Advancing Artificial Intelligence Integration Into the Pathology Workflow: Exploring Opportunities in Gastrointestinal Tract Biopsies.

This review aims to present a comprehensive overview of the current landscape of artificial intelligence (AI) applications in the analysis of tubular gastrointestinal biopsies. These publications cover a spectrum of conditions, ranging from inflammatory ailments to malignancies. Moving beyond the conventional diagnosis based on hematoxylin and eosin-stained whole-slide images, the review explores additional implications of AI, including its involvement in interpreting immunohistochemical results, molecular subtyping, and the identification of cellular spatial biomarkers. Furthermore, the review examines how AI can contribute to enhancing the quality and control of diagnostic processes, introducing new workflow options, and addressing the limitations and caveats associated with current AI platforms in this context.

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Utility of Wnt family member 9b (Wnt9b) immunohistochemistry in the cytologic diagnosis of metastatic breast carcinoma.

Wnt family member 9b (Wnt9b) has been demonstrated as a valuable marker for breast cancer diagnosis in surgical pathology. In this study, we examined the utility of Wnt9b in diagnosing metastatic breast carcinoma in cytology samples. Cell blocks from fine needle aspirations (FNA) and fluid specimens of 96 metastatic breast carcinomas and 123 primary and metastatic non-breast neoplasms from various organ systems were evaluated by Wnt9b and GATA3 immunohistochemistry (IHC). Wnt9b and GATA3 were positive in 81.3% and 92.7% of metastatic breast carcinomas, respectively. Conversely, 93.5% and 90.0% of non-breast, non-urothelial carcinomas were negative for Wnt9b and GATA3, respectively. Wnt9b expression was positive in rare gastrointestinal, gynecological, lung, pancreas, and salivary gland tumors. All twenty-eight urothelial carcinomas were negative for Wnt9b, while twenty-six (92.9%) were positive for GATA3. Wnt9b was slightly less sensitive but more specific than GATA3 in diagnosing metastatic breast cancer in cytology samples. Particularly, Wnt9b shows higher specificity in differentiating breast and urothelial primaries. The combined use of Wnt9b and GATA3 may increase diagnostic accuracy.

Whole slide image features predict pathologic complete response and poor clinical outcomes in triple-negative breast cancer.

INTRODUCTION: Breast cancers are complex ecosystem like networks of malignant cells and their associated microenvironment. Applications for machine intelligence and the tumoral microenvironment are expanding frontiers in pathology. Previously, computational approaches have been developed to quantify and spatially analyze immune cells, proportionate stroma, and detect tumor budding. Little work has been done to analyze different types of tumor-associated stromata both quantitatively and computationally in relation to clinical endpoints. METHODS: We aimed to quantify stromal features from whole slide images (WSI) including stromata (myxoid, collagenous, immune) and tumoral components and combined them with traditional clinical and pathologic parameters in 120 triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy (NAC) to predict pathologic complete response (pCR) and poor clinical outcomes. RESULTS: High collagenous stroma on WSI was best associated with lower rates of pCR, while combined high proportionated stroma (myxoid, collagenous, and immune) most optimally predicted worse clinical survival outcomes. When combining clinical, pathologic, and WSI features, Receiver Operator Characteristics (ROC) curves for LASSO features was up to 0.67 for pCR and 0.77 for poor outcomes. CONCLUSION: The techniques demonstrated in the present study can be performed with appropriate quality assurance. Future trials are needed to demonstrate whether coupling applications for machine intelligence, inclusive of the tumor mesenchyme, can improve outcomes prediction for patients with breast cancer.

In Search of Calcifications : Histologic Analysis and Diagnostic Yield of Stereotactic Core Needle Breast Biopsies.

