to equivocal, equivocal to positive, or vice versa). Five cases (0.8%) showed discordant HER2 IHC DIA and HER2 FISH results, but all these cases had relatively low HER2 copy numbers (between 4 and 6). HER2 IHC connectivity showed significantly better correlation with HER2 copy number than HER2/CEP17 ratio. Conclusions: HER2 IHC DIA demonstrates excellent concordance with pathologists' scores and accurately discriminates between HER2 FISH positive and negative cases. HER2 IHC connectivity has better correlation with HER2 copy number than HER2/CEP17 ratio, suggesting HER2 copy number may be more important in predicting HER2 protein expression, and response to anti-HER2-targeted therapy. [ABSTRACT FROM AUTHOR]

Objectives: Either immunohistochemistry (IHC) or in situ hybridization (ISH) can be used to determine human epidermal growth factor receptor 2 (HER2) status. Breast cancers (BCs) with HER2 IHC-negative (IHC-) and ISH-amplified (ISH+) results have been rarely reported but not well studied. We investigated the frequency of HER2 IHC-/ISH+ BCs and their response to anti-HER2 neoadjuvant chemotherapy (NAC).Methods: Seventeen BCs with HER2 IHC-/ISH+ results were identified from 1,107 consecutive invasive BCs (1.5%, 17/1,107).Results: Gene protein assay confirmed the original HER2 IHC and ISH results. Increased HER2 RNA level was detected in HER2 IHC-/ISH+ cases compared with HER2 IHC-/ISH- cases. Eight patients had anti-HER2 NAC; three had pathologic complete response, and five had residual tumors.Conclusions: A small percentage of patients (1.5%) showed discordant HER2 IHC and ISH results (IHC-/ISH+) and would have lost the opportunity for potentially beneficial anti-HER2-targeted therapy if only HER2 IHC testing had been used. [ABSTRACT FROM AUTHOR]

The Visiopharm human epidermal growth factor receptor 2 (HER2) digital imaging analysis (DIA) algorithm assesses digitized HER2 immunohistochemistry (IHC) by measuring cell membrane connectivity. We aimed to validate this algorithm for clinical use by comparing with pathologists' scoring and correlating with HER2 fluorescence in situ hybridization (FISH) results. Materials and Methods: The study cohort consisted of 612 consecutive invasive breast carcinoma specimens including 395 biopsies and 217 resections. HER2 IHC slides were scanned using Philips IntelliSite Scanners, and the digital images were analyzed using Visiopharm HER2-CONNECT App to obtain the connectivity values (0-1) and scores (0, 1+, 2+, and 3+). HER2 DIA scores were compared with Pathologists' manual scores, and HER2 connectivity values were correlated with HER2 FISH results. Results: The concordance between HER2 DIA scores and pathologists' scores was 87.3% (534/612). All discordant cases (n = 78) were only one-step discordant (negative to equivocal, equivocal to positive, or vice versa). Five cases (0.8%) showed discordant HER2 IHC DIA and HER2 FISH results, but all these cases had relatively low HER2 copy numbers (between 4 and 6). HER2 IHC connectivity showed significantly better correlation with HER2 copy number than HER2/CEP17 ratio. Conclusions: HER2 IHC DIA demonstrates excellent concordance with pathologists' scores and accurately discriminates between HER2 FISH positive and negative cases. HER2 IHC connectivity has better correlation with HER2 copy number than HER2/CEP17 ratio, suggesting HER2 copy number may be more important in predicting HER2 protein expression, and response to anti-HER2-targeted therapy. [ABSTRACT FROM AUTHOR]

