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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.

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.

ALK genomic alterations revealed by comprehensive genomic profiling in clinical cases of colorectal carcinoma

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN–ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831–40. ©2016 AACR.

Previously reported cases of colorectal carcinoma harboring ALK fusions

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.

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 β-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.

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.

PAX8 expression is frequently detected in renal, thyroidal, and Müllerian carcinomas, and PAX8 immunohistochemistry is often used to confirm the origin of these tumors. Tumors metastatic to the breast may masquerade as primary breast lesions. PAX8 is strongly expressed in tumors of Müllerian origin and largely negative in breast primaries, but an immunohistochemical expression of PAX8 in breast cancer has not been systematically evaluated in a large series. We analyzed 266 cases of invasive carcinoma of the breast on tissue microarrays and whole tissue sections with a PAX8 monoclonal antibody. Both the extent (focal or diffuse) and intensity (weak, moderate, or strong) of nuclear staining were assessed in the tumor cells. In total, 16 cases (6.02%) were positive for PAX8 (12 with weak and 4 with moderate staining). Expression was diffuse in 7 cases and focal in 9 cases. All 16 PAX8-positive tumors were histologic grade III invasive ductal carcinomas, 13 of these were triple-negative, 2 were HER2-positive, only and 1 was progesterone receptor-positive only. Strong PAX8 nuclear expression was not seen in any of the cases. PAX8 was negative in breast tumors with neuroendocrine features. Our study demonstrated a low rate of PAX8 expression in breast cancer. When present, PAX8 expression was only seen in high-grade invasive ductal carcinomas, mostly triple-negative. The presence of PAX8 immunoreactivity alone cannot exclude mammary origin, especially when only weak to moderate staining is observed, so the correlation with available clinical and pathologic data helps to ensure an accurate diagnosis.

Triple negative breast cancer (TNBC) is a heterogenous and lethal disease that lacks diagnostic markers and therapeutic targets; as such common targets are highly sought after. IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown. Here we show that IQGAP1 localizes to the centrosome, interacts with and influences the expression level and localization of key centrosome proteins like BRCA1 and thereby impacts centrosome number. Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation. TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways. These variants are defined, at least in part, by differential mis-localization or stabilization of IQGAP1-BRCA1 and rewiring of a novel Erk1/2-MNK1-JNK-Akt-β-catenin signaling signature. We discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer. These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine.

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.

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.

Purpose: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. Patients and Methods: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC­oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. Results: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8–76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5′ fusion partner ZC3H4. Conclusions: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC­oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with ALK-rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.

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).

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.

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. 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. 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

Objectives First-line regimens in the treatment of metastatic colorectal cancer (mCRC) combine a fluoropyrimidine with oxaliplatin (FOLFOX/XELOX) or irinotecan (FOLFIRI). There is limited efficacy data to guide the selection of one treatment over the other. This study investigated whether mutations affecting DNA damage response (DDR) could differentially influence the response to oxaliplatin and irinotecan-containing regimens. Methods We retrospectively analyzed 49 patients with mCRC for whom treatment outcomes and results of comprehensive genomic profiling of tumors were available. Specimens with at least 1 pathogenic mutation involving BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L were classified as DDR-mutated, while those without mutations were DDR-wild-type (WT). We compared the overall survival (OS), disease control rate, and response rate (RR) between the DDR-mutated and DDR-WT groups. Results DDR mutations occurred in 11 patients (22%). First-line treatment with an oxaliplatin-containing regimen was administered to 33 patients (31 FOLFOX, 2 XELOX), while 16 patients received FOLFIRI. Among DDR-mutated cases, first-line treatment with FOLFOX/XELOX correlated with a statistically significant improvement in median OS compared with FOLFIRI (3.4 vs.1.8 y; P=0.042) and numerically higher RR (50% vs. 33%; P=0.58). No significant difference in OS (2.4 vs. 2.5 y; P=0.42), RR, disease control rate was observed between the 2 regimens in patients with DDR-WT tumors. Conclusions Mutations in DDR genes were present in 22% of patients with mCRC. In patients with DDR-mutated tumors, initial treatment with FOLFOX/XELOX correlated with improved OS and a numerically higher RR compared with FOLFIRI.