OBJECTIVES: Stereotactic core needle biopsy (SCNB) is used in the diagnostic assessment of suspicious mammographic calcifications to rule out breast ductal carcinoma in situ (DCIS). With advances in imaging technology and increased biopsy tissue volume, the detection rate of calcifications and DCIS in SCNB is unclear. METHODS: This retrospective study included 916 consecutive SCNBs for calcifications performed on 893 patients in a 2-year period. RESULTS: We found the cancer detection rate was 27.1% (DCIS, 23.7%; invasive, 3.4%). The detection rate for calcifications was 74.8% with the standard 3 levels. Additional leveling of calcification-negative cases further increased the detection of both calcifications (to 99.4% of cases) and DCIS (to 32.9% of cases). Lobular neoplasia (LN) was diagnosed in 41 cases. Twenty-five (61.0%) cases of LN were incidental without associated calcification. Of 32 invasive carcinomas detected on SCNB, 87.5% were T1a or less, and calcifications were associated with atypical ductal hyperplasia/DCIS or LCIS. The common benign lesions associated with calcifications were fibrocystic change (32.5%), fibroadenomatous change (30.2%), and columnar cell change and hyperplasia (8.2%). CONCLUSIONS: We determined the up-to-date detection rates of calcification and DCIS in SCNB, as well as the common benign and malignant breast lesions associated with calcifications. Additional levels significantly increase the detection rate when standard levels show only stromal or scant/absent calcifications. Lobular neoplasia is often an incidental finding in SCNB for calcifications. When calcifications are present with LN, they are commonly florid, pleomorphic LCIS, or with concurrent invasive carcinoma.

Defining triple-negative breast cancer with neuroendocrine differentiation (TNBC-NED).

Primary breast neuroendocrine (NE) neoplasms are uncommon, and definitions harbor controversy. We retrospectively collected 73 triple-negative breast cancers (TNBC) and evaluated NE biomarker expression along with p53 aberrant staining (which correlates with TP53 gene mutation) and Rb protein loss by immunohistochemistry. In the study cohort, we found 11 (15%) cases of TNBC with neuroendocrine differentiation (TNBC-NED) showing positivity for one or more NE markers (synaptophysin/chromogranin/insulinoma-associated protein 1 [INSM1]). We also identified one separate small cell neuroendocrine carcinoma. Histologic types for these 11 TNBC-NED cases were as follows: 8 invasive ductal carcinoma (IDC) not otherwise specified (NOS), 2 IDC with apocrine features, 1 IDC with solid papillary features. INSM1 had the highest positivity and was seen in all 11 carcinomas. Seven (64%) cases showed p53 aberrant staining, 6 (55%) had Rb protein loss, while 6 (55%) had p53/Rb co-aberrant staining/protein loss. TNBC-NED was associated with Rb protein loss (p < 0.001), as well as p53/Rb co-aberrant staining/protein loss (p < 0.001). In 61 cases negative for NE markers, 37 (61%) showed p53 aberrant staining, while 5 (8%) had Rb protein loss. We also analyzed genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) PanCancer Atlas of 171 basal/TNBC patients. Transcriptomic analysis revealed mRNA expression of RB1 to be correlated negatively with SYN1 mRNA expression (p = 0.0400) and INSM1 mRNA expression (p = 0.0106) in this cohort. We would like to highlight the importance of these findings. TNBC-NED is currently diagnosed as TNBC, and although it overlaps morphologically with TNBC without NED, the unique p53/Rb signature highlights a genetic overlap with NE carcinomas of the breast.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2-mutant (NF2mut) and NF2-wild type (NF2wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P < .001). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P = .04) and immune cells (P = .013) were more frequent in NF2mut as compared to NF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B, SETD2, and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

"Growing fibroadenoma": Are there clinical and pathological features predicting a phyllodes tumor on surgical excision?

In cases of growth of FA on imaging, core needle biopsies (CNB) are often performed to rule out phyllodes tumor (PT). We aim to focus on "growing FAs" and to identify clinical and histopathologic features that are likely to predict a PT on excision. Thirty-four FAs with radiologic documentation of growth were included. Various clinical and pathological features such as age, body mass index (BMI), lesion size, and growth rate were recorded. On excision, 17 cases (50 %) were FAs, whereas 16 (47 %) were re-classified as benign PT despite only 19 % being suspicious for PT on CNB. PT patients were older (mean age 42.6) than those with FAs (mean age 28.2), p = 0.0002. All false negative cases demonstrated intracanalicular growth. Mitotic rate was the most significant histologic feature in PT on excision compared to others, such as lesion circumscription and stromal cellularity. Recognition and careful counting of mitotic rate, especially with intracanalicular patterns in growing FAs, can potentially prevent missing a PT on CNB. In patients with "growing FAs" who are ≥40 years of age, excision may be recommended due to the high likelihood of PT diagnosis on excision and high false negative rate on CNB.