Programmed cell death 1 (PD‐1) and its ligand (PD‐L1) are key physiologic suppressors of the cytotoxic immune reaction. However, to date, the combination of PD1/PD‐L1 expression and tumor‐infiltrating lymphocytes (TILs) and antigen‐presenting cells has been only minimally reported in breast carcinoma, in particular in relation to HER2‐positive cases. The goal of this study was to evaluate both cellular tumoral immune reaction and PD‐L1/PD1 distribution in HER2‐positive cases, as well as any associations with clinical outcome using conventional chemotherapy combined with HER2 blocking. Multicolor immunohistochemical multiplex assays simultaneously demonstrating PD1, PD‐L1, and CD8 or PD‐L1, CD3, and CD163 were performed on tissue microarrays (TMA) representing 216 pretreatment cases of HER2‐positive invasive breast carcinoma. PD‐L1 expression was identified in 38 cases (18%), including 12 cases (6%) with PD‐L1 labeling of tumor cells and 26 cases (12%) with PD‐L1 labeling of immune cells only. Ten of 12 cases with PD‐L1 staining of tumor cells showed staining of associated immune cells as well. With this assay method, PD1 was detectable in many fewer cases (6 cases or 3%). PD‐L1 expression was positively associated with high Nottingham grade, negative ER and PR, the absence of lymph node metastasis, and high levels of CD8+ cells. The overall survival by univariate analysis was positively associated with lower tumor stage, the absence of lymph node metastasis, PD‐L1 expression, and high levels of CD8+ cells. Therefore, our data suggest cytotoxic immune reaction mediated by CD8‐positive T cells and PD‐L1 expression may predict a better outcome in patients with HER2‐positive breast carcinoma managed with conventional chemotherapy and HER2‐blocking therapy. These findings recommend clinical trials utilizing checkpoint blocking immunotherapy in some form for HER2‐positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: To study the utility of the laminin immunostain in distinguishing invasive from noninvasive urothelial carcinoma (UC). The distinction is difficult but clinically significant as it can affect the decision to administer intravesical Bacillus Calmette-Guerin or can even lead to cystectomy.Materials and Methods: Representative sections of the transurethral resection of bladder tumor specimens from 25 cases of formalin-fixed paraffin-embedded invasive UCs and 25 cases of noninvasive UCs were selected for immunohistochemical (IHC) staining with laminin (Ventana, Oro Valley, AZ, USA). These cases were selected using a computer-assisted search of our laboratory information system (Cerner CoPath). Tissue from five paraffin-embedded tissue blocks containing unremarkable urothelial-lined bladder parenchyma was chosen as controls.Results: All five control cases demonstrated crisp linear staining of the basement membrane underlying the unremarkable urothelium. Similar findings were also noted in the 25 cases of noninvasive UC. All 25 cases of the invasive UC demonstrated a complete absence of the staining around invasive and malignant urothelial cells. Laminin staining was also noted in both the muscularis mucosae and the detrusor muscle, although the pattern of staining in these areas was granular and was distinguishable from the crisp linear staining of the basement membrane.Conclusion: Laminin IHC staining can be useful in differentiating invasive from noninvasive UC. [ABSTRACT FROM AUTHOR]

Context.--Increasing implementation of whole slide imaging together with digital workflow and advances in computing capacity enable the use of artificial intelligence (AI) in pathology, including breast pathology. Breast pathologists often face a significant workload, with diagnosis complexity, tedious repetitive tasks, and semiquantitative evaluation of biomarkers. Recent advances in developing AI algorithms have provided promising approaches to meet the demand in breast pathology. Objective.--To provide an updated review of AI in breast pathology. We examined the success and challenges of current and potential AI applications in diagnosing and grading breast carcinomas and other pathologic changes, detecting lymph node metastasis, quantifying breast cancer biomarkers, predicting prognosis and therapy response, and predicting potential molecular changes. Data Sources.--We obtained data and information by searching and reviewing literature on AI in breast pathology from PubMed and based our own experience. Conclusions.--With the increasing application in breast pathology, AI not only assists in pathology diagnosis to improve accuracy and reduce pathologists' workload, but also provides new information in predicting prognosis and therapy response. [ABSTRACT FROM AUTHOR]