We report eight cases of a distinctive, previously undescribed renal cell carcinoma associated with somatic mutations in the neurofibromin 2 (NF2) gene. All patients were adults, ranging from 51 to 78 years of age and of cases of known gender six of seven were males. The carcinomas were predominantly unencapsulated, and all had a rounded, nodular interface with the native kidney. The neoplasms were all solid with papillary architecture evident in most cases (7/8), while one was only tubular. All cases were biphasic, characterized by larger and smaller carcinoma cells. The smaller cells clustered around basement membrane material similar to the characteristic pattern of the t(6;11) renal cell carcinoma associated with TFEB gene fusions. In 6 of 8 carcinomas, branching nodules of small cells clustered around basement membrane material within larger acini yielding a distinctive glomeruloid pattern. In 6 of 8 carcinomas, the small cells were focally spindle-shaped and unassociated with basement membrane material. The stroma was sclerotic in all eight carcinomas, and all eight contained psammoma bodies that were abundant in two. In some carcinomas, focal or predominant areas had a less distinctive appearance; two had areas that resembled clear cell renal cell carcinoma, two had high-grade eosinophilic areas, while one had branching tubular architecture that resembled mucinous tubular and spindle cell carcinoma. Two carcinomas demonstrated cellular necrosis. While we have minimal clinical follow-up, one case presented with distant metastasis, progressed, and resulted in patient death. While NF2 mutations may be found in other established renal cell carcinoma subtypes (often as secondary genetic alterations), they are potentially the genetic driver of this distinctive entity.

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.

Hepatic angiosarcoma (HAS) is a rare and highly lethal malignancy with few effective systemic treatments. Relatively little is known about the genetic abnormalities that drive this disease. As a result, there has been minimal progress towards applying targeted therapies to the treatment of HAS. We describe the first reported case of a patient with HAS that harbored a fusion of ROS1 with GOPC/FIG. Similar to other rearrangements involving ROS1, the resulting fusion protein is believed to act as a major driver of carcinogenesis and may be subject to inhibition by drugs that target ROS1 such as crizotinib. We then queried the MSK-IMPACT clinical sequencing cohort and cBioportal datasets, demonstrating the previously unknown prevalence of ROS1-GOPC fusions in soft tissue sarcomas and hepatobiliary cancers. Amplification of these genes was also found to correlate with reduced overall survival. This is followed by a review of the role played by ROS1 rearrangements in cancer, as well as the evidence supporting the use of targeted therapies against the resulting fusion protein. We suggest that testing for ROS1 fusion and, if positive, treatment with a targeted therapy could be considered at the time of diagnosis for patients with angiosarcoma. This report also highlights the need for further investigation into the molecular pathophysiology of this deadly disease.

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.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.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.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.

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.

CIC-rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC-rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC-rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC-rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.

Gender confirmation surgery is increasingly common in persons with gender dysphoria. We describe changes seen in gonads from individuals seeking male-to-female physical adaptation. We studied 99 orchiectomies from 50 persons. The average age was 33 years (range, 21-63 years). Eighty-six (86.8%) of 99 testes were normal in size with an average size of 3.87 cm (range, 3.0-5.5 cm). Thirteen (13.1%) of 99 testes were hypotrophic and measured up to 2.5 cm. Seminiferous tubules were reduced in diameter compared with controls (0.137 mm versus 0.237 mm; P < .001) and showed peritubular fibrosis in 41 (82%) of 50 persons. In 40 (80%) of 50 persons, there was maturation arrest at the spermatogonia level. In 10 (20%) of 50 persons, the seminiferous tubules showed focal spermatids/spermatozoa up to 7 per 10 tubules mixed with partial maturation arrest at primary spermatocytes. Twenty-six (26%) of 99 testes showed seminiferous tubules with rare cells with large nuclei (3× size of Sertoli cells nuclei) and degenerative chromatin (cytomegaly). Leydig cells were absent in 50 (50%), markedly reduced in 30 (30%), and similar to controls (mean, 33/high-power field) in 20 (20%). A subset (20/99; 20%) of testes had epithelial hyperplasia of the proximal epididymis with stratification and micropapillae. There was no germ cell tumor, sex cord stromal tumors, or germ cell neoplasia in situ. In summary, the histologic changes include (1) decreased diameter of seminiferous tubules and expansion of the interstitium, (2) marked hypoplasia of germ cells, (3) rare cytomegaly, (4) hypoplasia or absence of Leydig cells, and (5) epididymal hyperplasia.