From Immunohistochemistry to New Digital Ecosystems: A State-of-the-Art Biomarker Review for Precision Breast Cancer Medicine.

Breast cancers represent complex ecosystem-like networks of malignant cells and their associated microenvironment. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are biomarkers ubiquitous to clinical practice in evaluating prognosis and predicting response to therapy. Recent feats in breast cancer have led to a new digital era, and advanced clinical trials have resulted in a growing number of personalized therapies with corresponding biomarkers. In this state-of-the-art review, we included the latest 10-year updated recommendations for ER, PR, and HER2, along with the most salient information on tumor-infiltrating lymphocytes (TILs), Ki-67, PD-L1, and several prognostic/predictive biomarkers at genomic, transcriptomic, and proteomic levels recently developed for selection and optimization of breast cancer treatment. Looking forward, the multi-omic landscape of the tumor ecosystem could be integrated with computational findings from whole slide images and radiomics in predictive machine learning (ML) models. These are new digital ecosystems on the road to precision breast cancer medicine.

Microinvasive breast cancer and the role of sentinel lymph node biopsy.

Whether sentinel lymph node biopsy (SLNB) should be performed in patients with microinvasive breast cancer (MIBC) has been a matter of debate over the last decade. MIBC has a favorable prognosis and while metastasis to the axilla is rare, it can impact treatment recommendations. In this study we evaluated clinical and histological features in both MIBC and background DCIS including ER, PR, and HER-2, number of foci of MIBC, the extent of the DCIS, nuclear grade, presence of comedo necrosis, as well as surgical procedures, adjuvant treatment and follow up to identify variables which predict disease free survival (DFS), as well as the factors which influence clinical decision making. Our study included 72 MIBC patients with a mean patient follow-up time of 55 months. Three patients with MIBC had recurrence, and two deceased, leaving five patients in total with poor long-term outcomes and a DFS rate of 93.1%. Performing mastectomy, high nuclear grade, and negativity for ER and HER-2 were found to be associated with the use of SLNB, although none of these variables were found to be associated with DFS. One positive lymph node case was discovered following SLNB in our study. This suggests the use of SLNB may provide diagnostic information to some patients, although these are the anomalies. When comparing patients who had undergone SLNB to those which had not there was no difference in DFS. Certainly, the use of SLNB in MIBC is quite the conundrum. It is important to acknowledge that surgical complications have been reported, and traditional metrics used for risk assessment in invasive breast cancer may not hold true in the setting of microinvasion.

Mass-forming ductal carcinoma in situ: An ultrasonographic and histopathologic correlation study.

Ultrasound (US) guided core needle biopsy (CNB) for mass lesions resulting in a diagnosis of ductal carcinoma in situ (DCIS) is often considered radiologically discordant and generates surgical planning difficulty. One hundred cases of US-guided CNB for mass lesions diagnosed as DCIS were collected from 2013 to 2021. Histological features were reviewed and correlated with radiology and surgical excision findings. Thirty (30%) were high-grade (HG), and seventy (70%) were low- to intermediate-grade. Seventy-one (71%) cases had a histological correlate of a mass-forming lesion, including 26 (26%) were associated with benign mass-forming lesions (category 1) such as papilloma, complex sclerosing lesion/radial scar, fibroadenoma, sclerosing adenosis, and ruptured cyst; 23 (23%) were HG with solid pattern, comedo necrosis, and stromal desmoplasia (category 2); and 22 (22%) had predominantly papillary architecture (category 3). Twenty-nine (29%) were discordant with no histologic correlate of a mass lesion (category 4). Follow-up excisions were available in 79 cases. Invasive carcinoma was identified in 14 cases (18%), of which 8 were from the radiologically discordant category (35%), 3 (17%) associated with HG DCIS with desmoplasia, 2 (10%) associated with benign mass lesion and 1(5%) was predominantly papillary architecture. US-guided CNB for mass-forming lesions with a DCIS diagnosis on CNB can be grouped into four categories. Radiology-pathology correlation is essential. This categorization emphasized rad-path correlation and had a clear difference in upgrade rate on follow-up excision. Rad-path discordant biopsy cases were more likely to be associated with a missed invasive carcinoma (p < 0.05).