Objectives: Thyroid-like follicular carcinoma of the kidney continues to confound the practicing pathologist with its close resemblance to the follicular variant of thyroid carcinoma, as well as other benign and malignant entities. Our goal is to expand the knowledge of this rare renal cell carcinoma subtype, which is morphologically similar to follicular carcinoma of the thyroid but lacks expression of characteristic thyroid immunohistochemical markers such as TTF-1 and thyroglobulin. Methods: We evaluated the gross, histologic, immunohistochemical, and fluorescence in situ hybridization (FISH) studies of a new case and performed a comprehensive review of the literature. Results: The lesion was spongy and well-circumscribed. Microscopically it showed variably sized follicular structures, filled with abundant, deeply eosinophilic, colloid-like material. At the periphery, it displayed areas resembling metanephric adenoma and early stages of nephrogenesis. The tumor cells strongly expressed CK7, PAX-8, PAX-2, vimentin, EMA, and CK19 immunostains. Other markers, such as CD10, RCC, HBME-1, thyroglobulin, and TTF-1, were not immunoreactive. The tumor was negative for trisomy of both 7 and 17 and showed borderline monosomies (losses) of both chromosomes in FISH studies. Conclusions: Five years of preoperative observation and lack of recurrence bring further insight into the slow progressive nature of this neoplasm and support a low malignant potential. Proper identification is important to secure adequate treatment and follow-up. [ABSTRACT FROM AUTHOR]

Background: Xp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS. Methods: Representative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data. Results: Three out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS. Conclusion: Our study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS. [ABSTRACT FROM AUTHOR]

Background: Whole slide imaging (WSI) offers a novel approach to digitize and review pathology slides, but the voluminous data generated by this technology demand new computational methods for image analysis. Materials and Methods: In this study, we report a method that recognizes stains in WSI data and uses kernel density estimator to calculate the stain density across the digitized pathology slides. The validation study was conducted using a rat model of acute cardiac allograft rejection and another rat model of heart ischemia/reperfusion injury. Immunohistochemistry (IHC) was conducted to label ED1+ macrophages in the tissue sections and the stained slides were digitized by a whole slide scanner. The whole slide images were tessellated to enable parallel processing. Pixel-wise stain classification was conducted to classify the IHC stains from those of the background and the density distribution of the identified IHC stains was then calculated by the kernel density estimator. Results: The regression analysis showed a correlation coefficient of 0.8961 between the number of IHC stains counted by our stain recognition algorithm and that by the manual counting, suggesting that our stain recognition algorithm was in good agreement with the manual counting. The density distribution of the IHC stains showed a consistent pattern with those of the cellular magnetic resonance (MR) images that detected macrophages labeled by ultrasmall superparamagnetic iron-oxide or micron sized iron-oxide particles. Conclusions: Our method provides a new imaging modality to facilitate clinical diagnosis. It also provides a way to validate/correlate cellular MRI data used for tracking immune cell infiltration in cardiac transplant rejection and cardiac ischemic injury. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma of chromophobe type is a malignant neoplasm with characteristic large cells that exhibit prominent cell membranes. Primary renal carcinoid tumors are rare tumors with the histological appearance similar to well-differentiated neuroendocrine tumors at other sites. Chromophobe renal cell carcinoma with neuroendocrine differentiation is exceedingly rare. The authors describe a case of a chromophobe renal cell carcinoma and carcinoid tumor of the kidney presenting as distinct masses in the same kidney in a 34-year-old male. The histologic and immunohistochemical features of both the tumors were characteristic with no overlapping features. The carcinoid tumor presented at a higher stage with nodal metastasis. To the best of the authors’ knowledge, this is the first case of 2 morphologically distinct tumors, one chromophobe renal cell carcinoma and the other primary carcinoid tumor in the same kidney. [ABSTRACT FROM AUTHOR]