Succinate dehydrogenase (SDH) is a key mitochondrial enzyme complex composed of 4 subunits. SDH histochemistry is routinely utilized in the assessment of muscle biopsies to reveal underlying pathology such as subsarcolemmal mitochondrial aggregates. In this study, we evaluated the utility of succinate dehydrogenase B (SDHB) immunohistochemistry (IHC) in 27 muscle biopsies, including 13 mitochondrial myopathies (MMs), 9 inflammatory myopathies, and 5 controls. SDHB IHC was performed on formalin-fixed, paraffin-embedded tissue sections with a mouse monoclonal antibody (Abcam 21A11AE7) in parallel with histochemical SDH stains on a fresh-frozen tissue. In all muscle biopsies, SDHB IHC exhibited granular immunoreactivity and highlighted the dark type 1 and lighter type 2 staining pattern observed by histochemistry. In all cases of MM, SDHB IHC showed subsarcolemmal granular aggregates involving the entire periphery of the fibers that were more distinct than those seen by SDH histochemistry. In 3 extraocular muscle biopsies, SDHB immunoreactive speckles of various sizes were distributed throughout the entire sarcoplasm that were more prominent than those seen on SDH histochemistry. Subsarcolemmal and cytoplasmic granular aggregates seen on SDHB IHC correlated with mitochondrial pathology on electron microscopy. In cases of inflammatory myopathy, there was diffuse sarcoplasmic SDHB immunoreactivity in degenerating fibers, but no evidence of subsarcolemmal aggregates. This study demonstrates that SDHB IHC is highly sensitive and specific in the identification of MM. The automation, reproducibility, and cost efficiency of SDHB IHC offer advantages over the labor-intensive histochemical method requiring frozen sections. As this technique is performed on formalin-fixed, paraffin-embedded tissues, it can be easily applied for retrospective studies.

ALK rearrangements have been observed in 0.05%-2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS, NRAS, or BRAF alterations. Here we present the case of a patient with metastatic CRC who was treatment naive at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture-based assays each identified an identical STRN-ALK fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay. Key points Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of KRAS, NRAS, BRAF, and microsatellite instability (MSI) status.ALK rearrangements are rare in CRC, but patients with activating ALK fusions have responded to targeted therapiesALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.

Primitive round- or spindle-cell EWSR1-negative undifferentiated sarcomas harboring CIC-DUX4 gene fusion are the most common form of Ewing-like sarcomas. These tumors primarily occur in peripheral soft tissues, but examples have been described within viscera and the brain. As far as we are aware, CIC-DUX4 positive primary epidural spinal sarcoma has not been reported. Herein, we describe a T5–T6 epidural tumor in a 15-year-old girl in which many neoplastic cells had moderate and focally abundant cytoplasm, including plasmacytoid or rhabdoid cells, rather than the more common Ewing-like morphology described in the majority of such tumors. The diagnosis was confirmed by fluorescent in situ hybridization after the tumor was found to be WT-1 positive, and comprehensive genomic profiling demonstrated breakpoints in exon 20 and exon 1 of the CIC and DUX4 genes, respectively. After treatment with local radiation and systemic chemotherapy, resected recurrent tumor demonstrated more pleomorphic neoplastic cells as well as intracytoplasmic eosinophilic globules and nuclear pseudoinclusions which may reflect therapy-related changes. Unfortunately, there was further progression of tumor including the development of intracranial lesions, and the patient succumbed to her tumor 22 months after the original resection.