A Rare Case of Esophagitis Dissecans Superficialis Occurring with Barrett's Esophagus.

Esophagitis dissecans superficialis (EDS) is a rare but benign disease of the esophagus often identified endoscopically by sloughing of the superficial esophageal mucosa. We present an asymptomatic 66-year-old patient found to have EDS in the setting of Barrett's esophagus. The association of EDS with Barrett's esophagus has not been previously reported. He was initiated on proton pump inhibitor therapy with rapid and complete resolution of the endoscopic abnormality. This case illustrates the importance of identification of EDS as prognosis relies on prompt diagnosis and treatment.

Utility of secretagogin as a marker for the diagnosis of lung neuroendocrine carcinoma.

Small-cell lung cancers (SCLC) and large-cell neuroendocrine carcinomas (LCNEC) are two types of high-grade pulmonary neuroendocrine carcinomas (NECs). Diagnostic neuroendocrine markers commonly include synaptophysin, chromogranin A, CD56, and insulinoma-associated protein 1 (INSM1). In this study, the utility of secretagogin (SCGN) was examined in the context of pulmonary NEC diagnosis. The study included 71 pulmonary NEC cases (18 SCLCs, 13 combined-SCLCs, 23 LCNECs, and 17 combined-LCNECs). Immunohistochemical stains of SCGN, synaptophysin, chromogranin A, CD56, and INSM1 were performed on whole tumor sections. The stains were evaluated based on combined staining intensity and the proportion of positive tumor cells. At least mild staining intensity in at least 1% of the cells was considered positive. Bioinformatic studies showed specific SCGN expression in neuroendocrine cells and NECs. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra-tumoral heterogeneity. The non-neuroendocrine components were negative. The sensitivity of SCGN was no better than the other established neuroendocrine markers based on all NECs combined or LCNECs/c-LCNECs only. However, the sensitivity of SCGN (71%) was higher than chromogranin A (68%) for SCLCs/c-SCLCs only. The average proportion of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P = 0.0332) in all NECs and 18% higher for SCLC and c-SCLC cases only (32% versus 13%, P = 0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose SCLC.

Xanthogranulomatous cholangitis mimicking cholangiocarcinoma: Case report and review of literature.

INTRODUCTION: Xanthogranulomatous cholangitis is an extremely rare diagnosis and is believed to be an extension of xanthogranulomatous cholecystitis, a benign inflammatory process characterized by lipid-laden foamy macrophages (called "xanthoma cells") occurring in a background of chronic inflammation consisting of lymphocytes, plasma cells, and eosinophils. Here, we report a case of xanthogranulomatous cholangitis mimicking cholangiocarcinoma. CASE PRESENTATION: A 72 year old male with history of recurrent cholangitis had preoperative workup highly suggestive of intrahepatic cholangiocarcinoma. He underwent right hepatectomy and portal lymphadenectomy, with pathology showing xanthogranulomatous cholangitis, with no evidence of malignancy. Interestingly, the patient did not have xanthogranulomatous cholecystitis. DISCUSSION: We reviewed the current literature on xanthogranulomatous cholangitis, and identified only 14 previously reported cases. In our case series, there were six female and eight male patients. Among the 14 patients, 11 presented to the hospital with jaundice. Twelve patients had preoperative workup concerning for malignancy. The diagnosis of xanthogranulomatous cholangitis was confirmed through pathology in 13 patients, and through endoscopic ultrasound biopsy in one patient. In our review, seven patients had associated xanthogranulomatous cholecystitis, three patients had an isolated case of xanthogranulomatous cholangitis, and four patients had unknown status. Our patient is the fourth case of isolated xanthogranulomatous cholangitis without xanthogranulomatous cholecystitis. CONCLUSION: Xanthogranulomatous cholangitis is a very rare phenomenon that can lead to benign strictures of the bile ducts, especially in the setting of recurrent cholangitis. It can mimic malignancies, such as cholangiocarcinoma, and should be considered in the differential diagnosis.