Primary adenocarcinoma of urinary bladder is an uncommon neoplasm and is a source of diagnostic confusion with adenocarcinomas arising in adjacent organs, especially colon. These tumors show varied histologic picture and degree of differentiation. Clinical association with bladder exstrophy and schistosomiasis has been well documented. Primary bladder adenocarcinomas have overlapping histologic and immunohistochemical features with adenocarcinomas arising from other primary sites and the suggested immunohistochemical panel includes cytokeratins 7 and 20, 34βE12, thrombomodulin, CDX2, and β-catenin. Clinical, imaging, histologic, and immunohistochemical correlation should be done while rendering this diagnosis, as prognosis and therapeutic options for primary versus metastatic adenocarcinoma vary widely. [ABSTRACT FROM AUTHOR]

Summary: Primary renal carcinoid tumors are rare neoplasms. Because of the rarity of these neoplasms, clinicopathologic and immunohistochemical characteristics have not been fully characterized. Immunohistochemistry for renal cell lineage transcription factors, such as paired box gene 2 and paired box gene 8, has not been studied in renal carcinoid tumors and may be useful in demonstrating nephrogenic differentiation. We studied the clinical, morphological, and immunohistochemical features in 9 primary renal carcinoid tumors from multiple institutions with particular emphasis on immunohistochemical findings, in particular, expression of paired box gene 2 and paired box gene 8. All 9 cases expressed at least 1 neuroendocrine marker (CD56, synaptophysin, chromogranin). The renal-associated (paired box gene 2/paired box gene 8), gastrointestinal (caudal-related homeobox–2), and pulmonary/thyroid (thyroid transcription factor–1) transcription factors were not expressed in renal carcinoids (0/9). Of interest, CD99 was expressed in 8 of 9 cases, with the one negative case representing an atypical carcinoid. Perinephric extension and nodal and distant metastases are common. The absence of expression of paired box gene 2 and paired box gene 8, although not conclusive, supports the theory that these are derived from nonnephrogenic elements. CD99 was expressed in almost all cases (8/9); recognition of this could prevent misdiagnosis of a renal primitive neuroectodermal tumor. [ABSTRACT FROM AUTHOR]

Testicular and paratesticular tumors resembling mullerian epithelium of the ovary are extremely uncommon. This study reports a case of paratesticular serous papillary adenocarcinoma (SPA) in an 87-year-old man that was misdiagnosed as malignant mesothelioma (MM) and is 37 years older than previous cases, highlighting that SPA does not occur exclusively in young patients as described. Immunohistochemistry revealed expression of pankeratin, CAM 5.2, CK7, CK903, Ber-EP4, vimentin, S100, and CEA and virtually no expression of CK5/6, CK20, calretinin, thrombomodulin, or glypican 3. Expression of adjacent nonneoplastic tunica vaginalis mesothelium was assessed in this patient and additional specimens. Profiles of paratesticular SPA and MM were summarized and compared with paratesticular mesothelium. Nontumoral stromal and entrapped mesothelial expression were 2 diagnostic pitfalls in this case that have not been previously described. Based on these data, a panel of markers and the use of sections containing nonneoplastic mesothelium to facilitate interpretation is recommended. [ABSTRACT FROM PUBLISHER]

Glomus tumor is a benign mesenchymal neoplasm of the subcutaneous tissue of the distal extremities and head and neck region. Glomus tumor rarely occurs in the visceral organs. This study reports the sixth case of a glomus tumor arising in the kidney in a 62-year-old man who presented with weight loss and an incidental kidney lesion detected by computed tomographic scan. Radiologically, the tumor was difficult to differentiate from a malignant lesion and was therefore excised by partial nephrectomy. The tumor was challenging to diagnose by routine hematoxylin and eosin microscopic examination, necessitating immunohistochemical analysis. Immunoreactivity was demonstrated for smooth muscle actin, vimentin, collagen IV, and CD57, with little to no expression of neuroendocrine, endothelial, or epithelial markers. To date, the tumor has followed a benign course without evidence of local recurrence or metastasis. [ABSTRACT FROM PUBLISHER]