Mesenchymal tumors involving the kidney include a wide range of benign and malignant tumors and are relatively rare compared to epithelial neoplasms. Within the last two decades, there have been major discoveries in the underlying genomic alterations that drive the neoplastic process in mesenchymal lesions of the kidney. Specifically, a variety of translocation-associated sarcomas have been described arising from the kidney, significantly expanding the differential diagnosis of mesenchymal tumors primary to the kidney. This chapter is devoted to the clinical, morphologic, immunohistochemical, and genomic alterations of mesenchymal tumors that primarily occur in adults, with discussion of the differential diagnosis of specific entities. In contrast to the childhood lesions, most of these entities occur primarily in somatic soft tissue sites, but are also described in the kidney and constitute an ever-increasing list that appear to have a predilection for this location. It must be recognized that many of the neoplasms reviewed also occur in children.

BackgroundCytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited.MethodsThis study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient’s age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival.ResultsCK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P = 0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2% of Grade 1 cases were GATA3 negative (P ConclusionsThis is the first study to characterize CK7 negative breast tumors in the context of clinicopathology. Profiling the CK7 negative and GATA3 negative breast cancers helps to understand the biology of these specific tumor subgroups and may aid in their diagnosis.

Rationale Many patients with adenocarcinoma of the prostate present with advanced and metastatic cancer at the time of diagnosis. There is an urgent need to detect biomarkers that will improve the diagnosis and prognosis of this disease. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) is playing a key role in cancer research and it can be useful to unravel the molecular profile of prostate cancer biopsies. Methods MALDI imaging data sets are highly complex and their interpretation requires the use of multivariate statistical methods. In this study, MALDI-IMS technology, sequential principal component analysis (PCA) and two-dimensional (2-D) peak distribution tests were employed to investigate tumor heterogeneity in formalin-fixed paraffin-embedded (FFPE) prostate cancer biopsies. Results Multivariate statistics revealed a number of mass ion peaks obtained from different tumor regions that were distinguishable from the adjacent normal regions within a given specimen. These ion peaks have been used to generate ion images and visualize the difference between tumor and normal regions. Mass peaks at m/z 3370, 3441, 3447 and 3707 exhibited stronger ion signals in the tumor regions. Conclusions This study reports statistically significant mass ion peaks unique to tumor regions in adenocarcinoma of the prostate and adds to the clinical utility of MALDI-IMS for analysis of FFPE tissue at a molecular level that supersedes all other standard histopathologic techniques for diagnostic purposes used in the current clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

Phyllodes tumors (PTs) of the breast constitute an uncommon group of fibroepithelial neoplasms that are classified into benign, borderline, and malignant categories based on a constellation of histologic characteristics including cytologic atypia, mitotic count, degree of stromal cellularity, stromal overgrowth, and microscopic margins. Accurately and reproducibly differentiating these tumors is a long-standing diagnostic challenge. In addition, the distinction between benign PT from cellular fibroadenoma (FA) is especially difficult because of overlapping microscopic features. We have previously shown differential expression of various collagens, including collagen type III α1 (Col3A) in breast carcinomas. In this study, we evaluated clinicopathological characteristics of 95 cases of fibroepithelial lesions including 56 PTs and 39 FAs (25 cellular FA, 14 typical FA) and correlated them with the immunohistochemical staining pattern for Col3A. We found that stromal Col3A expression was significantly increased in PTs when compared with FAs (P < .0001). Among the PT groups, there was significantly increased expression from benign tumors through borderline to malignant tumors. High Col3A expression was associated with PT type, irregular margin status, and high mitotic activity. A distinct periductal cuffing pattern of Col3A staining was unique to PTs and absent in FAs. These findings suggest that Col3A can be a potential adjunct marker for both differentiating FA from PT and assessing malignant potential in PTs.

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN–ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort. Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed. Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib. Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831–40. ©2016 AACR.