Stromal computational signatures predict upgrade to invasive carcinoma in mass-forming DCIS: A brief report of 44 cases.

Mass-forming ductal carcinoma in situ (DCIS) detected on core needle biopsy (CNB) is often a radiology-pathology discordance and thought to represent missed invasive carcinoma. This brief report applied supervised machine learning (ML) for image segmentation to investigate a series of 44 mass-forming DCIS cases, with the primary focus being stromal computational signatures. The area under the curve (AUC) for receiver operator curves (ROC) in relation to upgrade to invasive carcinoma from DCIS were as follows: high myxoid stromal ratio (MSR): 0.923, P = <0.001; low collagenous stromal percentage (CSP): 0.875, P = <0.001; and low proportionated stromal area (PSA): 0.682, P = 0.039. The use of ML in mass-forming DCIS could predict upgraded to invasive carcinoma with high sensitivity and specificity. The findings from this brief report are clinically useful and should be further validated by future studies.

Wnt Family Member 9b (Wnt9b) Is a New Sensitive and Specific Marker for Breast Cancer.

Confirming the tumor origin is often a diagnostic challenge in pathology and carries significant therapeutic impacts. Cytokeratin 7, estrogen receptor, and GATA binding protein 3 (GATA3) are well-established diagnostic markers frequently used to support a tumor's breast origin. However, their specificities still have room to improve. Many nonbreast tumors express cytokeratin 7 and estrogen receptor, and urothelial tumors frequently express GATA3. There is a practical need for a new breast lineage marker that is sensitive and specific. Wnt family member proteins play critical roles in embryo development, tissue homeostasis and tumor development through ß-catenin dependent and independent pathways. The current study evaluated Wnt9b and GATA3 expression in 163 primary breast cancers, 63 metastatic breast cancers, and 525 nonbreast epithelial tumors. The positive rates of Wnt9b and GATA3 in primary breast cancer were both 98.7%. The positive rates in metastatic breast cancer were 87.3% for Wnt9b and 96.8% for GATA3. For nonbreast tumors, including 64 cases of urothelial carcinoma, Wnt9b was negative in all except salivary gland carcinomas. The study demonstrated that Wnt9b is a breast cancer marker with similar sensitivity as GATA3 but with greater specificity than GATA3 and may ultimately become a useful diagnostic tool in routine surgical pathology practice.

Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer.

PURPOSE: The accuracy of biomarker assessment in breast cancer (BC) is paramount for therapy decisions and informs prognosis. We investigated neoadjuvant chemotherapy (NAC) response in HER2-positive BC with respect to immunohistochemistry (IHC) and in situ hybridization (ISH) results. We aimed to determine the role of HER2 protein expression in predicting NAC response and long-term outcome in two HER2-positive groups: IHC 3 + versus IHC 2 + ISH amplified groups. METHODS: This retrospective study included 192 consecutive HER2 + primary BCs diagnosed from 2007 to 2019 treated with NAC and HER2-targeted agent (NACH). There were 158 HER2 3 + and 34 HER2 2 + ISH + cases. Clinicopathological parameters and long-term outcomes were analyzed. RESULTS: The Pathological Complete Response (pCR) rate was 85.7% (72/84) in ER-/HER2 + BCs and was lower in ER + /HER2 + BCs (42.6%, 46/108). The pCR was 55.1% (86/156) in the HER2 3 + group and was only 17.6% in HER2 2 + ISH + group (p < 0.001). Patients who achieved pCR in HER2 2 + ISH + group did not show a significantly higher HER2/CEP17 ratio or HER2 copy number. The overall survival (OS) and progression-free survival (PFS) were significantly higher in pCR compared to non-pCR cases (p = 0.011 and p = 0.015, respectively). CONCLUSIONS: There is significant heterogeneity in response to the NACH regimens in HER2 + cases. Our findings indicate that HER2 IHC score and ER expression determine NACH response in HER2 + BC. We recommend considering HER2 protein expression and ISH value to better select patients and assess the response for HER2-targeted therapy.

Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies.

BACKGROUND: Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging. OBJECTIVE: To identify genomic alterations (GAs) in patients with RSs. DESIGN, SETTING, AND PARTICIPANTS: Comprehensive genomic profiling (CGP) was conducted on DNA/RNA extracted from formalin-fixed paraffin-embedded tissue using the FoundationOne Heme/Sarcoma assay in 13 adult, locally advanced or metastatic RSs of various histologic types. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed. RESULTS AND LIMITATIONS: CGP revealed 55 GAs (4.2 per tumor), 29 of which were clinically relevant genomic alterations (CRGAs; 2.2 per tumor). At least one CRGA was detected in nine (69%) cases. High-level amplifications (more than six copies) involving 4q12 amplicon of the KIT and PDGFRA genes were identified in four (31%) cases (two undifferentiated pleomorphic sarcomas [UPSs], one sarcomatoid renal cell carcinoma, and one myxofibrosarcoma). Both UPSs also had KDR gene amplification in addition to KIT and PDGFRA. Additional CRGAs were found in CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable, the mean TMB was 3.5 mutations/megabase (Mb), and none (0%) featured TMB >10 mutations/Mb. Limitations include the small sample size. CONCLUSIONS: RSs are characterized by diverse histology and genomic profiles including 31% of cases with 4q12 amplification harboring the KIT/PDGFRA/KDR genes. Of the tumors, 69% carry CRGAs, which could lead to potential benefit from targeted therapies; however, a low TMB also suggests that these cases are unlikely to respond to checkpoint inhibitors. PATIENT SUMMARY: This study provides insights into molecular biology of renal sarcoma, a rare aggressive subtype of kidney tumors. We demonstrated that renal sarcomas harbor unique, recurrent, clinically relevant molecular abnormalities that provide new opportunities for targeted therapies.

Validation and performance comparison of three SARS-CoV-2 antibody assays.

Serology testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly being used during the current pandemic of coronavirus disease 2019 (COVID-19), although its clinical and epidemiologic utilities are still debatable. Characterizing these assays provides scientific basis to best use them. The current study assessed one chemiluminescent assay (Abbott COVID-2 IgG) and two lateral flow assays (STANDARD Q [SQ] IgM/IgG Duo and Wondfo total antibody test) using 113 blood samples from 71 PCR-confirmed COVID-19 hospitalized patients, 119 samples with potential cross-reactions, and 1068 negative controls including 942 pre-pandemic samples. SARS-CoV-2 IgM antibodies became detectable 3-4 days post-symptom onset using SQ IgM test and IgG antibodies were first detected 5-6 days post-onset using SQ IgG. Abbott IgG and Wondfo Total were able to detect antibodies 7 to 8 days post-onset. After 14 days post-symptom onset, the SQ IgG, Abbott IgG and Wondfo Total tests were able to detect antibodies from 100% of the PCR-confirmed patients in this series; 87.5% sensitivity for SQ IgM. Overall agreement was 88.5% between SQ IgM/IgG and Wondfo Total and 94.6% between SQ IgG and Abbott IgG. No cross-reaction due to recent sera with three of the endemic coronaviruses was observed. Viral hepatitis and autoimmune samples were the main source of limited cross-reactions. The specificities were 100% for SQ IgG and Wondfo Total, 99.62% for Abbott IgG, and 98.87% for SQ IgM. These findings demonstrated high sensitivity and specificity of appropriately validated SARS-CoV-2 serologic assays with implications for clinical use and epidemiological seroprevalence studies.