Abstract: Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13–93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17–0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue. [ABSTRACT FROM AUTHOR]

Background: Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is an adapter protein which has been shown to play an active role in a wide variety of cellular processes, including interactions with proteins related to both tumor suppression and oncogenesis. Here we use immunohistochemistry to evaluate EBP50's expression in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). Methods: Tissue microarrays were immunohistochemically stained for EBP50, with the staining intensities quantified using automated image analysis software. The data were statistically analyzed using one-way ANOVA with subsequent Tukey tests for multiple comparisons. Eleven cases of NDP, 37 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 103 cases of PCa, and 36 cases of Mets were analyzed in the microarrays. Results: Specimens of PCa and Mets had the lowest absolute staining for EBP50. Mets staining was significantly lower than NDP (p = 0.027), BPH (p = 0.012), NAC (p < 0.001), HGPIN (p < 0.001), and PCa (p = 0.006). Additionally, HGPIN staining was significantly higher than NAC (p < 0.009) and PCa (p < 0.001). Conclusions: To our knowledge, this represents the first study comparing the immunohistochemical profiles of EBP50 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC and suggests that EBP50 expression is decreased in Mets. Given that PCa also had significantly higher expression than Mets, future studies are warranted to assess EBP50's potential as a prognostic biomarker for prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). Methods: Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays. Results: PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p < 0.05 in both cases) and NAC (p < 0.05 in both cases). PIN had a lower, but non-significant, staining score than PCa and Mets, but a statistically higher score than both BPH and NAC (p < 0.05 for both cases). No significant differences were observed between PCa, Mets, and PIN. Conclusions: To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis. [ABSTRACT FROM AUTHOR]

Perivascular epithelioid cell tumors are mesenchymal neoplasms defined by the presence of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell has no known normal tissue counterpart and coexpresses myoid and melanocytic markers. This tumor family shows marked female predominance and includes angiomyolipoma, clear cell sugar tumor, lymphangioleiomyomatosis, and a group of rare, morphologically and immunophenotypically similar tumors arising at a variety of visceral and soft tissue sites. This latter subset has been collectively termed perivascular epithelioid cell tumors-not otherwise specified. They are usually composed of epithelioid, but occasionally spindled, cells with clear to granular eosinophilic cytoplasm and focal perivascular accentuation. The mainstay of treatment is wide excision. Although most cases are benign, a subset behaves in a malignant fashion. Since few malignant cases have been reported, firm criteria for malignancy have yet to be established. This review focuses on the perivascular epithelioid cell tumors-not otherwise specified subset. [ABSTRACT FROM AUTHOR]

Summary: Whole slide images (WSIs), also known as virtual slides, can support electronic distribution of immunohistochemistry (IHC) stains to pathologists that rely on remote sites for these services. This may lead to improvement in turnaround times, reduction of courier costs, fewer errors in slide distribution, and automated image analyses. Although this approach is practiced de facto today in some large laboratories, there are no clinical validation studies on this approach. Our retrospective study evaluated the interpretation of IHC stains performed in difficult prostate biopsies using WSIs. The study included 30 foci with IHC stains identified by the original pathologist as both difficult and pivotal to the final diagnosis. WSIs were created from the glass slides using a scanning robot (T2, Aperio Technologies, Vista, CA). An evaluation form was designed to capture data in 2 phases: (1) interpretation of WSIs and (2) interpretation of glass slides. Data included stain interpretations, diagnoses, and other parameters such as time required to diagnose and image/slide quality. Data were also collected from an expert prostate pathologist, consensus meetings, and a poststudy focus group. WSI diagnostic validity (intraobserver pairwise κ statistics) was “almost perfect” for 1 pathologist, “substantial” for 3 pathologists, and “moderate” for 1 pathologist. Diagnostic agreement between the final/consensus diagnoses of the group and those of the domain expert was “almost perfect” (κ = 0.817). Except for one instance, WSI technology was not felt to be the cause of disagreements. These results are encouraging and compare favorably with other efforts to quantify diagnostic variability in surgical pathology. With thorough training, careful validation of specific applications, and regular postsignout review of glass IHC slides (eg, quality assurance review), WSI technology can be used for IHC stain interpretation. [Copyright &y& Elsevier]