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma (HCC) with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated HCCs. In the current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 HCCs and 374 gastrointestinal and nongastrointestinal carcinomas. AGXT1 exhibited granular cytoplasmic immunoreactivity in contrast to the diffuse cytoplasmic staining characteristic of arginase-1 in nonneoplastic and neoplastic hepatocytes. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. A small number of tumors expressed only 1 of the 2 markers. Sensitivity increased to 92.1% when the presence of either marker was considered positive. Excepting 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. Our data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1. AGXT1 may aid in diagnostic workup especially in conjunction with arginase-1 for HCCs that may otherwise defy conventional immunostaining patterns.

Renal cell carcinoma (RCC) linked to germline mutation of succinate dehydrogenase subunits A, B, C, and D (SDHA, SDHB, SDHC, and SDHD, respectively) has been recently included as a provisional entity in the 2013 International Society of Urological Pathology Vancouver classification. Most SDH-deficient tumors show SDHB mutation, with only a small number of RCC with SDHC or SDHD having been reported to date. Only one case of SDH-deficient renal carcinoma known to be SDHA mutated has been previously reported. Here we report an additional RCC harboring an SDHA mutation occurring in a 62-year-old man with right flank pain and nodal metastasis. The tumor was characterized by an infiltrative pattern with solid, acinar, and papillary components. Loss of SDHA and SDHB protein by immunohistochemistry confirmed the diagnosis. Hybrid capture-based comprehensive genomic profiling identified 3 genomic alterations in tumor tissue: (i) a novel single-nucleotide splice site deletion in SDHA gene, (ii) single-nucleotide deletion in NF2 gene, and (iii) EGFR gene amplification of 19 copies. This is the second report of SDHA-mutated RCC. With increased awareness, this rare tumor can be recognized on the basis of distinctive morphology and confirmation by immunohistochemistry and genomic profiling.

We report the case of an 11-year-old girl with Peutz-Jeghers syndrome and a unilateral ovarian tumor most consistent with Sertoli cell tumor associated with sex cord tumor with annular tubules. The ovary was replaced by a lobular, solid, yellow tumor. Microscopic examination showed 2 components that focally merged. The first was composed of uniform, cytologically bland cells arranged mostly in diffuse sheets and focally in tubules. The second showed typical sex cord tumor with annular tubules with extensive calcification. The predominant component of the tumor clearly fell in the sex cord category and most closely resembled Sertoli cell tumor. This case adds to the limited information on ovarian sex cord tumors, other than typical sex cord tumor with annular tubules, arising in association with Peutz-Jeghers syndrome, a topic reviewed herein.

Introduction Vital cellular processes such as proliferation and differentiation are regulated by chromatin remodeling complexes. A variety of neoplasms have been discovered to have genomic alterations (GAs) and loss of immunohistochemical (IHC) expression of chromatin remodelers ARID1A (BAF250A), SMARCA2 (BRM), SMARCA4 (BRG1), and SMARCB1 (INI1). SMARCA1 (SNF2L) is another member of the chromatin remodelers, and has not yet been studied in neoplasia. As SMARCA1 is located on chromosome X, could be potentially inactivated by a single hit. We aimed to evaluate GAs and protein expression of SMARCA1 in soft tissue tumors. Method The publically available cBioPortal.32e34 platform was queried to analyze data on soft tissue tumors from The Cancer Genome Atlas project (TCGA) related to SMARCA1 GAs. Our institutional archives were queried to collect 26 cases of soft tissue tumors including 10 undifferentiated sarcomas, 5 leiomyosarcomas, 6 liposarcomas, and 5 malignant peripheral sheath tumors (MPNST). IHC for SMARCA1 with an SNF 2C4 monoclonal antibody was performed on whole tissue sections. Results SMARCA1 GAs were present in 8/261 soft tissue sarcomas (3%) in the TCGA dataset. Leiomyosarcomas had most common SMARCA1 GAs in 6/99 cases. SMARCA1 deletions existed in 1/56 dedifferentiated liposarcomas and 1/48 undifferentiated sarcomas. No SMARCA1 GAs occurred in other sarcoma subtypes. SMARCA1 IHC was studied in the sarcoma subtypes with potential SMARCA1 alterations in our institutional cases. SMARCA1 nuclear expression was lost in 3/10 cases (30%) of undifferentiated sarcoma, and 2/5 cases of MPNST (40%). SMARCA1 expression was intact in all cases of leiomyosarcoma and liposarcoma. Conclusion This is the first study to demonstrate loss of expression of SMARCA1 in soft tissue sarcomas subtypes, including undifferentiated sarcoma. Our study highlights merit for further investigation on the role of SMARCA1 in the differentiation process and molecular mechanisms of SMARCA1 inactivation.