Abstract: Collision tumors, characterized by the coexistence of phenotypically and genotypically distinct tumors at the same site, are distinctly rare in the genitourinary tract and pose a diagnostic challenge. The goal of this study is to present a series of such cases from a single institution highlighting the unusual clinicopathologic features of these tumors. Six cases were retrospectively identified from our surgical pathology files and included internal and consultation cases (2006–2012). All tumors were identified by H&E and selected immunohistochemistry. There were 5 males and 1 female patients ranging in age from 57 to 84 years (average 73 years). The sites of these collision tumors were located in the kidney (3 cases), bladder (2 cases), and prostate. All collision tumors involved at least one malignant neoplasm. The diagnosis of collision tumors in the genitourinary tract is a perplexing task. Awareness of these rare entities, thorough sampling of the tumor mass, and appropriate use of ancillary techniques to demonstrate the different tumor components can help avoid an incorrect diagnosis, as well as with pathologic staging. [Copyright &y& Elsevier]

Abstract: The National Mesothelioma Virtual Bank (NMVB) was established to provide annotated biospecimens to the mesothelioma research community. The resource provides tissue microarrays (TMA) to evaluate the biomarkers along with a variety of other resected mesothelioma specimens. In this manuscript, we describe the immunohistochemical evaluation of the mesothelioma TMA with three key antibodies that are used in making the diagnosis of mesothelioma, and compared the immunohistochemical assessment between manual scoring and image analysis. The TMA was assessed for the immunohistochemical expression of calretinin (N =39), cytokeratin (CK) 5/6 (N =33), and D2-40 (N =37). Immunohistochemistry was evaluated by semi-quantitative (manual) scoring using light microscope (MS) and by automated image analysis (AS). Calretinin staining was seen in both cytoplasmic and nuclear locations. CK5/6 stain was localized to the cytoplasm. D2-40 stain showed only membranous expression in our cases. [•] Based on the pathologist's scores, calretinin was positive in 31 of the 39 cases (80%), CK 5/6 in 15 of the 33 cases (46%) and D2-40 in 18 of the 37 cases (49%). [•] The percent-positive agreement between manual scores and image analysis was 90% (35/39), 94% (31/33), and 95% (35/37) for calretinin, CK 5/6, and D2-40, respectively. There was a substantial agreement between manual and automated scores for calretinin (kappa=0.614) and an almost perfect agreement for CK5/6 (kappa=0.879) and D2-40 (kappa=0.892). Our study confirms that the immunohistochemical staining pattern of mesotheliomas in the NMVB UPMC TMA is similar to other studies. Our findings also show that automated image analysis provides similar results to manual scoring by pathologists, and provides a reproducible, objective, and accurate platform for immunohistochemical assessment of biomarker expression. [Copyright &y& Elsevier]

Abstract: Tumor-to-tumor metastasis is a very rare event. The recipient tumor may be benign or malignant. Renal cell carcinoma is the most common tumor recipient of metastasis while lung carcinoma is the most common donor tumor. We report a 57-year-old Caucasian male who presented with chest pain. On PET CT Scan, he was also found to have a large renal mass for which he underwent left nephrectomy. On histology of the renal mass, the tumor was a conventional renal cell carcinoma with areas of metastatic non-small cell lung carcinoma. The two components had a distinctive morphology which was confirmed on subsequent immunohistochemistry. The physiopathological mechanisms making clear cell renal cell carcinoma an avid recipient of a metastatic carcinoma have been speculated upon, but are still unknown. [Copyright &y& Elsevier]