Several markers of pancreatobiliary lineage have been described in the literature. However, none have demonstrated sufficient specificity and sensitivity to warrant diagnostic use. We evaluated the utility of T-complex-associated-testis-expressed 3 (TCTE3) as a pancreatobiliary marker. A set of 247 adenocarcinomas from the gastrointestinal (GI) tract was identified including 18 from the gastroesophageal junction (GEJ), 29 stomach, 17 ampullary, 62 pancreatic, and 16 common bile duct and gallbladder (CBD/GB), 13 non-ampullary small intestine, 32 colon, and 24 rectum. The remainder consisted of 16 cholangiocarcinomas, and 20 hepatocellular carcinomas (HCC). Additionally, 163 adenocarcinomas from the breast, gynecologic tract, prostate, urothelium, kidney, and lung were stained for comparison. Immunohistochemistry for TCTE3 and other gastrointestinal markers was performed. Positive expression of TCTE3 was characterized by a strong, well-defined membranous pattern with or without weak cytoplasmic staining. Expression was identified in the normal epithelial cells of pancreatobiliary tree, but staining was absent in normal epithelial cells of esophagus, stomach, and intestine. Hepatocytes, pancreatic acini and islets and other non-epithelial cells were also negative for staining. TCTE3 was expressed in 93.5% of pancreatic ductal adenocarcinomas, 37.5% of CBD/GB adenocarcinomas, 50% of cholangiocarcinomas, 76.4% of ampullary adenocarcinomas, and 33.3% of GEJ adenocarcinomas. Only 3.5% of the gastric, 7.7% of non-ampullary small intestinal and 6.25% of colonic tumors exhibited positive staining. Expression was absent in rectal carcinomas and HCCs. These results suggest that TCTE3 is a useful marker of pancreatobiliary differentiation and may aid in distinguishing these tumors from gastric and intestinal primary tumors.

Background Papillary renal cell carcinoma (PRCC) is a rare subset of RCC. The Cancer Genome Atlas (TCGA) data largely reflect localized disease, and there are limited data for advanced PRCC. Objective To characterize the frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling (CGP) was performed in the context of routine clinical care. Design, setting, and participants Formalin-fixed, paraffin-embedded tissue was obtained for 169 consecutive patients with confirmed PRCC. DNA was extracted and comprehensive genomic profiling was performed in a certified central laboratory. Measurements Hybrid-capture, adaptor ligation-based libraries of up to 315 genes were sequenced to a median coverage of 648×. All classes of GAs were identified, including substitutions, insertions/deletions, copy number alterations, and rearrangements. Results and limitations From 169 patients, either primary tumor tissue (102 patients, 60%) or metastatic tissue (67 patients, 40%) was collected. In patients with type 1 PRCC, commonly altered genes were MET (33%; 8 activating mutations, 5 amplifications at >6 copies), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In patients with type 2 PRCC, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%), and FH (13%); MET GAs (5 mutations, 3 amplifications) were observed in 7% of type 2 cases. Notable differences from TCGA data include higher frequencies of MET , NF2 , and CDKN2A/B GAs, association of alterations in SWI/SNF complex genes with type 2 PRCC, and observation of frequent CDKN2A/B alterations in both type 1 and type 2 disease. Conclusions Both the current study and the TCGA experience represent similarly sized cohorts of patients with PRCC. Key differences in GA frequency probably underscore the marked difference in stage distribution between these data sets. These results may inform planned precision medicine trials for metastatic PRCC. Patient summary Papillary renal cell carcinoma (PRCC) is a rare subtype of kidney cancer, and understanding of the biology of advanced PRCC is limited. This report highlights some of the unique biologic features of PRCC that may inform on future use of targeted therapies for the treatment of metastatic disease.